Vaccine safety messages (frequency of AEFIs): World Health Organization vaccine safety supporting document

How was this document developed? This document is part of a WHO series of supporting documents concerning events that could erode confidence in vaccination. Such events can be related to vaccine safety, adverse events following immunization, changes in the vaccination programme, negative public debate, outbreaks or pandemics. All documents were developed based on scientific evidence, laboratory research and fieldwork within psychology, social and behavioural science and communication and lessons learnt in countries. For an introduction to the theoretical background and evidence, refer to the WHO publication Vaccination and trust, available here: www.euro.who.int/ vaccinetrust. The supporting documents are intended for use by national • ministries of health • centers for disease control • immunization programmes • regulatory authority institutions. How to use this document This document presents key messages concerning vaccine safety and adverse events following immunization (AEFI) and includes supporting facts for each message. The document was developed based on the WHO Global Manual on Surveillance of Adverse Events Following Immunization, 2014, and the WHO Vaccine Safety Basics Learning Manual, 2013. You can refer to these materials for more information. Use the messages when asked about the safety of vaccines and to prepare for interviews or meetings with key stakeholders. World Health Organization vaccine safety supporting document Vaccine safety messages (frequency of AEFIs) EVENTS CAUSED BY REACTIONS TO THE VACCINE CONSTITUENTS EVENTS CAUSED BY AN ERROR EVENTS CAUSED BY OTHER FACTORS Below you will find suggested messages related to each of these kinds of AEFIs. Some supporting facts and data are also provided in tables. Reactions caused by the inherent properties of the vaccine product. Reactions caused by a quality defect in the vaccine. Inappropriate vaccine handling, prescribing or administration of the vaccine. Anxiety-related reaction. Coincidental event. Vaccine safety messages What kind of events can happen after vaccination? There are five categories of Adverse Events Following Immunization (AEFI): TIP If you would like to learn more about AEFIs, refer to • WHO Global Manual on Surveillance of Ad- verse Events Following Immunization, 2014: http://www.who.int/vaccine_safety/publica- tions/aefi_surveillance/en/. • WHO Vaccine Safety Basics Learning Manual, 2013: English: http://www.who.int/vaccine_safety/ initiative/tech_support/ebasic/en/ Russian: http://ru.vaccine-safety-training.org. TIP To know more about potential reactions caused by the vaccine product, refer to the WHO vaccine in- formation sheets posted here: http://www.who.int/ vaccine_safety/initiative/tools/vaccinfosheets/en/. The info sheets provide a summary of the vaccine products in common use, and the rates of mild and severe adverse events (local and systemic) following immunization. 1 2 3 4 5 1 Avoiding errors • In our country, great effort is invested in ensuring that error-related reactions do not happen. • Most error-related reactions can be avoided by proper planning and preparedness of pro- gramme managers and vaccinators. • Actions taken to avoid errors include the following. • Vaccinators are trained and closely supervised – so that they are equipped to store, handle, reconstitute and administer vaccines correctly. • The cold chain is maintained at all levels. • Only diluents supplied by the manu- facturer are used. • Vaccines are not stored together with other medicines or substances (other than diluents). • Vaccinators make sure that the vacinee is fit to be vaccinated (i.e. no contraindi- cations). • Proper syringes must be used. The use of syringes that can only be used once (auto-disable syringes) minimizes the risk of infection. • Any serious or unexpectedly severe AEFI is immediately and meticulously investigated to identify the cause and to correct practices accordingly. Messages concerning events caused by an error Error-related events • Error-related events are by nature preventable. • Some error-related events are serious, some are minor and temporaly. (Table 5) Vaccine regulations • Vaccines are safe, no matter which country they are produced in. • Some vaccines are slightly more reactogenic than others. But vaccines are highly regu- lated and considered safe. • Vaccine regulation includes a range of func- tions that cover the entire process from vac- cine development through licensure to use. • Before licensure, vaccines undergo exten- sive testing and review for safety, immu- nogenicity and efficacy in the laboratory, in animals and in three phases of clinical trials in human subjects. • Monitoring adverse vaccine reactions is a major safety component of pre-licensure clinical trials. (Table 3) • Even after the vaccine has been approved, safety monitoring continues. (Table 4) • In addition, WHO’s Global Advisory Committee on Vaccine Safety (GACVS) regularly reviews the safety of vaccines. Messages concerning events caused by reactions to the vaccine constituents Vaccine reactions • Most vaccine reactions are minor and temporary, such as a sore arm or mild fever. • Any serious injury or death caused by a vaccine is a tragedy. Fortunately, such events are extremely rare. (Table 1) • The dangers of vaccine-preventable diseases are far greater than any risks associated with vaccines. (Table 2) 2 A reaction can be strictly coincidental • Vaccinations are often scheduled in infancy and childhood, when other illnesses are common, or to protect the fragile health of older adults. • Taking into account normal incidence of disease and death in these age groups, such unfortunate events will sometimes happen shortly after vaccination. (Table 6) This becomes especially evident during a mass campaign when many people are vaccinated. • At first sight, the public and media, and maybe even health care workers, may see a causal link between the vaccine and the event, even when such a link does not exist. • In our country, any serious or unexpectedly severe adverse event following immunization is immediately and meticulously investigated to determine whether it was caused by the vaccine or simply an unfortunate coinciden- tal event. Messages concerning events caused by other factors Being vaccinated can cause an anxiety-related reaction • In anticipation of or as a result of any injection, individuals can experience fear or anxiety-related reactions. These can in- clude symptoms such as fainting, hyperven- tilation, vomiting, convulsions, dizziness and headache. • These are common and well-known reactions to fear of the injection and are not related to the vaccine itself. 3 Message: Very serious events following immunization are extremely rare Table 1: Frequency of vaccine adverse reactions of commonly used vaccines DTP VACCINES SUMMARY VACCINE ADVERSE REACTIONS Whole cell Pertussis vaccines • Fever 37.8°C - 38.9°C • Injection site Redness • Swelling • Pain (Severe-Moderate) • Fussiness (Severe-Moderate) • Drowsiness • Anorexia • Vomiting • Persistent screaming • Hypotonic-hyporesponsive episode (HHE) • Seizures • Encephalopathy • Anaphylaxis FREQUENCY CATEGORY Very common Very common Very common Very common Very common Very common Very common Common Uncommon to Rare Very rare Very rare Very rare A cellullar Pertussis vaccines • Fever 37.8°C - 38.9°C • Injection site Redness • Injectionsite swelling • Pain (Severe-Moderate) • Fussiness (Severe-Moderate) • Drowsiness • Anorexia • Vomiting • Persistent screaming • HHE • Seizures Common Common to Very common Common to Very common Uncommon to Common Common to Very common Very Common Very Common Very Common Uncommon Rare Very rare ROTAVIRUS VACCINES SUMMARY VACCINE ADVERSE REACTIONS • Intussusception FREQUENCY CATEGORY Very rare HIB VACCINES SUMMARY VACCINE ADVERSE REACTIONS • Fever • Injection site reaction FREQUENCY CATEGORY Common Very common RUBELLA VACCINES SUMMARY VACCINE ADVERSE REACTIONS • Fever • Injection site reaction • Acute Arthralgia (adults) • Acute Arthritis (adults) FREQUENCY CATEGORY Common Very common Very common Very common MUMPS VACCINES SUMMARY VACCINE ADVERSE REACTIONS • Injection site reaction • Parotid swelling • Aseptic meningitis FREQUENCY CATEGORY Very common Common Very common 4 MEASLES VACCINES SUMMARY VACCINE ADVERSE REACTIONS • Fever • Rash • Injection site reaction • Febrile seizures • Encephalomyelitis • Thrombocytopenia • Anaphylaxis FREQUENCY CATEGORY Common to Very common Common Very common Rare Very rare Very rare Very rare BCG VACCINE SUMMARY VACCINE ADVERSE REACTIONS • Injection site reaction (Papule, mild ulceration orscar) • Suppurative lymphadenitis • BCG osteitis • Disseminated BCG disease or systemic BCG-itis • Immunine Reconstitution Inflammatory Syndrome (IRIS) FREQUENCY CATEGORY Very common Uncommon to Rare Uncommon to Very rare Very Rare Very Rare Table 1 – continued HEPATITIS B VACCINES SUMMARY VACCINE ADVERSE REACTIONS • Fever • Headache • Injection site pain • Injection site redness • Injection site swelling • Anaphylaxis FREQUENCY CATEGORY Common Common Common to Very common Common Common Very rare HUMAN PAPILOMA VACCINES (HPV) SUMMARY VACCINE ADVERSE REACTIONS Bivalent HPV Vaccine • Fever • Headache • Injection site pain • Redness • Swelling • Rash • Arthralgia • Myalgia • Fatigue • Gastrointestinal disorders FREQUENCY CATEGORY Common Very common Very common Very common Very common Uncommon Very common Very common Very common Very common Quadrivalent HPV Vaccine • Fever 37.8°C - 38.9°C • Injection site Redness • Injectionsite swelling • Pain (Severe-Moderate) • Fussiness (Severe-Moderate) • Drowsiness • Anorexia • Vomiting • Persistent screaming • HHE • Seizures Very Common Common Common Common Common Common Common Common Common Very common Very rare TETANUS VACCINES SUMMARY VACCINE ADVERSE REACTIONS • Brachial neuritis • Anaphylaxis FREQUENCY CATEGORY Very rare Very rare KEY Very common > 1/10 > 10% Common > 1/100 and < 1/10 > 1% and < 10% Uncommon > 1/1000 and < 1/100 > 0.1% and < 1% Rare > 1/10 000 and < 1/1000 > 0.01% and < 0.1% Very rare < 1/10 000 < 0.01% VARICELLA VACCINES SUMMARY VACCINE ADVERSE REACTIONS • Febrile seizures • Fever > 39ºC • Injection site reaction • Site rash (local/generalized FREQUENCY CATEGORY Rare Very Common Common to Very Common Common POLIO VACCINES SUMMARY VACCINE ADVERSE REACTIONS Whole cell Pertussis vaccines • Vaccine – associated paralytic paralysis (VAPP) – Recipient VAPP – Total VAPP FREQUENCY CATEGORY Very Rare Very Rare Inactivated Polio Vaccine (IPV) • Injection site erythema • Injection site induration • Injection site tenderness Uncommon to Common Common to Very common Very Common Conjugated vaccine (PCV) • Fever > 39ºC • Injection site reaction Uncommon Very common PNEUMOCOCCAL VACCINES SUMMARY VACCINE ADVERSE REACTIONS Unconjugated vaccine (PPSV) • Fever > 39ºC • Injection site reaction FREQUENCY CATEGORY Uncommon Very common YELLOW FEVER VACCINES SUMMARY VACCINE ADVERSE REACTIONS • Vaccine-associated viscerotropic disease FREQUENCY CATEGORY Very rare Source: WHO Global Manual on Adverse Events Following Immunization, 2014. 5 Message: The dangers of vaccine-preventable diseases are far greater than any risks associated with vaccines. Message: Vaccines undergo extensive testing and review before licensure Clinical Trial Phase I Clinical Trial Phase II Clinical Trial Phase III Submission Introduction ACTIVITY Test the safety and immunogenicity of a vaccine candidate in a few low-risk individuals (usually healthy adults) to determine tolerability. Monitor safety, potential side effects, immune response, and determine optimum dosage and schedule. Address clinical efficacy in disease prevention and provide further safety information from more heterogeneous populations and longer times of observation. The vaccine application is submitted to regulatory authorities for approval to market. Involves making the vaccine available for use. SAMPLE SIZE (ESTIMATES) 10 – 100 100 – 1000 1000 – 10 000 — — Table 3: The process of clinical trials and assessment of vaccine safety a. Risks after natural measles are calculated in terms of events per number of cases. b. Risks after vaccination are calculated in terms of events per number of doses. c. Although there have been several reports of thrombocytopenia occuring after measles including bleeding, the risk has not been property quantified. d. This risk has been reported after measles – mumps – rubella (MMR) vaccination and cannot be only attributed to the measles component. Source: WHO Vaccine Safety Basics Learning Manual, 2013, adopted from P. Duclos, BJ Ward. Measles Vaccines, A Review of Adverse Events, Drug Safety 1998; Dec 19 (6): 435-454. Death Post-infectious encephalomyelitis (inflammation of the brain and spinal cord) Subacute sclerosing panencephalitis (chronic brain inflammation) Pneumonia Otitis (middle ear infection) Diarrhoea Anaphylaxis (serious allergic reaction) Thrombocytopenia (deficiency of platelets in the blood) MEASLES INFECTION (A) 0.1 – 1/1000 (up to 5 – 15%) 0.5/1000 1/100 000 1 – 6% 7 – 9% 6% 0 Not properly quantified (c) MEASLES VACCINE (B) 0 1/100 000–million 0 0 0 0 1/100 000–million 1/30 000 (d) Table 2: Serious health risks following infection vs following vaccination Source: WHO Vaccine Safety Basics Learning Manual, 2013. 6 Message: After the vaccine has been approved, monitoring continues Message: Some error-related events are serious, some are mild and temporary Table 4: Surveillance used to monitor the safety of vaccines after licensing Reporting from health care workers and patients Clinical trials Surveillance studies Linked databases Clinical centres Spontaneous reporting from health care workers is the cornerstone of most post-licensure safety monitoring systems because of its ability to capture unexpected events. Vaccines may undergo clinical trials after licensure to assess the effects of changes in vaccine formulation, vaccine strain, age at vaccination, number and timing of vaccine doses, simultaneous administration and interchangeability of vaccines from different manufacturers on vaccine safety and immunogenicity. To improve the ability to detect adverse events that are not detected during pre-licensure trials, some recently licensed vaccines in developed countries have undergone formal surveillance studies, involving cohorts as large as 100 000 and lasting four to six years. Large linked databases (LLDBs) are large administrative databases from defined populations that are linked to enable the sharing of data across platforms. These databases have become useful to vaccine safety surveil- lance: covering populations numbering from thousands to millions, they can detect very rare adverse events. Several clinics work to monitor immunization safety; address the gaps in scientific knowledge about rare and serious events following immunization; and conduct research e.g. on immunization-associated health risks; immunization-associated health risks and vaccine adverse events and the role of individual variation. Source: WHO Vaccine Safety Basics Learning Manual, 2013. IMMUNIZATION ERROR NON-STERILE INJECTION • Reuse of disposable syringe or needle leading to contamination of the vial, especially in multi-dose vials • Improperly sterilized syringe or needle • Contaminated vaccine or diluent RECONSTITUTION ERROR • Inadequate shaking of vaccine • Reconstitution with incorrect diluent • Drug substituted for vaccine or diluent • Reuse of reconstituted vaccine at subsequent session INJECTION AT INCORRECT SITE • BCG given subcutaneously • DTP/DT/TT too superficial • Injection into buttocks Vaccine transported/stored incorrectly Contraindication ignored POSSIBLE AEFI • Local injection site reactions (e.g., abscess, swelling, cellulitis, induration) • Sepsis • Toxic shock syndrome • Blood-borne transmission of disease, e.g., hepatitis B, HIV • Death • Local abcess • Vaccine ineffective (not strictly an AEFI, but a vaccine failure) • Effect of drug, e.g., insulin, oxytocin, muscle relaxants • Toxic shock syndrome • Death • Local reaction or abscess or other local reaction • Local reaction or abscess or other local reaction • Sciatic nerve damage • Increased local reaction from frozen vaccine • Ineffective vaccine (vaccine failure) • Avoidable severe reaction Source: WHO Vaccine Safety Basics Learning Manual, 2013. Table 5: Examples of immunization errors and possible AEFIs 7 COUNTRY Australia Cambodia China Japan Laos New Zealand Philippines NUMBER OF BIRTHS PER YEAR (N) 267 000 361 000 18 134 000 1 034 000 170 000 58 000 2 236 000 Week after immunization =(IMR×N/52)×nv×ppv 69 1293 16 948 161 424 15 3019 INFANT MORTALITY RATE PER 1000 LIVE BIRTHS (IMR) 5 69 18 3 48 5 26 Month after immunization =(IMRxN/12)×nv×ppv 300 5605 73 443 698 1836 65 13 081 Day after immunization =(IMR×N/365)×nv×ppv 10 185 2421 23 61 2 431 Table 6: Example of expected coincidental deaths following DTP vaccination (selected countries) Note: Assumes uniform distribution of deaths and children who are near to death will still be immunized. nv = number of immunization doses: assumed here to be three dose schedule; 3. ppv= proportion of population vaccinated: assumed here to be 90% for each dose; 0.9. Source: Infant mortality and births from 2008 Immunization summary, WHO/UNICEF (The 2010 edition). NUMBER OF INFANT DEATH DURING YEAR IN Document number: WHO/EURO:2015-3384-43143-60406 © World Health Organization 2015 All rights reserved. This information material is intended for a limited audience only. It may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means. Message: Taking into account normal incidence of disease and death in the relevant age groups, coincidental events are inevitable when vaccinating 8