Seasonal influenza vaccine use in low and middle income countries in the tropics and subtropics: a systematic review

Seasonal Influenza Vaccine Use in Low and Middle Income Countries in the Tropics and Subtropics A systematic review HIRVE, Siddhivinayak Global Influenza Programme Department of Pandemic and Epidemic Diseases World Health Organization Geneva January 2015

WHO Library Cataloguing-in-Publication Data Seasonal Influenza Vaccine Use in Low and Middle Income Countries in the Tropics and Subtropics. A systematic review. I.World Health Organization. ISBN 978 92 4 156509 7 Subject headings are available from WHO institutional repository © World Health Organization 2015

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CONTENTS Executive summary ................................................................................................................................................. 4 Abbreviations and acronyms .................................................................................................................................. 9 Introduction .......................................................................................................................................................... 10 Methods ............................................................................................................................................................... 13 Search of the literature ..................................................................................................................................... 13 Eligibility criteria and Information sources ....................................................................................................... 13 Study quality appraisal ..................................................................................................................................... 14 Data synthesis ................................................................................................................................................... 14 Results .................................................................................................................................................................. 15 Seasonal influenza immunization policy ........................................................................................................... 16 Influenza vaccine supply and availability .......................................................................................................... 20 When to vaccinate? .......................................................................................................................................... 21 Which vaccine formulation to use? .................................................................................................................. 25 Seasonal influenza vaccination coverage ......................................................................................................... 35 Effectiveness of Seasonal Influenza Vaccine in the tropics .............................................................................. 38 Vaccine effectiveness in elderly.................................................................................................................... 39 Vaccine effectiveness in healthy children..................................................................................................... 40 Vaccine effectiveness in healthy adults ........................................................................................................ 41 Vaccine effectiveness in pregnant women ................................................................................................... 42 Vaccine effectiveness in high risk individuals ............................................................................................... 43 Critical knowledge gaps ................................................................................................................................ 47 Discussion ............................................................................................................................................................. 48 Conclusion ............................................................................................................................................................ 51 Acknowledgements .............................................................................................................................................. 52 References ............................................................................................................................................................ 53 Appendix ............................................................................................................................................................... 69

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List of Figures Figure 1: Seasonal influenza vaccine composition meeting (VCM) to vaccine availability ................................... 11 Figure 2: Flow diagram of selection and exclusion of articles .............................................................................. 15 Figure 3: Tropical and subtropical countries with national seasonal influenza vaccination policy ...................... 16 Figure 4: Seasonal influenza vaccine formulation used by countries in the tropics and subtropics .................... 17 Figure 5: Tropical and subtropical countries that vaccinate pregnant women against seasonal influenza ......... 18 Figure 6: Influenza circulation and vaccination timing in South and Southeast Asia ........................................... 22 Figure 7: Countries that shared influenza virus with WHO CCs for the NH 2014-15 vaccine formulation ........... 26 Figure 8: Countries that shared influenza virus with WHO CCs for the SH 2015 vaccine formulation................. 26 Figure 9: Seasonal influenza virus isolates analyzed by WHO region ................................................................... 27 Figure 10: Seasonal influenza vaccine doses distributed in the tropics and subtropics (2011) ........................... 35 List of Tables Table 1: National policy for seasonal influenza vaccination ................................................................................. 19 Table 2: Vaccination timing and influenza activity in Latin America and the Caribbean (2002 – 13)................... 25 Table 3: Antigenic and genetic relatedness of circulating influenza virus and contemporary vaccine strain ...... 30 Table 4: Seasonal influenza vaccine coverage in the tropics ................................................................................ 37 Table 5: Seasonal influenza vaccine effectiveness in the tropics ......................................................................... 45 List of Appendices Appendix A: Strategies and keywords used for literature search ........................................................................ 69 Appendix B: List of countries and territories in the tropics and subtropics included in the review ..................... 70 Appendix C: National policies of tropical and subtropical countries on seasonal influenza vaccination ............. 71 Appendix D: Seasonal influenza vaccine doses distributed in the tropics and subtropics ................................... 77 Appendix E: Seasonal influenza vaccine effectiveness in the elderly in the tropics and subtropics .................... 84 Appendix F: Seasonal influenza vaccine effectiveness in children in the tropics and subtropics ........................ 88 Appendix G: Seasonal influenza effectiveness in healthy adults in the tropics and subtropics ........................... 92 Appendix H: Seasonal influenza vaccine effectiveness in pregnant women in the tropics and subtropics ......... 94 Appendix I: Seasonal influenza effectiveness in high risk individuals in the tropics and subtropics .................... 96

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Executive summary

EXECUTIVE SUMMARY Background Over the last decade an increasing number of Low and Middle Income Countries in the tropics have actively considered initiating or expanding their national policy and guidelines for seasonal influenza vaccination. This is critical following the WHO recommendation for giving the highest priority for maternal immunization against seasonal influenza. The biannual WHO recommendations for influenza vaccine composition are suitable for countries located in the temperate regions with distinct seasonality in influenza activity. Tropical and subtropical countries with variable seasonality patterns need to make evidence-based decisions regarding which population subgroups to vaccinate, which vaccine composition to use, when to vaccinate and what public health benefits to expect. Objectives The overall aim of this review is to assess the scientific evidence on seasonal influenza vaccine use and effectiveness in Low and Middle Income Countries in particular those situated in the tropical regions. Specifically it aims to review the – 1. 2. 3. 4. Status of national policies on seasonal influenza vaccination in Low and Middle Income Countries in the tropics and subtropics Seasonal influenza vaccine supply, availability and coverage in the tropics and subtropics Seasonal influenza vaccine use in the tropic and subtropics with reference to timing of vaccination and the vaccine composition recommended biannually by the WHO, and Effectiveness of the seasonal influenza vaccine in the tropics and subtropics in the context of seasonality and virological characteristics of the circulating influenza viruses

Methods We searched multiple global and regional health databases using different combinations of pre-identified search terms (with synonyms and closely related words) such as ‘seasonal influenza vaccine’, ‘tropics’, ‘effectiveness’, ‘timing’, ‘policy’, ‘campaign’, ‘Africa’, ‘Pacific’, ‘Latin America’ and ‘Africa’. Duplicates were removed and the title and abstract was screened for eligibility by two reviewers independently. Articles were included based on consensus discussions between the two reviewers. The full text of all included articles was further assessed for eligibility. We included articles that were newly identified through cross-references from articles that were already included. We contacted institutions and individuals involved in influenza research for currently ongoing influenza vaccine related studies with a request to share preliminary summaries of unpublished studies to assess their eligibility for inclusion in the review. An effort was made to identify unpublished studies by searching conference proceedings and agency reports. We restricted our inclusions to articles in the English language or any other language provided an abstract was available in English, articles related to policies and guidelines for seasonal human influenza vaccine use in tropical and subtropical countries, articles that referred to seasonal influenza vaccine composition, timing of vaccination, vaccination supply, availability and coverage and vaccine effectiveness. We supplemented our literature search by analysing four global databases. In addition, we administered an online survey to all the WHO Member States situated in the tropics and subtropics to update information on influenza seasonality, vaccination policy, timing, composition and coverage. We excluded studies that focused on the avian or pandemic influenza vaccine or pandemic preparedness. Studies on safety and immunogenicity of influenza vaccines, determinants of influenza vaccine uptake, licensing and regulatory aspects of influenza vaccine were also excluded. Studies that focused solely on influenza seasonality, disease burden and genetic or antigenic characteristics of the influenza virus without any linkage to seasonal influenza vaccine were beyond the scope of this review. We captured the heterogeneity amongst studies based on study population, ascertainment of seasonal influenza vaccination 4

Executive summary

and endpoint variables such as influenza-like illness, hospitalization, and laboratory confirmed influenza, potential confounding and risk of bias. For all other articles, data extraction and synthesis was descriptive. Wherever possible, we triangulated different data sources to validate the information extracted from literature. Results Of the 3637 articles and 34 unpublished papers identified, 3247 were deemed ineligible based on the screening of the title and abstract. A further 178 articles were excluded after a full-text appraisal. A total of 215 published and 31 unpublished articles and four global databases were included in the final review. Most developed countries had national policies on immunization against seasonal influenza. In contrast, 64 of the 138 (46%) Low and Middle Income Countries from the tropics and subtropics had a national vaccination policy against seasonal influenza. Notably, populous countries such as Bangladesh, China, India, Pakistan and Sri Lanka in Asia representing about 45% of the world’s population did not have a national vaccination policy against influenza. Thirty-eight countries used the NH formulation, 21 used the SH formulation whereas four countries (Brunei Darussalam, Marshall Islands, Peru and Singapore) used both formulations. Five countries situated in the southern hemisphere tropics used the NH formulation whereas eight situated in the northern hemisphere tropics used the SH formulation. Moreover, three countries (El Salvador, Guatemala and the Philippines) situated in the northern hemisphere tropics switched from a NH to a SH formulation in recent years. National policies of most tropical countries recommended targeted seasonal influenza vaccination of the elderly, children, and individuals with chronic illness and healthcare professionals. However the age groups recommended for vaccination varied. Thirty-five (55%) of the 64 tropical countries recommend seasonal influenza vaccination of pregnant women. A few countries in Asia required seasonal influenza vaccination for Hajj pilgrims. Seasonal influenza vaccine was available through the private sector in most countries. Vaccination campaigns in most tropical countries were timed prior to the onset of the typical influenza season. Vaccination campaigns in Latin America and the Caribbean occurred in April – May prior to the influenza season except in Cuba and Costa Rica which are reconsidering the timing of their vaccination campaign and using the SH formulation. The vaccination campaign timing in Brazil was appropriate for its southern region but may have been late for its northern region where the influenza season frequently occurs earlier. In most countries in the Asia Pacific, vaccination was timed prior to the onset of their influenza season. However, several countries reported vaccination timings that were inconsistent with their influenza peaks. Philippines recently switched to the most recent SH vaccine formulation to time it prior to its influenza peak activity. The vaccine and circulating virus antigen match has averaged 55 – 60% in both hemispheres since the introduction of the biannual vaccine composition recommendation by the WHO in 1998. Since the introduction of the first TIV in 1978 till the end of 2014, a total of 50 changes were recommended by the WHO (A/H3N2 – 23; A/H1N1 – 9; influenza B – 18). The genetic / antigenic match between the vaccine and the circulating virus varied in different seasons with a better match seen for influenza B viruses except in 2002 when the B/Victoria lineage re-emerged. Typically, there was a one-season delay before the circulating virus was covered by the influenza vaccine. Sometimes virus strains persisted locally or seemed re-seeded by international travellers and hence matched poorly with the vaccine strain that had subsequently changed in line with antigenic shifts in the influenza viruses globally. Though the global seasonal influenza vaccination coverage increased two-fold in recent years, it remained low in all targeted groups in most Low and Middle Income Countries (<5 per 1000 pop.). Higher coverage was not correlated with higher level of economic development. Furthermore, higher coverage was seen when the vaccine was offered free through the public sector.

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Vaccine efficacy (VE) against seasonal influenza varied widely in different high risk groups in Low and Middle Income Countries. VE against laboratory-confirmed influenza in the elderly was lower (0 – 42%) in Low and Middle Income Countries than in High Income Countries. In children in Low and Middle Income Countries, VE against laboratory-confirmed influenza ranged widely from 20 – 77% depending on antigenic match but was largely comparable with High Income Countries. Similarly, VE against laboratory-confirmed influenza in healthy adults in Low and Middle Income Countries ranged from 50 – 59% and was comparable with that in High Income Countries. Vaccinating pregnant women against seasonal influenza prevented laboratory-confirmed influenza in both mothers (VE: 50%) and their new born (VE: 49 – 63%). VE against laboratory-confirmed influenza was 71% amongst COPD patients in Low and Middle Income Countries comparable to that in High Income Countries. Discussion The tropics where an estimated 41% of the world’s population resides, is an important region that faces a similar if not higher burden of influenza. Latin America and the Caribbean have led the introduction of seasonal influenza vaccine into their immunization campaigns since the 1990s. Large parts of sub Saharan Africa and the Indian subcontinent have yet to formulate national policies against seasonal influenza though the vaccine is available through the private sector in many countries in the region. Even as some High Income Countries expand their policies to vaccinate all persons above 6mo age unless medically contraindicated, targeted vaccination of high risk population subgroups remains the main strategy to reduce influenza disease burden. National policies recommended vaccination of pregnant women against seasonal influenza in countries in Latin America and the Caribbean but this has yet to happen in the South and Southeast Asia. Historically countries in the tropics selected the WHO recommended NH or SH vaccine formulation largely based on whether they were situated north or south of the equator. Countries also timed their vaccination campaigns according to when the respective vaccine formulation became available irrespective of the influenza seasonality pattern in the country. Recent evidence suggested that vaccination campaigns in tropical countries (in both hemispheres), where peak influenza activity frequently coincides with the rainy season, should be timed with the availability of the SH vaccine formulation. For countries such as Brazil, China and India with a large latitudinal spread, a staggered approach that allows vaccination at different times in the year to cover multiple influenza activity periods using the most recent vaccine formulation may be more appropriate. Antigenic and genetic studies from the tropics indicate a good antigenic match between the influenza virus strains that circulated during peak activity and the appropriate vaccine strain that was recommended during that period. Overall seasonal influenza vaccination coverage was less than 1% in most parts of Africa and Asia. In contrast, reported coverage in Latin America and the Caribbean countries was higher at times than that of High Income Countries. Higher coverage was not correlated with the level of economic development but uptake improved when the vaccine was offered free through the public sector. Evidence on the cost-effectiveness of seasonal influenza vaccine in Low and Middle Income Countries interested in improving coverage or expanding vaccination to pregnant women is scarce. Although the benefit of influenza vaccines has been questioned recently by several studies, vaccine effectiveness in Low and Middle Income Countries was comparable to that seen in High Income Countries. However comparison of VE estimates between studies is subject to inherent challenges. The Global Action Plan for influenza vaccines provides for expanding influenza vaccine production in Low and Middle Income Countries in the tropics and subtropics to ensure greater equity, sustainability and public 6

Executive summary

health benefits. The wide-scale manufacturing, supply and use of seasonal influenza vaccine globally is inextricably linked with pandemic preparedness. To be able to respond quickly to a pandemic, there must exist a high capacity to produce seasonal influenza vaccine. Only then can the production capacity be adapted and up-scaled quickly to meet the urgent demand of a pandemic situation. However, global demand for seasonal influenza vaccination is low and from an economic perspective, investment in further expanding production capacity may be difficult to justify without a concomitant demand and market expansion to use the supply. Understanding the temporal and geographic circulation of influenza is important to develop and apply vaccination control strategies. As Low and Middle Income Countries consider introducing seasonal influenza vaccination, surveillance systems need to be strengthened to better understand the epidemiology and seasonality of influenza, to enable evidence-based decision on when to vaccinate, which groups to target, what vaccine benefits to expect and so on. Conclusion The bulk of scientific evidence on vaccine use and effectiveness in the tropics comes from Latin America and the Caribbean and Asia with large parts of Africa underrepresented. As more and more countries in the tropics and subtropics consider vaccinating their populations at risk for influenza, their capacity to make critical decisions on which vaccine to use, when to vaccinate, how much health benefit to expect etc., is greatly restricted by the limited evidence that is available about the epidemiology and virology of the viruses that circulate in their regions. Newly emerged evidence suggests that the timing of vaccination and the choice of formulation should be solely guided by laboratory-confirmed influenza data facilitated by strengthening capacity throughout the Global Influenza Surveillance and Response System. Countries in the tropics, especially those nearer to the equator, countries with large latitudinal spread, countries with varying seasonality, countries with influenza identifiable year-round, may need to consider a staggered approach that allows vaccination at different times in the year to cover multiple or year-round influenza activity periods based on their local seasonality pattern and the availability of the most recent WHO recommended formulation. There is probably no ‘one size that fits all’ strategy to influenza vaccination. Influenza disease and virological surveillance need to be strengthened to enable a better prediction and selection of the biannual updates for the influenza vaccine composition. Research is needed to evaluate alternate strategies for vaccination timing with the WHO recommended vaccine formulations that have the most recent vaccine virus strains for countries in the tropics and subtropics. Key Messages 1) The bulk of scientific evidence on vaccine use and effectiveness in the tropics comes from Latin America and the Caribbean and Asia; Africa remains underrepresented. 2) Latin America and the Caribbean countries have led the seasonal influenza vaccination amongst Low and Middle Income Countries in the tropics and subtropics. Most of Asia and Africa are yet to introduce seasonal influenza vaccine into their national policy and program. Majority (61%) of the countries for which information was available, prioritized pregnant women for vaccination against seasonal influenza. 3) Vaccination campaigns in tropical countries (in both hemispheres) where increased influenza activity frequently coincides with the rainy season, should be timed with the availability of the SH vaccine formulation. The timing of vaccination and the choice of formulation in the tropics should be guided by laboratory-confirmed influenza seasonality data facilitated by a strengthened surveillance capacity throughout the Global Influenza Surveillance and Response System. 4) Countries with a large latitudinal spread, countries with varying seasonality patterns, countries with more than one influenza peak or with identifiable activity year-round, should evaluate the impact of a staggered approach that allows vaccination at different times in the year to cover multiple or year-

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round influenza activity periods using the most recent vaccine formulation. There may be no single approach that fits the requirement of all tropical and subtropical countries. 5) Surveillance systems in tropical countries need to be strengthened to better understand seasonality, epidemiology and virological aspects of influenza in the tropics so as to optimize the WHO recommendation for the seasonal influenza vaccine composition for the tropics. 6) Future research is needed to evaluate the impact of alternate vaccination strategies including the staggered approach, making the seasonal influenza vaccine available year-round, for countries in the tropics and subtropics. More studies are needed to evaluate the impact of vaccinating pregnant women at the time of their identification and / or during influenza season.

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Abbreviations and acronyms

ABBREVIATIONS AND ACRONYMS AFRO ARI CDC CVD COPD EMRO GISRS IFPMA ILI LCI LAIV NH PAHO P&I QIV RCT SEARO SH TIV UNICEF VE WHA WHO WPRO African Regional Office Acute Respiratory Infections Centers for Disease Control and Prevention Cardio Vascular Disease Chronic Obstructive Pulmonary Disease Eastern Mediterranean Regional Office Global Influenza Surveillance and Response Systems International Federation of Pharmaceuticals and Manufacturers Association Influenza-like Illness Laboratory Confirmed Influenza Live Attenuated Influenza Vaccine Northern Hemisphere Pan American Health Organization Pneumonia and Influenza Quadrivalent Influenza Vaccine Randomized Controlled Trial South East Asia Regional Office Southern Hemisphere Trivalent (Inactivated) Influenza Vaccine United Nations Children’s Fund Vaccine Effectiveness / Efficacy World Health Assembly World Health Organization Western Pacific Regional Office

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Introduction

INTRODUCTION Background Influenza disease impacts Low and Middle Income countries as much if not more than High Income Countries [1, 2]. Vaccination remains the mainstay strategy to protect populations against influenza and its complications. The WHO recommends a targeted annual vaccination against seasonal influenza for five priority high risk population groups [3]. The World Health Assembly (WHA 56.19) resolved in 2003 to increase the use of seasonal influenza vaccine to protect individuals at high risk for influenza and related complications [4]. The WHO Global Action Plan for Influenza Vaccines launched in 2006 aims to promote demand for seasonal influenza vaccine and increased use by Member States as a strategy towards pandemic preparedness [5]. The continuing antigenic drift in the hemagglutinin gene necessitates a regular update of the vaccine strain composition to confer protection against currently circulating influenza viruses. The WHO Global Influenza Surveillance and Response System (GISRS) – previously the Global Influenza Surveillance Network – that monitors the antigenic and genetic characteristics of the influenza virus globally and selects the candidate vaccine virus strains for the seasonal influenza vaccine composition for the northern and southern hemispheres biannually, is well established [6]. Seasonal influenza vaccination in Low and Middle Income Countries in the tropics and subtropics provides not only public health benefits to its population but may also deter the emergence and global spread of variant and novel influenza viruses [7]. A quick primer on seasonal influenza vaccination and timing Vaccines are the mainstay for reducing the burden of seasonal influenza. They are safe and well tolerated. Inactivated influenza vaccines available since the 1940s, have been recommended for anyone at risk for influenza or its complications. For countries considering initiation or expansion of seasonal influenza vaccination programs, the WHO recommends pregnant women to have the highest priority. Additional risk groups include children aged 6 – 59 months, the elderly, individuals with specific chronic medical conditions and healthcare workers. It advises countries to make informed decisions on seasonal influenza vaccination strategies based on their disease burden and vaccine cost-effectiveness [3]. Nasally administered cold-adapted live attenuated influenza vaccines (LAIV) first developed in the 1960s were licensed in the United States only after 2003 [8]. They are recommended only for non-pregnant healthy individuals of 2 – 49y of age. LAIV is not recommended in pregnancy, in children <2y or children <4y with a recurrent wheezing or reactive airway disease and in the elderly with a chronic medical condition. Inactivated influenza vaccines are more effective in healthy adults than in younger children or the elderly [9]. Influenza vaccines with adjuvants are promising as they provide improved immune response at lower antigen dose [10, 11]. LAIVs are more effective than inactivated vaccines in children [12]. Two doses of the vaccine are recommended for children <9y of age who have not received influenza vaccines in earlier seasons. Influenza vaccination induces antibodies against hemagglutinin and neuraminidase surface glycoproteins [13]. However, the correlates for protection continue to rely on serum antibody titres even when LAIV induce immunity through other immune pathways [14]. The immune response peaks at 2 – 4wks and has been sometime seen to decline within the same season [15-17]. The efficacy of influenza vaccines ranges between 70 – 90% in controlled trials but is lower in immunization program settings and depends on the age and immune competence of the vaccine recipient and the antigenic similarity of the vaccine strain to the circulating influenza virus strain amongst other factors. Seasonal influenza activity peaks during the winter months (November – February for the NH and May – October for the SH) in countries with temperate climate [18] whereas it is more variable and complex in tropical and subtropical climates with identifiable year-round activity that frequently coincides with the rainy season [19, 20]. The vaccine production cycle from vaccine strain selection to vaccine delivery takes about 6 – 8mo (a finely balanced reconciliation between scientific requirement for detailed antigenic characterization of viruses, manufacturing practicalities and regulatory requirement) and is timed such that the vaccine is

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Introduction

available before the next influenza season [21, 22]. A short cycle time may maximize the chances of a correct match between the vaccine strains in the vaccine composition and the putative circulating strains [23]. The production cycle may take longer if a new strain is recommended for inclusion in the vaccine as this then may require revalidation of the manufacturing process for the new strain and an evaluation of the immunogenicity and safety of the new vaccine formulation [21]. Two such cycles are undertaken each year. The WHO formally selects the candidate strains for the NH vaccine in February based on the most recent circulating virus strains in the current season for it to become available in October prior to the next season (November – April) in the northern hemisphere [24].

Figure 1: Seasonal influenza vaccine composition meeting (VCM) to vaccine availability

Similarly, for the SH vaccine cycle, the candidate strain selection for the SH vaccine takes place in September based on the most recent strains of the circulating influenza viruses for it to become available in April prior to the start of the next influenza season (May - October) in the southern hemisphere (see Figure 1). Gaps and opportunities Over the last decade an increasing number of Low and Middle Income Countries, more so following the 2009 A/H1N1 pandemic, have actively considered initiating or expanding their national policy and guidelines for seasonal influenza vaccination [25, 26]. This is critical given the WHO Strategic Advisory Committee of Experts on Immunization recommendation in 2012 to prioritize the vaccination of pregnant women against seasonal influenza at any stage of their pregnancy. The biannual WHO recommendations for influenza vaccine composition are suitable for countries situated in the temperate regions with distinct seasonality in influenza activity. However countries situated in the tropics and subtropics have variable seasonality patterns often with influenza identifiable year round. The evidence-base needed for decision making regarding influenza vaccination for many Low and Middle Income Countries is lacking [27]. Countries in the tropical and subtropical regions need to make evidence-based decisions about which subgroups to target, which vaccine composition to use, when to vaccinate and the anticipated disease and economic burden impact of vaccination. Following the WHO Strategic Advisory Committee of Experts on Immunization recommendation in 2012, there have been increased international collaborative efforts to implement the Global Action Plan for Influenza Vaccines. One such effort is a Bill & Melinda Gates Foundation grant to the WHO to optimize the process of seasonal influenza vaccine composition recommendation for tropical regions. The scope of this grant is to further the WHO efforts through its global network (GISRS) to (1) review scientific evidence for influenza 11

Introduction

seasonality, virus characteristics and seasonal influenza vaccine use in tropical and subtropical countries, (2) assess and optimize the current process of WHO biannual influenza vaccine composition recommendations to take into consideration the needs for tropical areas, and (3) pilot and evaluate the optimized guidance for tropical and subtropical countries. This manuscript systematically reviews the experiences, use and effectiveness of seasonal influenza vaccine in Low and Middle Income Countries in the tropics and subtropics. It complements another concurrent systematic review of seasonality and virology of seasonal influenza in the tropics. Together, they would serve to optimize the current vaccine composition recommendations and provide guidance regarding the use of seasonal influenza vaccination specific to Low and Middle Income Countries in the tropics and subtropics. Objectives The overall aim of this review is to assess the scientific evidence on seasonal influenza vaccine use and effectiveness in Low and Middle Income Countries in particular those situated in the tropical regions. Specifically it aims to review the – 1. 2. 3. Current status of national policies on seasonal influenza vaccination in Low and Middle Income Countries in the tropics and subtropics Seasonal influenza vaccine supply, availability and coverage in the tropics and subtropics Experiences of tropical and subtropical countries in the use of seasonal influenza vaccine with reference to timing of vaccination and the vaccine composition recommended biannually by the WHO, and Effectiveness of the seasonal influenza vaccine in the tropics and subtropics in the context of seasonality and virological characteristics of the circulating influenza viruses

4.

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Methods

METHODS SEARCH OF THE LITERATURE We aimed to systematically review experiences of Low and Middle Income Countries in the use of Seasonal Influenza Vaccine following the biannual recommendation of vaccine composition by the WHO and the subsequent outcome on vaccine effectiveness in the tropical and sub-tropical regions. We searched the United States National Library of Medicine (PubMed), the Cochrane Library, the World Health Organization Library Information System (WHO LIS), the Latin American and Caribbean Health Sciences Literature (LILACS), the National Databases of Indian Medical Journals (IndMed) using different combinations of pre-identified search terms (with synonyms and closely related words) such as ‘seasonal influenza vaccine’, ‘tropics’, ‘effectiveness’, ‘timing’, ‘policy’, ‘campaign’, ‘Africa’, ‘Pacific’, ‘Latin America’ and ‘Africa’ (see Appendix A). After removing duplicates from the results of the search of different databases, the title and abstract of all articles were screened by two reviewers (SSH, HM) to independently determine eligibility. Consensus was reached through discussions between the two reviewers in case of discordance on whether to include or exclude. Articles that did not meet the eligibility criteria based on the title and abstract were excluded. The full text of all included articles was further assessed for eligibility by the first reviewer (SSH). In addition, we included articles that were newly identified through cross-references from articles that were already included. In addition to the published literature, we contacted institutions and individuals known to be involved in influenza research for currently ongoing influenza vaccine related studies. An effort was made to identify unpublished studies by searching conference proceedings and agency reports. Researchers were requested to share preliminary summaries of unpublished studies to assess their eligibility for inclusion in the review. We also took the support of the Immunization, Vaccines and Biologicals (IVB) cluster in the WHO to contact the vaccine industry to access summaries of information on country wise sales of seasonal influenza vaccine in the tropics. We also searched and identified global databases and surveys on seasonal influenza vaccine use maintained by the WHO, UNICEF and the vaccine industry. Finally we developed and administered a short online survey on Seasonal Influenza Vaccine Use in Member States of the WHO that are situated in the tropical zone.

ELIGIBILITY CRITERIA AND INFORMATION SOURCES Inclusion criteria We restricted our inclusions to articles in the English language or any other language provided an abstract was available in English. Published and unpublished studies that were related to policies and guidelines for seasonal human influenza vaccine use in tropical countries were included in the review. We limited the countries to be included in the review as those that were situated partly or wholly between the Tropic of Cancer (23° 26’ 16” N) latitude in the northern hemisphere and the Tropic of Capricorn (23° 26’ 16” S) latitude in the southern hemisphere. We additionally included countries in the subtropics situated between the tropic th circle of latitude and the 38 parallel in both hemispheres. We included the WHO position papers on vaccination against seasonal influenza, studies that documented which of the seasonal influenza vaccine composition (Northern or Southern Hemisphere formulation) was used, vaccination timing and strategies, vaccine coverage, vaccine effectiveness in the general population and in priority or vulnerable groups including pregnant women. We also included studies that documented issues of production, supply and distribution of the seasonal influenza vaccine. Published and unpublished literature was included if available or accessed on th or before 30 September 2014. We also supplemented our literature search by examining two databases that carried country specific information on seasonal influenza vaccination policy, vaccine procurement, supply and 13

Methods

coverage viz. the UNICEF – WHO Joint Reporting Form (2013) and the WHO Global Influenza Vaccine Survey (2010). We requested the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) Influenza Vaccine Supply task force to provide seasonal influenza vaccine sales and coverage (2008 – 2011) for the tropical regions. In addition, we administered an online survey to all countries situated in the tropics and subtropics to update information on influenza seasonality, vaccination policy, timing, composition and coverage. Exclusion criteria Studies that focused on pandemic influenza vaccine were excluded from the review. So also were studies that dealt primarily with avian influenza vaccines or pandemic influenza preparedness. Randomized control trials that focused on safety and immunogenicity of specific seasonal or pandemic influenza vaccines were also excluded. Studies that examined the cross protective effect of seasonal and pandemic influenza vaccine on pandemic influenza were excluded. We also excluded compliance studies that focused on seasonal influenza vaccine uptake – their determinants or predictors, or KAP studies of either providers or recipients of seasonal influenza vaccine. Position papers on guidelines for seasonal influenza vaccination for international travellers were outside the scope of this review. Similarly, studies that addressed the regulatory aspects of seasonal influenza vaccine viz. licensing, lot release etc. were beyond the scope of this review. Studies that referred solely to influenza disease burden without seasonality or studies on the antigenic or genetic characteristics of the influenza virus without any linkages to seasonal influenza vaccine use were excluded. Finally studies related to different aspects of seasonal influenza vaccine use were excluded if they were based on populations from countries in the temperate zone.

STUDY QUALITY APPRAISAL The methodological quality of all seasonal influenza vaccine effectiveness studies that were included was assessed by one reviewer (SH). We included studies that had already been graded for quality in other systematic reviews and meta-analysis. We qualitatively assessed each study based on clarity of information about study population, representativeness and comparability, ascertainment of seasonal influenza vaccination and endpoint variables such as influenza-like illness, hospitalization, and laboratory confirmed influenza, potential confounding and risk of bias. Wherever possible, we triangulated different data sources (influenza vaccine survey data, WHO-UNICEF Joint Reporting Form data) to validate the information extracted from literature.

DATA SYNTHESIS We extracted information on the main characteristics of each study. Heterogeneity was captured through characteristics of the study like study design, study population, target groups, case definitions used to ascertain exposure and outcome, type of vaccine etc. Vaccine effectiveness was calculated as 100% - odds or risk ratio separately for each target group as defined by the studies. For all other studies data extraction and synthesis was descriptive.

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Results

RESULTS A search of the major healthcare libraries identified 3637 and 34 articles in the published and grey literature respectively. After screening the title and abstract for eligibility, 3247 articles were excluded as they dealt primarily with pandemic or avian influenza vaccine, or studies that focused on safety and immunogenicity amongst other reasons. After assessing the full text of the remaining 424 articles, a total of 178 articles were excluded (153 articles were based on populations situated outside the tropical and subtropical regions, 20 articles dealt with determinants of influenza vaccination uptake and five articles focused on influenza vaccination for international travellers from High Income Countries (see Figure 2).

Figure 2: Flow diagram of selection and exclusion of articles

A total of 215 published articles and 31 unpublished articles / conference presentations were included in the final review. In addition, four global databases (UNICEF – WHO Joint Reporting Form (2013), the Global Influenza Vaccine Survey (2010), the Survey of the National Influenza Centres in the GISRS (2014) and the Seasonal Influenza Vaccine use in the Tropics survey (2014) were analysed. The review covers 138 countries and territories representing about 79% of the world’s population situated in the tropical and subtropical regions (see Appendix B).

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Results

SEASONAL INFLUENZA IMMUNIZATION POLICY A consolidated analysis of the UNICEF – WHO Joint Reporting Form data (2013), the Global Influenza Vaccine Survey (2010), the 2014 Survey of the National Influenza Centres in the GISRS and the Seasonal Influenza Vaccine use in the Tropics survey (2014) data showed that 64 of the 138 (46%) countries and territories from the tropics and subtropics had a national vaccination policy against seasonal influenza (Figure 3) [28, 29].

Figure 3: Tropical and subtropical countries with national seasonal influenza vaccination policy

Most (90%) of countries in Latin America and the Caribbean had seasonal influenza vaccination policies except Guyana, Haiti and the territories of Saint Kitts & Nevis and Saint Vincent & the Grenadines [30]. Only six countries (Côte d’Ivoire, Egypt, Libya, Mauritius, Tunisia and South Africa) in Africa had national immunization policies or guidelines against seasonal influenza (see Table 1). A total of 18 countries comprising 93% of the population in the WHO Western Pacific region had established policies for seasonal influenza vaccination. An additional seven countries in this region recommended influenza vaccination for high risk individuals whereas eleven countries had no policies or recommendations [31]. Eleven countries in this region, largely island nations but also Cambodia, Democratic People’s Republic of Korea, Lao People’s Democratic Republic and Papua New Guinea did not have a policy for seasonal influenza vaccination. Most countries in the Indian subcontinent (Bangladesh, India, Pakistan and Sri Lanka) and neighbouring China did not yet have a national vaccination policy against influenza. In contrast, the majority of the High Income Countries situated in the temperate regions in the northern and southern hemisphere had national policies on immunization against seasonal influenza [28, 32]. Policy guidelines for influenza vaccine formulation National policy guidance on the seasonal influenza vaccine formulation was available for 63 countries (see Table 1). Refer to Appendix C for country-specific details. Thirty-eight countries used the NH formulation, 21 used the SH formulation whereas three countries (Brunei Darussalam, Marshall Islands and Singapore) used both formulations (see Figure 4). Additionally, Peru experimented with both formulations in 2012 but reverted to a single formulation subsequently. Interestingly, five countries / territories (Democratic Republic of the Congo, Ecuador, American Samoa, French Polynesia and New Caledonia) situated in the southern hemisphere tropics close to the equator used the NH formulation in their vaccination program. On the other hand, the SH 16

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formulation was used by eight countries (Cameroon, Kenya, Uganda in Africa and Colombia, Nicaragua and Panama in Latin America and the Caribbean and Thailand and Malaysia in Southeast Asia) situated in the northern hemisphere tropics. Additionally, El Salvador, Guatemala and the Philippines situated in the northern hemisphere tropics switched from a NH to a SH formulation in recent years.

Figure 4: Seasonal influenza vaccine formulation used by countries in the tropics and subtropics

Policy guidelines for targeted influenza vaccination In the US, the Advisory Committee on Immunization Practices recommends annual influenza vaccination for everyone 6mo or older if there are no medical contra-indications such as vaccine allergy [33]. The WHO recommends targeted vaccination against seasonal influenza for five priority groups viz. children aged 6mo to 5y, elderly persons aged 65y and above, persons with specific chronic illness, pregnant women, and healthcare professionals [3]. It recommends that all countries have a policy to vaccinate at least one priority group by 2016. Refer to Appendix C for country-specific details. Latin America and the Caribbean countries have been quick in adopting influenza vaccination recommendations [34]. Thailand’s influenza vaccination policy has evolved rapidly from a seasonal vaccination focus on healthcare professionals and poultry cullers following the A/H5N1 outbreak in 2005 to providing free vaccination to the elderly and persons with chronic conditions in 2008 and to children aged 6mo – 2y and pregnant women in 2010 [35]. The United States advocates vaccination against seasonal influenza in all trimesters of pregnancy in the influenza season since 2004 [36]. For countries considering initiating or expanding seasonal influenza vaccination, the WHO recommends since 2011 that pregnant women become the highest priority for influenza vaccination [3]. All six countries in Africa, 15 (48%) of 31 countries in Latin America and the Caribbean, 11 (69%) of 16 countries in Asia and 3 (75%) of 4 countries in the Middle East for whom information was available, recommended seasonal influenza vaccination for pregnant women (see Table 1, Figure 5). Most of these countries included pregnant women as a priority group for influenza vaccination after the 2009 pandemic [34]. In contrast, less than half of the countries in Europe prioritized pregnant women for seasonal influenza vaccination.

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Figure 5: Tropical and subtropical countries that vaccinate pregnant women against seasonal influenza

Most countries with national influenza vaccination policies targeted children (see Table 1). However, the age groups recommended for vaccination varied between countries. Globally, about half the countries targeted children 6mo – 2y, whereas about a third of the countries included children aged 2 – 5y as a priority group [28]. The United States recommends universal immunization for all children aged 6mo – 18y. Few countries in Europe recommend universal immunization for all children aged 6mo – 2y or 3y. Countries such as the United Kingdom are now considering expanding influenza immunization to school-age children. Influenza vaccination is recommended for children only if they are at risk for influenza complications due to severe underlying disease in Asia, South Africa and Australia [37]. Similarly, almost all countries with a national influenza vaccination policy targeted the elderly though the age at which influenza vaccination is targeted varied between countries [38]. Similarly, the majority of countries in Europe and Latin America and the Caribbean with a national influenza vaccination policy prioritized individuals with underlying chronic illnesses compared to countries in other regions (see Table 1). Many countries recommend and reimburse vaccination of healthcare professionals against influenza [34]. Interestingly there was no correlation between the development status of the country and free influenza vaccination to healthcare professionals [39]. Nine out of 13 tropical and subtropical countries surveyed in 2005 recommended influenza vaccination to healthcare professionals [25]. A more recent survey in 2009 showed that 32 of the 35 Latin America and the Caribbean countries administered influenza vaccines to their healthcare professionals through the public systems [40]. Healthcare professionals were more commonly targeted for vaccination after the 2009 pandemic [34]. Many High Income Countries recommend seasonal influenza vaccination for international travellers intending to travel during the influenza season [41-43]. Saudi Ministry of Health recommends influenza vaccination to all Hajj pilgrims especially those with underlying chronic illnesses. The vaccine is mandatory for all health professionals working in the Hajj pilgrimage centres of Mecca and Medina [44]. Countries like Brunei Darussalam, India, Indonesia and Malaysia (the latter three countries despite not having a national influenza vaccination policy) mandate or recommend seasonal influenza vaccination as a prerequisite for people intending to travel to Saudi Arabia for the Hajj pilgrimage (see Table 1). However it was unclear whether the influenza vaccination cost was borne by the traveller or by the public health system.

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Table 1: National policy for seasonal influenza vaccination

Countries (%) with National seasonal influenza vaccination policy Vaccine formulation recommended - NH - SH - Both - None Target groups in policy - Elderly - Children - Persons with chronic illnesses - Pregnant women - Healthcare professionals - Hajj travellers 4 Availability of influenza vaccine - public sector only - private sector only - both sectors Vaccination free in public sector Countries able to meet WHA 56.19 resolution 5 (coverage>75% in elderly) 1 2

Europe, N America [32] (n=27) 1 76%

Asia Pacific [31] (n=38) 26% 18% 11% 8% 63%

Central, South Americas [40] (n=39) 90% 56% 31% 0% 13% 87% 79% 79% 41% 74%

Africa (n=48) 8% 2% 2% 0% 96% 8% 4% 4% 0% 4%

Middle East (n=13) 62% 23% 0% 0% 77% 31% 23% 23% 23% 23%

100% 22% 100% 37% 85%

2

26% 16% 16% 16% 26% 3 8% 0% 37% 21% 13% 13%

4%

10% 13% 59% 56% 33%

0% 25% 4% 2% 0%

0% 0% 23% 15% 15%

This percentage is based on a denominator of 53 countries in the WHO EURO region [45]. This percentage and others below it in the Europe column are based on a denominator of 27 countries of Europe [32]. 3 Brunei Darussalam, India, Malaysia 4 Includes countries with or without national influenza vaccination policy 5 Data source – as reported by the Global Influenza Vaccine Survey 2010

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INFLUENZA VACCINE SUPPLY AND AVAILABILITY The 58 World Health Assembly (WHA58.5) in 2005 mandated the WHO to work with international and national partners to increase access to influenza vaccines [46]. Since its launch in 2006, the WHO Global Action Plan for Influenza Vaccines aims to boost evidence-based demand for seasonal influenza vaccine, increase its production, licensing and use by countries and promote influenza vaccine research and development that would in turn serve to stimulate an increased pandemic preparedness [5, 47]. The immediate goal is to increase by 2016, the global vaccine production capacity to produce enough vaccine to equitably immunize 70% of the world population with a pandemic vaccine that gives an adequate protection within 6mo of vaccine seed transfer to manufacturers in the event of a pandemic [48]. Seasonal influenza vaccine production increased from 350 million doses in 2006 to around 900 million in 2009. An industry sponsored survey of seasonal influenza vaccine distribution in 157 countries showed an increase of 87% between 2004 and 2011 but only 3% per annum in the last three years [49]. Fourteen manufacturers from Low and Middle Income Countries (Brazil, India, Indonesia, Democratic People’s Republic of Korea, Thailand etc.) received technology transfer support that has resulted in a current pandemic capacity of 330 million doses which is predicted to reach 795 million doses by 2016 [50-53]. Of the 25 countries with seasonal influenza vaccine manufacturing facilities in 2010, twelve were Low and Middle Income Countries situated in the tropics and subtropics, most of them had yet to start production. Despite the emergence of new manufacturers in Low and Middle Income Countries, more than 80% of the global seasonal influenza vaccine was produced by the seven large manufacturers located in High Income Countries (United States, Canada, Australia, Western Europe, Russia, China and Japan) [54]. There was, as yet, no production capacity in the Eastern Mediterranean region, Central Asia and sub-Saharan Africa except one facility in South Africa capable of filling imported bulk vaccine and packaging [55]. India, Indonesia and Thailand have since registered and started production of seasonal influenza vaccine. Brazil, Mexico, South Africa, Egypt, the Islamic Republic of Iran, Thailand and Viet Nam are expected to have production capacity within 5 – 10y [56]. China’s five multinational and eleven domestic manufacturers with a maximum production capacity of 126 million doses, supplied 32.5 million doses (2% of the total population) of seasonal influenza vaccine in 2008-09 season against an estimated domestic need based on national recommendations, of 570 million doses per year (43% of the total population) [57]. Though the vaccine supply in China has increased by 18% annually since 2005, the gap to meet domestic needs remains large. Less than half of all countries include seasonal influenza vaccination in their national programs with large regional variation [28]. Some countries introduced influenza vaccine only through the public sector. Whereas most Latin America and the Caribbean countries additionally ensured some degree of vaccination coverage through the private sector at times to cover more than 50% of the vaccination needs [30]. Other countries that did not have a national influenza vaccination policy (e.g. China, India, etc.), the vaccine was available at cost through the private sector. Countries that targeted health professionals for influenza vaccination, the vaccine was made available free through the public health system (e.g. most Latin America and the Caribbean countries and the Pacific region) [34]. Only 14 of the 31 countries surveyed in Africa reported availability of the seasonal influenza vaccine – six in the private sector (Democratic Republic of the Congo, Senegal, Togo, Uganda, Zambia and Zimbabwe) and the remaining eight in both public and private sectors (Cameroon, Côte d’Ivoire, Egypt, Kenya, Madagascar, Mauritius, Morocco and South Africa) [58]. Latin America and the Caribbean The developing countries of Latin America and the Caribbean have often led the introduction of new or underused vaccines. The Latin America and the Caribbean region have a strong tradition of manufacturing vaccines through the public sector. Technology transfer of the entire process of influenza vaccine production was initiated between a major vaccine manufacturer in France with Brazil in 1999 [30, 59, 60]. Another th

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agreement established a capacity to formulate, fill and package seasonal influenza vaccine with a State-owned manufacturer in Mexico in 2009 [61]. Brazil, Cuba and Mexico in Latin America and the Caribbean region showed the greatest self-sufficiency in national vaccine production. These countries have created markets for new and underused vaccines by improved and equitable access to health services, accelerated disease control and improved public health infrastructure [62]. The PAHO’s ProVac Initiative to develop country expertise to make the best technical decisions, take ownership and reduce dependence on external sources to pay for and distribute vaccines supported by strong international partnerships has worked well to achieve higher and equitable vaccine coverage in Latin America and the Caribbean. Tax exemptions for importation of vaccines, creation of national vaccine funds, legislation that requires obligatory use of the PAHO’s Revolving Fund to purchase influenza and other vaccines intended for public use has ensured cost-effective and sustainable management of immunization programs in Latin America and the Caribbean [63]. As part of the Global Action Plan for Influenza Vaccines, the WHO has strengthened capacity of national regulatory authorities in Brazil and Cuba in licensing vaccines within the WHO prequalification framework. Challenges for the tropics The capacity of Ministries of Health to make evidence-based policy decisions on introduction or expansion of influenza vaccination programs is an important challenge in settings where information on disease burden, vaccine cost-effectiveness is lacking [64]. First, the demand for seasonal influenza vaccine is variable and often unpredictable influenced by the timing and severity of influenza activity, public perception and awareness of vaccination and availability of vaccine [65]. Second, there is gross regional disparities in vaccine supply and availability in the tropics. It is estimated that Africa, Eastern Mediterranean and Southeast Asia receive only 1 – 4% of the global supply of the seasonal influenza vaccine [66]. Third, vaccine cost and low vaccine production capacity in developing countries further contribute to low availability and usage of the seasonal influenza vaccine. Fourth, when vaccines are introduced or their supply expanded in Low and Middle Income Countries, vaccine supply chains are overburdened, bottlenecks created with reduced availability of both influenza and other EPI vaccines. The choice of target populations for influenza vaccination and the limited time-frame of 2 – 3mo available to deliver the vaccine prior to the influenza season can adversely affect the flow of all vaccines in the supply chain. A simulation of Thailand’s vaccine supply chain showed that trying to cover 25% of the population recommended for influenza vaccination, would hinder overall vaccine availability so that only 62% of potential vaccines who arrive at clinics would receive vaccine [67]. Fifth, national regulatory systems in many Low and Middle Income Countries in the tropics lack capacities to perform core functions of vaccine licensing, laboratory testing, lot release systems, Good Manufacturing Practices inspections, monitoring and evaluation of clinical trials and post-marketing surveillance. This in turn undermines confidence and credibility of manufacturers to produce within weak regulatory environments [30].

WHEN TO VACCINATE? Challenges for the tropics Though the timing of the annual production cycle has worked well for NH and SH temperate regions, its applicability to the tropical region face several challenges. First, the biggest challenge for the tropics is the diversity of seasonal patterns that occasionally lacks synchronicity with influenza activity in the temperate regions [68, 69]. In tropical regions, influenza can be identified throughout the year and frequently demonstrates one or two epidemic periods. Countries in the subtropics can also occasionally have two epidemic periods. The occurrence of two peaks in some tropical countries in some years was sporadic as seen in Nicaragua [70]. Viet Nam and Cameroon show high influenza activity identifiable year-round [71, 72]. Some show within-country diversity in seasonality patterns [73]. For reasons not yet fully understood, influenza activity in the tropics frequently coincides with the rainy season [74-77]. Example, there is a wide variation in 21

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the timing of the rainy season in Bangkok and Kuala Lumpur, only 1100 km apart but with influenza peaks at opposite times of the year. Second, the timing of the vaccine selection – production cycle may not be optimal for the tropical region with less distinctive seasonality patterns though WHO recommendations reflect progressive antigenic changes in the circulating viruses and therefore relevant to all regions of the world. Third, the dearth of evidence from some tropical regions about the influenza disease burden and seasonality makes it difficult for countries to make rational decisions about when to vaccinate their populations against influenza. Fourth, a lack of a national policy on immunization against influenza, weak surveillance systems and poor capacities of national regulatory authorities makes informed decisions related to vaccine virus manufacture, licensing and release difficult in many tropical Low and Middle Income Countries. Asia Pacific A few recent efforts have addressed the question of vaccination timing for tropical regions. A cumulative analysis of influenza activity from 2006 to 2011 in ten tropical countries of South and Southeast Asia found two major patterns of influenza activity – a distinct summer / monsoon peak between June and October (corresponding to the winter peaks in the SH) in Bangladesh (June to September), Cambodia (July to December), India (June to August), Lao People’s Democratic Republic (August to December), Philippines (June to October), Thailand (June to November) and Viet Nam (July to August) [78]. Furthermore, countries such as India (northern region) and Thailand showed an additional secondary peak between December and March (corresponding to the winter peaks of the NH) (see Figure 6). This suggested that the tropical countries in South and Southeast Asia even though situated in the NH may not follow the typical winter peaks of temperate countries of the NH. However, some of these tropical countries with large latitudinal spread and situated further away from the equator may additionally have a secondary minor peak that follows the typical NH winter peak [79].

Figure 6: Influenza circulation and vaccination timing in South and Southeast Asia

Countries such as Indonesia and Malaysia closer to the equator showed identifiable influenza activity yearround with variable peaks in some years. Despite some possible carry-over protection from previous years vaccination, a NH influenza vaccine delivered in October would be too late to cover the current influenza season and too early to offer optimal protection for the next influenza season due to declining vaccine induced antibody titres [80]. Instead the authors proposed the most recent formulation of the SH influenza vaccine

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that becomes available in April for these tropical countries prior to the influenza season (June to October) [78]. Furthermore, countries such as Thailand and China, Hong Kong SAR with a secondary peak, may benefit from a second vaccination schedule – the NH vaccine (available in October) prior to the secondary winter peak (November to February) [79, 81-83]. The additional health benefit needs to be weighed against the cost and effort of providing a second vaccination campaign against the second and smaller epidemic. Singapore with biannual peaks provides formulations and schedules recommended for both the northern and southern hemispheres [19]. This proposed vaccination timing relates well with the timings of vaccination campaigns conducted by some of these countries as seen from questionnaire based surveys on seasonal influenza vaccine policy, recommendation and practice administered to EPI managers in 36 countries in the Western Pacific region [28, 31]. Most countries in the Western Pacific region (American Samoa, China, French Polynesia, Guam, China, Hong Kong SAR, Marshall Islands, the Federated States of Micronesia, China Macao SAR, New Caledonia, Palau, Democratic People’s Republic of Korea, Viet Nam and Wallis and Futuna) reported influenza peaks typical of the NH winters (December to April). However some countries (Niue, Philippines, Pitcairn Islands and Tokelau) reported peak activity from June to November while a few countries (Brunei Darussalam, Cambodia, Cook Islands, Malaysia and Singapore) reported identifiable activity year-round. Most of these countries conducted their seasonal influenza vaccination campaigns in the months before or during peak influenza activity though several countries (French Polynesia, Guam, the Federated States of Micronesia, China Macao SAR and Niue) reported vaccination timings that were not aligned with their influenza epidemics [31]. A realization in the Philippines that the NH formulation was being administered after the June / July peak in seasonal influenza activity brought about a policy shift to use the SH formulation in 2002 [35]. Latin America and the Caribbean An ongoing CDC study used laboratory confirmed ILI and SARI surveillance data from 2002 – 2013 from 16 countries from Latin America and the Caribbean to explore timing of influenza epidemics during a hypothetical calendar year to ascertain the optimal month for vaccination [84]. After excluding the pandemic years (2009 – 10) and the years with less than 25 specimens, preliminary analysis of a total of 95y of surveillance data indicated that influenza activity in tropical Latin America and the Caribbean countries (with the exception of Guatemala and Mexico that followed a NH seasonality pattern, and Jamaica that had epidemics as early as February) typically started in May (± two months) and lasted for about 4mo. In 56% of study years in most countries of Latin America and the Caribbean (with the exception of the Dominican Republic and tropical Mexico that followed a SH and NH seasonality pattern respectively), a second smaller influenza epidemic typically started in November (± two months) and lasted for about 4mo (see Table 2). Furthermore, the predominant strain of the circulating virus had a good antigenic match with the SH formulation in 77% of years compared to 60% match with the NH formulation [84]. Countries of Latin America and the Caribbean, with the exception of Guatemala, Jamaica and Tropical Mexico, should consider vaccination in April prior to the primary influenza season from May to September. Vaccination campaigns in most countries in this region, use the SH formulation which becomes available just before the influenza season. Ecuador and the Bolivarian Republic of Venezuela are the only two countries in South America that use the NH vaccine formulation. Both NH and SH formulations are available in Nicaragua – the SH formulation through the public sector and the NH formulation in the private sector [40]. El Salvador and Guatemala in Central America which used the NH formulation in the past, switched over to the SH formulation in recent years. Interestingly, it was seen that Cuba and Honduras vaccinated its population in November using the NH formulation (that became available in October) after the end of the influenza season and several months ahead of the next season. On the other hand, Costa Rica used the NH formulation in February – March (several months later after its availability) to target the influenza season (July – November). Costa Rica and Honduras are now considering timing their vaccination campaign in April – May using the most recent SH

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formulation while Cuba has already changed to this new schedule. Similarly the Bolivarian Republic of Venezuela, Costa Rica, and Ecuador should explore the potential impact of switching their vaccination policy from the NH to the SH formulation as they accrue more years of laboratory-confirmed influenza data. Brazil The timing of influenza vaccination poses a paradox for Brazil which has a large latitudinal spread. Influenza activity peaks in the northern region of Brazil (near the equator) in March and April. It peaks later (May to June) in the south of Brazil (near the tropic of Capricorn). The vaccination campaign in all of Brazil begins in April when the SH vaccine becomes available. By the time the vaccine rolls out, it is too late for the vaccine to have an optimal protective effect as the influenza activity in north Brazil is almost at an end whereas in south Brazil the influenza activity has already started [85]. Historically, the success rate of vaccination campaigns in both north and south Brazil (as judged by the proportion of influenza seasons from 1999 – 2007 where strains were correctly matched in terms of composition and timing of vaccine delivery) is 30%. A study simulating the effect of different vaccination formulations and timings showed that a SH vaccine if delivered 3mo earlier (by January) would increase the vaccination campaign success rate to 70% in both north and south Brazil whereas a NH formulation delivered in October would increase the campaign success rate to 65%. Paradoxically, the SH vaccine delivered in April may not be the optimal choice for Brazil [23]. A more practical approach with existing vaccine delivery schedules would continue to use the SH formulation in south Brazil where most of its population lives with an optional second schedule during October using the NH formulation for the northern regions of Brazil. The Brazil vaccination timing dilemma may also be relevant to other large tropical countries such as China and India. As in Brazil, influenza activity starts earlier in the north and moves towards the central and southern regions [86]. China Similar to the latitudinal gradient in the timing of influenza activity in Brazil, a spatiotemporal modelling using surveillance data from 2005-11 identified three provincial regions in China with distinct seasonality patterns that broadly aligned with climatic zones. Northern provinces of China (latitudes >33° N) experienced winter peaks (January); southernmost provinces (latitudes <33° N) experienced spring peaks (April – June); whereas provinces at intermediate latitudes experienced semi-annual peaks (March and October). Vaccination timing is further complicated by differences in the seasonality of influenza A and B especially in south China. It may not be possible for a single annual influenza vaccination campaign to be effective against both virus types and in all provinces of China. A NH vaccination schedule (October) would be optimal for Northern China. In contrast, to have an effect on the spring peak (April – June), a SH vaccination schedule (albeit a month earlier in March) would be optimal for Southernmost China. The situation was more complex in the intermediate provinces of China due to the semi-annual peaks and longer periods of influenza activity to suggest an effective vaccination strategy [87]. India Similar to other countries with a large latitudinal spread, the seasonality pattern varies in different regions of India. Limited influenza activity is seen year-round with a distinct peaking of activity from June to August during the rainy season throughout the country. In addition Tamil Nadu State in the southern India has a second spell of rains (the North East Monsoon) from October to December. Moreover, a second albeit smaller, peak in influenza activity occurs in the winter months from December – February in the northern regions of India that follows a NH temperate pattern [77, 88]. Though India is yet to formulate a vaccination policy against seasonal influenza, it may consider a staggered schedule – SH formulation in April – May in the whole country prior to the main influenza season and a second schedule with the NH formulation in October prior to the secondary winter peak (November to February) in northern India as also for the northeast monsoon peak during the same period in Tamil Nadu in South India [89-91]. 24

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Table 2: Vaccination timing and influenza activity in Latin America and the Caribbean (2002 – 13)

Years (2009 – 10 excluded) Central America Costa Rica 2006 – 12 Cuba Dominican Republic El Salvador Guatemala Honduras Jamaica Mexico (Tropical) Nicaragua Panama Bolivia (Plurinational State of) Brazil Colombia 2011 – 13 2011 – 13 2005 – 12 2007 – 12 2008 – 13 2011 – 13 2011 – 13 2008 – 12 2008 – 12 2011 – 13

Influenza epidemic period

Vaccination campaign timing

Vaccine formulation used

Good match between circulating and NH formulation 5 / 7y

Good match between circulating and SH formulation 5 / 7y

Jun – Jul Nov – Jan Apr – Sep Apr – Aug May – Jul Sep – Oct Jan - Jun Jul – Dec Feb – Apr Sep – Nov Oct – Mar Jun – Nov May – Sep May – Oct

February – March November

NH NH NH SH

2 / 4y 5 / 7y 3 / 5y

3 / 4y 5 / 7y 4 / 5y

April December

SH NH (<2012) NH NH NH

April - May April – May May – June

SH SH SH

3 / 5y 1 / 3y

4 / 5y 2 / 3y

Ecuador Paraguay

2003 – 13 2002 – 07, 2011 – 13 2011 – 13 2003 – 05, 2011 – 13 2003 – 08, 2011 – 13

Mar – Jul Apr – Jul Dec – Jan Jul – Sep Jan – Mar Jun – Jul Oct – Jan Apr – Aug

April March

SH SH

5 / 7y

5 / 7y

NH April SH 2 / 5y 5 / 5y

Peru

Dec – Mar (N&E); May – Sep (rest)

SH

WHICH VACCINE FORMULATION TO USE? The WHO GISRS comprises of year-round testing of clinical specimens for influenza virus by more than 103 NICs in 99 countries and timely sharing of representative virus isolates with WHO CCs for further antigenic and genetic analysis [29, 69, 92]. The majority of countries that shared viruses for the NH 2014-15 and SH 2015 vaccine formulation were High Income Countries situated in the temperate regions (see Figure 7 and Figure 8).

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Figure 7: Countries that shared influenza virus with WHO CCs for the NH 2014-15 vaccine formulation

(Data source: WHO CCs reports for the WHO influenza composition consultation in February 2014, Map production: WHO GISRS Team, WHO)

Figure 8: Countries that shared influenza virus with WHO CCs for the SH 2015 vaccine formulation

(Data source: WHO CCs reports for the WHO influenza composition consultation in September 2014, Map production: WHO GISRS Team, WHO) South and Southeast Asia contributed viruses for composition selection of both hemisphere vaccines whereas countries in Latin America and the Caribbean contributed viruses primarily for the SH 2015 vaccine formulation.

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Figure 9: Seasonal influenza virus isolates analyzed by WHO region

(Source: Global Influenza Surveillance and Response System, WHO) Figure 9 shows the distribution of the number of seasonal influenza viruses analysed by the WHO CCs for the NH 2013-14 and SH 2014 vaccine formulation. The majority of the viruses analysed were from the Western Pacific region, mostly from mainland China, China, Province of Taiwan and China, Hong Kong SAR. Fewer viruses were analysed from Europe relative to the countries from Latin America and the Caribbean. The number of influenza viruses from countries in the tropics and subtropics that were analysed by the WHO CCs for the biannual vaccine formulations were far fewer compared to China and the Americas. Based on antigenic and genetic analysis by the WHO CCs coupled with human serology data and epidemiology data, the WHO recommends the influenza vaccine composition for the next season for the NH and SH. It is presumed that a vaccine strain that has a match with the circulating virus as determined by antigenic characterization is more likely to confer protection against clinical influenza. The addition of a separate recommendation for the SH in 1998 by the WHO improved the antigenic match for the A/H3N2 viruses from 31% to 59% in the southern hemisphere and made it comparable with that in the NH [93]. Since then, vaccine antigenic match has averaged 55 – 60% in both hemispheres. However, the antigenic match for the influenza B virus decreased from ~100% to 33 – 54% in both hemispheres following the unexpected resurgence of the B/Victoria lineage in 1997. Challenges for the tropics Though this process has worked well for countries with temperate climates, its application to countries with tropical and subtropical climates faces a few challenges. First, the NH and SH vaccine formulations were largely based on evidence from temperate countries of the respective hemispheres where an estimated 57% and 2% of the world’s population reside. The relative dearth of evidence from the tropical regions (where 41% of the world’s population reside) on the antigenic and genetic characteristics of the viruses, prevalence, geographic distribution and rate of spread – evidence that forms the basis for vaccine strain recommendation – made it difficult to determine whether a NH and / or SH vaccine strain was more appropriate for a country in the tropics. Second, it was unclear how much representation and weightage the viruses from tropical regions had, in the final consideration for the vaccine recommendation. Third, the antigenic drift of the influenza virus was 27

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more likely to occur with year-round transmission often seen in the tropics. Fourth, the co-circulation of rapidly evolving strains of the A/H3N2 virus in the same season made it difficult to assess the match between the different circulating viruses and the recommended vaccine strain. Only a few studies from the tropics indicated which strains were dominant or otherwise. Moreover the co-circulation of both the B/Victoria and B/Yamagata lineage of the influenza B viruses especially in the tropics, made prediction of which lineage would circulate in the next season, difficult. The dominant circulating influenza B lineage matched in only 5 out the last 10 seasons with the recommended vaccine strain [94]. Fifth, most genetic studies reported on the virus strains aggregated for the year of circulation. As the month of circulation of the virus was not reported it was difficult to determine which vaccine formulation the virus strain clustered with. The influenza virus subtype A/H3N2 is known for its rapid evolution and dominance in most seasonal epidemics since 1968 when it first appeared in humans. Since the introduction of the first TIV in 1978 till the end of 2014, a total of 50 changes were recommended by the WHO – A/H3N2 (23); A/H1N1 (9); and influenza B (18) including recommendation for both lineages of influenza B since 2013. In the 1987 – 1997 decade, the circulating strains differed in antigenicity from the vaccine strains in 5 of the 10 seasons [95]. Modelling the antigenic change has shown that the current vaccine virus selection has historically matched well with the subsequently circulating influenza virus except in 1997/98 due to the late emergence of the A/Sydney/5/97like virus in mid-1997 and again in 2003/04 due to non-availability of a suitable vaccine candidate for the emergent A/Fujian/411/2000-like virus [92]. Latin America and the Caribbean There was a partial to poor match between the vaccine and the circulating virus (especially A/H3N2 virus subtype) in most influenza seasons in Latin America and the Caribbean countries (see Table 3). Typically, there was a one to two season delay before the influenza vaccine covered a circulating A/H3N2 virus strain [96, 97]. The genetic / antigenic match between the vaccine and the circulating virus varied in different seasons with a better match seen for influenza B viruses [98-100] except in 2002 when the B/Victoria lineage reappeared [101]. Similarly a poor antigenic match was seen for influenza B virus and the vaccine strain from 2001-13 in Brazil [102]. Genetic studies of influenza A/H3N2 viruses circulating in South America from 1999 to 2007 indicated that multiple clades co-circulated during most influenza seasons. Different genetic lineages cocirculated in large countries like Brazil, Argentina and Chile and even in smaller countries like Uruguay. Only vaccine strains recommended for the 2007 influenza season shared the same cluster with the circulating influenza viruses in that season [103]. A genetic survey of influenza A/H3N2 viruses circulating from 1999 – 2012 in Brazil showed that the strains circulating in 1999 and 2003 were significantly different from the vaccine strains for those seasons. Moreover both A/Perth/2009-like and A/Victoria/2009-like strains co-existed in different regions of Brazil during 2010 to 2012. The circulating virus strain matched with the SH vaccine formulation in only 5 out of 13 seasons [104]. In contrast to an earlier study in Brazil [23], this study found that the vaccine formulation (NH or SH) was irrelevant in the northeast regions, whereas the SH formulation was superior in the south and southeast regions of Brazil. Africa A study in Kenya showed that 78% and 89% of the influenza virus strains circulating between May – October and November – April respectively between 2007 – 2012 had antigenic relatedness with the corresponding SH and NH vaccine formulation for that season [105]. The circulating virus matched with the SH formulation in 2007 but was delayed by one season in 2008 [106]. As influenza activity in Kenya showed seasonality patterns seen in both northern and southern hemispheres, it remains to be seen if a vaccination strategy using both NH and SH vaccine formulations would be cost-beneficial in Kenya. Influenza dynamics in Africa is complex and differences in influenza activity cannot be explained by the simple dichotomy between northern and southern hemisphere [107]. Here again, the genetic / antigenic match between the vaccine and the circulating virus varied in different seasons with often a one-season delay before the influenza vaccine covered a circulating 28

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A/H3N2 virus strain [108, 109]. A poor match often resulted when both lineages of influenza B co-circulated or when the B/Victoria lineage re-emerged in 2002 [109, 110]. Asia Pacific Southeast and East Asia has been hypothesized to be the source reservoir for new strains to seed and spread globally [69, 111]. Here again, the genetic / antigenic match between the vaccine and the circulating virus varied in different seasons with often a one-season delay before the influenza vaccine covered a circulating virus strain [112-122]. Strains sometimes persisted locally or were re-seeded by international travellers and hence matched poorly with the newer vaccine strain [91, 123]. Here again, a poor match resulted when both lineages of influenza B co-circulated or when the B/Victoria lineage re-emerged in 2002 [116, 124]. The decision about which vaccine formulation to use depends on the antigenic match between the vaccine virus strain and the circulating influenza viruses within the country. In the absence of such evidence, irrespective of whether the country lies north or south of the equator, practical considerations of which vaccine formulation is or would be available prior to or at the time of peak influenza activity in the country determines the choice of the vaccine formulation. Example, countries like American Samoa, China, French Polynesia, Guam, China, Hong Kong SAR, Marshall Islands, the Federated States of Micronesia, New Caledonia, Palau, Democratic People’s Republic of Korea, Wallis and Futuna used the NH vaccine formulation that becomes available in October, as they had influenza peaks from December to April. Whereas countries that used the SH vaccine formulation that becomes available in April (Niue, Philippines, Pitcairn Islands and Tokelau) reported influenza peaks from June to November (except China Macao SAR that reported influenza activity in February and March). Countries (Brunei Darussalam, Cook Islands, Malaysia and Singapore) that used both NH and SH vaccine formulations reported influenza activity throughout the year [31]. Another interesting example is of Cambodia and Viet Nam. Though situated in the northern hemisphere, seasonal influenza activity in Cambodia and Viet Nam often peaks between May and November. Furthermore, the virus shows close antigenic relatedness to the SH vaccine strains [118, 120].

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Table 3: Antigenic and genetic relatedness of circulating influenza virus and contemporary vaccine strain

(Note: A match between the vaccine strain and the circulating virus is inferred based on antigenic characteristics testing. However, some studies infer a match based on the location of the vaccine strain within the same clade as the circulating viruses in a phylogenetic tree. Seasons in which circulating virus matches with corresponding vaccine strain are highlighted in red) Reference Country (Vaccine) Latin America and the Caribbean Uez Argentina (1998) (SH) [96] Savy Argentina (1999) (SH) [97] Pontoriero (2003) [99] Motta (2006) [101] LagunaTorres (2009) [98] Douce (2011) [100] Africa Argentina (SH) Brazil (SH) Peru (NH / SH) Season A/H1N1 A/H3N2 B

1990, 1993 19941997

19951999 19992002 20062008

1995-97, 1999 virus  poor match; 1998 virus  good match

1990, 1993 virus  closer to vaccine strain for subsequent rather than corresponding season 1994-97 virus  partial match with vaccine strain; Two seasons delay for circulating virus to be matched with the SH formulation 1995-98 virus  poor match; 1999 virus  good match

1995-97, 1999 virus  good match; 1998  poor match 2002 virus  poor match with NH 200102, SH 2002 due to reappearance of Victoria lineage 2006-07 virus  SH 2006, NH 2006-07, SH 2007, NH 2007-08; 2008 virus  SH 2008, NH 2008-09

Ecuador (NH)

20062010

2006 virus  SH 2006, NH 2006-07; 2006 virus (jungle region)  NH 2007-08, SH 2008; 2007 virus  NH 2007-08, SH 2008; 2008 virus  NH 2008-09, SH 2009 2006-07 virus  poor match; 2008-09 virus  good match

2006 virus  SH 2007; 2007-08 virus  SH 2008

2006-07 virus  good match; 2008 virus  poor match; 2010 virus  good match

2006 virus  SH 2006, NH 2006-07; 2007-08 virus  SH 2008; 2009 virus  SH 2009

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Reference Niang (2012) [109]

Country (Vaccine) Senegal (NH)

Season 19962009

A/H1N1 1999 virus  NH 1998-99, SH 1999; 2000 virus  SH 2000, NH 2000-01; 2003 virus  SH 2003, NH 2003-04; 2008 virus  NH 2008-09, SH 2009

A/H3N2 1997 virus  NH 1997; 2003 virus  SH 2004; 2009 virus  SH 2010

B 1997, 1999 virus  SH 2001; 2001 virus  SH 2001, NH 2001-02; 2002 virus  poor match as Victoria lineage re-emerges; 2007 virus  NH 2006-07, SH 2007; 2008 virus  SH 2008, NH 2008-09

Bulimo (2012) [106] Byarugaba (2011) [108] Heraud (2012) [107]

Kenya (SH) Uganda (SH) Cameroon (SH) Côte d’Ivoire (NH) Madagascar (SH) Niger (--) Senegal (NH) Tunisia (NH)

20072008 20082009 20082009

2007 virus  SH 2007; 2008 virus  SH 2009 2008-09 virus  SH 2010, NH 2010-11

2008 virus  NH 2008-09, SH 2009

2009 virus  SH 2010, NH 2010-11

El Moussi (2013) [110] Asia Pacific Chadha India (--) (2012) [91]

20082011

2009 virus  good match; 2010-11 virus  Poor match (Yamagata lineage not included in NH 2010-11) 2005-07 virus  good match; Late 2005  early seeding of A/Brisbane/59/2007-like virus; 2008 virus  NH 2008-09, SH 2009 2004 virus  good match; A/Panama/2007/99 persisted in Delhi till Sept 2005  poor match; 2004-05 virus  NH 2005-06, SH 2006; 2006 virus  SH 2005 (virus re-seeded due to international travel) 2005-2007 virus  SH 2008, NH 2008-09; 2008-2009 virus SH 2010, NH 2010-11; Virus strain precedes vaccine strain by 1 – 2y 2004-08 virus  good match with predominant lineage; both lineages circulated

20042008

Agrawal (2010) [112] Roy (2014) [113]

India (--)

20052009

2006-07 virus  NH 2007-08 2009 virus  SH 2009 Virus strain precedes vaccine strain by 1 – 2y

India (--)

20072009

2007-09  NH 2009-10

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Reference Barr (2003) [125]

Thawatsu pha (2003) [126] Chutinimit kul (2008) [114] Chittagan pitch (2011) [83]; Waicharoe n (2008) [127]; Suwannak arn (2010) [128] Dapat (2009) [115] Hsieh (2005) [129]

Country (Vaccine) Thailand (SH) Malaysia (SH) China-Taiwan(NH) New Caledonia (NH) Thailand (SH)

Season 20002002

A/H1N1 A/H1N2 virus – H1 gene matched with vaccine strain

A/H3N2 A/H1N2 virus – N2 gene matched with vaccine strain

B 2002 virus  NH 2002-03, SH 2003;

2001

2001 virus  good match

2001 virus  good match

2001 virus  good match

Thailand (SH)

20062007

2006-07 virus  NH 2007-08

2006-07 virus  NH 2007-08

Thailand (SH)

20042010

2004-08, 2010 virus  good match; 2009 virus  partial match (due to emergence of pandemic virus)

2004, 2007, 2009 virus  partial match; 2005-06, 2008, 2010 virus  good match

2004, 2009-10 virus  good match; 2005-08 virus  partial match

Myanmar (--)

20052007 19972004

2005 virus  NH 2007-08;

2005 virus  NH 2006-07; 2007 virus  SH 2008, NH 2008-09; 1997-2004 virus  good match (53%)

2005 virus  partial match; 2007 virus  good match 1997 – 2004 virus  good match (47%)

China-Taiwan (NH)

1997-2004 virus  good match (82%)

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Reference Shih (2005) [116] Tsai (2006) [124] Lee (2009) [130] Shu (2005) [119] Nguyen (2007) [131] Li (2008) [117]

Country (Vaccine) China-Taiwan (NH)

Season 20002004

A/H1N1 1999-2000 virus  NH 2000-01; 2000-02 virus  good match; 2003-04 virus  good match;

A/H3N2 1999-2000 virus  partial match; 2000-03 virus  good match; 2003-04 virus  NH 2004-05;

B 1999-2001 virus  good match; 2001-02 virus  partial match as both lineages co-circulated; 2002-04  good match; 1999-2000, 2002-03 virus  good match; 2001, 2004-05 virus  partial match as both lineages co-circulated; 2006-07 virus  good match; HA gene of Victoria lineage, NA gene of Yamagata lineage

China-Taiwan (NH)

19982005

China-Taiwan (NH) China (NH)

20062007 2004 2004 virus  mutations from NH 2004-05, SH 2005 2001-03 virus  good match 2001-03 virus  good match

Viet Nam (NH)

20012003 20012006

2001 virus  good match; 2003 virus  good match

Viet Nam (NH)

Vuong (2013) [120]

Viet Nam (NH)

20012009

2001-06 virus  good match; One 2006 virus (A/Hanoi/BM344/06) clustered with A/Solomon Islands/3/06 later included in NH 2007-08 2001-05 virus  good match; 2006-07 virus  poor match

2002 virus  clustered between NH 200102 and NH 2004-05; 2003-04 virus  SH 2005; 2005 virus  NH 2005-06; 2001-04  poor match; 2003-04  SH 2005; 2004 virus  SH 2004; 2005 virus  SH 2005; 2008 virus  SH 2008; 2009 virus  SH 2010 2006-08 virus  good match

Mardy (2009) [118]

Cambodia (--)

20062008

2007 virus  good match; 2008 virus  NH 2008-09

2007-08 virus  good match

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Reference Kosasih (2013) [121]

Country (Vaccine) Indonesia (--)

Season 20032007

A/H1N1 2003-06 virus  good match; A/Solomon Islands/3/06 virus first detected in 2006 – included in NH 2007-08

A/H3N2 2003 virus  SH 2004, NH 2004-05; 2004 virus  NH 2005-06; 2005 virus  NH 2005-06, SH 2006; 2006-07 virus  good match; A/California/7/04 virus first detected in 2004 – included in NH 2005-06; A/Wisconsin/67/05 virus first detected in 2005 – included in NH 2006-07 2005 virus  NH 2005-06; 2006 virus  NH 2006-07, SH 2007; 2007 virus  SH 2008; 2008 virus  SH 2008; 2009 virus  SH 2010 2005-07 virus  poor match

B 2003 virus  good match; 2004-05 virus  poor match; 2006-07 virus  good match

Saat (2010) [122]

Malaysia (SH)

20052009

2005 virus  SH 2005, NH 2005-06; 2006 virus  SH 2006, NH 2006-07; 2007 virus  NH 2007-08, SH 2008; 2008 virus  NH 2008-09, SH 2009;

2005 virus  SH 2004; 2006 virus  SH 2006; 2007 virus  SH 2008; 2008 virus  SH 2008; 2009 virus  NH 2009-10, SH 2010

Middle East Moattari (2010) [132] Soltani (2009) [123]

Iran (Islamic Republic of) (NH) Iran (Islamic Republic of) (NH)

20052007 20052007

2005-07 virus  good match

2005-07 virus  good match

2005-07 virus  NH 2003-04 (previous vaccine strain)

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SEASONAL INFLUENZA VACCINATION COVERAGE Challenges for the tropics Initiatives to document vaccine use are recent [25, 28, 31, 66]. There are several challenges for estimating influenza coverage in Low and Middle Income Countries. First, national data on seasonal influenza vaccine coverage remains scarce and not routinely available. Second, most countries (up to 88% in the WHO regions of the eastern Mediterranean and Africa) were unable to estimate coverage by target groups in the absence of reliable group-specific population denominators. Vaccine coverage was available only for four out of 14 countries in Africa that reported availability of seasonal influenza vaccine [58]. Third, though there have been efforts to create global databases on seasonal influenza vaccine coverage (annual WHO UNICEF Joint Reporting Form, Global Survey on Seasonal Influenza Policy Development and Implementation 2010, seasonal influenza vaccine sales consolidated from the vaccine manufacturers), the coverage was estimated as a proportion of procured doses that were administered or as a proportion of doses distributed to an estimated population. Fourth, few countries had information on vaccines doses that were returned, unused or wasted. Fifth, the WHO-UNICEF Joint Reporting Form and other databases do not capture vaccine coverage amongst pregnant women separately. Sixth, it was often unclear whether the estimated coverage for children less than 9y age was based on a one-dose or two-dose schedule. Overall vaccination coverage The global use of seasonal influenza vaccine increased two-fold between 1994 – 2003 with highest coverage in High Income Countries – 344, 311, 286 per 1000 population in Canada, Democratic People’s Republic of Korea and the United States respectively [25]. Coverage, estimated as the proportion of seasonal influenza vaccine doses distributed in the general population, was less than 1% in 2011 in all of Africa (except Algeria, Mauritius, Morocco, Namibia, Tunisia and South Africa) and most countries in Asia (Bangladesh, India, Indonesia, Myanmar, Nepal and Sri Lanka) (see Appendix D). Though the greatest rate of growth (2008 – 11) was seen in Asia, the total number of seasonal influenza vaccine doses distributed remained relatively small at 8.2 million in 2011. In contrast, Europe showed a decline of 29% in influenza vaccine use during this period. Most countries of Latin America and the Caribbean (except Guatemala, Guyana, Haiti and Jamaica), Mauritius and China, Hong Kong SAR, had vaccine coverage >100 doses per 100,000 population (see Figure 10) [49].

Figure 10: Seasonal influenza vaccine doses distributed in the tropics and subtropics (2011)

(Source: adapted from data provided by IFPMA Influenza Vaccine Supply International Task Force) 35

Results

Higher vaccination coverage was not correlated with higher level of economic development. Higher coverage, however, was seen when the vaccine was offered free through the public sector [25]. Seasonal influenza vaccination coverage remains low in Low and Middle Income Countries [11]. In Africa seasonal influenza vaccine coverage varied from <0.5 – 2% of the population and was not associated with World Bank indicators of income level [58]. Seasonal influenza vaccine sales in ten Southeast Asian countries increased from <5 to about 10 per 1000 population post-pandemic. Vaccine sales were low in Indonesia (<2 per 1000) and higher in Thailand (about 6 – 7 per 1000). The coverage was higher (7 – 12 per 1000) in Singapore despite influenza vaccines being offered at a cost in public hospitals [133]. The coverage in China was less than 5% of that in High Income Countries like the United States and Canada and similar to Low and Middle Income Countries [25, 26, 57, 134, 135]. Children Routine influenza immunization in children was first recommended in the United States in 2004 for those aged 6 – 23 months. This was further expanded to include children aged 2 – 4y in 2006 and 5 – 18y in 2008 [136]. Coverage in children in High Income Countries has varied with seasons but have overall remained low (4 – 19% in Europe) [137] (see Table 4). In the United States, influenza vaccine coverage was 35% for children aged 6 – 23mo and about 15% for children aged 13 – 18y. Coverage in children has generally been lower than in the elderly, but higher than for adults. Seasonal influenza vaccine coverage varied markedly in a ten-country survey in Africa, Asia Pacific, Central America and the Middle East during the influenza seasons of 2005 and 2006 [138]. Coverage was higher amongst children (range: 23 – 62% when public funded, 8 – 10% when not) and reflected the generally high coverage with other childhood vaccines seen in children in Low and Middle Income Countries. Most countries in Latin America and the Caribbean had coverage in children of more than 80%. Lower coverage was reported by Peru (23%), Uruguay (26%), Paraguay (35%), Bolivia (Plurinational State of) (36%), and Honduras (45%) [139]. Coverage varied from 32% amongst pre-school children aged above 6mo to 72% amongst children in elementary school in China, Province of Taiwan [140]. On the other hand, coverage amongst young children in Thailand was less than 2% [141]. Elderly The 56 World Health Assembly (WHA56.19) resolved to immunize at least 75% of its elderly population against seasonal influenza [4]. Most countries lagged far behind this target (see Table 4). The Latin America and the Caribbean countries performed better in being able to meet the WHA target compared to other regions including Europe where only the Netherlands was able to attain this goal followed closely by the United Kingdom [28]. Influenza vaccination coverage amongst the elderly varied from 14 – 70% in Europe [137]. Within Europe, there have been large disparities (40-fold difference) in coverage amongst the elderly [32, 142]. Few countries (around half of all countries in the WHO WPR, less than a third in the PAHO region, two of nine countries in the WHO EMR, one country in the WHO European region and none in Africa or South and Southeast Asia, are set to achieve this target [45]. On the other hand, Latin America and the Caribbean countries (Chile, Costa Rica, Dominican Republic, El Salvador, Honduras, Mexico, and Nicaragua) have consistently achieved coverage of more than 75% amongst the elderly since 2005 though others like Argentina, Belize, Bolivia (Plurinational State of), Colombia, Ecuador, Panama, Paraguay, Peru and Uruguay have shown declining coverage in recent years [40, 139]. The influenza vaccine coverage in Argentina was 36% in the overall population and 30% amongst the elderly [143]. Brazil has sustained an influenza vaccine coverage between 70 – 90% since 1999 [144]. Population surveys to estimate influenza vaccination coverage are rare amongst Low and Middle Income Countries. A review of VE in Brazil [144] identified ten studies that also presented seasonal influenza vaccine coverage amongst elderly population [145-151] and elderly patients attending outpatients clinics [152-154]. Vaccine coverage generally ranged from 66 – 88%. In three surveys, differences of 20 – 25% points were seen between the survey coverage and those reported by the Ministry of Health [145, 151, 152]. Coverage was generally 36 th

Results

higher when the influenza vaccination was public funded [138]. It ranged from 14 – 41% in Low and Middle Income Countries with public funded immunization programs whereas it was less than 10% where influenza vaccination was not publicly funded. On the other hand, a government funded influenza vaccination program in Thailand and China, Province of Taiwan reported coverage of 12% and 40% respectively amongst the elderly [140, 141]. Coverage was high in Republic of Korea (41%) and Chile (25%) and lowest in Turkey (5%). Coverage was lower amongst healthy adults aged 18 – 65y (16% when public funded and 5% when not). A strong recommendation together with public funding of immunization campaigns may increase influenza vaccination coverage [138]. Chronically ill Influenza vaccine coverage amongst chronically ill patients in High Income Countries varied from 11 – 72% [32, 136, 137] (see Table 4). No influenza vaccination coverage data was available for chronically ill patients from Low and Middle Income Countries. Pregnant women Despite the WHO recommendation that pregnant women should have the highest priority for seasonal influenza vaccination [3], influenza vaccination in pregnancy remains low (2 – 49%) [136]. In the US, coverage ranges from 32 – 49% [155, 156] (see Table 4). National data on influenza vaccine coverage amongst pregnant women in Low and Middle Income Countries is scarce. None of the 1000 pregnant women attending an antenatal clinic in a hospital in India received influenza vaccination during pregnancy in the 2012 – 13 influenza seasons [157]. Studies from China, Hong Kong SAR and Thailand reported coverage from 1 – 4% amongst pregnant women [141, 158, 159]. Healthcare professionals Influenza vaccination coverage amongst healthcare professionals varies widely based on their category. Most often the vaccine coverage amongst healthcare professionals are low (17 – 26%) even in High Income Countries but can reach up to 89% for those working with high risk patients [136, 137, 142, 160-163]. Vaccination coverage for healthcare professionals averaged 30 – 34% in Europe [32]. Coverage amongst healthcare professionals are higher (44 – 62%) in the United States [164]. Coverage amongst healthcare professionals in Low and Middle Income Countries have been estimated between 20 – 56% in the postpandemic years [165-167] (see Table 4). Table 4: Seasonal influenza vaccine coverage in the tropics

Seasonal influenza vaccine coverage Children

High income countries 4 – 19% [137]; 1 – 83% [32]; 55% (6mo – 23mo), 38% (2 – 4y), 27% (5 – 12y), 15% (13 – 18y) [136]

Low and Middle Income Countries Argentina, Belize, Chile, Colombia, Ecuador, El Salvador, Mexico, Nicaragua, Panama: >80%; Bolivia (Plurinational State of), Honduras, Paraguay, Peru, Uruguay: 23 – 45% [139]; Public funded: 23 – 62%, User paid: 8 – 10% [138]; China, Province of Taiwan: 32 – 72% [140]; Thailand: <2% [141]

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Seasonal influenza vaccine coverage Elderly

High income countries 14 – 70% [137]; 2 – 82% [142]

Low and Middle Income Countries Chile, Costa Rica, Dominican Republic, El Salvador, Honduras, Mexico, and Nicaragua: >75%; Argentina, Belize, Bolivia (Plurinational State of), Colombia, Ecuador, Panama, Paraguay, Peru and Uruguay: 20 – 69% [40, 139, 143]; Brazil: 66 – 90% [144-154]; Public funded: 14 – 41% (Republic of Korea (41%)); User paid: <10% (Turkey (5%)) [138]

Chronically ill

Pregnant women Healthcare professionals

11 – 56% [137]; 33 – 72% [32]; 19 – 40% [136] 32 – 49% [155, 156] 17 – 89% [32, 136, 137, 142, 160-163]

0 – 4% (India, China, China, Hong Kong SAR, Thailand) [141, 157-159] 20 – 56% [165-167]

EFFECTIVENESS OF SEASONAL INFLUENZA VACCINE IN THE TROPICS Challenges for the tropics Evidence for vaccine efficacy and effectiveness has been almost exclusively derived from studies in High Income Countries [168, 169]. There are several inherent challenges in applying efficacy trial results to population effectiveness [170]. First, the continuing antigenic evolution of the influenza virus, the different types and subtypes of the virus with varying virulence, transmissibility and seasonality, and the relative prevalence of each type or subtype of virus means that the vaccine effect varies between seasons and locations. Second, the lack of a standardized outcome to measure effectiveness makes it difficult to interpret and compare VE across seasons, locations and populations. Immune correlates of vaccine protection are not reliable end-points especially in groups that respond less well to vaccination viz. children, elderly and the immunocompromised. Case ascertainment by laboratory confirmation varies due to variations in virology testing both within and between laboratories. Clinical case ascertainment is subject to even more variability due to the generally low specificity of clinical case definitions. Vaccine impact on more severe outcomes like hospitalization or mortality though easier to ascertain differs from the vaccine impact on less severe disease; ascertaining mortality impact also requires large samples. Third, the estimate of vaccine efficacy depends upon the comparator used against the test vaccine. Relative vaccine efficacy measured against a comparator vaccine (e.g. pneumococcal vaccine) is likely to be lower than the absolute vaccine efficacy measured against a placebo. Fourth, VE at the population level is typically greater than the vaccine efficacy at the individual level due to the herd protective effect of vaccination. Information on factors that influence herd immunity such as infectivity of the virus strain, the individual’s susceptibility, population mixing, vaccine coverage are difficult to measure in most trials. Fifth, the earlier inactivated influenza vaccines were considered identical and comparable. However, with the advances in the purity and potency of newer vaccines, it is a challenge to compare vaccine efficacy and effectiveness between these specialized vaccine products [171]. Sixth, VE varies with how well the antigenicity of the vaccine virus strain matches with that of the circulating influenza virus. Notwithstanding these challenges, VE data is critical for policy decisions by countries to introduce and evaluate influenza vaccination programs.

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VACCINE EFFECTIVENESS IN ELDERLY Vaccine effectiveness has been extensively studied in two higher priority groups – elderly (60y or 65y and older) in the general population and residents of nursing homes or long-term care facilities. It is believed that vaccines in general are less effective in the elderly as the immune response diminishes at later ages. A literature search for seasonal influenza vaccine effectiveness in the elderly identified ten systematic reviews [27, 172-179] with 10 to 75 studies. A total of 26 studies including three unpublished, nine cohorts, four RCTs, four case control, seven ecological and two non-RCTs, from the tropics and subtropics were identified [143, 153, 180-203]. One review [27] that focused on VE in Low and Middle Income Countries included ten studies on the elderly of which nine were from the tropics and subtropics. For details, refer to Appendix E. Table 5 summarizes the VE against influenza outcomes in the elderly. Influenza-like illness The pooled efficacy from different reviews against ILI or ARI varied from 36% [172] to 56% [177]. The studies from Low and Middle Income Countries yielded a pooled efficacy of 4% (not significant) for LAIV and 59% (95% CI: 44 – 70) for TIV [27]. The VE against ILI ranged widely from no effect [153] to 76% [194, 195] in the tropical studies. A study from South Africa was inconclusive about the relative efficacy of LAIV and TIV [190]. Laboratory confirmed influenza Both Inactivated Influenza Vaccine and LAIV were found to be efficacious against laboratory-confirmed influenza in the elderly. The pooled efficacy in Low and Middle Income Countries for LAIV and TIV was 43% (25 – 56) and 58% (23 – 78) respectively [27]. This compared well with the pooled efficacy estimates from High Income Countries [172, 173] as well as with individual studies from the tropics [187, 198] . Pneumonia The pooled efficacy of the vaccine in preventing influenza related complication of pneumonia in the elderly ranged between 30% and 53% [173, 174, 177, 193]. The efficacy was at least 10% points higher with a good antigenic match between the vaccine and circulating virus strain [177]. Hospitalization The pooled VE estimate for preventing all-cause hospitalization in the elderly was 50% [174, 177]. The pooled efficacy estimate for preventing hospitalization due to P&I or cardiovascular or respiratory cause was lower (range 25% – 33%) [172, 176, 178]. In contrast, neither LAIV nor TIV had a significant effect in preventing hospitalization in the elderly in Low and Middle Income Countries [27]. Two studies from the tropics showed no effect of LAIV or TIV in preventing any or P&I related hospitalization in the elderly [187, 188]. Four other studies from Brazil showed a modest reduction in hospitalization in the elderly [182, 184, 189, 191]. However more recent studies from the tropics showed a significant reduction in hospitalization related to P&I (range 31% – 77%) and cardiovascular disease (range 15% – 41%) in the elderly similar to that seen in High Income Countries [143, 180, 185, 193, 196, 199-201]. Mortality The majority of the studies that were included for meta-analysis in the systematic reviews after quality appraisal were from High Income Countries. VE was higher when laboratory-confirmed influenza rather than ILI or ARI were used as outcomes for evaluation. The effectiveness of the vaccine against ILI, laboratoryconfirmed influenza and pneumonia ranged widely and was unclear in the tropical settings. However barring two studies (one RCT and one cohort), more recent studies showed significant protection against influenza related and all-cause mortality in the elderly in the tropics that was comparable with that seen in High Income 39

Results

Countries. The pooled efficacy estimate for preventing influenza related mortality in the elderly varied from 8% to 30% [173, 174]. The VE was higher for preventing all-cause mortality (range 36% – 68%) [172, 174, 176-178]. Two individual studies from the tropics showed no vaccine effect on preventing mortality [187, 188]. In contrast more recent trials from the tropics showed a significant reduction in influenza related mortality (range 20% – 53%) [181, 183, 200] and all-cause mortality (range 24% – 44%) [183, 193, 199, 200]. Excepting the two studies that showed no effect, VE against influenza related mortality in tropical studies appeared to be higher than that in High Income Countries whereas the VE against all-cause mortality was seen to be lower in the tropical studies compared to that from High Income Countries. The benefit of influenza vaccines in the elderly has been questioned recently with at best a 4% reduction in mortality in the elderly [204]. Excess mortality studies were unable to confirm a decline in elderly mortality since 1980 despite an increase in vaccination coverage from 15 – 65%. Frailty bias and use of non-specific endpoints like all-cause mortality have possibly led cohort studies to overestimate vaccine effectiveness [205].

VACCINE EFFECTIVENESS IN HEALTHY CHILDREN LAIV and TIV have been extensively evaluated for safety and efficacy in children aged > 6mo for whom the vaccine is currently licensed for use. A literature search for seasonal influenza vaccine effectiveness in children identified 14 systematic reviews [13, 27, 169, 206-216] that meta-analysed up to 47 studies most of which were from High Income Countries. Most studies included in the reviews evaluated laboratory-confirmed influenza as the primary outcome separately for LAIV and TIV further stratified by antigenic match. A total of 13 studies including three unpublished – 8 RCTs, one cohort and 4 case controls, were identified from the tropics [180, 195, 217-227]. One review [27] that focused on VE in Low and Middle Income Countries included 12 studies on healthy children of which six were from the tropics and subtropics. For details refer to Appendix F. Table 5 summarizes the VE against influenza related adverse outcomes in healthy children. Influenza-like illness The pooled efficacy for both LAIV and TIV from different reviews against ILI or ARI varied from 31% – 45% in High Income Countries. This compared well with the 36% and 27% efficacy for LAIV and TIV respectively in Low and Middle Income Countries [27]. The pooled efficacy against ILI with a poor antigenic match between the vaccine strain and the circulating virus was 32% (95% CI: 27 – 36). It increased to 41% (95% CI: 31 – 49) in the presence of a good antigenic match [212]. The vaccine efficacy against ILI ranged widely from 8% to 85% in two tropical studies from China [195, 218]. Laboratory confirmed influenza In High Income Countries the overall vaccine efficacy in preventing laboratory-confirmed influenza in healthy children ranged between 67% – 74% [209, 212, 213]. In contrast, vaccine efficacy varied widely from 20% – 77% in Low and Middle Income Countries from the tropics [180, 223, 224, 226, 227]. In High Income Countries, the pooled efficacy varied from 62% – 83% [169, 206, 207, 211-213] and 48% – 67% [206, 207, 211-213] for LAIV and TIV respectively. The pooled efficacy for LAIV (72%, 95% CI: 65 – 77) and for TIV (81%, 95% CI: 58 – 92) seen in Low and Middle Income Countries was comparable with that seen in High Income Countries [27]. In contrast, vaccine efficacy for LAIV (range: 64% – 72%) [219-221] and for TIV (range: 33% – 62%) was lower in individual studies from Low and Middle Income Countries from the tropics. In both high and low income settings, the LAIV was more efficacious than TIV in preventing laboratory-confirmed influenza in healthy children. However, new observational data from the Flu Vaccine Effectiveness Network unexpectedly showed no effect of the LAIV against the A(H1N1)pdm influenza virus when compared with the inactivated influenza vaccine in children aged 2 – 8y [228]. 40

Results

In High Income Countries, the pooled efficacy in the presence of a good antigenic match between the vaccine strain and the circulating virus (range 61% – 88% and 48% – 81% for LAIV and TIV respectively) was higher than for a poor antigenic match (range 60% – 87% and 49% – 56% for LAIV and TIV respectively) [207, 215] except in two reviews [208, 212]. In Low and Middle Income Countries from the tropics, the vaccine efficacy in the presence of a good antigenic match was comparable (range for LAIV: 70% – 78%) [219-221] with that for High Income Countries. In High Income Countries, the pooled efficacy increased from 58% with one dose to 75% with two doses of LAIV [210]. A similar increase was also seen for LAIV and TIV in the Low and Middle Income Countries from the tropics [219, 225] though one study from China showed a significant protective effect only after two doses of TIV [223]. The protection persisted into the second year without re-vaccination [219] whereas there was no protective effect of the vaccine at the end of one year [224]. In High Income Countries, the pooled efficacy against influenza A virus ranged widely between 31% – 91% whereas the efficacy was 45% against influenza B infection [214]. In contrast the efficacy against influenza A (range: 25% – 57%) and influenza B (range: no effect – 50%) was lower in Low and Middle Income Countries from the tropics [217, 218]. Herd effect following vaccination of children In High Income Countries, vaccinating children with seasonal influenza vaccine provided up to 30% protection against ARI amongst family members [216, 229, 230]. One RCT showed a significant protection of 61% against laboratory-confirmed influenza amongst contacts [231]. This was similar to the efficacy of 61% (6 – 85) seen in a RCT from Sao Paulo, Brazil against laboratory-confirmed influenza amongst household contacts [232]. The majority of the studies that were included for meta-analysis in the systematic reviews, after quality appraisal, were from High Income Countries. Though the vaccine efficacy studies of LAIV and TIV with and without good antigenic match from high and Low and Middle Income Countries were comparable, the vaccine effectiveness varied widely in Low and Middle Income Countries from the tropics.

VACCINE EFFECTIVENESS IN HEALTHY ADULTS Healthy adults excepting healthcare professionals and pregnant women are not considered high priority for immunization against seasonal influenza. A literature search for efficacy and effectiveness studies of the seasonal influenza vaccine in healthy adults identified seven systematic reviews that meta-analysed between 10 to 46 studies predominantly from High Income Countries [13, 27, 169, 207, 215, 233, 234]. Most studies included in the reviews evaluated laboratory-confirmed influenza as the primary outcome separately for LAIV and TIV and further stratified by antigenic match. A total of eight studies including one unpublished, one RCT, three cohorts and three case controls, were identified from Low and Middle Income Countries in the tropics [195, 235-240]. All these six studies evaluated efficacy of TIV. One review [27] that focused on VE in Low and Middle Income Countries included 10 studies on healthy adults of which five were from the tropics and subtropics. For details refer to Appendix G. Table 5 summarizes the VE against influenza related adverse outcomes in healthy adults. Influenza-like illness In High Income Countries, the pooled vaccine efficacy against ILI was 10% for LAIV [233] and ranged from 20% – 69% for TIV [169, 233, 234]. The pooled vaccine efficacy of 62% (45 – 73) for TIV in Low and Middle Income Countries [27] was comparable to that in High Income Countries. The vaccine efficacy for TIV ranged from 39% – 73% in individual studies from the Low and Middle Income Countries in the tropics [235-238]. 41

Results

Laboratory confirmed influenza In High Income Countries, the pooled vaccine efficacy for TIV was higher (range: 57% – 80%) when there was a good antigenic match compared to a poor match (range: 44% – 52%) [207, 215, 233, 234]. The pooled efficacy against laboratory-confirmed influenza for TIV irrespective of antigenic match ranged from 59% – 61% [169, 207, 233]. In contrast, the pooled vaccine efficacy against laboratory-confirmed influenza for TIV was high at 82% (61 – 92) in Low and Middle Income Countries [27]. Only three studies from the tropics evaluated laboratory-confirmed influenza as the outcome. The vaccine effectiveness (all ages) varied between no effect to 67% in different influenza seasons in South Africa [239, 240]. The study from Singapore showed a high efficacy of 84%, 33% and 84% against the pandemic influenza virus, influenza A(H3N2) virus and influenza B virus infection respectively [238]. In contrast, the pooled efficacy from a review that analysed 34 RCTs (five from the tropics) was lower for TIV at 64% and 52% against influenza A and B infection respectively [215]. The majority of the studies that were included for meta-analysis in the systematic reviews, after quality appraisal, were from High Income Countries. There were no studies from Low and Middle Income Countries in the tropics that evaluated the efficacy of LAIV. The vaccine efficacy for TIV in Low and Middle Income Countries from the tropics appeared to be at the lower end of the range of vaccine efficacy seen in High Income Countries.

VACCINE EFFECTIVENESS IN PREGNANT WOMEN Maternal immunization with TIV is a safe and cost-effective strategy to reduce the risk of influenza related complications in mothers and also offers indirect protection to the new born till they are 6mo old, an age which has a significant influenza disease burden, yet for whom the vaccine is not licensed for use [241]. There have been no RCTs to assess the safety of LAIV or adjuvant TIV or efficacy in preventing maternal or neonatal disease. TIV is recommended for pregnant women during the influenza season in several High Income Countries including Australia, Canada, United Kingdom and the United States [242]. TIV in pregnancy reduces the influenza disease burden amongst pregnant women as well as in the new born through breast milk and trans-placental transfer of maternal antibodies [243, 244]. The WHO recommends that pregnant women should have the highest priority for seasonal influenza vaccination [3]. Though TIV has been administered to millions of pregnant women in developed countries without safety concerns, few studies have looked at its efficacy and effectiveness in preventing adverse outcomes in the mother, foetus and infant. A literature search for seasonal influenza vaccine effectiveness in pregnant women and their new born identified eleven systematic reviews [13, 241, 242, 245-252] that reviewed a total of 13 studies (RCTs – 2, cohorts – 10 and case control – 1) of which the sole study from the tropics (a RCT) was from Bangladesh [253]. Two recent reviews [245, 248] identified three additional ongoing RCTs on efficacy of TIV in the tropics (Bangladesh, Nepal and Mali) [254-256] and one RCT amongst HIVinfected pregnant and non-HIV pregnant women in South Africa which was published recently [257]. For details refer to Appendix H. Table 5 summarizes the VE against influenza related adverse outcomes in mothers and infants following maternal immunization with TIV. Adverse outcomes in mothers and their new born assessed by VE studies following maternal immunization with TIV varied. Most studies from High Income Countries from temperate climates used cohorts or case control design to assess VE against clinical end-points such as ILI or ARI [258-261]. None of these studies from High Income Countries assessed VE against laboratory-confirmed influenza in either mothers or their infants – instead some studies assessed VE using serological correlates for protection against influenza [262-267].

42

Results

VE against laboratory-confirmed influenza and clinical ILI in mothers: Laboratory-confirmed influenza was significantly reduced in both healthy mothers (VE: 50%, 95%CI: 15 – 71) and HIV infected mothers (VE: 58%, 95%CI: 0.2 – 81) following maternal immunization with TIV in South Africa [257]. The vaccine significantly reduced the risk of clinical ILI in healthy mothers (VE: 36%, 95%CI: 4 – 57) in Bangladesh [253] but had no effect in reducing clinical ILI in both healthy and HIV-infected mothers in South Africa. Similarly, the vaccine had no significant effect in reducing clinical ILI or ARI in mothers in the United States [258, 261] except in one study (VE: 44%, 95%CI: 9 – 65) [264]. VE against laboratory-confirmed influenza and clinical ILI in new born infants of women vaccinated in pregnancy: Seasonal influenza vaccination of healthy pregnant women significantly reduced the risk of laboratoryconfirmed influenza in the infant – VE varied from 49% (95%CI: 12 – 70) in South Africa to 63% (95%CI: 5 – 85) in Bangladesh. However, this effect (VE – 27%) was not significant for infants born to HIV-infected mothers. The vaccine given to healthy pregnant women significantly reduced the risk of clinical ILI in their infant (VE: 29%, 95%CI: 7 – 46) in Bangladesh but had no effect in reducing clinical ILI in the infant of both healthy and HIV-infected women in South Africa. Similarly, the vaccine had no significant effect in reducing clinical ILI or ARI in infants of mothers who received the vaccine in pregnancy in the United States [258, 260]. VE against adverse new born outcomes of women vaccinated in pregnancy: VE against both prematurity and intra-uterine growth retardation in the United States varied from no effect [268, 269] to 72% (95%CI: 26 – 89) when pregnant women were vaccinated during peak influenza season [270]. Maternal immunization showed no significant effect against prematurity or intra-uterine growth retardation in Bangladesh [253]. A study based on seasonal influenza data from the US, models the timing of seasonal influenza vaccination on effectiveness. Infants and mothers benefited the most when pregnant women were vaccinated within four weeks of vaccine availability. Once all women who were pregnant at time of vaccine availability were vaccinated, vaccination of newly pregnant women benefited the mothers but not their infants. The study predicted reduction in VE when vaccination was delayed beyond November [271]. Such modelling studies need to be tested in tropical settings that lack distinct influenza seasons. Earlier studies were suggestive though not definitive of the benefits of maternal immunization with TIV to reduce influenza related morbidity in pregnancy and in the new born. These observational studies that were based on retrospective cohorts and case control designs used clinical ILI or ARI as end-points and were suboptimal to assess VE. However, recent evidence from RCTs from Bangladesh and South Africa [253, 257] provide clear evidence that maternal immunization can be an effective strategy in low-resource settings to combat the significant influenza related morbidity during pregnancy and in the new born. In the tropics and sub-tropics, various influenza virus types and subtypes may circulate for most part of the year thereby potentially exposing every pregnancy and the new born to the risk of influenza infection all year round. Introducing the most recent TIV in the antenatal immunization program year-round may be the most effective strategy to reduce influenza related morbidity in pregnancy and in infants in tropical settings.

VACCINE EFFECTIVENESS IN HIGH RISK INDIVIDUALS High risk individuals comprised those with underlying conditions such as COPD, coronary heart disease, diabetes, cancer and immunocompromised conditions that put them at greater risk for developing complications if infected by the influenza virus or those individuals (e.g. healthcare professionals) who had a 43

Results

greater exposure to and / or had greater possibility to transmit the infection to other high risk individuals such as patients, elderly etc. For details refer to Appendix I. Table 5 summarizes the VE in high risk individuals. COPD patients A literature search for seasonal influenza vaccine efficacy in COPD patients identified a Cochrane review [272] that included eleven RCTs (ten of which were from High Income Countries). A total of three studies were identified from Low and Middle Income Countries (India, Thailand) in the tropics [273-275]. In High Income Countries, the pooled efficacy estimate (VE – 11%) against ARI was not significant. In contrast, vaccine efficacy against ARI ranged from 60% – 85% amongst COPD patients from Low and Middle Income Countries in the tropics [274, 275]. Only one study from the tropics evaluated laboratory-confirmed influenza as the outcome [273]. The VE against laboratory-confirmed influenza amongst COPD patients in Thailand was 71% that was comparable to the pooled vaccine efficacy estimate of 81% (95% CI: 52 – 93) from High Income Countries. The vaccine was 72% effective in preventing ARI related hospitalization amongst COPD patients in India comparable to the pooled efficacy estimate seen in High Income Countries [274]. Seasonal influenza vaccination had no effect on mortality amongst COPD patients [272]. Coronary heart disease patients A literature search for seasonal influenza vaccine efficacy in coronary heart disease patients identified a Cochrane review [276] that included three studies (one from the tropics). A total of two studies (Argentina and Thailand) were identified from Low and Middle Income Countries in the tropics [277-279]. The 66% (95% CI: 29 – 83) efficacy of the vaccine in preventing coronary heart disease related mortality amongst coronary heart disease patients in Argentina was similar to the pooled efficacy estimate of 61% (95% CI: 23 – 80) for High Income Countries [276, 278]. However, the Thai study did not show any significant protective effect against coronary heart disease related mortality [277]. HIV infected and other immunocompromised patients A literature search for seasonal influenza vaccine efficacy in HIV infected patients identified two systematic reviews that included up to four studies, all from High Income Countries [280, 281]. One study amongst HIV infected adults from South Africa was additionally identified [282]. The vaccine efficacy for TIV of 76% (95% CI: 9 – 96%) amongst South African HIV infected adults against laboratory-confirmed influenza was higher than the efficacy of 27% – 78% seen in High Income Countries. The South African study did not show any significant protective effect against clinical ARI [282]. In another study from Brazil amongst recipients of bone marrow transplants, seasonal influenza vaccination showed a protective effect of 80% against laboratory-confirmed influenza infection [283]. Healthcare professionals A literature search for efficacy of seasonal influenza vaccination of healthcare professionals who care for the elderly who live in long-term care institutions identified one Cochrane review that included three RCTs, all of which were from High Income Countries [284]. In addition one study from Singapore evaluated the VE in healthcare professionals providing care to hospital patients for protecting themselves from influenza related adverse outcomes [285].

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Vaccination of healthcare professionals who took care of elderly residents living in long-term care institutions in High Income Countries did not show any protective effect against laboratory-confirmed influenza and influenza related hospitalization or mortality in the elderly who received care from the healthcare professionals [284]. On the other hand, the Singapore study showed a vaccine efficacy (in the event of a good antigenic match) of 51% (95% CI: 34 – 63) against ILI amongst healthcare professionals involved in providing care to patients in hospitals. This protective effect was not significant if the antigenic match was poor [285]. Pilgrims The annual congregation of thousands of pilgrims (mostly from Low and Middle Income Countries in the tropics) in Saudi Arabia for Hajj during the last month of the Islamic calendar is thought to possibly facilitate spread of influenza globally. Some countries in the tropics prioritize Hajj pilgrims to target seasonal influenza vaccination. A literature search for efficacy of seasonal influenza vaccination of pilgrims traveling to Saudi Arabia for Hajj identified two studies from Pakistan and Malaysia [286, 287]. The vaccine efficacy against ILI ranged between 38% – 77% with a pooled efficacy of 72% (95% CI: 59 – 80) [27]. Table 5: Seasonal influenza vaccine effectiveness in the tropics

Outcome

Pooled efficacy from reviews in High Income Countries

Pooled efficacy from reviews in Low and Middle Income Countries 4 – 59% 43 – 58%

Vaccine efficacy from individual studies in Low and Middle Income Countries in tropics 0 – 76% 0 – 42% 0 – 43% 31 – 77% --1

Elderly ILI Laboratory-confirmed influenza Pneumonia Hospitalization - influenza related - all-cause Mortality - influenza related - all cause Children ILI Laboratory-confirmed influenza - overall - LAIV - TIV - LAIV good match - TIV good match - LAIV poor match - TIV poor match - 1 dose 2 doses - influenza A - influenza B Healthy adults ILI - LAIV - TIV

36 – 56% 50 – 77% 30 – 53% 25 – 33% 50% 8 – 30% 36 – 68% 31 – 45%

No effect No effect

20 – 53% 1 24 – 44% LAIV: 36% TIV: 27% 8 – 85%

1

67 – 74% 62 – 83% 48 – 67% 61 – 88% 48 – 81% 60 – 87% 49 – 56% 58% 75% 31 – 91% 45%

72% 81%

20 – 77% 64 – 72% 33 – 62% 70 – 78%

58% 74% 25 – 57% 0 – 50%

2

10% 20 – 69%

62%

39 – 73%

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Outcome

Pooled efficacy from reviews in High Income Countries

Pooled efficacy from reviews in Low and Middle Income Countries

Vaccine efficacy from individual studies in Low and Middle Income Countries in tropics

Laboratory-confirmed influenza - TIV good match - TIV poor match - TIV any match - TIV influenza A - TIV influenza B Pregnant women ILI (mother) - healthy mothers - HIV infected mothers Laboratory-confirmed influenza (mother) - healthy mothers - HIV infected mothers ILI (infant) - healthy mothers - HIV infected mothers Laboratory-confirmed influenza (infant) - healthy mothers - HIV infected mothers Preterm / IUGR (infant) High risk individuals COPD patients - ARI - Laboratory-confirmed influenza - Hospitalization (ARI) Coronary heart disease patients - Coronary heart disease mortality HIV infected patients - ARI - Laboratory-confirmed influenza Healthcare professionals

57 – 80% 44 – 52% 59 – 61% 64% 52%

82%

50 – 59% H1N1pdm – 84% H3N2 – 33% 84%

0 – 44%

0 – 36% No effect 50% 58%

No effect

0 – 29% No effect 49 – 63% 3 27% No effect

0 – 72% 3

11% 81% 3 67% 61%

60 – 85% 71% 72% 0 – 66% No effect 76% 51% against ILI if good antigenic match; no effect if poor antigenic match

27 – 78% No effect on laboratory-confirmed influenza, hospitalization or mortality in elderly who received care from healthcare professionals

Pilgrims - ILI 1 2

38 – 77% Pooled efficacy – 72%

No effect in 2 studies One study showed protective effect only after two doses 3 Not significant at 5% significance level

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CRITICAL KNOWLEDGE GAPS Vaccine effectiveness studies can provide additional information in hindsight to the vaccine composition selection process. Even as an increasing number of Low and Middle Income Countries from the tropics and sub-tropics introduce influenza into their immunization program, the evidence base for vaccine efficacy and effectiveness face critical knowledge gaps in these settings. First, though recent efforts review data from Low and Middle Income Countries [27, 85, 288] or for certain risk groups like pregnant women in Low and Middle Income Countries [241], most studies included in these reviews provide data on safety, immunogenicity and disease burden and lack information on vaccine effectiveness and efficacy. Second, the majority of VE studies were performed in urban settings in middle income countries. Third, the high prevalence of underlying infections, malnutrition, tuberculosis, limited access to antibiotics for treatment of secondary bacterial infections in Low and Middle Income Countries may increase the risk of influenza related complications or may influence vaccine effectiveness. However, no studies assessed vaccine effectiveness in patients with tuberculosis or malnourished individuals. Fourth, though children and the elderly are at high risk of severe influenza outcomes, few studies from Low and Middle Income Countries in the tropics assessed severe outcomes such as influenza-related hospitalization or mortality. Fifth, almost a third of the studies from Low and Middle Income Countries were observational and prone to bias due to self-assessment of the influenza outcomes. Sixth, only a few studies from Low and Middle Income Countries evaluated vaccine effectiveness stratified by antigenic match or reported data on vaccine coverage, influenza incidence and seasonality. Lastly, waning immunity in the months following vaccination may decrease vaccine benefits in tropical and subtropical settings where influenza activity prevails all year round.

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DISCUSSION The tropics where an estimated 41% of the world’s population resides, is an important region that faces a similar if not higher burden of influenza [289-291]. This systematic review is the first to present a comprehensive global overview of experiences of tropical and subtropical countries in the use of seasonal influenza vaccine in the context of the WHO recommendations for vaccine composition for the northern and southern hemispheres. Main findings Latin America and the Caribbean have led the introduction of seasonal influenza vaccine into their immunization campaigns since the 1990s. Large parts of sub Saharan Africa and the Indian subcontinent are yet to formulate national policies against seasonal influenza though the vaccine is available through the private sector in many countries in the region. Targeted vaccination remains the main strategy to minimize the impact of influenza in high risk individuals for more than four decades even as High Income Countries expand their policies to vaccinate all persons aged > 6mo unless medically contraindicated [26]. National policies recommended vaccination of pregnant women against seasonal influenza in countries in Latin America and the Caribbean but not yet in the South and Southeast Asia. Historically countries in the tropics selected the WHO recommended NH or SH vaccine formulation largely based on whether they were situated north or south of the equator and timed their vaccination campaigns according to when the respective vaccine formulation became available irrespective of the timing of influenza epidemics in their country. Recent evidence indicated that in many such instances, the vaccination campaign occurred too late to cover the influenza season or too early to offer optimal protection for the upcoming influenza season. Recent evidence suggested that vaccination campaigns in many tropical countries (in both hemispheres), where peak influenza activity frequently coincides with the rainy season, should be timed with the availability of the SH vaccine formulation. Several countries (e.g. Cuba, El Salvador, Guatemala and the Philippines) situated in the northern hemisphere that switched from a NH to a SH vaccine formulation in recent years need to be evaluated for vaccination impact. Recent studies from Brazil, China and India indicated that a staggered approach that allows vaccination at different times in the year to cover multiple influenza activity periods using the most recent vaccine formulation may be more appropriate for countries with a large latitudinal spread. The addition of a separate recommendation for the SH in 1998 by the WHO improved the antigenic match for the influenza viruses from 31% to 59% in the southern hemisphere and made it comparable with that in the NH [93]. Despite the inherent limitations in the vaccine composition selection process, the vaccine – virus match has averaged 55 – 60% in both hemispheres. Simulation modelling of antigenic change suggested that the vaccine selection had historically matched well with the circulating virus strains in the subsequent season for which the vaccine was targeted. The genetic / antigenic match between the vaccine and the circulating virus varied in different seasons with a better match seen for influenza B viruses except in 2002 when the B/Victoria lineage re-emerged. In the years of mismatch, there was typically a one-season delay before the circulating virus was covered by the influenza vaccine. Virus strains persisted locally or were re-seeded by international travellers and consequently matched poorly with the vaccine strain. Overall vaccination coverage was low in most parts of Africa and Asia. In contrast, coverage in Latin America and the Caribbean countries was higher than even among High Income Countries. Higher coverage was not correlated with the level of economic development but uptake improved when the vaccine was offered free through the public sector [25]. Increasing seasonal influenza coverage in the Low and Middle Income Countries in the tropics faces several challenges. First, competing health agendas, lack of information on influenza disease burden, vaccine effectiveness and impact, a poor definition of individuals at risk of influenza-related complications, and a low perceived severity of influenza disease, places seasonal influenza vaccination low on 48

Discussion

the list of a country’s public health priorities [292]. Second, a lack of a cogent immunization policy, high vaccine costs coupled with limited resources for supply and delivery along with public adverse opinions against vaccination impede wider usage of the vaccine in the Low and Middle Income Countries from the tropics. Third, the low vaccine demand and poor coverage further contributes to the already poor or absent vaccine production capacity to make sustainability a major challenge for the influenza vaccine industry in Low and Middle Income Countries. The benefit of influenza vaccines has been questioned recently by several studies – the vaccine was about 59% effective in adults – far lower than the 70 – 90% previously believed – with at best a 53% reduction in mortality in the elderly in the tropics. Vaccine effectiveness against laboratory confirmed influenza varied widely in Low and Middle Income Countries in the tropics and subtropics amongst the elderly (no effect – 42%) and children (20 – 77%) based on antigenic match. While the VE appears modest in comparison to other vaccines, the direct effect of influenza vaccination in averting hospitalizations and deaths may be substantial as was seen in the United States [293]. The Global Action Plan for influenza vaccines provides for expanding influenza vaccine production in Low and Middle Income Countries in the tropics and subtropics to ensure greater equity, sustainability and public health benefits [64, 294]. Furthermore, the wide-scale manufacturing, supply and use of seasonal influenza vaccine globally is inextricably linked with pandemic preparedness [56]. Pandemic and seasonal influenza vaccines share inherently similar infrastructure, manufacturing and regulatory processes. To be able to respond quickly to a pandemic, there must be a high capacity to produce seasonal influenza vaccine. Only then can the production capacity be adapted and scaled up quickly to meet the urgent demand of a pandemic situation. However, global demand for seasonal influenza vaccination is low and from an economic perspective, investment in further expanding production capacity is difficult to justify without a concomitant demand and market expansion to use all the supply [22]. Sustainable demand also serves as a stimulus to invest in research and adopting newer vaccine technologies to enhance vaccine production, immunogenicity and efficacy. Critical gaps in evidence Understanding the temporal and geographic circulation of the influenza is important to develop and apply vaccination control strategies. As Low and Middle Income Countries consider introducing seasonal influenza vaccine into their national policy and program, their surveillance systems need to be strengthened to better understand the epidemiology and seasonality of influenza to enable evidence-based decision on when to vaccinate, which groups to target and so on. Countries need to regularly monitor the antigenic characteristics of the influenza viruses that circulate every season to ensure that an optimal selection of the vaccine formulation occurs. This needs to be supplemented by routine monitoring of vaccine effectiveness each influenza season in the tropics and subtropics. Additionally, gaps in knowledge remain about vaccination delivery and regulatory systems, marketing and vaccine uptake at the country-level [64]. Limitations Our review though systematic was subject to several methodological and substantive limitations. First, we excluded articles in languages other than English. However we took efforts to search regional databases such as LILACS especially for articles in Spanish language as countries from Latin America and Caribbean have contributed substantially to influenza research in the recent past. Another review of influenza (seasonal and pandemic) vaccine effectiveness in Low and Middle Income Countries identified 132 articles of a total of 361, in languages other than English [27]. More than 75% of these non-English language articles were from Russia, another 15 articles were from Romania, countries that were outside the scope of our review. Nevertheless, our review may be limited to some extent by the exclusion of potential studies from China.

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Discussion

Second, there was wide disparity in the geographic distribution of studies. For example, of the 26 studies from the tropics and subtropics of VE amongst the elderly, eleven (including Brazil (9)) were from countries in Latin America and the Caribbean, twelve from Asia Pacific (including China, Hong Kong SAR (4), China – Province of Taiwan (2), Thailand (3)) and three from Africa (all from South Africa). Most of sub-Saharan Africa and the Middle East were not represented in the review. Large populous countries like Bangladesh, India, Indonesia, Pakistan and Sri Lanka were relatively under-represented in the review. Third, most of the evidence from the tropics and subtropics came from urban settings and may not adequately represent rural populations. Fourth, the seasonal influenza vaccination scenario in the tropics and subtropics is dynamically evolving. Several seasonal influenza studies initiated in Low and Middle Income Countries in the recent past are at various stages of implementation and their results are not yet available for dissemination. Fifth, there was a wide heterogeneity in terms of study design, study population groups, case definitions used for influenza and related complications, the limited years of surveillance data, and the ecologic diversity of the study settings. This may affect the extent but not the overall trend of comparability. Sixth, the seasonal influenza vaccination coverage estimated by various studies was potentially biased. Studies based on the seasonal influenza vaccination databases used the proportion of seasonal influenza vaccine doses distributed per 1000 population as a crude estimate for vaccination coverage. This may overestimate coverage to the extent of unaccounted wastage, non-usage or return of unused vaccines. Moreover it was at times unclear if the denominator used to estimate the coverage referred to the general population or to the high risk population groups targeted for vaccination in a country. Furthermore, the coverage estimated from the IFPMA database did not account for the seasonal influenza vaccine distributed by non-IFPMA vaccine manufacturers that accounts for about 21% of the total seasonal influenza vaccines distributed predominantly to Low and Middle Income Countries in the tropics and subtropics [49, 56]. Nevertheless, we feel that the coverage though crude and possibly biased, is still indicative of global trends. Except in a few instances, the coverage as estimated from different data sources such as the UNICEF – WHO Joint Reporting Form, the global influenza vaccine surveys and the data from IFPMA were reasonably correlated.

50

Conclusion

CONCLUSION The bulk of scientific evidence on vaccine use and effectiveness in the tropics comes from Latin America and the Caribbean and Asia with large parts of Africa underrepresented. As more and more countries in the tropics and subtropics consider vaccinating their populations at risk for influenza, their capacity to make critical decisions on which vaccine to use, when to vaccinate, how much health benefit to expect inter alia, is greatly restricted by the limited evidence that is available on the epidemiology and virology of the viruses that circulate in their regions. Newly emerged evidence suggests that the vaccine formulation recommended by the WHO for the northern and southern hemispheres and the time at which it becomes available may not be appropriate for some tropical countries when this decision is based solely on the country’s geographical location. Countries that are situated in the tropics especially those nearer to the equator, countries with large latitudinal spread, countries with varying seasonality, countries with influenza identifiable throughout the year, may need to consider alternate approaches in their vaccination timing based on their local seasonality pattern and the availability of the most recent WHO recommended formulation. There probably is no ‘one size that fits all’ strategy for influenza vaccination. Influenza disease and virological surveillance need to be strengthened to enable a better prediction and selection of the biannual updates for the influenza vaccine composition. Future research is needed to evaluate the impact of alternate strategies for vaccination timing with the WHO recommended vaccine formulations that have the most recent vaccine virus strains, for countries in the tropics and subtropics.

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Acknowledgements

ACKNOWLEDGEMENTS This review was funded through a grant no. OPP1084574 from the Bill & Melinda Gates Foundation. The author would like to acknowledge the support of Eduardo Azziz-Baumgartner, Joshua Mott, Fatimah Dawood, Katie Lafond, Kimberly Lindblade, Gina Samaan and Marc-Alain Widdowson of the Centers for Disease Control and Prevention, US for sharing data from their ongoing work on influenza seasonality. Thanks are also due to Jorge Jara, Guatemala and Mark Katz for sharing some of their preliminary findings of ongoing work. Thanks are due to Alba Maria Ropero Alvarez and Nathalie El Omeiri of PAHO, Kimberly Fox and Jinho Shin of WPRO, Pushpa Wijesinghe of SEARO, Bartholomew Dicky Akanmore of AFRO and Nadia Abd El-Aziz Teleb of EMRO, and to all the Member States for participating in the Survey of Vaccine Use in the Tropics. Thanks are due to my colleagues Oona Bilbao and Giovanna Gutierrez of WHO HIP department for the Spanish translation of the Survey. I also acknowledge the sharing of information and support given by Laure Dumolard, Erin Sparrow and Joachim Hombach of the WHO. I value the summary data on seasonal influenza vaccine distribution shared by Margarita Xydia-Charmanta of IFPMA. I gratefully acknowledge the critical feedback on the review manuscript provided by John Paget of NIVEL, Netherlands, Justin Ortiz and Philipp Lambach from WHO IVB, Jan Hendriks from WHO PHI, and Theodore Ziegler, Julia Fitzner, Katelijn Vandemaele, Terry Besselaar and Wenqing Zhang of the WHO Global Influenza Program for their critical feedback on the review. Lastly, I would like to thank Maja Lievre for creating the maps and Hannah Moak of George Washington University, DC for screening for eligibility all the literature that was retrieved during the literature search.

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Appendix

APPENDIX Appendix A: Strategies and keywords used for literature search

Set #1 #2

3 4 5 6 7

Query “influenza vaccines”[mesh] AND (“seasonal” [tiab] OR "seasons"[mesh] OR “seasonal influenza vaccination”[tiab]) “Tropics”[tiab] OR “Asia”[mesh] OR “Africa”[mesh] OR “Pacific”[tiab] OR “Latin America”[mesh] OR “Tropical”[tiab] OR “subtropical”[tiab] OR “Africa South of the Sahara”[mesh] OR “sub-Sahara”[tiab] OR “AFRO”[tw] OR “Algeria”[tw] OR “Angola”[tw] OR “Benin”[tw] OR “Botswana”[tw] OR “Burkina Faso”[tw] OR “Burundi”[tw] OR “Cameroon”[tw] OR “Cabo Verde”[tw] OR “Central African Republic”[tw] OR “Chad”[tw] OR “Côte d'Ivoire”[tw] OR “Congo”[tw] OR “Equatorial Guinea”[tw] OR “Eritrea”[tw] OR “Ethiopia”[tw] OR “Gabon”[tw] OR “Gambia”[tw] OR “Ghana”[tw] OR “Guinea”[tw] OR “Guinea-Bissau”[tw] OR “Kenya”[tw] OR “Liberia”[tw] OR “Madagascar”[tw] OR “Malawi”[tw] OR “Mali”[tw] OR “Mauritania”[tw] OR “Mauritius”[tw] OR “Mozambique”[tw] OR “Namibia”[tw] OR “Niger”[tw] OR “Nigeria”[tw] OR “Rwanda”[tw] OR “Senegal”[tw] OR “Sierra Leone”[tw] OR “South Africa”[tw] OR “Togo”[tw] OR “Uganda”[tw] OR “Tanzania”[tw] OR “Zambia”[tw] OR “Zimbabwe”[tw] OR “EMRO”[tw] OR “Afghanistan”[tw] OR “Israel” [tw] OR “Bahrain”[tw] OR “Djibouti”[tw] OR “Egypt”[tw] OR “Iran”[tw] OR “Iraq”[tw] OR “Jordan”[tw] OR “Kuwait”[tw] OR “Libya”[tw] OR “Morocco”[tw] OR “Oman”[tw] OR “Pakistan”[tw] OR “Qatar”[tw] OR “Saudi Arabia”[tw] OR “Somalia”[tw] OR “Sudan”[tw] OR “Tunisia”[tw] OR “United Arab Emirates”[tw] OR “Yemen”[tw] OR “PAHO”[tw] OR “Anguilla”[tw] OR “Antigua”[tw] OR “Barbuda”[tw] OR “Argentina”[tw] OR “Bahamas”[tw] OR “Barbados”[tw] OR “Belize”[tw] OR “Venezuela”[tw] OR “Bolivia”[tw] OR “Brazil”[tw] OR “Cayman Islands”[tw] OR “Chile”[tw] OR “Colombia”[tw] OR “Costa Rica”[tw] OR “Cuba”[tw] OR “Dominica”[tw] OR “Dominican Republic”[tw] OR “Ecuador”[tw] OR “El Salvador”[tw] OR “Grenada”[tw] OR “Guatemala”[tw] OR “Guyana”[tw] OR “Haiti”[tw] OR “Honduras”[tw] OR “Jamaica”[tw] OR “Mexico”[tw] OR “Montserrat”[tw] OR “Netherland Antilles”[tw] OR “Nicaragua”[tw] OR “Panama”[tw] OR “Paraguay”[tw] OR “Peru”[tw] OR “Saint Kitts and Nevis”[tw] OR “Saint Lucia”[tw] OR “Saint Vincent ”[tw] OR “Grenadines”[tw] OR “Suriname”[tw] OR “Trinidad”[tw] OR “Tobago”[tw] OR “Turks”[tw] OR “Caicos”[tw] OR “Uruguay”[tw] OR “SEARO”[tw] OR “Bangladesh”[tw] OR “Bhutan”[tw] OR “India”[tw] OR “Indonesia”[tw] OR “Maldives”[tw] OR “Myanmar”[tw] OR “Nepal”[tw] OR “Sri Lanka”[tw] OR “Thailand”[tw] OR “Timor-Leste”[tw] OR “WPRO”[tw] OR “Brunei Darussalam”[tw] OR “Cambodia”[tw] OR “China”[tw] OR “Cook Islands”[tw] OR “Fiji”[tw] OR “French Polynesia”[tw] OR “Guam”[tw] OR “Hong Kong”[tw] OR “Kiribati”[tw] OR “Lao”[tw] OR “Malaysia”[tw] OR “Marshall islands”[tw] OR “Nauru”[tw] OR “New Caledonia”[tw] OR “Papua New Guinea”[tw] OR “Philippines”[tw] OR “Samoa”[tw] OR “Singapore”[tw] OR “Solomon islands”[tw] OR “Taiwan”[tw] OR “Tonga”[tw] OR “Vanuatu”[tw] OR “Viet Nam”[tw] #1 AND #2 AND (“effectiveness”[tiab] OR “efficacy”[tiab]) #1 AND #2 AND (“timing” [tiab] OR “composition” [tiab]) #1 AND #2 AND “policy”[tiab] #1 AND #2 AND (“campaign”[tiab] OR “coverage”[tiab] OR “uptake”[tiab]) #1 AND #2 AND (“production” [tiab] OR “availability” [tiab] OR "manufacturing"[tiab] OR "manufacturer"[tiab])

Results 1982 1248012

76 17 12 50 25

Note: [tiab] – title abstract; [tw] – text word; [mesh] – medical subject heading;

69

Appendix

Appendix B: List of countries and territories in the tropics and subtropics included in the review

AFRO

EMRO

PAHO

SEARO WPRO

EURO

Algeria, Angola, Benin, Botswana, Burkina Faso, Burundi, Cabo Verde, Cameroon, Central African Republic, Chad, Congo (the), Côte d'Ivoire, Democratic Republic of the Congo, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Liberia, Madagascar, Malawi, Mali, Mauritania, Mauritius, Mozambique, Namibia, Niger, Nigeria, Rwanda, Senegal, Sierra Leone, South Africa, Togo, Uganda, United Republic of Tanzania, Zambia, Zimbabwe Afghanistan, Bahrain, Djibouti, Egypt, Iran (Islamic Republic of), Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Pakistan, Qatar, Saudi Arabia, Somalia, Sudan, Syrian Arab Republic, Tunisia, United Arab Emirates, Yemen Anguilla, Antigua and Barbuda, Argentina, Bahamas, Barbados, Belize, Bolivia (Plurinational State of), Brazil, Cayman Islands, Chile, Colombia, Costa Rica, Cuba, Dominica, Dominican Republic, Ecuador, El Salvador, Grenada, Guatemala, Guyana, Haiti, Honduras, Jamaica, Mexico, Montserrat, Netherland Antilles, Nicaragua, Panama, Paraguay, Peru, Saint Kitts and Nevis, Saint Lucia, Saint Vincent and the Grenadines, Suriname, Trinidad and Tobago, Turks and Caicos Islands, Uruguay, Venezuela (Bolivarian Republic of) Bangladesh, Bhutan, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand, Timor-Leste American Samoa, Brunei Darussalam, Cambodia, China, China, Hong Kong SAR, China – Province of Taiwan, Cook islands, Democratic People’s Republic of Korea, Fiji, French Polynesia, Guam, Kiribati, Lao People's Democratic Republic, Malaysia, Marshall islands, Nauru, New Caledonia, Niue, Palau, Papua New Guinea, Philippines, Samoa, Singapore, Solomon islands, Tonga, Vanuatu, Viet Nam Israel

70

Appendix

Appendix C: National policies of tropical and subtropical countries on seasonal influenza vaccination

Country Africa Algeria Angola Benin Botswana Burkina Faso Burundi Cabo Verde Cameroon Central African Republic Chad Congo (the) Côte d'Ivoire Democratic Republic of the Congo Djibouti Egypt Equatorial Guinea Eritrea Ethiopia Gabon Gambia Ghana Guinea Guinea-Bissau

National Policy

Year introdu ced

Sector

Free

Children

Elderly

Chronic illness

Health care Profess ional

Pregna ncy

Vaccine timing

Formulat ion

Climate 1 region

no no no no no no no no no no no yes no no yes no no no no no no no no 1999

private private private

yes

NH subtropics SH tropics NH tropics SH tropics NH tropics SH tropics NH tropics

both

SH

NH tropics NH tropics NH tropics

private both private both both yes no no yes yes

yes yes yes yes NH NH yes yes yes NH

SH tropics NH tropics SH tropics NH tropics NH subtropics NH tropics NH tropics NH tropics SH tropics NH tropics NH tropics NH tropics NH tropics

71

Appendix

Country Kenya Liberia Libya Madagascar Malawi Mali Mauritania Mauritius Morocco Mozambique Namibia Niger Nigeria Rwanda Senegal Sierra Leone Somalia South Africa Sudan Tanzania, United Republic of Togo Tunisia Uganda Zambia Zimbabwe Asia

National Policy no no yes no no no no yes no no no no no no no no no yes no no no no no no no

Year introdu ced

Sector both

Free

Children

Elderly

Chronic illness

Health care Profess ional

Pregna ncy

Vaccine timing

Formulat ion SH

Climate 1 region NH tropics NH tropics NH subtropics

2007 both

no

no

yes SH

SH tropics SH tropics NH tropics NH tropics

both both

yes yes

yes yes

yes yes

yes yes

yes yes

SH NH

SH tropics NH subtropics SH tropics SH tropics NH tropics NH tropics SH tropics

private

no

NH

NH tropics NH tropics NH tropics

both

no

yes

yes

yes

yes

yes

SH

SH subtropics NH tropics SH tropics

private private private private SH

NH tropics NH subtropics NH tropics SH tropics SH tropics

72

Appendix

Country Afghanistan American Samoa Bangladesh Bhutan Brunei Darussalam Cambodia China China, Hong Kong SAR China, Province of Taiwan Cook Islands Fiji French Polynesia Guam India Indonesia Kiribati Korea, Democratic People's Republic Lao People's Democratic Republic Malaysia Maldives Marshall islands Myanmar Nauru Nepal New Caledonia

National Policy no no no no yes no no yes yes no no yes yes no yes no no no yes yes yes no no no yes

Year introdu ced

Sector

Free

Children

Elderly

Chronic illness

Health care Profess ional yes

Pregna ncy

Vaccine timing

Formulat ion

Climate 1 region NH subtropics

2003

both private

yes

yes

yes

yes

NH

SH tropics NH subtropics NH subtropics

2010 1998

both private both both private private

yes no no yes yes no

yes yes yes yes

yes yes yes yes

yes yes yes yes

yes yes yes yes

yes yes yes yes

Both NH

NH tropics NH tropics NH subtropics NH tropics NH subtropics

SH no yes yes no yes yes no yes yes no yes yes no Hajj NH NH

SH tropics SH tropics SH tropics NH tropics NH tropics SH tropics SH tropics NH subtropics

2002 1996 2009

both both private both private private no no yes yes no no

yes no

yes no no yes yes no yes no yes yes

yes yes yes

yes no no Jun-Aug All year

NH SH Both

NH tropics NH tropics NH tropics NH tropics NH tropics SH tropics NH subtropics

1988 2002

both both private private

1994

both

no

yes

yes

yes

no

NH

SH tropics 73

Appendix

Country Niue Pakistan Palau Papua New Guinea Philippines Samoa Singapore Solomon islands Sri Lanka Thailand Timor-Leste Tonga Vanuatu Viet Nam Latin America and the Caribbean Anguilla Antigua and Barbuda Argentina Bahamas Barbados Belize Bolivia (Plurinational State of) Brazil Cayman Islands Chile Colombia

National Policy yes no yes no no no yes no no yes no no no yes yes yes yes yes yes yes yes yes yes yes yes

Year introdu ced 2013 1996 2011

Sector

Free

Children no no

Elderly yes yes yes yes

Chronic illness no yes yes yes

Health care Profess ional

Pregna ncy

Vaccine timing

Formulat ion

Climate 1 region SH tropics NH subtropics NH tropics SH tropics

private no private private

no no no yes

yes yes

yes yes

yes yes

May-Dec Dec-Feb

NH-->SH Both

NH tropics SH tropics NH tropics SH tropics NH tropics

2004

both

yes

yes

yes

yes

yes

Jun-Aug

SH

NH tropics SH tropics SH tropics SH tropics

private 2005 2007 1993 2005 2006 2008 2011 1999 1990 1975 2005 both both both both private both both private both

no

yes

yes yes

yes

yes yes

no

NH NH NH

NH tropics NH tropics NH tropics SH subtropics NH subtropics NH tropics NH tropics SH tropics SH tropics NH tropics SH subtropics NH tropics

yes yes yes yes no yes yes yes yes yes no yes yes no yes yes yes

yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes no no no yes yes yes yes Mar-Apr Apr Oct-Nov May-Jun Feb-Nov

SH NH NH NH SH SH NH SH SH

74

Appendix

Country Costa Rica Cuba Dominica Dominican Republic Ecuador El Salvador Grenada Guatemala Guyana Haiti Honduras Jamaica Mexico Montserrat Netherlands Antilles Nicaragua Panama Paraguay Peru Saint Kitts and Nevis Saint Lucia Saint Vincent and the Grenadines Suriname Trinidad and Tobago Turks and Caicos Islands

National Policy yes yes yes yes yes yes yes yes no no yes yes yes yes yes yes yes yes yes no yes no yes yes yes

Year introdu ced 2004 1998 2011 2006 2006 2004 2007 2007

Sector both both private both public both public both private private

Free yes no yes yes yes yes

Children yes yes yes yes yes yes yes yes

Elderly yes yes yes yes yes yes yes yes

Chronic illness yes yes yes yes no no no yes

Health care Profess ional yes yes yes no yes no yes

Pregna ncy no yes no no yes no no

Vaccine timing Feb

Formulat ion NH NH

Climate 1 region NH tropics NH tropics NH tropics NH tropics SH tropics NH tropics NH tropics NH tropics NH tropics NH tropics

Sep-Nov Oct-Dec May-Sep

NH NH NH-->SH NH NH-->SH

2003 2006 2004 2009 2007 2007 2005 2005 2008 2006

both both both

yes yes yes

yes yes yes yes yes

yes yes yes no yes yes yes yes yes yes

yes yes yes no yes yes yes yes yes yes

yes yes yes no no yes yes yes yes yes

no no yes no no yes yes no yes no

Dec Oct-Feb

NH NH NH NH NH

NH tropics NH tropics NH subtropics NH tropics NH tropics NH tropics NH tropics SH tropics SH tropics NH tropics NH tropics NH tropics

both both both both public public

yes yes yes yes

yes yes yes yes

Apr-May Apr-May Dec-Mar; May-Sep

SH SH SH NH SH NH

2009 2007 2006

both both

yes yes

yes yes yes

yes yes yes

yes yes yes

yes yes yes

yes no no

NH NH NH

NH tropics NH tropics NH tropics 75

Appendix

Country Uruguay Venezuela (Bolivarian Republic of) Middle East Bahrain Iran (Islamic Republic of) Iraq Israel Jordan Kuwait Lebanon Oman Qatar Saudi Arabia Syrian Arab Republic United Arab Emirates Yemen 1

National Policy yes yes

Year introdu ced 1996 2006

Sector both both

Free yes yes

Children yes yes

Elderly yes yes

Chronic illness yes yes

Health care Profess ional yes yes

Pregna ncy yes yes

Vaccine timing Apr

Formulat ion SH NH

Climate 1 region SH subtropics NH tropics

yes yes yes yes no yes no yes no yes no yes no 2006 2000 2004 2005 2009

both

yes

yes no yes no no

yes yes yes no no yes no

yes yes yes yes yes yes yes yes yes

yes

yes yes

NH

NH subtropics NH subtropics NH subtropics NH subtropics NH subtropics NH subtropics NH subtropics NH tropics NH subtropics

both both

yes

yes no

yes yes

yes no

NH NH

NH subtropics NH subtropics NH subtropics NH tropics

Climate region for a country is defined by its geographical location in relation to the Tropic of Cancer, Equator and Tropic of Capricorn

76

Appendix

Appendix D: Seasonal influenza vaccine doses distributed in the tropics and subtropics

77

Appendix

78

Appendix

79

Appendix

80

Appendix

81

Appendix

82

Appendix

83

Appendix

Appendix E: Seasonal influenza vaccine effectiveness in the elderly in the tropics and subtropics

Reference

Study type, year, place Metaanalysis

ILI

Breteler (2013)[27]

LAIV: 4% (ns); TIV: 59% (44 – 70) 36% (ns) ~40%

Laboratoryconfirmed influenza LAIV: 43% (25 – 56); TIV: 58% (23 – 78) 77% (ns) ~50%

Pneumonia

Hospitalization

Mortality

Remarks

All-cause (LAIV): 8% (ns); P&I (LAIV): no effect; P&I (TIV): 26% (ns)

Darvishian (2014)[172] Beyer (2013)[173] Jefferson (2010)[174] Moreno (2009)[175] Rivetti (2006)[176]

Metaanalysis Metaanalysis Metaanalysis Metaanalysis Metaanalysis

P&I: 25% (6 – 40) ~30% Healthy elderly: 41%; Healthy elderly: 50%; At risk elderly: 26% 20% – 26% P&I: 27% (21 – 33) Respiratory: 22% (15 – 28) CVD: 24% (18 – 30) P&I: 33% (27 – 38) Respiratory: 30% (25 –35) 50% (28 – 65)

All-cause: 36% (8 – 56) P&I: ~30% P&I: 8%; All-cause: 61%

All-cause: 47% (39 – 54)

RCTs (7), cohort (2), case control (1) 9/10 studies from tropics Low middle income countries 1/14 studies from tropics (China, Province of Taiwan) Jefferson 2010 review reanalysed 1/75 studies from tropics (China, Hong Kong SAR) 1/28 studies from tropics (China, Province of Taiwan) Review updated by Jefferson in 2010; 0/64 studies from tropics

Vu Meta(2002)[178] analysis Gross Meta(1995)[177] analysis Studies from the tropics Forrest RCT (2011)[190] (2002) South Africa Gutierrez Cohort (2001)[153] (2000) Sao Paulo, Brazil Isahak Non-RCT (2007)[194] (2003-04) Malaysia

All-cause: 50% (45 – 56) All-cause: 68% (56 – 76) 0/20 studies from tropics

ARI: 56% (39 – 68) inconclusiv e 6% (ns)

53% (35 – 66)

LAIV v/s TIV

TIV

55% to 76%

TIV v/s placebo

84

Appendix

Reference

Study type, year, place Non-RCT (2004-05) Thailand RCT (1996-97) China RCT Thailand Cohort (1995-2003) Brazil Ecological (1998-2002) Brazil

ILI

Laboratoryconfirmed influenza

Pneumonia

Hospitalization

Mortality

Remarks

Plasai (2006)[197] Jianping (1999)[195] Praditsuwan (2005)[198] Façanha (2005)[188] Brondi (2000)[182] Daufenbach (2009)[184] Ferrer (2008)[189] Francisco (2004)[191] De Villiers (2009)[187]

48%

TIV v/s no vaccine

74%

TIV Control group unclear Significant reduction No effect No effect TIV v/s placebo No effect on reduction of serious complications

56% (14 – 77)

Modest reduction

Articles in Portuguese – not retrieved; Identified through crossreferences

RCT (2001) South Africa Cohort (2008-09) China, Hong Kong SAR Case control (2006-09) China, Province of Taiwan

Good match: 42% (23 – 57); Any match: 42% (22 – 57); 43% (36 – 49)

P&I: Inconclusive

Inconclusive

LAIV v/s placebo

Hung (2010)[193]

CVD: 41% (21 – 56); ICU: 55% (6 – 78); Stroke: 33% Stroke: 24% (3 – 40)

All-cause: 35% (23 – 45)

Lin (2014)[196]

TIV v/s PPV v/s TIV+PPV v/s placebo; VE against myocardial infarction (48%) TIV VE increases as no. of vaccinations in previous seasons increases

1

85

Appendix

Reference

Study type, year, place Case control (2003-04) South Africa Case control (2013) Central, South America

ILI

Laboratoryconfirmed influenza

Pneumonia

Hospitalization

Mortality

Remarks

Van Vuuren (2009)[199] Anonymous (unpub)[180 ]

CVD: 15% (ns); Respiratory: 15% (ns) Influenza: Chile: 45% (7 – 65); Brazil: 77% (62 – 86); Argentina, Colombia, Costa Rica, El Salvador, Honduras, Panama, Paraguay: 57% (43 – 68) Influenza: 47% (5 – 71)

All-cause: 24% (1 – 41)

TIV

TIV

Dawood (2014)[185]

Case control (2010-11) Thailand Cohort (1993) Argentina Cohort (2001) China, Province of Taiwan

Stamboulian (1999)[143] Wang (2004)[201] Wang (2007)[200]

Yung (unpub)[202 , 203]

Cohort (2010-12) Singapore

P&I: 38% (21 – 51); P&I (elderly high risk): 45% (29 – 58); Overall: 11% (8 – 14) high risk elderly: All-cause: 20% (16 – 23) Stroke: 4% (ns) CVD: 9% (ns) P&I: 31% (17 – 42) Low risk elderly: All-cause: 33% (19 – 26) Stroke: 36% (24 – 46) CVD: 16% (2 – 29) P&I: 33% (18 – 47) All-cause emergency: 11% (7 – 15)

All-cause: 44% (40 – 48); Pneumonia: 53% (35 – 66); Stroke: 65% (55 – 73); CVD: 22% (4 – 36);

TIV Vaccination coverage low; Vaccine and virus strain match good TIV Vaccination coverage: 6 – 30% TIV VE against mortality from renal disease (60%), diabetes (55%), COPD (45%)

75% (70 – 80)

TIV All ages, all cause emergency hospitalizations

86

Appendix

Reference

Study type, year, place Ecological (1998-2002) Sao Paulo, Brazil

ILI

Laboratoryconfirmed influenza

Pneumonia

Hospitalization

Mortality

Remarks

Antunes (2007)[181]

P&I: 26%

Francisco (2005)[192]

De Padua Mansur (2009)[186] Chan (2013)[183]

Ecological (1980-2000) Sao Paulo, Brazil Ecological (1980-2006) Sao Paulo, Brazil Cohort (2010-11) China, Hong Kong SAR

All-cause (men): 7%; All-cause (women): 6%

IHD: 46% (1 – 71)

All-cause: 28% (5 – 46); P&I: 20% (2 – 38)

TIV P&I mortality reduced by 26% after vaccination campaign (1998-2002) compared to before vaccination (1993-97) TIV VE (1998-2000) after vaccination compared to before vaccination (1993-97) Articles in Portuguese – not retrieved; Identified through crossreferences TIV

1

PPV – Pneumococcal Polysaccharide Vaccine

(ns) – Not statistically significant at the 5% significance level

87

Appendix

Appendix F: Seasonal influenza vaccine effectiveness in children in the tropics and subtropics

Reference Breteler (2013)[27] Luksic (2013)[206]

Study type, year, place Meta-analysis Low middle income countries Meta-analysis

ILI LAIV: 36% (28 - 54); TIV: 27% (21 - 33) LAIV: 31% (25 – 40); TIV: 32% (20 – 53)

Laboratory confirmed Influenza LAIV (good match): 72% (65 - 77); TIV (good match): 81% (58 - 92) LAIV: Good match: 82% (77 - 89); Any match: 77% (69 – 86); TIV: Any match: 67% (58 - 78) LAIV: Good match: 77% (67 - 86); Poor match: 60% (44 – 71); TIV: Good match: 65% (57 – 72); Poor match: 56% (43 – 66); LAIV: 83% (69 – 91) LAIV: Any match: 80% (70 – 87) Good match: 88% (83 – 92); Poor match: 80% (50 – 92); TIV: Any match: 48% (31 – 61) Good match: 48% (15 – 68); Poor match: 49% (3 – 73); 69% (55 – 78);

Remarks RCTs (10), cohorts (2) 6/12 studies from tropics; LAIV (P&I hospitalization): no effect LAIV: RCTs (12), cohorts (4) 2/16 studies from tropics TIV: RCTs (11), cohorts (5), case control (2) 1/18 studies from tropics RCTs (34) 5/34 studies from tropics VE against mismatched influenza A (LAIV-75%, TIV-62%) significantly higher than mismatched influenza B (LAIV-42%, TIV-52%) respectively RCTs (6); 3/6 studies from tropics RCTs or CCTs (30) 2/30 studies from tropics (Cuba, multi-site, Asia); LAIV efficacy better than TIV in children

Tricco (2013)[215]

Meta-analysis (1970-2009)

Osterholm (2012)[169] DiazGranados (2012)[207]

Meta-analysis (1967-2011) Meta-analysis

Michiels (2011)[209]

Meta-analysis

36% (24 – 46)

RCTs (3), CCT (1); 0/4 studies from tropics;

88

Appendix

Reference Carter (2011)[208]

Study type, year, place Meta-analysis

ILI

Laboratory confirmed Influenza LAIV v/s placebo: Good match:69%(53-80); Poor match:87%(77-93); Otitis-85%(78-90) LAIV v/s TIV: Good match:53%(27-69); Poor match:54%(42-65); Otitis-54%(27-72) Good match (2 doses): 75% (71 - 79); Good match (1 dose): 58% (49 - 66);

Remarks RCTs (8); 5/8 studies from tropics; LAIV more effective than TIV in children with recurrent ARI and adolescents with asthma LAIV v/s placebo: Otitis-85%(78-90) LAIV v/s TIV: Otitis-54%(27-72) RCTs (9); 4/6 LAIV-placebo studies from tropics; 1/3 LAIV-TIV studies from tropics; Good match (H1N1): 85% (78 - 90); Good match (H3N2): 76% (70 - 81); Good match (B): 73% (63 - 80); LAIV more effective than TIV in children RCTs (17), cohorts (19), case control (11); 2/47 studies from tropics; RCTs (19); 1/19 studies from tropics; Otitis Media: Overall: 51% (21 – 70); LAIV: 78% (25 – 90); TIV: 32% (ns); RCTs (13); 1/13 studies from tropics RCTs (7); 0/7 studies from tropics; Otitis Media: 32% - 36% TIV Control group unclear

Rhorer (2009)[210]

Meta-analysis (LAIV)

Jefferson (2008)[211] Manzoli (2007)[212]

Meta-analysis Meta-analysis

LAIV: 33% (28 – 38); TIV: 36% (24 – 46) Overall: 36% (31 – 40); LAIV: 35% (30 – 40); TIV: 45% (33 – 55); Good match: 41% (31 – 49); Poor match: 32% (27 – 36); Overall: 33% (29 – 36); LAIV: 34% (3 – 38); TIV: 33% (22 – 42);

LAIV: 82% (71 – 89); TIV: 59% (41 – 71) Overall: 67% (51 – 78); LAIV: 72% (38 – 87); TIV: 62% (45 – 75); Good match: 61% (40 – 75); Poor match: 78% (63 – 87); Overall: 74% (57 – 84); LAIV: 80% (53 – 91); TIV: 65% (45 – 77); Influenza A: 31% - 91%; Influenza B: 45%;

Negri (2005)[213] Ruben (2004)[214]

Meta-analysis (1985-2001) Review

Studies from the tropics Jianping RCT (1999)[195] (1996-97) China

85%

89

Appendix

Reference Cowling (2010)[218] Jain (2013)[217]

Study type, year, place RCT (2009) China, Hong Kong SAR RCT (2010-11) Bangladesh, Dominican Republic, Honduras, Lebanon, Panama, Philippines, Thailand RCT (2001-02) Argentina, Brazil, South Africa RCT (2000-03) China, China, Hong Kong SAR, India, Malaysia, Philippines, Singapore, China, Province of Taiwan, Thailand RCT (2002-03) Bangladesh, China, Hong Kong SAR, Malaysia, Mexico, Philippines, Singapore, Thailand RCT (2004-05) Asia (3), Middle East

ILI 8% (ns)

Laboratory confirmed Influenza A(H1N1): 25% (ns); A(H3N2): 50% (ns); B: no effect Good match: 48% (16% - 67%); Any match: 59% (41% - 72%); Influenza A: 57% (36 – 71); Influenza B: 50% (17 – 70); Any severity: 55% (39 - 67); Mod to severe: 73% (47 - 86); 3 – 4 y: 35% (ns); 5 – 8 y: 68% (50 - 79) LAIV (1 dose) any match: 56% (43 – 67); LAIV (1 dose) good match: 58% (45 – 68); LAIV (2 doses) any match: 72% (62 – 80); LAIV (2 doses) good match: 74% (64 – 81); LAIV good match: 70% (61 – 77); LAIV any match: 68% (59 – 75)

Remarks TIV v/s placebo

QIV v/s hepatitis A vaccine

Bracco Neto (2009)[219]

Tam (2007)[220]

LAIV Two doses provided additional protection; nd protection persisted into 2 year without revaccination LAIV v/s placebo

Lum (2010)[221]

Good match (LAIV): 78% (51 – 91); Any match (LAIV): 64% (36 – 80)

LAIV v/s placebo

Belshe (2007)[222]

Good match: 45% (22% - 61%); Poor match: 58% (47% - 67%); Any match: 55% (45% - 63%);

LAIV v/s TIV Subjects from 3 countries in Asia (6%), United States (49%), Europe, Middle East (45%)

90

Appendix

Reference He (2013)[224] Fu (2013)[223] Yang (2012)[225]

Study type, year, place Case control (2010-12) Guangzhou, China Case control (2009-10) Guangzhou, China Case control (2013) Central, South America

ILI

Laboratory confirmed Influenza 2010-12: 34% (5 – 54); 6mo-3y (2 doses): 47% (9 – 70); 6mo-3y (1 dose): 5% (ns) 2010 (2 doses): 58% (44 – 68); 2010 (1 dose): 33% (16 – 46); 2009 (2 doses): 52% (41 – 60); 2009 (1 dose): 32% (19 – 43) Brazil: 20%; Chile: 75% (32 – 98); Colombia: 77%; Costa Rica, El Salvador, Honduras, Panama: 48% (22 – 66) 33% (6 – 52); Contacts: 19% (ns) 2011-12: 62% (0 – 91); 2012-13: 37% (0 – 76)

Remarks TIV Partial vaccination had no protective effect; Till 6mo: 35% (5% - 55%); After 6mo till 1y: no protection TIV

Anonymous (Unpub)[180]

TIV

Victor (unpublished) (2013)[226] Kittikraisak (unpublished)[227]

RCT (2009-10) Senegal Cohort (2011-13) Thailand Herd effectiveness amongst family contacts Kim Review (2014)[230] Jordan Review (2006)[216] Glezen Review (2006)[229] Studies from the tropics Gattas RCT (unpublished)[232] (2009) Brazil, Sao Paulo

TIV v/s inactivated polio vaccine

TIV

ARI: 24 – 30% ARI: No effect – 30% ARI: 8 – 18%

61% No effect

RCTs (3), non-RCT (1); 0/4 studies from tropics RCTs (8), non-RCTs(3); 0/11 studies from tropics RCTs (2); 0/2 studies from tropics TIV v/s meningococcal and varicella vaccine Effectiveness of vaccination of children against influenza in household contacts

Family contacts: 61% (6 – 85)

(ns) – Not statistically significant at the 5% significance level

91

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Appendix G: Seasonal influenza effectiveness in healthy adults in the tropics and subtropics

Reference Breteler (2013)[27] Tricco (2013)[215]

Study type, year, place Meta-analysis Low middle income countries Meta-analysis (1970-2009)

ILI 62% (45 – 73); ARI: 75% (ns)

Laboratory confirmed Influenza TIV: 82% (61 – 92) TIV: Good match: 65% (54 – 73); Poor match: 52% (37 – 63); Poor match (influenza A): 64% (23 – 82); Poor match (influenza B): 52% (19 – 72) LAIV: Any match: 39% (16 – 55) Good match: 8% (ns); Poor match: 53% (15 – 74); TIV: Any match: 59% (50 – 66) Good match: 57% (43 – 68); Poor match: 50% (22 – 68); TIV: 59% (51 – 67) LAIV: Any match: 62% (45 – 73) Good match: 56% (19 – 76); Poor match: 64% (18 – 84); TIV: Any match: 61% (48 – 70) Good match: 73% (54 – 84); Poor match: 44% (23 – 59); TIV: Good match: 80% (56 – 91); Poor match: 50% (27 – 65)

Remarks RCTs (5), cohorts (5) 5/10 studies from tropics RCTs (34) 5/34 studies from tropics

DiazGranados (2012)[207]

Meta-analysis

RCTs or CCTs (14) 2/14 studies from tropics; LAIV efficacy better than TIV in children

Osterholm (2012)[169] Jefferson (2010)[233]

Meta-analysis (1967-2011) Meta-analysis

TIV: 69% (60 – 93) LAIV: Any match: 10% (4 – 16) Good match: 8% (ns); Poor match: 11% (3 – 18); TIV: Any match: 20% (11 – 29) Good match: 30% (17 – 41); Poor match: 7% (ns); TIV: 30% (17 – 41)

RCTs (11); 1/11 studies from tropics RCTs (35) 2/35 studies from tropics; LAIV: Pneumonia: 75% (ns) TIV: Pneumonia: 20% (ns) Hospitalization: 11% (ns) RCTs (38), CCTs (8); 2/46 studies from tropics;

Demicheli (2014)[234]

Meta-analysis

Studies from the tropics Jianping RCT (1999)[195]

39%

TIV Control unclear

92

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Reference Hui (2008)[235] Samad (2006)[236] Morales (2004)[237] Ho (2014)[238] Ntshoe (2014)[240]

Study type, year, place Cohort (2008) Malaysia Cohort (2001) Malaysia Cohort (2000-01) Colombia Case control (2010-13) Singapore Case control (2005-09) South Africa

ILI 53%

Laboratory confirmed Influenza

Remarks TIV Dental students and faculty TIV Factory workers TIV Bank employees

73%

63%

McAnerny (unpublished)[239]

Case control (2010-12) South Africa

A(H1N1)pdm: 84% (78 – 88); A(H3N2): 33% (4 – 57); B: 84% (79 – 86) 2005: 49% (5 – 73); 2006: no effect; 2007: 12% (ns); 2008: 67% (12 – 90); 2009: no effect 2010: 58% (7 – 81); 2011: 59% (22 – 78); 2012: 50% (40 – 85)

TIV

TIV All ages

TIV All ages

(ns) – Not statistically significant at the 5% significance level

93

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Appendix H: Seasonal influenza vaccine effectiveness in pregnant women in the tropics and subtropics

Reference Moriarty (2014)[248] Adegbola (2012)[245]

Study type, year, place Review

Maternal outcome 1. 2. 3. 4.

Infant outcome

Remarks RCTs (20) presently ongoing in safety, immunogenicity and efficacy of TIV in pregnant women; 4/20 are efficacy studies from tropics;

Steinhoff (2014)[250]

Review

Galvao (2013)[247] Omer (2012)[249] BlanchardRohner (2011)[246] Ortiz (2011)[241] Skowronski (2009)[251] Naleway (2006)[163]

Review

Review

Effect of vitamin A on Inactivated Influenza Vaccine response in mothers and infants [254]; Field trial of Maternal Influenza Immunization in Asia [255]; Maternal Flu Vaccine Trial in Bamako, Mali [256]; Vaccination of HIV-uninfected Pregnant Women With Trivalent Influenza Vaccine in the Prevention of Influenza Illness During Early Infancy and in Mothers: Randomized Controlled Phase III Trial Evaluating Safety, Immunogenicity and Efficacy [257] ILI or laboratory-confirmed ILI or laboratory-confirmed Hospitalization Other infant outcomes influenza influenza Preterm: 16% (ns)[268], 25%[269], 73%[270]; SGA: 7% (ns)[269], 25%[268], 71%[270]; LBW: 27% (5 -44)[269] ILI: Significant reduction Significant reduction; Preterm, SGA, Still ARI: no effect birth, neonatal mortality: no effect ILI: no effect[258, 261], 44% ARI: no effect[258, 260], No effect[258, Preterm: (9 – 65)[264], 36%[253]; 41%[259] – 63%[253]; 261], 39%[259], 40% (6 – 62); Ab titres: high titres [253, Ab titres: higher[263, 26545% – During peak: 72% (26 – 263, 265], similar[262, 264] 267] 48%[156], 89); 92%[295]; SGA: Ab titres: 69% (25 – 87) [270]; increased[266, 267]

RCTs (8); 4/8 studies on pandemic vaccine; 1/4 studies on TIV from tropics;

RCT (1), cohorts (7); 1/8 studies from tropics RCTs (2), cohorts (10), Case control (1); 1/13 studies from tropics; Most studies did not use laboratory-confirmed influenza as outcomes

94

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Reference Mak (2008)[242]

Study type, year, place Review

Maternal outcome ARI: no effect (United States studies)

Infant outcome

Remarks 1/8 studies from tropics;

Myers (2011)[271]

Modelling (2006-07) USA

61% (9 – 84)[253]; ILI: 65%; ARI: no effect (United States studies) Once all pregnant women are vaccinated at time of vaccine availability, vaccination of newly pregnant women benefits mothers but not infants; VE reduces as starting date of vaccine availability is delayed; All reduction in infant morbidity is seen within the first 4 weeks of vaccine availability; HIV infected mothers: LCI: 58% (0.2 – 81); ILI: no effect HIV non-infected mothers: LCI: 50% (15 – 71); ILI: no effect ILI: 36% (4 – 57); HIV infected mothers: LCI: 27% (ns); ILI: no effect HIV non-infected mothers: LCI: 49% (12 – 70); ILI: no effect ILI: 29% (7 – 46); LCI: 63% (5 – 85);

Studies from the tropics Madhi RCT (2014)[257] (2011-12) South Africa

TIV

Zaman (2008)[253]

RCT 2004-05 Bangladesh

Preterm: 28% (ns); SGA: 37% (ns)

TIV v/s PPV

Note: PPV: Pneumococcal Polysaccharide Vaccine; LCI: Laboratory confirmed influenza (ns) – Not statistically significant at the 5% significance level

95

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Appendix I: Seasonal influenza effectiveness in high risk individuals in the tropics and subtropics

Reference

Study type, year, place

ILI

laboratoryconfirmed influenza 81% (52 – 93)

Hospitalization

Mortality

Remarks

COPD patients Poole Meta-analysis (2006)[272] Studies from the tropics Kositanont RCT (2004)[273] (1997-98) Thailand Menon Cohort (2008)[274] (2004-06) India Wongsurakait (2004)[275] RCT (1997-98) Thailand Coronary heart disease patients Keller Meta-analysis (2008)[276] Studies from the tropics Phrommintikul RCT (2011)[277] (2007-08) Thailand Gurfinkel Cohort (2002)[279]; (2001) Gurfinkel Argentina (2004)[296] HIV patients Anema Meta-analysis (2008)[280]

ARI: 11% (ns)

67% (ns)

No effect

RCTs (11); 1/11 studies from tropics TIV v/s placebo COPD patients

71%

ARI: 67% (p=.005); Mild COPD: 60% (ns); Mod. COPD: 60% (ns); Severe COPD: 75% (p=.02) Mild COPD: 84%; Mod. COPD: 45%; Severe COPD: 85%

ARI: 72% (p=.02)

TIV COPD patients

TIV v/s placebo COPD patients

Coronary Heart Disease: 61% (23 – 80)

RCTs (3); 1/3 studies from tropics; Acute MI: 15% (ns) TIV v/s no vaccine CVD patients TIV MI patients; Ischemic events: 41% (14 – 96) RCTs (3), Case control (1); 0/4 studies from tropics

Acute coronary: 32% (2 – 53); Heart failure: 38% (ns)

38% (ns)

Coronary Heart Disease: 66% (29 – 83);

34% (18 – 64)

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Appendix

Reference

Study type, year, place Meta-analysis

ILI

Atashili (2006)[281]

laboratoryconfirmed influenza 27% - 78%

Hospitalization

Mortality

Remarks

RCT (1), non-RCT (2), outbreak investigation (1); 0/4 studies from tropics TIV v/s placebo

Studies from the tropics Madhi RCT (2011)[282] (2011) South Africa Immunocompromised patients Machado Cohort (2005)[283] Sao Paulo, Brazil Healthcare professionals Thomas Meta-analysis (2013)[284]

8% (ns); ARI: 16% (ns)

76% (9 – 96)

80%

TIV Bone marrow transplant recipients Respiratory: no effect Respiratory: no effect RCTs (3); 0/3 studies from tropics

No effect on those who receive care from HWs Good match: 51% (34 – 63); Poor match: no effect 72% (59 – 80); ARI: 55% (ns)

Studies from the tropics Kheok Cohort (2008)[285] (2004-05) Singapore Pilgrims Breteler Meta-analysis (2013)[27] Low middle income countries Studies from the tropics Qureshi Cohort (2000)[287] (1999) Pakistan Mustafa Case control (2003)[286] (2000) Malaysia

TIV

Cohorts (2); 2/2 from tropics

38% (29 – 45)

TIV Haj pilgrims TIV Haj pilgrims

77% (69 – 83)

(ns) – Not statistically significant at the 5% significance level 97