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Made in Viet Nam vaccines: efforts to develop sustainable in-country manufacturing for seasonal and pandemic influenza vaccines: consultation held in Viet Nam, April - June 2016

January 25, 2017 World Health Organization

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Made in Viet Nam Vaccines : efforts to develop sustainable in-country manufacturing for seasonal and pandemic influenza vaccines

Consultation held in Viet Nam April - June 2016

Ordering code: WHO/HIS/TTi/17.2

This publication is available on the internet at: http://www.who.int/influenza_vaccines_plan/objectives/GAP_Projects/en/

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Made in Viet Nam Vaccines: efforts to develop sustainable in-country manufacturing for Seasonal and pandemic influenza vaccines

CONTENTS ABBREVIATIONS AND ACRONYMS ....................................................................................... v SUMMARY ......................................................................................................................... vi 1 2 3 4 5 5.1 Background ...............................................................................................................1 Global Action Plan (GAP) for influenza vaccines .........................................................2 Objectives .................................................................................................................2 Methods and approach .............................................................................................2 Findings ....................................................................................................................3 Policy environment and health-care system 3

5.1.1 Vaccination as part of pandemic influenza preparedness (PIP)................................... 3 5.1.2 Status of EPI and long term immunization goals ......................................................... 5 5.1.3 National Regulatory System ....................................................................................... 7 5.1.4 The National Immunization Technical Advisory Group (NITAG) .................................. 8 5.1.5 Health Insurance ........................................................................................................ 9 5.1.6 International Free Trade Agreements ........................................................................ 9 5.2 Surveillance networks and influenza-specific evidence 10 5.2.1 Human influenza surveillance .................................................................................. 10 5.2.2 National Influenza Centres ....................................................................................... 12 5.2.3 Burden estimates of human seasonal influenza ....................................................... 12 5.2.4 Animal influenza surveillance network ..................................................................... 13 5.2.5 Economic cost-benefit studies of seasonal vaccine from ASEAN countries ............... 13 5.2.6 Ongoing longitudinal cohort studies as a platform for influenza research ................ 14 5.2.7 Uptake of seasonal influenza vaccine ....................................................................... 15 5.2.8 Non-EPI fee-for-service Immunization...................................................................... 16 5.2.9 Vaccine prices .......................................................................................................... 16 5.3 Vaccine manufacturing in Viet Nam - review of current status 17 5.3.1 5.3.2 5.3.3 5.3.4 5.3.5 5.3.6 5.3.7 6 IVAC (Institute of Vaccines and Medical Biologicals)................................................. 18 VABIOTECH .............................................................................................................. 19 POLYVAC .................................................................................................................. 20 Procedures for annual strain updates of seasonal influenza vaccines ....................... 21 Proposed pandemic vaccine regulatory pathway ..................................................... 22 Additional regulatory issues ..................................................................................... 22 Veterinary vaccine manufacturers ........................................................................... 23 Recommendations and Action Points ...................................................................... 25

REFERENCES ...................................................................................................................... 27

iii

LIST OF TABLES AND ANNEXES Table 1. Immunisation schedule for Viet Nam national Expanded Program on Immunization, 2015. Table 2. Estimated production capacity of vaccines produced by Viet Nam state-owned enterprises, 2016. Table 3. Sentinel sites for active surveillance of human seasonal and zoonotic influenza. Table 4. Number of doses of seasonal influenza vaccine imported to Viet Nam, based on Lot Release data from NICVB, 2010-2015. Table 5. Poultry H5 vaccines licensed and used in Viet Nam. Figure 1. Schematic diagram of the National Regulatory Agencies. Figure 2. Active surveillance of avian influenza in live bird markets: A) districts included for monthly collection of swabs for HPAI H5 detection (ducks, chickens); B) provinces included for periodic intensive collection of swabs for LPAI H7N9 detection (chickens only). Annex 1. Checklist interview questions in English/Vietnamese Annex 2. Selected additional planning documents of relevance to influenza disease control and prevention. Annex 3. List of vaccines licensed for use in Vietnam and available through fee-forservices at vaccination clinics. Annex 4. List of interviewees and stakeholders who participated in the assessment survey and roundtable discussions.

Made in Viet Nam Vaccines: efforts to develop sustainable in-country manufacturing for Seasonal and pandemic influenza vaccines

ABBREVIATIONS AND ACRONYMS AEFI AIV ASTT BARDA CVV DAV FAO GDPM GLP GMP GVAP HA HI HPAI ILI IVAC LAIV MA MARD MOH MONRE MOST NEPI NICVB NIHE NIC NITAG NRA OHPZ OOP OPI PAHI PIP PIVDI QC/QA QMS SARI TIV TPP USCDC VNG WPRO Adverse Events Following Immunization Avian influenza virus Administration of Science Technology and Training Biomedical Advanced Research and Development Agency (USA) Candidate Vaccine Virus Drug Administration of Viet Nam FAO – Food and Agriculture Organization of the United Nations General Department of Preventive Medicine Good Laboratory Practices Good Manufacturing Practices Global Vaccine Action Plan Hemagglutinin (of influenza virus) Hemagglutinin Inhibition Highly pathogenic avian influenza Influenza-like Illness Institute for Vaccines and Medical Biologicals (state-owned company) Live Attenuated Influenza Vaccine Marketing Authorization Ministry of Agriculture and Rural Development Ministry of Health Ministry of National Resources and the Environment Ministry of Science and Technology National Expanded Immunization Program National Institute for Control of Vaccines and Biologicals National Institute for Hygiene and Epidemiology National Influenza Center National Immunization Technical Advisory Group National Regulatory Authority One Health Partnership on Zoonoses Out of Pocket (spending) Operational Program for Avian and Human Influenza Partnership on Avian and Human Influenza Pandemic Influenza Preparedness Pandemic Influenza Vaccine Deployment Initiative Quality Control/ Quality Assurance Quality Management Systems Severe Acute Respiratory Illness Trivalent Influenza Vaccine Trans Pacific Partnership United States Centers for Disease Control Government of Viet Nam World Health Organization Regional Office for the Western Pacific

SUMMARY Vietnam has received support from the WHO Technology Transfer initiative to set up local production of influenza vaccines within the scope of the Global Action Plan for influenza vaccines. Strengthening of domestic vaccine manufacturing is been a key component of pandemic preparedness. As part of an integrated strategy to ensure and sustain the health systems and the infrastructure required for pandemic vaccines, it is considered equally important to establish a strong seasonal influenza vaccination system. This assessment report examines the current status of influenza vaccine manufacturing capacity in Viet Nam, and the complexities and challenges of the multi-sectoral policy environment required to support domestic influenza vaccine manufacturing. Policy environment i) While mitigating the risks of zoonotic influenza emergence is well recognized as a significant public health priority in Viet Nam, control of human seasonal influenza is not viewed as a significant priority relative to other concerns. Specific objectives relating to the control of seasonal influenza have not been incorporated within the larger conceptual framework of pandemic preparedness. ii) To date there is no government supported procurement of human seasonal influenza vaccines. Usage of seasonal influenza vaccines within the private sector is low but shows a trend of gradual increase. Regarding public sector use of seasonal vaccine, there are currently no programmatic initiatives to create demand for seasonal vaccines, nor programmes designed to promote awareness of influenza disease. However, the General Department of Preventive Medicine (GDPM) has developed a planning document that identifies target risk groups, estimates future ‘demand’ for vaccines, and articulates a long term vision for domestic vaccine production. iii) The overriding perception within the public health community is that other communicable diseases dwarf influenza in terms of public health burden. Influenza vaccines are perceived as having relatively poor efficacy, and the concept that natural immunity is superior to vaccine-induced immunity was articulated by several key leaders. Given the current policy environment, it is unlikely that seasonal influenza disease interventions will be prioritized in the near future. iv) On the other hand, the government continues to spend substantial resources to control AIV in the poultry reservoir. Poultry H5 vaccination constitutes the largest fraction of expenditures within the government avian influenza control program. The majority of poultry H5 vaccines used in Viet Nam are sourced from China, however, one state-owned Vietnamese enterprise (NaVetCo, located in Ho Chi Minh City), produces an inactivated recombinant H5 vaccine that has been licensed since 2012. In May, the Ministry of Agriculture and Rural Development (MARD) signed a Decision #1756/QD-BNN-TY to establish a high level Steering Committee to promote in-country veterinary vaccine manufacturing. The Decision defines and highlights the need for improved poultry H5 vaccines as a national priority. Surveillance system and influenza-specific evidence i) Human influenza surveillance programmes have been well-established since 2006, and have generated substantial data on influenza virus circulation over the past 10 years; each year, approximately 30-40 Vietnamese virus isolates are shared with WHO influenza

Made in Viet Nam Vaccines: efforts to develop sustainable in-country manufacturing for Seasonal and pandemic influenza vaccines

global reference centres. The active surveillance networks comprise routine monitoring for Influenza-like-illness (ILI) and Severe Acute Respiratory Illness (SARI) in hospital settings (in 15 and 11 provinces, respectively), as well as passive reporting of Severe Viral Pneumonia (SVP) from all provincial general hospitals. Sustained funding to support these networks remains a challenge. ii) Despite the wealth of data generated on clinical influenza cases, to date there have been no systematic assessments of the Viet Nam-specific influenza disease burden. The lack of Viet Nam-specific disease burden analysis, or analysis of vaccine cost-effectiveness is perceived as a contributing reason to why seasonal influenza vaccines are not subsidized or promoted within the health care system. National statistics on numbers of reported fatal cases associated with influenza are very small, due to difficulties in capturing mortality health statistics. Existing surveillance data could be mined more effectively and incorporated into larger global efforts to improve burden estimates, however to date this has not been done. Current fragmentation of the different regional systems in place for ILI and SARI, means there is little data sharing among agencies, and few opportunities for national scale analyses. iii) Uncertain funding for core functions of national sentinel surveillance systems underlies many of the problems with data quality generated by human ILI/SARI surveillance [i.e. intermittent breaks in funding and complex contributions from multiple donors to different surveillance networks]. There is a need for stronger coordination of surveillance activities, to ensure that surveillance data contributes substantively to assessing epidemiological trends and guiding implementation of intervention strategies. iv) Regarding surveillance of influenza in the animal health sector, active surveillance for highly pathogenic avian influenza (HPAI) in Live Bird Markets (LBM) has been wellestablished since 2010, and specific additional monitoring systems are in place for detection of low pathogenic H7 subtype viruses in 9 northern provinces near the ChineseViet Nam border. Data on clade diversity of H5 viruses are used to guide poultry vaccine strain selection at the district/province level. Routine preventative use of poultry H5 vaccines is common in the commercial sector but not in backyard poultry. Government expenditures for poultry vaccination (US$37 million for 2014-2018) supports routine preventive campaigns in high risk provinces and emergency use during outbreaks. The cost-effectiveness of poultry H5 vaccination has not been systematically evaluated. A stated objective of Pandemic Preparedness is to reduce reliance of the poultry sector on H5 vaccines. Manufacturing capacity and the regulatory system i) Investments in IVAC (the state-owned vaccine manufacturer supported by GAP) have been greatly successful. Significant progress has been made towards licensure of IVAC’s pandemic human H5 vaccine (Phase 2 ongoing), as well as a seasonal trivalent influenza vaccine (TIV, Phase 2 study in preparation). Submission for licensure of both vaccines is targeted for end 2017. ii) Market demand for locally produced seasonal TIV is poor, and there is a lack of a good ‘business model’ to sustain production. IVAC’s long term business strategy is to obtain WHO prequalification for the seasonal TIV, with hopes of exporting on the international market. iii) Several regulatory obstacles to registering and licensing of human influenza vaccines were identified. Among these were continued needs to strengthen technical capacity of the NRA, and to clarify the role of NICVB. NICVB is currently designated as the agency responsible for receipt/storage/distribution of CVVs, Master Seeds, and other reference vii

standards. However, NICVB does not maintain a repository of live viruses, and without improved technical capacity to conduct virological and cell-based assays, it is unclear how they can fulfill their mandate as currently written in Decision No 3100/ QD-BYT. iv) The regulatory infrastructure for veterinary vaccines is far less developed than for human vaccines, and this presents an obstacle to vigilance for monitoring quality control for poultry H5 vaccines (strain identity), as well as an obstacle to licensing new products or updated formulations. There is evidence to suggest that NaVetCo has produced a modified bivalent H5 formulation but has not updated the product license.

viii

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

Background

Viet Nam is considered a hotspot for influenza virus evolution, both for human seasonal influenza strains, as well as emergence of zoonotic variants with pandemic potential [1,2]. Highly pathogenic avian influenza (HPAI) H5 viruses have been endemic in Vietnamese poultry ever since the first major epizootic waves in 2005, that caused losses of >20% of the standing poultry population (45 million dead or destroyed). At that time, Viet Nam was the country with the most reported human cases (93 confirmed humans cases at the time, 61 during 2005). It was a time of increasing fear, when stamping out campaigns were not effective in controlling spread within domestic poultry, the number of human cases was increasing, and Viet Nam was facing a public health and food security crisis. Poultry vaccination against H5 influenza was introduced during this era as one of the major components of intervention strategies, in the form of biannual mass vaccination campaigns of all farm flocks. Federally subsidized mass campaigns for poultry vaccination continued from 2005-2011; the biannual campaigns were suspended in 2011 due to antigenic drift in clade variants, and evidence that the imported Chinese poultry vaccines were no longer effective against local dominant strains. Although the federal government no longer supports routine preventative H5 poultry vaccination, veterinary H5 vaccine usage is still very high, because sporadic poultry H5 outbreaks continue to be reported throughout the country. Subdepartments of animal health use discretionary budget on H5 vaccines imported from China, and overall expenditures on AI vaccines constitutes the major component control programs. Despite continued widespread endemicity of H5 in domestic poultry, human case numbers for H5 influenza in Viet Nam from recent years have been very low; there were 19 cases (15 fatal) from 2006-2009; 15 cases (7 fatal) from 2010-2014; and no cases reported since 2015. Importantly, the lack of recent human cases of H5 viruses suggests that control measures to prevent zoonotic infections are effective. The overall budget for the Viet Nam H5 avian influenza plan for 2014 to 2018 for the agriculture sector is approximately US$ 39 million, comprising US$ 6.04 million at the central level, US$ 26.1 million by provinces and US$ 6.74 million by farmers (to pay for administration of vaccines). Poultry vaccination represents the largest component of these costs. It is likely that the budget to 2020 will be similar, depending on the progress made by 2018 and whether poultry vaccination continues to be the main item of expenditure. Regarding H7N9 subtype viruses, despite ongoing transmission of H7N9 in poultry of China and more than 700 recorded sporadic human zoonotic cases, to date there has been no incursion of H7N9 into Viet Nam. The lack of incursion of H7N9 to Viet Nam from China has also been heralded as evidence for success of cross-border trade controls and other interventions in livestock management. Viet Nam is a rapidly developing country, with one of the fastest growing economies in the world. The country was declared a middle income country in 2009 by the OECD, and as a result of improvements in health status, the country is rapidly undergoing several epidemiological transitions. Viet Nam’s elevation to a lower-middle income country is a great achievement that paves the way for improved living conditions and societal development, however the health system faces a number of challenges, not least of which is the widespread withdrawal of external funding support for continuing health care activities. The transition from internationally-supported programmes to reliance on domestic government resources also creates a strong need for prioritizing targets and strategic planning. Health care costs are increasing, and a considerable portion of the population still faces problems in affording basic care.

Global Action Plan (GAP) for influenza vaccines

The World Health Organization Global Action Plan for Influenza Vaccines (GAP) was initiated in 2006 to address the scarcity of, and inequitable access vaccines in the event of a pandemic through three avenues: • increased evidence-base seasonal influenza vaccine use • increase influenza vaccine production capacity, and expansion of production to developing countries • development of influenza vaccines with improved efficacy (broader cross-immunity and protection, longer duration of immune response), and improved production characteristics (higher-yielding, faster to produce). Within the framework of GAP, WHO supported 14 developing countries to establish or expand influenza vaccine manufacturing. One of the 14 countries with significant GAP investments was Viet Nam, where efforts have focused largely on establishing production of influenza vaccine manufacturing capacity (for humans) at IVAC, one of 4 state-owned vaccine enterprises. The GAP will come to an end this year and a final consultation will take place in November 2016 to mark it's closing.

Objectives

This report aims to provide the Government of Viet Nam with a review of the current status of domestic influenza vaccine manufacturing capacity and challenges to sustainability of vaccine production. It aims to summarize the discussions held during the consultation, and to highlight areas for further development.

Methods and approach

The WHO Country Office in Viet Nam supported the assessment through coordinating a series of interviews and meetings with key stakeholders, representing the different government agencies involved in influenza surveillance and research, pandemic preparedness, the agencies comprising the National Regulatory Authority, as well as private sector vaccine manufacturers and other relevant institutes. The interviews were guided by the “sustainability checklist” originally developed by WHO to guide the country reviews in a holistic, multi-dimensional and inter-disciplinary manner. A bilingual English-Vietnamese translation of the checklist was adapted to the Viet Nam context and is provided in Annex 1. The institutes/agencies contacted and a detailed list of stakeholders interviewed is provided in Annex 4. In addition to interviews, a desk review was undertaken of major program developments in Viet Nam relevant to assessing influenza pandemic preparedness and aspects of the health system, such as the current status of human and animal influenza surveillance networks, priorities for immunization strategies (EPI and non-EPI vaccine programs), developments within parastatal vaccine manufacturing units, and NRA institutional development. The full list of documents reviewed is provided in References. A roundtable discussion was held in Hanoi at the Drug Administration on 5 October 2016 to present the initial findings of the assessment to the relevant departments and agencies of the ministry of health, local influenza manufacturers and international partners. The findings of the assessment were discussed and a set of recommendations and action points to promote sustainable production of influenza vaccine in Vietnam was agreed upon. 2

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

Findings

5.1 Policy environment and health-care system The Viet Nam health-care system is formed by federal and local public entities, and in recent years has been characterized by increasingly important role of private sector clinics and hospitals. The preventive medicine system is widely distributed from the central level to local level, with active involvement of the entire political system in prevention of infectious diseases, as evidenced most clearly through investments in the National Expanded Program of Immunization (NEPI) as well as commitment to routine and sentinel surveillance activities. Viet Nam is one of the few countries in region that supplies most of the vaccines to support NEPI through domestic vaccine manufacturing. In addition, Viet Nam has a long history of producing high quality vaccines for export to other countries. Due to the long and successful history of routine childhood vaccination through NEPI, that is backed up by a communication network of village workers, there is a highly effective and efficient system for maintaining immunisation coverage in Viet Nam [3]. Although difficult to document and assess the prevailing attitudes/perceptions towards vaccination, a few studies have addressed this topic within the context of changing health seeking behaviors [4–6]. Importantly, the majority of government supported immunization programs have targeted pediatric populations. Attitudes and perceptions regarding repeated annual vaccination of healthy adults with seasonal influenza vaccines would likely differ significantly from attitudes towards traditional childhood vaccines. To date there is relatively little out-of-pocket (OOP) expenditure on vaccinations, and the pervasive expectation is that important (essential) vaccines will be provided free of charge if deemed necessary by government authorities. Expenditures on additional non-EPI vaccines through fee-for-services is a relatively new phenomenon, associated with a growing middle class and a larger fraction of the population seeking health care through private clinics. One recent study in southern Viet Nam indicated that 25% of mothers seek care from private health care clinics, and this shift to private sector health care is mostly evident in urban centers [5]. There is no current official policy regarding seasonal influenza vaccination. However, an ongoing USCDC project aims to encourage such policy formation, through a variety of advocacy approaches, including a Knowledge-Attitude-Practices (KAP) survey regarding seasonal vaccination among health care workers (completed in 2016, study results not yet available), and plans to introduce seasonal influenza vaccine to selected risk groups. This pilot project to introduce influenza vaccine (n=10,000) is not intended to generate outcome data on vaccine efficacy/effectiveness, since no sample collections or laboratory analyses are planned. Rather, the project is designed to improve understanding of the willingness/receptivity of health care workers to receiving influenza vaccines when offered for free. The project may also explore the widespread perception among Vietnamese people that immunity induced by natural infections provides superior protection than vaccine-induced immunity. Interestingly, the perception that ‘natural immunity is better than vaccine-induced immunity’ was expressed by several stakeholders interviewed during the present assessment, underscoring the general negative perception of the efficacy and benefits of repeated annual seasonal influenza vaccination, in particular among healthy adults. 5.1.1 Vaccination as part of pandemic influenza preparedness (PIP) Since 2003, Viet Nam has made successive improvements toward a multi-sectoral approach to address emerging infectious diseases and health threats such as those posed by HPAI. National 3

control plans to address HPAI were first documented under the ‘green book’ Operational Plan on Influenza, 2006-2010. A subsequent planning document, the ‘blue book’ Operational Plan on Avian Influenza, Pandemic Preparedness and Emerging Infectious Diseases (AIPED) 20112015, took a broader focus on emerging and re-emerging diseases. Most recently, the national One Health Plan, 2016-2020, outlines collective engagement across sectors to prevent and control zoonotic diseases, and is intended to address many diseases other than just influenza. Importantly, vaccination against seasonal influenza has not been addressed or considered within the framework of these larger preparedness plans. One of the pillars of GAP project has been to promote the concept that seasonal influenza vaccine production is important not only for reducing the burden of seasonal influenza epidemics, but is an essential component of ensuring the sustainability of local influenza vaccine production to support potential needs in the event of a pandemic. The rationale is that having yearly seasonal vaccine production in place will help ensure that manufacturers are available to quickly switch to pandemic vaccine production if such a need arises. Steps to improve industrial preparedness for an influenza pandemic through improved manufacturing---such as construction of new vaccine production plants meeting higher biosafety standards, vaccine development research, investigations of candidate vaccine prototype libraries, or adjuvants, or antigen sparing techniques----were not mentioned in the AIPED ‘blue book’, nor in the current OHP for 2016-2020. Lack of mention of any such interventions or long term plans targeting human seasonal influenza ---in particular, human vaccination programs--- reflects the over-riding focus of these documents on managing disease threats at source, within the poultry reservoir. Human vaccination programmes, and especially development of routine annual human vaccine campaigns, have not been viewed as an integral component of preparedness. Interviews with key stakeholders also support this finding. The only specific reference to vaccination within the AIPED blue book is the stated objective ‘that reliance on poultry H5 vaccination should be reduced in future and gradually phased out’. Similarly, the recently finalized OHP 2016-2020 document focuses exclusively on poultry sector management. It devotes several pages to addressing issues about optimizing use of poultry H5 vaccines, and articulates the following goals for the next 5 year period: Mandatory duck vaccination completed in selected provinces; Post-vaccination monitoring to demonstrate the extent of poultry vaccination coverage in selected provinces; Biennial reviews of results from poultry vaccination to determine whether changes are needed to the programme; Introduction of new vaccine antigens to poultry vaccines when required; Establishing selected H5 infection-free agricultural production zones. Other countries that have committed to maintaining pandemic vaccine preparedness have issued government contracts to human vaccine manufacturers to produce investigational vaccines and conduct H5 vaccine clinical trials [WHO document TRS 963 (2007)]. Although there are no such plans in place in Viet Nam to guarantee procurement of human H5 vaccines, there is significant political will to improve Viet Nam’s overall vaccine manufacturing capacity, as this is viewed as key to ensuring the long term supply of affordable vaccines needed for EPI. The long term vision is to promote vaccine production as a source of revenue through enhancing potential vaccine exports on the international market; as such, achieving WHO prequalification for a number of vaccine products is an important strategic goal. The GDPM has developed a document called “The plan for development of influenza vaccines in Viet Nam” (hereafter referred to as the ‘GDPM 2013 Vision’) that explicitly articulates government commitment and long term strategy regarding in-country influenza vaccine 4

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

manufacturing. This key document provided projected estimates of ‘demand’ for seasonal and pandemic vaccine, defined target populations, and stated the following goals: • The period of 2016–2020: Commissioning the production chains of seasonal influenza vaccine at IVAC; continue to maintain and improve production technology of influenza A (H5N1) vaccine at VABIOTECH; clinical trial and register influenza A (H7N9) product*; Enhance the capacity of quality control of influenza vaccines; continue research on novel influenza vaccine platforms. [Note that further development of the H7N9 vaccine has been paused since 2015.] • Period of 2021–2030: Sustainable production of seasonal vaccine, reach WHO prequalification for the TIV formulation, ensure domestic supply of influenza vaccines, stockpiling and export. 5.1.2 Status of EPI and long term immunization goals The Expanded Program on Immunization (EPI) was launched in Viet Nam in 1985 with 6 vaccines, and by 2015 was expanded to vaccines listed in Table 1: tuberculosis, diphtheria, pertussis, tetanus, hepatitis B, measles, polio, Japanese B encephalitis, cholera, typhoid, rubella and Haemophilus Influenza Type b (Hib). All EPI vaccines used in Viet Nam are domestically produced, with the exception of two imported products, namely the combined 5-in-1 vaccine to protect against DPT, HepB and Hib (Quinvaxem) and measles-rubella vaccine (Table 2). The EPI program uses approximately 35-40 million doses a year, comprising approximately 92% of all vaccines used in the country. Other than EPI, there are no other major immunization initiatives supported by the government. Of relevance to the current report is the inclusion of pregnant women as risk group for targeted vaccination with TT, since this suggests that if the MOH were to consider introduction of seasonal influenza vaccine for women during pregnancy, there would be an existing delivery system in place to facilitate uptake, at least in selected ‘high risk’ provinces. Similar to most other countries, influenza control activities in Viet Nam are administered and implemented separately from classical ‘vaccine-preventable’ diseases, and have never been included within EPI. The multiyear plan for immunisation 2011-2015 identified 12 main strategies for programme development, including achieving measles elimination by 2012, improved control of hepatitis B and JE, elimination of invasive Hib disease by 2015, introduction of other new and under-utilized vaccines including Measles-rubella (MR), pneumococcal conjugate vaccines (PCV), HPV and rotavirus and finally continuation of ‘special vaccines’ (Typhoid and Cholera) in high risk areas. The major push for EPI programme development in the period 2016-2020 will be 1) introduction of IPV (inactivated polio vaccine) in 2017; 2) introduction of rotavirus vaccine in 2018; and 3) potential HPV or PCV in coming years.

Table 1. Vaccination schedule of the Viet Nam National Expanded Program on Immunization (NEPI), 2016. Vaccine BCG HepB OPV DPT-HepB-Hib Measles Measles-rubella DPT Japanese Encephalitis Typhoid Cholera Tetanus toxoid Birth X X 2M 3M 4M 9M 18M

X X

X X X

X X 2 doses in the first year at 1-2 weeks interval, and 3rd dose at 1 year interval 1 dose for 3-10 years old (in high risk areas) 2 doses at 1 month interval for 2-5 years old (in high risk areas) Pregnant women or childbearing age women (in high risk areas)

Table 2. Estimated production capacity of vaccines produced by Viet Nam state-owned enterprises, 2016. Manufacturer Vaccine Measles Measles-Rubella [received technology transfer from KDSV, Japan] [R&D conducted with support of USCDC, WHO, MoH; licensed since 2012] Licensed in Vietnam since 1960 Current status Capacity 7.5 mil doses Demand market in country 2-3 mil doses (EPI) Ph3 Clinical Trial began May 2016; target licensure in 2017

projected capacity is 7.5 mil doses

Rotavirus Polyvac tOPV

4 mil doses

20 mil doses**

40 mil doses

10 mil doses

bOPV

In process changing from tOPV to bOPV. Scheduled for prod'n 2017 Under Ph2 clinical trial

40 mil doses

not yet in routine prod'n

IPV (Sabin strain) DTP BCG TT Td Seasonal influenza TIV Hep B Hep A JEV (produced in SMB) Vabiotech JEV (vero-grown) Oral cholera Rabies vaccine (verogrown)

at laboratory scale 15 mil doses 8 mil doses 20 mil doses 10 mil doses

not yet in routine prod'n 3-4 mil doses (EPI) 2-4 mil doses (EPI & private market) 6-9 mil doses (EPI & private market) 0.1 doses (private market)

IVAC

Completed Ph1 clinical trial; Ph2 planning ongoing Recomb formulation licensed since 2001 licensed since 2003 Licensed since 1997 Completed Ph1 clinical trial; Ph2 8-10 mil doses clinical trials planned in 2017 20 mil doses 0.3 mil doses 6 mil doses

licensure targeted for 2017 2-2.5 mil doses (EPI & private market) 0.35-0.4 mil doses 5.5 mil dose (EPI & private market) not yet in routine prod'n 0.5 mil doses (EPI & private market) not yet in routine prod'n

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

5.1.3 National Regulatory System The National Regulatory Authority (NRA) in Viet Nam is the government agency responsible for ensuring quality, safety and efficacy of vaccines and pharmaceutical products. As with other countries, the NRA’s roles include oversight of the following primary functions of the regulatory system: marketing and licensing authorizations (MA), lot release (LR), laboratory access (LA), pharmacovigilance (PV) including monitoring of adverse events following Immunization (AEFI), regulatory inspections (RI) and oversight/authorization/approval of clinical trials (CT). The current structure of agencies involved is depicted in Figure 1.

Vietnam National Regulatory Authority Minister of Health Vice Minister NRA Steering Committee

NICVB

ASTT LR CT SYSTEM

DAV MA RI

GDPM

NRA Office

Figure 1. The Viet Nam National Regulatory Authority (NRA) comprises multiple agencies: NICVB, National Institute for Control of Vaccines and Biologicals; ASTT, Administration of Science, Technology, and Training; DAV, Drug Administration of Viet Nam; and GDPM, General Department of Preventive Medicine. The functions include LA, Laboratory Access; LR, Lot Release; CT, Clinical Trials; Regulatory Systems; MA, Market Access; RI, Regulatory Inspections; and PV, Pharmocovigilance. Viet Nam has had an internationally registered set of NRA standards since 2001. In May 2013, the MOH strengthened the organization of vaccine management agencies through the development of a comprehensive plan to accelerate the NRA’s progress towards meeting WHO standard assessments. Major investments in institutional development have been made, including reorganization and restructuring of agencies involved. Key government circulars/decisions/ and decrees were developed to address each of the regulatory functions, for example i) circular 44/TT-BYT on MA/license, ii) circular 03/TT-BYT on clinical trial management, iii) decision 3100/QD-BYT on LA & Lot release, iv) circular 12/TT-BYT on management and use of vaccines, and guideline on surveillance of AEFI. In addition, hundreds of standard operating procedures (SOP) were developed within each of the agencies, including ten manuals on quality management systems. Hundreds of meetings and more than 40 training courses were conducted in Viet Nam and abroad between 2013 and 2015, involving nearly 1 500 NRA officials. Investments were made in the infrastructure of NICVB (equipment purchases, construction of new laboratories, adoption of improved testing methodology). An inter-agency coordinating office for management of the disparate functions of the NRA for vaccines was established. In April 2015, the Viet Nam NRA for vaccines achieved a landmark success when a WHO evaluation team determined the country's NRA capable of fulfilling all required functions. 7

Good Manufacturing Practices (GMP) Over the last two decades, Viet Nam’s pharmaceutical and biomanufacturing industry has seen major improvements, with many domestic enterprises satisfying GMP-ASEAN standards for producing quality medicines for domestic use and export. The first legislative decision on GMP standards was adopted on 9 September 1996 (No. 1516/BYT-QD) specifying the required GMP principles and standards applicable to all western medicine-producing establishments. The original GMP-ASEAN principles and standards were based on WHO recommendations, and have been repeatedly updated in subsequent years to comply with changing international standards; a key document to establish GMP standards was #47/2007/QD-BYT. 5.1.4 The National Immunization Technical Advisory Group (NITAG) Several different advisory committees have played a role in guiding implementation and development of vaccination policies. A ministerial decision in 1997 created the “Committee for Vaccine for Utilization,” for which the legal status and roles/responsibility were revised in 2010 under the name “Committee on the use of Vaccine and Biological Products”. Subsequently in October 2013, the committee was designated at Viet Nam’s NITAG (Decision Number 4250/QD-BYT) in order to achieve the GVAP indicator related to improving evidence-based immunization decision making. Further clarifications detailing the NITAG’s functioning, duties, working principles and specific tasks of the NITAG’s members were specified in MOH Decision No. 5127/QĐ-BYT, including suggested procedures on handling potential conflicts of interest. The Chair of the NITAG is Prof. Quan Huan Trinh, retired vice-minister of Health; the Secretariat is hosted by GDPM; and the main point of contact is Dr Nguyen Minh Hang, Deputy Director. The committee is mandated to meet twice per year, and has also held ad-hoc meetings to address emergency response planning or issues related to AEFI and vaccine safety. Members are generally senior government representatives; external experts and partners (WHO, UNICEF etc) are not members but are invited to attend at the request of the Chairman. As an advisory body, NITAG does not have direct decision-making authority, however it represents an important strategic effort to promote scientific evidence-based decision making within the government, and to make recommendations. In Viet Namese, the terms ‘Recommendations’ (khuyén cáo, lới khuyên) and ‘Guidelines’ (qui đinh, hương dân) are distinct, with the former implying optional implementation, and the latter implying stricter requirements for compliance. The MOH has articulated recommendations for influenza vaccination within the ‘Plan for Development and Long term Use of Influenza Vaccines’, GDPM 2013 (hereafter called the ‘GDPM 2013 Vision’). However, if for instance the MOH were to decide to procure a certain number of doses of influenza vaccine for use within NEPI or other immunization programs, then a set of ‘guidelines’ would need to be issued. In 2015, the NITAG recommended use of Tetanus and Diphtheria Toxoids Adsorbed (Td) vaccine for pregnant women and women of childbearing age to replace previous tetanus vaccines used in EPI (assuming cost equivalence of Td vaccine and previous Tetanus vaccine). Recommendations regarding other vaccination targets or surveillance systems targeting pregnant women are of particular interest, since this could provide an opportunity to integrate influenza vaccination within existing distribution and delivery systems. 8

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

From 2012-2015, NITAG functioning was supported by Agence de Médicine préventive (AMP) under the Gates Foundation-funded SIVAC initiative (Supporting Independent Immunization and Vaccine Advisory Committees). Starting in 2016, WPRO began supporting the costs for sustaining biannual NITAG committee meetings, and providing technical support to build capacity through training activities for the secretariat and members. A new workplan to develop an annual agenda is in development, which includes proposed trainings for committee members on methods for assessing and reviewing available research data and economic analysis. 5.1.5 Health Insurance Many policies on health insurance have been promulgated in the last few years, most notably the Law on Health Insurance (2008) and revisions proposed in 2015. The government has developed and approved a roadmap for moving towards universal health insurance, with goals of achieving at least 70% of the population enrolled in health insurance by 2015. In 2012, approximately 67% of the population was covered by health insurance, however health access for remote rural areas remains a challenge and particularly impacts ethnic minorities. There are still nearly 30 million people without health insurance, and only 25% of the near poor are enrolled. Health insurance currently covers a large number of medical services, from examination and treatment to rehabilitation services; to date, however, the focus has been on curative care, and costs for prevention (including fee-for-service vaccines) are not covered. The household out-of-pocket (OOP) payment share of total health spending in Viet Nam is much higher than the WHO recommendation (30-40%) [7]. Household OOP spending on health accounts for from 8.3 to 11.0% of household capacity to pay and approximately 4.6 to 6.0% of total household expenditure. Although a downward trend has been seen in recent years, household OOP spending on health remains high. The health insurance share of total health spending and insurance reimbursed medical service volume have increased over time. This result can be attributed to some recent social and health policies, especially policies on healthcare for the poor and children under age 6, and healthcare subsidies for beneficiaries of social welfare policies. State budget spending on health has increased by 34.2% per year on average in the period 2008–2013, higher than the pace of increase in overall state budget recurrent spending. Some 1.7 billion VND from the state budget was allocated to the national health target programs in 2012. Viet Nam now spends a considerably larger proportion of GDP on health care than its richer neighbours Malaysia, Singapore and Thailand [8]. 5.1.6 International Free Trade Agreements One critically important issue regarding future prospects of Viet Nam’s vaccine manufacturing industry is the current and future impact of international trade agreements on national and regional markets, as well as impacts on government procurement policies. In January 2016, Viet Nam and the European Union agreed on the final text of a Free Trade Agreement (VN/EU FTA), and in February 2016, Viet Nam signed the Trans-Pacific Partnership (TPP). Importantly, neither of these agreements has entered into force yet, as both are still undergoing the final ratification process from all contracting parties. Therefore, at the present moment, neither of these agreements are legally binding. Both agreements contain chapters addressing provisions relating to government procurement, and lay down the principles of ‘national treatment and non-discrimination,’ i.e. an obligation for governments to treat foreign producers in the same way as domestic producers. The WHO Technology Transfer Initiative (TTI) 9

examined the implications of these new trade agreements regarding preferential procurement of influenza vaccines from domestic producers in several countries, including Viet Nam. The operative question is whether Viet Nam could preferentially procure influenza vaccine from a local or regional manufacturer without breaching legal obligations under these new agreements. Each of the agreements prohibits discrimination of foreign producers, but also include articles on exceptions when ‘it is necessary to protect (a) public morals, order or safety; or (b) necessary to protect human, animal, or plant life or health.” These exceptions are described broadly as focusing on health and security reasons, and to date it is not yet clear how the Appellate Body will evaluate exceptions involving vaccine procurements. Once the TPP and VN/EU FTA come into force, it may be difficult for Viet Nam to justify a preferential system of procurement from local producers, because the interpretation of exceptions has historically been very stringent, and other contracting parties could dispute that such measures are arbitrary or unjustifiably discriminatory. Furthermore, before adopting a policy that favours national producers, Viet Nam would need to prove the ‘necessity’ of such measures, i.e. that no other alternative measures could be introduced to provide equivalent health protection for the population. Clearly the full implications of these trade agreements remains to be seen, but it is important for stakeholders and leaders to acknowledge the complexities at this early stage, and to consider how these externalities may influence the business case for vaccine pre qualifications. 5.2 Surveillance networks and influenza-specific evidence

5.2.1 Human influenza surveillance Influenza-like illness (ILI) has been a reportable disease in Viet Nam since 1979. The routine reporting system for infectious diseases involves reports of the aggregated number of syndromic cases, but without retaining a case-based record and typically lacking laboratory confirmation. In 2006, the Viet Nam National Influenza Surveillance System (NISS) was established with support from the USCDC. Originally consisting of 15 ILI and 5 severe acute respiratory infection (SARI) sentinel surveillance sites, plus passive surveillance of severe viral pneumonia (SVP) in all provincial and national hospitals throughout Viet Nam, the NISS has undergone several modifications over the years (changes in sentinel sites and enrolment procedures, revised case definitions, updated protocols for lab testing). Virology surveillance data is entered into FluNet, the platform used by WHO for global influenza surveillance. Approximately 30–50 isolated human clinical viruses are shared with WHO reference laboratories each year, making Viet Nam one of the most significant contributors of influenza strains from tropical developing countries. To date, the surveillance system has generated substantial epidemiological and virologic information on respiratory infections that has led to numerous peer-reviewed papers in international journals. These include papers investigating seasonality [9], patterns of migration [10], and strain characterizations [11]. Routine ILI notification data from 1979 onwards has demonstrated that ILI is seasonal in the north of Viet Nam but this seasonality disappears at lower latitudes in the south [9]. National surveillance datasets have also been used to investigate the associations between ILI notifications and influenza virus activity, and studies of ILI detections in sentinel sites versus informal reporting from community General Practioner clinics (M Boni Nature Communications, in press). Characterising relationships of seasonality and ILI notification data from different sources may eventually be used to inform vaccination schedules.

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

The past decade of ILI surveillance in Viet Nam has clearly shown that influenza viruses circulate year-round, and laboratory confirmed influenza accounts for approximately 12-25% of all patients with ILI symptoms presenting to sentinel sites (i.e. outpatient wards of general provincial hospitals). In contrast to influenza detections within ILI surveillance, the average positivity of influenza infection (laboratory confirmed) for SARI and SVP patients ranged from 12% to 17% [12]. The year 2016 is a transition year, insofar as funding support for NISS has changed. As of 2016, ILI sentinel sites will no longer be directly supported by USCDC, as financing for the system will shift to federal sources from VNG. The USCDC will continue to support SARI surveillance in 11 sites, and WHO will support an additional 4 sites (Table 3). The majority of influenza virus isolates generated each year from the routine culture activities at the NICs are generated from ILI cases, rather than SARI, which may reflect the fact that most SARI cases present to hospital and are admitted/sampled after multiple days post-onset, thus lowering observed viral loads. The higher rates of virus isolation from ILI than SARI samples may also reflect differences in sample handling, storage, and referral. These differences in virus recovery rate may prove important if future resources allocations for surveillance activities decide to prioritize SARI over ILI surveillance. The SARI sampling frame involves weekly enrolment of 10 cases/wk/site, for a total of 500 cases/site/year or 4000 total cases per year for the whole program. Within the SARI sentinel sites, patients are enrolled from the Intensive Care Units (ICU), and/or general infectious disease wards. SARI case enrolment data includes information on pregnancy status, however analysis of at least 3 years of data shows that only very small numbers of pregnant women have been enrolled. For ILI case detection, case data does not include information on pregnancy status. Thus, it is unlikely that structure and reporting requirements of the current surveillance system will generate informative data on disease burden from pregnant women. Pregnant women have been identified by WHO/SAGE as the highest priority risk group to receive seasonal influenza vaccines [13], and the paucity of burden data from this target group is a well recognized gap. Recent efforts to adopt ‘One Health’ approaches to influenza surveillance have led to development of the Longitudinal Information Surveillance Network (LISN activities) in 2 provinces (Dong Thap and Quang Ninh). This is a joint program administered jointly by DAH and NIHE, designed to promote the sharing of routine surveillance data between the human and animal health sectors.

Table 3. Sentinel sites for active surveillance of human seasonal and zoonotic influenza. Sentinel Sites 1 Region Name of surveillance point/site ILI X X X X X X X X X X X X X X X X X X X X X X X X X X X X X SARI LISN

Cao Lộc DH, Lạng Sơn province Kiến Xương DH, Thái Bình 2 province 3 Polyclinic 103 Bà Triệu National Hospital of Pediatrics 4 (Hanoi) 5 NHTD (Hanoi) North Quảng Ninh PGH 6 (planned from 10/2016) Nam Định PGH 7 (planned from 10/2016) 8 Lào Cai PGH 9 Hà Giang PGH 10 Khánh Hòa PGH Ninh Hòa regional general 11 Central hospital, Khánh Hòa province 12 Huế Central Hospital 13 Đắk Lắk PGH Central Highlands 14 Kon Tum PGH 15 Hồ Chí Minh City HTD 16 Children’s Hospital 1 17 Tây Ninh PGH South 18 Đồng Tháp PGH 19 Cần Thơ PGH 20 An Giang PGH PGH = Provincial General Hospital; HTD = Hospital Tropical Diseases

5.2.2 National Influenza Centres There are two National Influenza Centres (NIC) in Viet Nam, located at NIHE Hanoi (established in 2007) and at the Institute Pasteur-Ho Chi Minh City (established in 2009). These national entities are responsible for coordinating the influenza surveillance activities, performing virus isolations and preliminary viral characterizations, and shipping representative clinical specimens and isolates to WHO Collaborating Centres to support global networks. The NICs have provided research input and commentary regarding the suitability of WHO recommendations on composition of influenza vaccines for Viet Nam. Evidence has been presented in workshops and conference proceedings suggesting that vaccine formulations for Viet Nam should potentially follow the southern rather than northern hemisphere formulations [14]. Surveillance data also indicates co-circulation of both Yamagata and Victoria lineages of influenza B, and significant differences in the seasonality of influenza A versus B [11]. 5.2.3 Burden estimates of human seasonal influenza Although the surveillance system is extensive, and allows for identification of epidemiological trends impacting influenza and other respiratory infections, robust estimates of disease burden using local datasets have not yet been reported from Viet Nam. Until relatively recently, tropical countries were believed to have a low burden of seasonal influenza, however, subsequent to major investments in establishing ILI surveillance in many countries, there are now numerous studies demonstrating that influenza is a common cause of respiratory illness in the tropics [15], and hospitalisation rates may even exceed those in temperate regions [16].

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

Every year, Viet Nam reports approximately 1.6 to 1.8 million cases of seasonal ILI [12]. Data on influenza-associated mortality are extremely low, and clearly indicate the weakness of the surveillance system for capturing reliable data on disease outcome. Data reporting and diagnostic confirmations were greatly intensified in 2009-2010, particularly during the first five months of H1N1pdm transmission; during this period there were 11,305 cases with positive test results to influenza A (H1N1pdm) reported from all 63 provinces/cities throughout the country, with 61 deaths distributed in all 4 regions. Deaths reported and attributed to pdmH1N1 were 2 in 2011; 3 in 2013. Total deaths attributed to all influenza subtypes (both A and B) in 2011 were 6. Regarding zoonotic influenzas with pandemic emergence potential, there have been no human cases of H5 since 2014, and no evidence of incursion of influenza A (H7N9) from China into either humans or poultry (despite ongoing intensive surveillance in LBM of 9 border provinces, and screening of >200,000 pooled swab samples). Risk factors for seasonal and zoonotic influenza have been well-studied both globally and within the SE Asian region [15,17], and although Viet Nam-specific data on risk factors for influenza are not available, they are likely to be very similar to those reported elsewhere. With regard to loss of productivity, time-off-from-work, other indirect costs or burden associated with seasonal influenza infections, no surveys have yet been conducted in Viet Nam. 5.2.4 Animal influenza surveillance network Viet Nam has a well-developed system for the active surveillance of highly pathogenic avian influenza (HPAI) strains within live bird markets (LBMs). From 2010-2015, surveillance focused primarily on monitoring genetic diversity and ongoing evolution of HPAI H5 subtype viruses within duck populations (Figure 2) [18]. Starting in 2013, additional surveillance activity was initiated in provinces along the Chinese border to promote early detection of H7N9 viruses, and was focused largely on collections from chickens and environmental samples. To date, this second surveillance activity has screened more than 33,480 pooled chicken oropharyngeal swabs and environmental samples, however no A/H7N9 viruses have been identified in Viet Nam [19].

Figure 2. Active surveillance of avian influenza in live bird markets: A) districts included for monthly collection of swabs for HPAI H5 detection (ducks, chickens); B) provinces included for periodic intensive collection of swabs for LPAI H7N9 detection (chickens only). 5.2.5 Economic cost-benefit studies of seasonal vaccine from ASEAN countries A recent review of nine economic evaluations of seasonal influenza vaccine use and costeffectiveness in Lower-Middle income countries (LMICs) [20] pointed to the shortage of transparent economic evaluations being available, and to the challenges associated with providing a clear statement on cost-effectiveness or cost saving achieved by influenza vaccination. The authors highlight the serious methodological limitations that do not allow 13

drawing conclusions. While overall, most studies have demonstrated cost-effectiveness of seasonal influenza vaccination in specific target groups (e.g. elderly, children with high-risk conditions, infants, health care personnel and COPD patients), it is difficult to generalize across contexts and conduct meta-analyses, dues to differences in study approaches, populations, outcomes measured, and definitions. In general, the evidence on value for money generated from these studies was in line with investigations from high-income countries, where influenza vaccination has been found to be cost-effective among elderly, children, pregnant women, and even among healthy adults. One study in Thailand concluded that vaccination might not be cost-effective for community-dwelling elderly aged 60 years and above [21]. Two RCTs from China found that influenza vaccination was cost-beneficial for elderly and healthy adults with regard to influenza-related and non-related outcomes (e.g., cardiovascular disease). Other reviews of influenza vaccine sales and national policies from ASEAN countries have identified a trend of increasing influenza vaccine usage in the private sector [22]. For Cambodia, Lao PDR and Viet Nam, no seasonal influenza vaccine was purchased by the government for use in the public sector during 2008 through mid-2011, (and for Viet Nam this remains the current status as of 2016). In Singapore, influenza vaccines are routinely offered in public hospitals, but are not free of charge. Indonesia, Myanmar, and Malaysia purchased vaccine for use in the public sector during the survey period, but did not report the number of doses (in Malaysia, programs targeted health care workers). The Philippines purchased seasonal vaccine beginning in 2011 (with estimated usage of 1608 doses per 100,000). In Thailand in 2011, combined private and public sector sales in Thailand exceeded 7 million doses equal to 10,333 doses per 100,000 persons. For Viet Nam, data from NICVB on imported vaccine doses also supports a trend of increased influenza vaccine usage in the private sector (see section below on vaccine uptake). Whereas reliance on supranational/regional data on cost-effectiveness may be valuable for assessing the overall epidemiological situation, it is unclear whether statistically valid extrapolations or modeling studies from other countries would be considered compelling evidence to national leaders regarding Viet Nam’s current influenza burden. Typically, Vietnamese MoH has been conservative regarding acceptance of data from other countries for policy decision-making or for regulatory/licensing issues. This is evidenced, for instance, in the standing requirement to conduct clinical trials prior to licensing all imported vaccines, regardless of whether substantial data exists from large-scale systematic trials and high caliber post-marketing surveillance conducted elsewhere. 5.2.6 Ongoing longitudinal cohort studies as a platform for influenza research NIHE has been involved in several different long term longitudinal cohort studies to support public health research on infectious diseases. Two of these cohorts have now been running for nearly a decade, the Nha Trang birth cohort and demographic surveillance program (led by NIHE/Nagasaki partners since 2006), and the Ha Nam longitudinal household transmission cohort (led by NIHE/Oxford University Clinical Research Unit partners since 2007). The Ha Nam cohort in particular has focused on understanding of influenza transmission dynamics, and has yielded robust estimates of attack rates [23]; household secondary attack proportions, and risk factors for household transmission [24]; effects of age and HI titer on homotypic and heterotypic infection [25]; the role of non-influenza viral infections in household ILI (Diep NTN et al., 2016). Sera from the Ha Nam cohort ----serial monitoring of participations with known infection histories of seasonal influenza-- has been used to study ‘antibody landscapes’ to H3 subtype viruses [26], to evaluate how infection with new variants impacts the boosting of 14

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

immune memory, and the concept of ‘original antigenic sin’. The possibility of using retrospective data available from these cohorts, and promoting these study sites for prospective analyses could be explored with NIHE. 5.2.7 Uptake of seasonal influenza vaccine To date, uptake of influenza vaccine through the private fee-for-service health sector in Viet Nam has been low. The MOH does not currently attempt to maintain stockpiles of seasonal or pre-pandemic vaccines. Regarding antivirals for treatment of severe cases (e.g. Oseltamivir, Zanamivir, Amantadine, Ribavirin), a small reserve stock of Tamiflu is maintained at the National Hospital for Tropical Diseases in Hanoi. As with other drugs and medical devices, procurement of antivirals for provincial hospitals is relatively decentralized, and is the responsibility of each general hospital. Six types of seasonal influenza vaccines are currently licensed for use in Viet Nam: Vaxigrip (Sanofi Pasteur, comprising the vast majority of doses imported), Fluarix (GSK), Influvax (Abbott), Inflexal (Berna, for which there have not been any imports since 2013 as the manufacturer no longer exists), and Agrippal (Novartis, which was licensed in 2012 but has never been imported) [Table 4]. The number of influenza vaccine doses imported in previous years, based on lot release data from NICVB during 2006-2015, suggests a trend of gradual increase in usage over time. Interestingly, for 2013-2015, the actual number of imported seasonal vaccine doses exceeded the projected estimates (as per the GDPM 2013 Vision document) by a factor of 3-4.5. Table 4. Number of doses of seasonal inactivated influenza vaccine imported to Viet Nam, based on lot release data from NICVB, 2010-2015 [updated from the GDPM 2013 Vision document].

Influenza vaccines in Viet Nam are sold mostly through private clinics and some vaccination centers, but generally are not available through hospitals. It is believed that the majority of imported doses are purchased by selected larger companies to provide employees through internal health promotion campaigns, or through institutions or universities. For instance, NIHE purchases approximately 2,000-3,000 doses per year, that are made available to the public through their immunization services clinic, and NIHE staff are recommended (but not required) to receive vaccination. (Of interest, laboratory staff of the National Influenza Center, 15

who work on virus isolation and propagating strains in eggs and cell culture, are not required to receive influenza shots.) At the present time, it is difficult to obtain distribution data on non-EPI vaccines, or to ascertain what fraction of imported non-EPI vaccines are actually used. Reporting of vaccine usage data was first mandated by MoH Circular #12 in 2014, which required all vaccination clinics to provide aggregated monthly information on EPI vaccines to GDPM. This reporting requirements were recently expanded by Decree #104 (dated 1 July 2016), to include reporting on fee-for-service vaccines. Thus, the system for reporting and compiling such information is under development, and we anticipate the availability of summary statistics in the near future. 5.2.8 Non-EPI fee-for-service Immunization Viet Nam currently operates a “dual system” of EPI immunisation and “non-EPI” fee-forservice vaccines available in health facilities across the country. If decisions are made to actively promote influenza vaccine usage, these programmes would most likely use the existing distribution network of fee-for-service vaccines at local commune health centres. At the moment, all vaccine services are heavily focused on pediatric populations. Future programmes to promote influenza vaccine use among pregnant women would likely require outreach to Commune Health Workers through new education programmes. Available ‘fee-for-service’ vaccines include rotavirus vaccine, pentavalent 5-in-1 and hexavalent 6-in-1 vaccines, rabies, MMR, meningococcal and pneumococcal vaccines, and others (Annex 3). The dual system of EPI and non-EPI fee-for-service vaccines has generated some concerns regarding how the two systems are co-administered; the worry is that existence of a separate, private sector distribution system may complicate delivery of routine (free) EPI vaccines, and potentially create dual standards of care, confusion in implementation schedules, or difficulties in reporting for vaccine coverage estimates. Regarding the key challenge of tracking and monitoring immunization data at the individual level, the GDPM is developing a new webbased electronic system, with plans to pilot the system in three provinces (Bac Ninh, Hanoi, and Ho Chi Minh City) in 2016. This system could greatly improve the ability of government agencies to assess trends in vaccine uptake, to conduct research on population immunity, and to assist in many aspects of strategic planning. [Note that one challenge for implementing such information systems at the individual level for pediatric vaccines is the fact that unique numeric identifiers are not assigned at birth; tax ID codes are typically assigned at age 15 or 16 years of age.] 5.2.9 Vaccine prices Pricing and financing issues continue to be an important deterrent for more pro-active promotion of influenza vaccine uptake. The challenge of establishing reliable independent financing for EPI vaccines (i.e. secure 100% funding from VNG sources) has already been mentioned, and will remain a critical issue for coming years that will constrain the available MOH budget to work on non-priority diseases such as seasonal influenza. In 2012, a set of new regulations on competitive tendering for procurement of drugs (especially generic drugs) and vaccines were developed [27]. Currently in 2016, there appear to be some difficulties in negotiating vaccine procurement for EPI using UNICEF-negotiated pricing mechanisms. This has to do with the decentralized way in which procurement is conducted through different distributors, and different aspects of how bidding laws apply to imported 16

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

foreign vaccines. A national competitive tendering model for drug and vaccine procurement has not yet been developed, however work is ongoing to develop a centralized management entity within Ministry of Finance to address these needs. The current imported Sanofi and GSK flu vaccines are sold in Viet Nam for approximately VND 150,000-220,000 per dose (US$ 7-10/dose). IVAC leaders suggest that their seasonal vaccine (once it has achieved licensure) will be sold at approximately ~VND 60,000-80,000 per dose (US$ 3-4/dose). Thus, the locally-produced IVAC influenza vaccine will likely be cost competitive relative to imported vaccine alternatives. However, this price may still be considered too expensive for widespread uptake. Comparing prices for domestic vaccines versus alternative international commercial products is complicated by the way in which MOH fixes prices for domestic vaccine products; prices for domestic vaccines produced by POLYVAC, VABIOTECH, and IVAC are dictated by MOH policy, and have remained largely static since 2008. The EPI programme has always prioritized purchasing vaccines through state-owned suppliers, as long as those domestic vaccines could meet sufficient quality standards. Quality assurances have been provided by the Viet Nam NRA, and significant investments have been made to ensure that domestic manufacturers continue to upgrade facilities in order to meet international GMP requirements as those standards evolve [see Annex 3]. Although there is no doubt that the costs of production have increased over the past decade, yet those costs have not been reflected in the pricing mechanisms. Thus, although purchasing from the local state-owned enterprises is widely assumed to be cost competitive, it is unclear whether the price differential reflects the true unit costs, or how the difference may be influenced by subsidies or customs/import fees/taxes or other factors that determine the cost of comparable international products. Government expenditures on vaccines are divided into two flows, routine expenditures for EPI (for which the budget is based on census population, with numbers of doses required provided by EPI managers), and a fund for ‘emergencies and epidemic response.’ Expenditures for feefor-service vaccines are, by definition, out-of-pocket. To date, there is little data available on how many vaccine doses are delivered through fee-for-service, and not clear how much the relative prices of fee-for-service vaccines would impact demand (i.e. demand ‘elasticity’). GDPM has estimated that of the ~35 million total vaccine doses use per year (all types combined), approximately 8% (2.5-3 million) are fee-for-service vaccines. 5.3 Vaccine manufacturing in Viet Nam - review of current status Currently there are 4 state-owned vaccine manufacturers in Viet Nam: IVAC, POLYVAC, VABIOTEC, and DAVAC. The two companies located in Hanoi were originally integrated within NIHE, and then subsequently separated as independent enterprises in 1994 (POLYVAC), and 2007 (VABIOTECH). Each of the enterprises are now para-statal, with 50% publically traded stocks/shares, with the government retaining at least 50% ownership. The four manufacturers are also members of DCVMN (Developing Country Vaccine Manufacturing Network), which continues to facilitate training opportunities and provide support for technology transfer. Having achieved the milestone of a fully recognized NRA, Viet Nam’s vaccine manufacturers are eager to pursue increased export of vaccines through achieving prequalification (PQ) status for selected products. A 3-day workshop was held by WHO in April 2016 to brief representatives from the three major state-owned vaccine manufacturers on the prequalification process. In addition to purchase by UN agencies, WHO Prequalification may also expedite 17

approval in other countries. Priority vaccines identified for PQ development within each of the 3 major vaccine companies of Viet Nam (IVAC, VABIOTECH, and POLYVAC) are discussed further below. The following primary criteria were discussed in interviews with manufacturers regarding the export potential of a given vaccine product: i) the existing evidence-base for costeffectiveness; ii) the availability of documentation to support product-specific GMP evaluations; and iii) the estimated selling price of the vaccine. 5.3.1 IVAC (Institute of Vaccines and Medical Biologicals) IVAC was established in 1978 as a state-owned unit under the control of MOH. It currently produces 13 products, including 4 vaccines used in NEPI (DPT, BCG, TT, Td) [Table 1], and two influenza vaccines under development (seasonal trivalent inactivated vaccine, TIV and H5 inactivated pandemic vaccine). The VNG’s official support for IVAC’s influenza vaccine development plan has been evidenced through at least two mechanisms. First, the Ministry of Science and Technology (MOST) decision document (No. 2682/QD-BKHCN, dated 8/10/2014) identified IVAC’s seasonal TIV influenza vaccines as a ‘national product’. Document No 2682 specified commitment of 15,962,000 VND [approximately US$760,000] for the period of 2014-2019 (with 7,530,000 VND coming from government sources and 8,432,000 VND from budget of IVAC)] to support product development. The Decision also clarifies that management and oversight of the vaccine development project will be under Ministry of Science and Technology (MOST). The second major example of support for IVAC’s work is the GDPM 2013 Vision document, cited extensively already. The GDPM 2013 Vision does not provide details on financing mechanisms. The second line of evidence showing explicit government support for IVAC’s influenza vaccine development project is the GDPM 2013 Vision, already cited extensively, which provides a very clear statement of both immediate near-term and long-term influenza vaccination targets. Interestingly, the plan mentions development/licensing Live Attenuated Influenza Vaccines (LAIV). IVAC currently has two facilities, one in the city center of Nha Trang, and a production facility and chicken farm about 22 km from the city, called Sưoi Đau. Influenza vaccine development at IVAC began in 2005, with government support to conduct research on egg-based inactivated vaccines. WHO support began in 2008, when IVAC joined the GAP program; at that time, IVAC had not yet developed their production platform, and government support for the unit was minimal. Since 2008 IVAC has received financial and technical support from WHO, BARDA and PATH to construct a manufacturing facility and egg farm, for process development, and for preclinical and clinical studies. They have completed the conduct of a phase 1 trial of pandemic H1N1 vaccine, a phase 1 trial of seasonal TIV and a phase 1 and 2 trial of pandemic H5N1 vaccine. IVAC is now initiating a phase 3 trial of their H5N1 candidate and a phase 2/3 of their seasonal TIV. The animal facilities of Sưoi Đau are extensive, including two flock houses to support egg production, as well as numerous barns and rearing facilities for species used for other products (e.g. horses used for tetantus toxoid antiserum production, rabbits, guinea pigs, mice, hamsters). The flock management at Sưoi Đau involves routine monitoring for bacterial agents, as well as serological and virological testing for a number of avian pathogens to meet requirements for ‘clean eggs’ for vaccine production. The flock management does not meet SPF (Specific Pathogen Free) standards, as this is not required for inactivated virus production. A small number of SPF eggs are imported (typically from Germany) for each new Master Seed and Working Seed lot production during changes in strain formulation. 18

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

Discussions are ongoing to secure complete funding for the Phase 3 trial of H5 vaccine and the phase 2/3 trial of seasonal TIV vaccine, with target licensure by end of 2017. In summary, the WHO/PATH/BARDA project to support IVAC’s development of the TIV and H5 vaccines are targeted to achieve registration/ licensure of both the H5 and TIV vaccine by the end of 2017. They are also on track to complete their clinical development of their H5N1 vaccine. Adverse Events Following Immunization (AEFI). IVAC does not have a history of direct involvement in responding to AEFI cases for any of their vaccine products, and to date, has never been required to recall any products. On occasion, there have been times when selected Preventive Medicine Centers (PMC) returned vaccines from EPI stocks when they suspected the vaccines of having been improperly stored. In those cases, IVAC re-supplied the needed doses to the EPI programme. IVAC does not currently have a mechanism for post-marketing surveillance (PMS), however they have proactively established an ‘internal science committee’ for review of AEFI events, and this committee could be mobilized to assist with AEFI investigations if needed. Ambitions to establish PQ status for IVAC products. IVAC has only recently begun considering the procedures required to obtain PQ status for any of their products. The cost estimates required to obtain PQ status for influenza TIV vaccine have been estimated by IVAC leadership as US$ 1 million. Management leaders have developed a ‘Master plan for PQ of influenza seasonal vaccine’ that delineates anticipated future challenges and time lines for improvements. Establishing a system for post-marketing surveillance will be an important challenges for obtaining PQ status. The total planned capacity for IVAC’s TIV product is ~1.5 million doses/year. IVAC leaders believe the domestic ‘demand’ may be ~300,000 doses/year during the first years postlicensure, thus leaving a remainder of 1.2 million doses that could potentially be exported. During the April 2016 workshop on vaccine PQ procedures, IVAC expressed keen interest in achieving PQ for several products, and both the seasonal TIV and BCG vaccines were discussed as candidates. Given the long history of GAP support for IVAC’s TIV development, and the substantial support from PATH/BARDA to develop the product dossier, it would seem that the TIV product is further advanced along the pipeline for PQ status than BCG. However, the market demand and sustainability issues are a perceived obstacle. It is unclear whether overseas market sales of TIV---even if achieved at a rate of 1.2 million doses/year---would provide a sufficient profit margin be sustainable. However, it is unclear which countries may be the potential purchasers of the IVAC TIV, whether IVAC prices would be cost-competitive on the international market, how the distribution network could be achieved, and whether new trade agreements (such as Trans Pacific Partnership, TPP and the Viet Nam/EU FTA, see above) may procurement policies, especially within Viet Nam. Most stakeholders interviewed during the consultation thought that TPP would not directly impact vaccine pricing, because the expected trading partners for Viet Nam vaccines would be lower income countries and not members of TPP. [Please refer to section 5.1.6 for further discussions of potential impacts of international trade agreements.] 5.3.2 VABIOTECH VABIOTECH is the largest vaccine manufacturer and supplier for NEPI, and currently produces 4 GMP-qualified vaccines: Hepatitis B, Hepatitis A, Japanese Encephalitis, and Oral 19

cholera. The company also imports and acts as a distributor for several other vaccines and biologicals, including Mumps, Rubella, Meningococcal and Varicella. The product profolio includes a series of diagnostic kits for detection of HBsAg, anti-HBs, anti-HCV and anti-HIV. VABIOTECH’s efforts to develop influenza vaccines began in 2005, in response to requests from MOH to work on human pre-pandemic H5 vaccines using their existing primary monkey kidney cell (PMKC) production system (which was already in place for Hep A vaccines). These early efforts were supported by visits from Yoshi Kawaoka’s research group, to provide technical training on propagation of PR8-recombinant H5 candidate vaccine strains (CVV). Pilot production was completed, and a dossier submitted to the DAV/NICVB in 2013, however development was subsequently abandoned when it became apparent that GMP standards for H5 vaccine production would require too many upgrades to the existing manufacturing facility. (The requirements specified a dedicated space for exclusive production of H5 influenza vaccine, and would disallow the ability to produce other vaccine products in a ‘campaign’ production approach.) Thus, further investments in H5 vaccine production at VABIOTECH will require construction of new facilities. There is a long term plan to do so, involving relocating the entire enterprise to the new ‘High Tech park’ in Hoa Lac to the west of Hanoi (near where the new NIHE campus will also be located). However, financing for this plan has not yet been secured and the timeframe for the project is unclear. Although further development of H5 vaccines has not been pursued since 2013, VABIOTECH continues to conduct small-scale research efforts on production of seasonal vaccine (TIV) produced in MDCK continuous cell lines. A H1N1pdm vaccine product was developed in 2011, but not licensed due to technical challenges in scaling-up production in MDCK cells. VABIOTECH is now considering development of an LAIV formulation, although these plans are in very early stage. The concept is to work with PATH to build a model similar to the Serum Institute of India (SII), which has recently achieved PQ for an egg-grown seasonal trivalent LAIV product (NasoVac-S). Importantly, this would constitute the first live viral vaccine product made by VABIOTECH. Anticipated challenges include the stringent GMP requirements of testing for residual DNA and ‘oncogenes’ derived from production in continuous cell lines. Priorities for development of PQ vaccines at VABIOTECH include their oral cholera vaccine, since this is perceived to have a unique niche in the world market. Very few other manufacturers are making oral cholera vaccines, it is considered highly cost-effective, and the production platform is already validated. The current target is to reach PQ for the oral cholera product by 2017. An additional target for PQ development is the Hepatitis B vaccine (potentially by 2019), which could then be incorporated into a 5-in-1 domestically produced alternative to Quinvaxem. 5.3.3 POLYVAC POLYVAC was established through separation from the production department of NIHE on 16 January 1994 in Hanoi, under the MOH decision #79/QĐ-BYT. POLYVAC has played an important role in production of polio and measles vaccines to support NEPI, and contributed to the success of polio eradication in Viet Nam in 2000. In 2007, WHO supported several trainings on GMP, including ‘mock inspection’ processes for learning how to navigate GMP regulations. The company achieved GMP certification for measles vaccine production in 2008, and the inspection process has been renewed every 2 years since then. POLYVAC

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

maintains animal facilities, but only for use in quality control testing. These facilities use guinea -pigs and rabbits sourced from IVAC’s Suoi Dau farm in Nha Trang. Influenza vaccine development at POLYVAC was conducted for a short period during 20092010, during the first phase of interest in pandemic H1 vaccine development. At that time, MOH encouraged each manufacturing unit to explore all possible production platforms, so POLYVAC pursued production of inactivated monovalent H1pdm vaccine in their only qualified cell line, Vero cells. Similar to the other vaccine manufacturers in Viet Nam, decision making at POLYVAC regarding production output, vaccine pricing, development of new products follows directives from MOH. The ‘business plan’ regarding vaccine production is not considered or evaluated as it would be within the private sector, and to date the company does not have staff dedicated economic analysis, marketing, advertising, communications, or public relations. The MOH is currently considering the possible consolidation of state-owned vaccine production companies into a single enterprise, under the umbrella of a ‘mother company’. Prof. Hien, Director of POLYVAC expressed a positive viewpoint on creation of single management entity, as it might provide opportunities for joint advocacy and a mechanism for increasing profits. He also mentioned that prices for government purchase of vaccines ---for measles and OPV---have been determined by contracts written in 2008, with fixed prices per vaccine dose have not increased in the last 7 years. Neither POLYVAC nor the other stateowned operations have negotiating power to change the vaccine pricing scheme, and these policies pose challenges for corporate financial management. The pricing structure negatively impacts the amount of resources available for Research and Development, and for reinvestment into company infrastructure (for example, to maintain GMP status). 5.3.4 Procedures for annual strain updates of seasonal influenza vaccines In Viet Nam, as with other countries, seasonal influenza strain updates are considered a ‘variation’. The process for renewals of registration numbers was indicated in Chapter V of Guidance on Evaluating Annual Strain Update Dossier for Influenza Vaccine Registered in Viet Nam (official letter No. 7333/QLD-DK dated 28/11/2007 of DAV). This guidance document was developed primarily to assist registration of imported influenza vaccines. Subsequently, during the early phases of the PATH/BARDA support for IVAC’s influenza vaccine project, an additional document entitled ‘Guidelines for Influenza Vaccine Registration’ was developed, with the goals of making the registration process of domestically produced influenza vaccine publicized and transparent, as well as increasing the efficiency of public governance in this area. The document is a detailed 58 page-long document that provides both general and influenza-specific details about dossier requirements, application forms, checklists, and sections on each aspect of quality assessment. Although the document was officially recognized (as stated in #38/QD-QLD dated 12 March 2013), NICVB was not involved in the development of the document, nor were they included on circulation/distribution lists once it was approved. As mentioned previously, IVAC has already gone through one strain update of the seasonal TIV, such that the Phase 1 trials were conducted with different H3 viruses that the strains included in Phase 2. As such, this demonstrates proof of principle that procedures are in place and may not cause undue delay. 21

5.3.5 Proposed pandemic vaccine regulatory pathway In Viet Nam, ‘Fast Track Procedures’ for vaccine registration in the event of emergencies, natural disaster, or epidemics is covered under general procedures described in Article 31 of Circular #44. This article applies to all drugs, vaccines, and biologicals (it does not specifically mention influenza), and is intended to enable broad authority by the MOH to waive registration requirements under special circumstances. It does not specify measures for evaluating potential risks and benefits should a pandemic influenza vaccine be needed for use before the licensure process can be completed (e.g. when there are limitations of the data available that would be required to support licensure). Rather, it simply provides a legal mechanism whereby the Minister may override any regulatory requirements. To date, this ‘Fast Track’ mechanism has not been implemented for any vaccines. The IVAC H5 vaccine is a whole virus inactivated monovalent formulation, adjuvanted with alum, for which the production process is nearly identical to seasonal TIV influenza vaccine. (The seasonal vaccine differs in that it is trivalent and split virion). IVAC’s intention is to license the TIV, but not the pre-pandemic H5N1 vaccine, with the understanding that should a pandemic virus emerge, then the necessary strain changes will be made and licensure will be fast-tracked. In that scenario, nonclinical safety investigations will not need to be repeated, provided that no other manufacturing processes have been changed and that all procedures have been performed in accordance with relevant NRA requirements. Thus, when followed through to completion, the evaluation and approval of IVAC’s seasonal vaccine core dossier would accelerate the registration of a pandemic vaccine if needed. In the event of a pandemic emergency, speed would be needed for batch release tests. The Vietnamese NRA has not yet developed procedures for batch release of pandemic vaccine. However, once IVAC’s seasonal vaccine has successfully been licensed, provisions for batch release of pandemic vaccines could be developed and included in future national pandemic influenza preparedness plans. It would be necessary for NICVB to perform tests in parallel with IVAC and/or to perform only a subset of the tests normally done on seasonal influenza vaccines (e.g. SRID tests). 5.3.6 Additional regulatory issues Among the issues raised during stakeholder interviews, was a concern about the specific roles/responsibilities/mandate of NICVB regarding receipt of candidate vaccine viruses from WHO reference centers, and their technical capacity to manage Seed Lot systems. According to decision No 3100/ QD-BYT of MOH issued 21/8/2008 (Article 5 Chap II, Section D), the function and duties of NICVB include the following: “To request international centers supply international standard reference, original strain relevant to vaccines and biologicals and perform the receipt; To produce, store and distribute national reference material to quality control systems and manufacture unit. To manage microbiological strains and cell lines used in production and quality control”. To date, the candidate vaccine viruses (CVV) used by Viet Nam’s vaccine manufacturing units have been provided directly from international reference centers, or through bilateral technical transfer from other overseas manufacturers. For example, IVAC received the CVVs for updating seasonal TIV directly from TGA; VABIOTECH is in process of obtaining Master Seed of LAIV in partnership with WHO and the Institute of Experimental Medicine, St Petersburg, Russia. After producing their own Master Seed and Working Seeds, the 22

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

manufacturers provide samples to NICVB for quality control testing. In order to ensure smooth management of NICVB, there may need to some clarifications of their role for importing, distributing, and maintaining repositories of CVVs. Currently, NICVB does not maintain live virus isolates, and does not have extensive virological expertise to manage such an inventory. Furthermore, leadership at NICVB expressed the need for further trainings on influenzaspecific testing procedures. Communications and information flow among the different NRA agencies is also an area for improvement. For example, the 2013 document ‘Guidance on registration of Influenza Vaccines’ was not shared with NICVB leaders when it was first developed, nor were they aware of its existence during the 2016 assessment. Furthermore, although the document provides clarification on regulatory procedures, it does not include technical details on required laboratory assays, nor specify which entity has responsibility to perform which tests (manufacturer versus NICVB). Further development of protocols to explain testing policies, and detailed standard operating procedures for specific assays would be a significant contribution to assist NICVB workflow. 5.3.7 Veterinary vaccine manufacturers According to the One Health Action Plan (OHPZ, 2016), the overall government budget for H5 avian influenza disease control for 2014 to 2018 for the agriculture sector is approximately US$ 39 million, comprising US$ 6.04 million at the central level, US$ 26.1 million by provinces and US$ 6.74 million by farmers (to pay for administration of vaccines). Vaccination represents the largest component of these costs. There are currently five major veterinary vaccine manufacturers in Viet Nam, of which three are state-owned. The largest of these is Navetco, which has been producing poultry H5 vaccines since 2012, and the others are Vetvaco, RTD, Hanvet, and Marphavet. Navetco produces an inactivated oil-in-water emulsion H5 vaccine based on egg-based production of recombinant high growth strains. The product has been marketed as Navet-Vifluvac, and to date over 300 million doses have been used in Viet Nam (in chickens, ducks, and quails, although government programs have largely focused on ducks). Most government programs to support poultry vaccination have procured vaccines from Harbin China, and have comprised inactivated vaccines with oil-in-water adjuvant (Table 5 summarizes poultry H5 vaccines licensed for use since 2004). The DAH considers that restricting the number of licensed vaccines is an important component of control efforts that can help to simplify providing vaccine usage guidance to sub-departments of animal health; typically only one or two different vaccine formulations have been in use at any given time. This is in contrast to Indonesia, for instance, where >20 different H5 poultry vaccines are widely used.

Table 5. Poultry H5 vaccines licensed and used in Viet Nam. Licenced in Recombinant Vietnam backbone Usage history (M=million) 2005 Fowlpox vector w/ HA ~40-55 M doses/yr in 2005-2006; and NA of H5N1 discontinued use in 2007 due to poor performance Bioflu (Merial) 1 A/chicken/Italy/22A/98 H5N9 2006 Inactivated, whole ~7 M doses used for Muscovy ducks virus H5N9 in 2007; discontinued use in 2008 Nobilis Influenza North Am. A/chicken/Mexico/232/94/CPA H5N2 2005 Inactivated whole ~9.5 M doses used in 2009, for (Intervet) lineage virus chickens only Product name Trovac AIV (Merial) (Chinese company) Re-1 (Harbin) Eurasian A/Turkey/England/N28/73 H5N2 lineage 0 A/goose/Guangdong/1/1996 H5N1 2006 Never used in federally funded programs, only in commercial operations Inactivated, Rg in PR8 ~300 M doses used/yr throughout country from 2005-2010; 110 M doses in 2011-2012*; manufacturing ceased in 2011 but use continued until stocks depleted Inactivated, Rg in PR8 In current use, 2013-present*** Inactivated, oil-inIn current use, 2013-present*** water emulsion, Rg in PR8 Inactivated, oil-inIn current use, 2013-present*** water emulsion, Rg in PR8 live, HVT vector strain Registered; licensure pending field FC126 trials in 2016; applied at hatchery inactivated, NDV Registered; licensure pending field vector with HA trials in 2016; applied at hatchery recombinant subunit live, HVT vector In development thru DAH/NCVD/ZELS project Inactivated, Rg in PR8 Registration commenced Feb 2016 Inactivated, for chickens only H5 HA Clade 0 Manufacturer's purported seed strain A/Turkey/Ireland/1378 H5N1

2005

Re-5 (Harbin) Re-6 (Harbin)

2.3.4 A/duck/Anhui/1/2006 H5N1 2.3.2.1b A/duck/Guangdong/S1322/2010 H5N1 1 NIBRG-14; A/duck/VN/1194/2004 H5N1

2011 2012

Navetco vifluvac

2013

Vectormune 2.2 unknown [Clade 2.2 Egyptian H5] pending (Ceva)** NDV-H5 NA synthetic HA, designed to contain pending (Boehringer composite epitopes Mannheim) HVT-H5 2.3.2.1c A/duck/Vietnam/NCVD-1544/2012 pending (Pirbright) and 1.1 H5N1 Re-8 (Harbin) 2.3.4.4 A/chicken/Guizhou/4/13(H5N1) pending *: in 13 southern provinces only **: Licensed and stockpiled for emergency use in USA ***: Total estimated usage for 2014 of Re-5, Re-6, and Navetco vaccine was ~185 million doses

Development of veterinary vaccine biomanufacturing has been supported by several government initiatives, however to date there remains a lack of in-country expertise on the use of reverse genetics for ‘home-made’ master seed generation. Indeed, to date there are no examples of licensed vaccine products in Viet Nam---neither for human nor veterinary applications---for which the master seeds were generated in-country. In previous consultations of WHO/OIE/FAO in the region, the feasibility of cross-sectoral (‘One Health’) collaborations for producing human pandemic vaccines in veterinary manufacturing facilities, or vice versa, has been explored. However, such a concept has never been promoted or discussed in Viet Nam, and to date there have been few interactions between the human and veterinary vaccine manufacturing sectors. To date, none of the current domestic veterinary vaccine manufacturers within Viet Nam have developed extensive laboratory capacity for use of reverse genetics methodology, nor have they obtained intellectual property rights that would facilitate vaccine development research using in-country produced recombinant CVVs. However, interested manufacturers are encouraged to conduct a systematic patent search to clarify whether particular patents are publicly available in Viet Nam or protected, and thus the technology could be pursued without hindrance. 24

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

Despite compelling evidence that bivalent formulations for AIV vaccines will be required to adequately protect against antigenically divergent H5 strains, to date no licensed bivalent formulations for AIV vaccines are in the pipeline. Regulatory obstacles and prolonged delays significantlly hinder poultry vaccine development efforts. No regulations are in place to enable renewal of influenza vaccine registrations with strain updates; hence, each strain update is considered an entirely new registration application. The Ministry of Agriculture and Rural Development (MARD) has recently signed a Decision #1756/QD-BNN-TY to establish a high level Steering Committee to promote in-country veterinary vaccine manufacturing for major livestock diseases. The Decision defines and highlights the need for improved domestic production of poultry H5 vaccines as a national priority. The mandate of the committee is to define research gaps and development priorities, but does not specifically address regulatory hurdles.

Recommendations and Action Points

The recommendations below were discussed in joint stakeholder meetings held at offices of DAV on 5 October 2016, and subsequently finalized and agreed upon. Participants in the meeting included interviewees and other agency representatives, as listed in Annex 4. Short term: GDPM to convene a meeting of the national immunization technical advisory group (NITAG) to discuss influenza vaccination policies and the business case for IVAC’s TIV product. i) NITAG should assess the relative merits of introducing IVAC’s TIV into various target risk groups (e.g. health care workers, pregnant women), and review the formulations, schedules, timing and age recommendations on the impact and cost of vaccination. NITAG to commission further research as needed. Several data sets have been collected on influenza in Viet Nam and are available: GDPM to serve as focal point to coordinate more in-depth analysis of existing datasets, and to promote future influenza research. i) ILI and SARI surveillance datasets could be used to derive estimates of influenza disease burden, and in combination with published studies from the region, these could support modeling efforts to understand cost/benefits of vaccination within specific risk groups. GDPM should promote using current resources (e.g. existing longitudinal cohort studies in Nha Trang and Ha Nam) to build research capacity and inform evidenced-based policy making. ii) GDPM to continue improving existing reporting system on current use of fee-forservice vaccines, to better understand potential demand for influenza vaccines. MoH to clarify functions and obligations of the NRA, to further strengthen regulatory systems, in particular as regards pandemic preparedness i) NICVB to develop more detailed Standard Operating Procedures for management of the seed lot system, and testing policy for updating influenza vaccine strains. ii) NICVB to implement their institutional development plan with support from WHO, in particular for advanced laboratory training on strain identity and potency testing (sequence analysis; antigenic characterisation, SRID test). iii) GDPM to clarify plans for developing post-marketing surveillance networks. iv) ASTT to improve workforce development and training opportunities in vaccinology. 25

IVAC to ensure all work is conducted for the finalization of ongoing clinical trials and registration of the TIV vaccine. Long term: MoH and MoF to discuss mechanisms for direct public financing of seasonal influenza vaccines to sustain a minimal annual production of seasonal vaccine at IVAC. This analysis should include an assessment of how many doses would be required---and at what price---to reach a sustainable ‘break-even’ point for IVAC influenza vaccine production capacity. IVAC to engage and participate in these discussions as well, to develop the business case for TIV vaccine before external support for product development is finished (end 2017). MoH to discuss the possibility of including seasonal influenza vaccination into the social insurance scheme. MoH to work together with MoF to develop pricing policy for domestic vaccine products.

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

REFERENCES [1] Gilbert M, Xiao X, Pfeiffer DU, Epprecht M, Boles S, Czarnecki C, et al. Mapping H5N1 highly pathogenic avian influenza risk in Southeast Asia. PNA 2008;105:4769– 74. Russell C a, Jones TC, Barr IG, Cox NJ, Garten RJ, Gregory V, et al. The global circulation of seasonal influenza A (H3N2) viruses. Science 2008;320:340–6. UNICEF. National EPI Review Vietnam 2015. Hanoi, Vietnam: 2015. Nielsen A, Lan PT, Marrone G, Phuc HD, Chuc NTK, Stålsby Lundborg C. Reproductive Tract Infections in Rural Vietnam, Women’s Knowledge, and HealthSeeking Behavior: A Cross-Sectional Study. Health Care Women Int 2016;37:392–411. Thac D, Pedersen FK, Thuong TC, Lien LB, Ngoc Anh NT, Phuc NN. South Vietnamese Rural Mothers’ Knowledge, Attitude, and Practice in Child Health Care. Biomed Res Int 2016;2016. Nguyen H V, Nguyen TH. Factors associated with self-medication among medicine sellers in urban Vietnam. Int J Heal Plan Manag 2015;30:219–31. GDPM GD of PM. JOINT ANNUAL HEALTH REPORT (JAHR) 2015 “ STRENGTHENING PRIMARY HEALTH CARE AT THE GRASSROOTS TOWARDS UNIVERSAL HEALTH COVERAGE .” Hanoi, Vietnam: 2016. Ramesh M. Health Care Reform in Vietnam: Chasing Shadows. J Contemp Asia 2013;43:399–412. Thai PQ, Choisy M, Duong TN, Thiem VD, Yen NT, Hien NT, et al. Seasonality of absolute humidity explains seasonality of influenza-like illness in Vietnam. Epidemics 2015;13:65–73. Le MQ, Lam HM, Cuong VD, Lam TT, Halpin RA, Wentworth DE, et al. Migration and Persistence of Human Influenza A Viruses , 2013;19:2001–8. Thanh LT, Hang PT, Hien P thi, Le Khanh Hang N, Thach NC, Phuong HVM, et al. Circulation of influenza B lineages in northern Viet Nam, 2007–2014. WPSAR 2015;6:1–7. One Health Partnership V. Epidemiology and Laboratory Collaborative Information Sharing System. Hanoi, Vietnam: 2015. WHO. WHO consultation on influenza vaccines for pregnant and lactating women. Geneva: 2014. Saha S, Chadha M, Al Mamun A, Rahman M, Sturm-Ramirez K, Chittaganpitch M, et al. Influenza seasonality and vaccination timing in tropical and subtropical areas of southern and south-eastern Asia. Bull World Health Organ 2014;92:318–30. Simmerman JM, Uyeki TM. The burden of influenza in East and South-East Asia: A review of the English language literature. Influenza Other Respi Viruses 2008;2:81–92. Chiu SS, Lau YL, Chan KH, Sang WH, Peiris JM. Influenza-related hospitalizations among children in Hong Kong. N Engl J Med 2002;347:493–501. van Noort SP, Codeço CT, Koppeschaar CE, van Ranst M, Paolotti D, Gomes MGM. Ten-year performance of Influenzanet: ILI time series, risks, vaccine effects, and careseeking behaviour. Epidemics 2015;13:28–36. Nguyen DT, Bryant JE, Davis C, Loth L, Nguyen L V, Inui K, et al. Prevalence and Distribution of Avian Influenza A ( H5N1 ) Virus Clade Variants in Live Bird Markets of Vietnam , 2011 – 2013. Avian Dis 2014;58:2011–3. FAO. EMPRES Animal Health 360. Empres Heal 360 2014;44:Rome. Ott JJ, Klein Breteler J, Tam JS, Hutubessy RCW, Jit M, de Boer MR. Influenza vaccines in low and middle income countries: a systematic review of economic evaluations. Hum Vaccin Immunother 2013;9:1500–11. 27

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[21] [22] [23] [24] [25] [26] [27] Praditsuwan R. The efficacy and effectiveness of influenza vaccination among Thai elderly persons living in the community. J Med Assoc Thail 2005;88:256–64. Gupta V, Dawood FS, Muangchana C, Lan PT, Xeuatvongsa A, Sovann L, et al. Influenza Vaccination Guidelines and Vaccine Sales in Southeast Asia: 2008-2011. PLoS One 2012;7:2008–11. Horby P, Mai LQ, Fox A, Thai PQ, Thi Thu Yen N, Thanh LT, et al. Epidemiology of Interpandemic and Pandemic Influenza in Vietnam, 2007-2010. Am J Epidemiol 2012;175:1062–74. Cauchemez S, Horby P, Fox A, Mai LQ, Thanh LT, Thai PQ, et al. Influenza Infection Rates, Measurement Errors and the Interpretation of Paired Serology. PLoS Pathog 2012;8. Fox A, Quynh L, Thi L, Nguyen L, Hoa M, Bryant JE, et al. Hemagglutination inhibiting antibodies and protection against seasonal and pandemic influenza infection. J Infect 2014. Fonville JM, Wilks SH, James SL, Fox a., Ventresca M, Aban M, et al. Antibody landscapes after influenza virus infection or vaccination. Science (80- ) 2014;346:996– 1000. GDPM GD of PM. Joint Annual Health Review, 2013: Towards Universal Health Coverage. Hanoi, Vietnam: 2013.

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

ANNEX 1 Sustainability Element Lead agency or organization Status Currently exists In progress Does not exist Is this a challenge in your specific context? Yes No Comment

Policy environment and health-care system (government representatives are expected to have the information required below) Political will for in-country influenza vaccine manufacture Political will for pandemic influenza preparedness International influenza recommendations to shape national policies Coherence among relevant national health policies and programmes Seasonal influenza vaccination and control policies developed as means to sustain pandemic preparedness and national security Target groups for seasonal influenza immunization established, and part of the immunization policy Price of the vaccine not a barrier for the government to provide it free to target groups Vaccine delivery infrastructure in place and maintained Efforts made to overcome possible bureaucratic obstacles to establish vaccine manufacturing National and regional procurement and distribution policies to promote in-country production and sourcing of materials Vaccine distribution system in place and efficient Vaccine available at the hospital, health-care centre and pharmacy levels Policies created to generate a skilled local workforce for local vaccine production Policies created to influence the development and size of the good manufacturing process (GMP) biomanufacturing environment Target groups for pandemic influenza immunization established and part of the pandemic preparedness plan Understanding of how multilateral and bilateral agreements affect commercialization and import and export of products

Sustainability Element

Lead agency or organization

Status Currently exists In progress Does not exist

Is this a challenge in your specific context? Yes No

Comment

Influenza-specific evidence (government representatives are expected to have the information required below) Surveillance system for virological surveillance in place (sentinel cites, technology and human resources) Accurate and timely surveillance reporting Design of data collection driven by surveillance objectives Annual surveillance reports with risk-factor data produced Data aggregated and reported on international data sharing platforms Burden of influenza known in the country Cost-effectiveness of seasonal influenza vaccine in target groups known Data on impact of influenza expressed in a way that resonates with priorities of policies makers Product development and manufacturing (this section is answered by local manufacturers) Business plan based on analysis of production costs, price of product and return on investment Reliable and stable supply of utilities A proportion of the revenues is planned to be re-invested in research and development Reliable supply chain for all components Technologies selected based on cost–benefit analysis of initial investment, operating costs, time to market and product approval More than one product manufactured in the vaccine manufacturing facility Access to and retention of skilled workforce Complies with and is certified for good manufacturing practice (GMP) In-house skills to design and administer clinical trials for vaccine production System in place at the manufacturing or governmental level to monitor adverse events after product commercialization

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

Sustainability Element Animal facility for the conduction of preclinical studies is available and under good laboratory practice (GLP) Partnerships with public or private entities to acquire know-how and technology, conduct clinical trials, conduct post marketing surveillance, distribute the product, etc. Participation in manufacturers’ networks or associations for advocacy, exchange experiences, training, etc.

Lead agency or organization

Status Currently exists In progress Does not exist

Is this a challenge in your specific context? Yes No

Comment

Product approval and regulations (this section is answered by representatives of the national regulatory authority) National Regulatory Authority (NRA) “functional” in WHO prequalification terms Effective working relation between manufacturers and NRA Manufacturer’s full awareness of regulatory requirements for the product in the country Manufacturer’s full awareness of the requirements to submit a dossier for WHO prequalification Regional regulatory approvals harmonized and integrated Communication for influenza vaccination (government representatives are expected to have the information required below) Key functions established and strong relationships among stakeholders with a public communication role Well-trained and skilled communication staff Operational research and metrics for influenza communication outcomes Mechanisms for ongoing listening and feedback to update communication strategies and tactics Integrated communication strategy with other policies (with clear behavioural objectives for priority groups) Routine use of sound communication methodologies, tools and scientific expertise Regular evaluation of public campaigns and feedback to stakeholders Awareness among the public and health-care workers of the benefits of seasonal influenza vaccination

ANNEX 2 Selected additional planning documents of relevance to influenza disease control and prevention The Vietnam national strategy on preventive medicine to 2010 and orientations towards 2020 (Decision 225/2006- QĐ-TTG) Health sector plans Health Master Plan for the period 2016-2030 with a vision to 2050 (forthcoming) National Program on occupational health (Decision 05/2016/QĐ-TTg) Vietnam Integrated National Operational Program on Avian Influenza, Pandemic Preparedness and Emerging Infectious Diseases (AIPED), 2011-2015. Partnership on Avian and Human Pandemic Influenza Guidelines for coordinated prevention and control of zoonotic diseases (Interministerial Circular No. 16/2013/TTLT-BYT-BNN&PTNT) National One Health Roadmap Zoonoses National HPAI Plan National Agriculture sector plan for avian influenza prevention and control National plan on prevention and control of avian influenza H5N1 (438/QDBNNTY) Action Plan for emergency response to influenza viral strains capable of causing human disease Action plan for preventing and controlling avian influenza A/H7N9 (No 1126 /QĐ-BYT) Circular No. 47/2007/QD-BYT. On the application of GMP principles and standards, GLP practice principles, Good storage practice principles and Good distribution practice to establishments that manufacture, test, trade in, distribute, import, export, stockpile and store vaccines and medical biologicals Circular No. 45/2011/TT-BYT. Amending and revising the previous 2007 document Guidance on Clinical Trial of Influenza Vaccine; Hanoi, Vietnam, Administration of Science Technology and Training Circular No.: 03/2012/TT-BYT. Guiding Clinical Drug Trial Circular No. 44/2014//TT-BYT. On Drug Registration 2010-20 2016-30 2016-20 2011-2015 2013 2015-2016 2013-2017 2014-2018 2014-2018 2014 2013

2007 2011 2013 2012 2014 2008 2013 2013 2013 2014 2016 2015 2016

Decision #3100/2008-QĐ-BYT. On the organization and Operation of National Institute for Control of Vaccine and Biologicals Decision No.: 3861/QĐ - BYT. Stipulating functions, tasks, powers and organizational structure of the Drug Administration of Viet Nam The Plan for Development and Use of Influenza Vaccines, Period of 2012-2020; vision up to 2030. (GDPM 2013 Vision document) Guidelines for registration of influenza vaccine. (Approved by Decision No. 38/QD-QLD dated 12 March 2013) Decision No. 2682/ QD-BKHCN. On approval the project of science and technology for developing national product initiated since 2015. [Establishes IVAC influenza vaccines as National Product] Decision 827/QD-BYT on issuing plan on prevention of infectious disease in 2016 Surveillance Guidelines on the surveillance of Severe Acute Respiratory Infections Standard operating procedure for Risk Communications for Public Health Communications Emergencies, GDPM

National Regulatory System

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

ANNEX 3 Vaccines licensed for use in Vietnam, and available through 'fee for services' at vaccination centers, 2016. (source, NICVB) Antigen(s) Meningococcus Diphtheria, Tetanus, acellular Pertussis, Hepatitis B, Haemophilus influenzae type b (Hib), IPV Diphtheria, Tetanus, acellular Pertussis, IPV, Haemophilus influenzae Type B (Hib) Diphtheria, Tetanus, Pertussis, Hepatitis B recombinant and Haemophilus influenzae type b (Hib) Diphtheria, Tetanus, Pertussis Diphteria, Tetanus, acellular Pertussis, IPV Haemophilus influenzae type b Tetanus Vaccine name VA-MENGOCBC Meningococcal A+C Infanrix hexaTM Notes Neisseria meningitis serogroups B + C, purified capsular polysaccharide; 0,01 % Thiomersal Neisseria meningitis serogroups A + C, polysaccharide Manufacturer FINLAY InstituteCuba Sanofi Pasteur S.AFrance GlaxoSmithKline Biologicals S.A

Pentaxim

Sanofi Pasteur S.AFrance

Quinvaxem*

Berna Biotech

Adacel TETRAXIM Quimi-Hib TETAVAX Tetanus antitoxin Streptococcus pneumoniae serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B,17F, 18C, 19A, 19F, 20, 22F, 23F, 33F (25 ug/ea) Salmonella enterica serovar Typhi, cell surface Vi polysaccharide, Ty2 strain Quadrivalent: types 6, 11, 16 & 18 Bivalent: types 16 & 18 inactivated, GBM strain grown on MRC5 Virsomal. Hepatitis A virus (RGSB strain), and influenza hemagglutinin (A/Singapore/6/86; H1N1)

Sanofi Pasteur S.AFrance Sanofi Pasteur S.AFrance Center for Genetic Engineering - Cuba Sanofi Pasteur S.AFrance Sanofi Pasteur S.AFrance

Strepococcus pneumonia, 23 serotypes

Pneumo 23

Salmonella

TYPHIM Vi GARDASILTM CervarixTM AVAXIM 80U, 160U Epaxal

Sanofi Pasteur S.AFrance MSD GlaxoSmithKline Biologicals S.A Sanofi Pasteur S.AFrance Berna Biotech

Human papillomavirus (HPV) Hepatitis A Hepatitis A & influenza A (H1)

Antigen(s)

Vaccine name Gene-Hbvax* Euvax B

Notes

Manufacturer Vabiotech, Vietnam LG - Sanofi Pasteur FINLAY InstituteCuba Berna Biotech GlaxoSmithKline Biologicals S.A GlaxoSmithKline Biologicals S.A

Hepatitis B

Heberbiovac HepavaxGen TF Engerix B Recombinant, Thiormersal-Free Recombinant absorbed antigen, prefilled syringe

Hepatis A and B

Twinrix TM MMRII Priorix live attenuated Measles Schwarz Strain, Mumps Jeryl Lynn Strain, Rubella Wistar Ra 27 3 Strain single dose and 10 dose Measles Schwarz Strain, Mumps Jeryl Lynn Strain, Rubella Wistar Ra 27 3 Strain

MSD GlaxoSmithKline Biologicals S.A Sanofi Pasteur S.AFrance Sevapharma -Séc

Measles, Mumps, and Rubella

ROR (Trimovax) Trivivac Rubella Ấn Độ Rubella Croatia

Rubella

Human Biological Ấn Độ Sevapharma –Séc Mumps virus, live attenuated, lyophilized Rabies virus (WISTAR strain PM/WI 38-1503-3M) produced on VERO cell line, inactivated arid purified, lyophilized Rabies Virus (L.Pasteur 2061) grown on Vero, inactivated with beta-propiolactone. Thiomersol @ 0.01% Inactivated, strain Flury LEP Inactivated, grown in embryonated duck eggs Varicella zoster virus, attentuated, OKA strain Varicella zoster virus, live attentuated, OKA strain, grown on MRC cells Varicella zoster virus, live attenuated MAV/06 strain, lyophilized Sevapharma -Séc Sanofi Pasteur S.AFrance

Mumps

Pavivac

Veorab

Rabies virus

Âhayrab

Human Biological Ấn Độ

Rabipur Lysavac N Varilrix Okavax

Chiron Behring Italia Cadila Ấn Độ GlaxoSmithKline Biologicals S.A Biken -Sanofi Pasteur Green Cross Corp., Rep. Korea

Varicella

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

Antigen(s)

Vaccine name Rotavin

Notes live, oral, pentavalent; indicated for prevention of G1, G2, G3, G4; 3 dose series for infects 6-32 weeks live, oral: indicated for genotypes G1, G3, G4 & G9 live attenuated 17D-204, grown in embryonated chicken eggs Inactivated Type 1 (Mahoney), Type 2 (MEF1) and Type 3 (Saukett) grown on Vero, inactivated by formaldehyde Inactivated, suckling-mouse derived, requires 3 shots Inactivated, Nakayama strain, genotype III Inactivated trivalent, split virion Inactivated, trivalent or quadrivalent, split viron Inactivated, trivalent, sub-unit

Manufacturer Polyvac, Vietnam MSD

Rotavirus

Rotateq Rotarix

Yellow fever

Stamaril

GlaxoSmithKline Biologicals S.A Sanofi Pasteur S.AFrance Sanofi Pasteur S.AFrance

Polio

Imovax Polio

Jevax* Japanese Encephalitis Japanese Encephalitis Vaxigrip Influenza Fluarix Influvac

Vabiotech, Vietnam Green Cross Corp., Rep. Korea Sanofi Pasteur S.AFrance GlaxoSmithKline Biologicals S.A Abbott

*These vaccines are used within EPI programs, but are also available through fee-for-services at immunization centers.

ANNEX 4 List of interviewees and stakeholders who participated in the assessment survey and roundtable discussions Name Dr Le Thi Tuyet Lan Mr Ha Hoang Phuong MsTran Thi Minh Giang Dr Pham Van Hung Dr Nguyen Hoang Tung Ms Kim Linh Ms Nguyen Thi Ly Ms Luu Thi Dung Ms Le Thi Hoi Yen Mr Kim Bach Ms Nguyen Thi Hoa Dr Trinh Xuan Tung Title Secretary of NRA office, NRA Drug Quality Management Div Drug Business Management Vice-Director of NICVB - NRA Head of Quality Management Systems Staff of Departments of QM, QC, Viral Vaccine, and Reference Standards Division of Vaccine and Laboratory Testing Management Vice-Director Genaral Department Preventive Medicine (GDPM) Administration of Science Technology Training (ASTT) Administration of Science Technology Training (ASTT) Ministry of Health, Department of Health Insurance Ministry of Health, Division of Health Policy - Finance and Planning Department Ministry of Health, Finance and Planning Department NIHE NIHE, National Influenza Centre NIHE, NEPI group Agency Drug Administration of Vietnam (DAV), NRA DAV NICVB NICVB

Dr Nguyen Ngo Quang

Dr Hoang Hoa Son

Head, Division for Clinical Trials, management of ASTT- NRA General Director

Dr Tong Thi Song Huong

Dr Hoang Ha

Head

Dr Le Thanh Cong Dr Nguyen Cong Sinh Dr Dang Duc Anh Dr Le Quynh Mai Dr Duong Thi Hong Dr Pham Quang Thai

Deputy Director Vice-Director Director Vice-Director Deputy Director Division of Epidemiology

Key elements for the sustainable production of influenza vaccine in Brazil in the framework of the Global Action Plan for influenza vaccines

Name Dr Le Van Be Dr Duong Huu Thai Dr Nguyen Thi Lan Phuong Dr Do Tuan Dat Mr Trinh Tuan Viet Dr Nguyen Dang Hien Ms Huong Dr Jeff McFarland Mr David Payne Ms Trang Tran Dao Dr Vu Minh Huong Dr Nguyen Tuyet Nga Mr Nguyen vu Cuong Ms Mona Byrkit Dr Trinh Dinh Thau Ms Carmen Amelia Rodriguez Hernandez Mr Emmanuel Eraly Ms Dorothy Leab

Title Director Head of Production Head of QC/QA Director Head of Production; Head of QC/QA Director Head of QC/QA Influenza focal point Secretariat Director Program Manager BARDA project Dean, Faculty of Veterinary Medicine Prequalification team - Vaccines Assessment Technical officer, Health Information and Technology Director

Agency IVAC

VABIOTECH

POLYVAC USCDC One Health Partnership office PATH

Vietnam National University of Agriculture WHO Geneva WHO country office Agence Medicale Preventative/ GaneshAID

Key facts

Organisation World Health Organization (WHO)

Document type Technical Documents

Adoption date January 25, 2017

Source World Health Organization