Global Vaccine Safety

Global Advisory Committee on Vaccine Safety,
15-16 June 2016

The Global Advisory Committee on Vaccine Safety (GACVS), an independent expert clinical and scientific advisory body, provides WHO with scientifically rigorous advice on vaccine safety issues of potential global importance.1 GACVS held its 34th meeting in Geneva, Switzerland, on 15–16 June 2016.2 The Committee examined 3 generic issues: (i) a new initiative to promote health product vigilance in low- and middle-income countries (LMICs); (ii) the harmonization of the definition of health events for pharmacovigilance studies in pregnancy and early childhood; and (iii) a proof-of-concept study to assess rare events through multi-country collaboration. The Committee also reviewed vaccine-specific safety issues on routine infant vaccination in India and initial post-licensure data related to dengue vaccine.

New initiative on health product vigilance

Access to novel medical products in LMICs is increasing. New treatments are available, or in preparation, for HIV/AIDS, tuberculosis and malaria. Likewise, vaccines targeting cervical cancer, diarrhoeal diseases and conditions that prevail mostly in LMIC, such as Ebola virus disease, dengue, epidemic meningitis and malaria, are at various stages of implementation in those countries.

The availability of post-licensure data is essential for local regulators as well as for public health programmes in developing strategies based on adequate benefit and risk analyses. For products that are used globally, safety data are usually available from high-income settings only, and differ from LMICs in terms of their health-care systems, health profiles and population demographics. While many LMICs participate as national centres in the WHO Programme for International Drug Monitoring (PIDM), their capacity to undertake data collection and contribute to the international database of drug safety may be limited. For example, with vaccines, 60% of the PIDM database comprises reports from some countries in Europe, and the USA, and this may not fully satisfy the needs of local authorities with limited capacity to analyse data and take necessary action.

The Bill & Melinda Gates Foundation (BMGF) has acknowledged the need to build pharmacovigilance capacity in LMICs. In 2013, the BMGF Safety Surveillance Working Group convened and highlighted the need to develop a strategy for post-marketing surveillance given the existing challenges.3 Their report called for leveraging existing scalable platforms (WHO PIDM and its network of national centres), using current standards for safety, and building on current harmonization platforms. The report also recommended devising a single system for both vaccines and medicines, with adjustments only when required.

The BMGF proposed support for the WHO Safety and Vigilance (SAV) team in implementing a strategy for LMICs that would include a regulators network to strengthen pharmacovigilance systems. This would involve continued work with other participants such as the GAVI Alliance (GAVI), UNICEF, PATH and sub-Saharan African regulatory agencies, as well as the engagement of industry to promote alignment between participants/agencies to support implementation as accountable license holders.

GAVI, meanwhile, has prioritized the monitoring of vaccine safety in its data strategy for 2020. The aims are to improve the ability to identify and investigate, to respond efficiently and effectively, and to address related public concerns. GAVI already funds a number of initiatives, partly through its grants for strengthening health systems for capacity-building in LMICs for the surveillance, investigation and management of adverse events following immunization (AEFI) and for the establishment of surveillance systems and the development of tools, guidelines and AEFI training. Surveillance which covers the safety of other drug products, including substandard and falsified drugs and vaccines, remains a specific challenge.

The BMGF, SAV and GAVI presented strategies and approaches relating to vaccine safety to GACVS. Additionally, GAVI set out its resourcing plans including funding for its Data Strategic Focus Area (SFA) and vaccine safety activities. Currently, GAVI Data SFA does not include enhanced investigation capacity and guidance on communication and response; this is an area that needs to be addressed.

GACVS acknowledged both the increased attention being given to the pharmacovigilance of drug products – especially to capacity-building in safety monitoring, and to the work of WHO SAV and its promotion of, and collaboration on, vigilance activities with public health programmes, and the response to safety concerns and international crises. The aims of the BMGF in its support for pharmacovigilance and vaccine safety were also recognized, and included capacity-building through country training supported by GAVI and WHO SAV – training that has recently focused on countries in sub-Saharan Africa. GACVS also identified the very different pharmacovigilance needs of vaccine products compared with other drug products, especially in LMICs where programme delivery of vaccines and drugs may vary and pose unique challenges. Merging is to be considered with caution, although lessons learned from vaccine vigilance could be applied to some of the unique drug product classes as outlined above.

GACVS welcomes future collaboration with, and contribution to, this endeavour as well as providing input to identified gaps and evolving priorities.

Serious AEFI during primary infant vaccination series in South India

India is currently using pentavalent (DwPT-HepB-Hib) vaccine from local manufacturers. The vaccination series is carried out nationwide via a stepwise introduction process initiated in December 2011. To accompany this effort and address safety concerns on the potential of AEFI, the Indian authorities, with INCLEN Trust International, conducted a prospective dynamic cohort study in 2 southern districts (Kollam, Kerala and Coimbatore, Tamil Nadu). This study evaluated the association between routine pentavalent and oral poliovirus (OPV) vaccination and all-cause deaths and hospitalizations (referred to as serious AEFI) among infants after receipt of each of the 3 doses of vaccine in the primary immunization schedule. The 2 districts were selected on the basis of their low infant mortality (reducing the background of coincidental events), high coverage with the primary vaccination series, well established use of pentavalent vaccine, and robust primary health-care infrastructure.

The primary study objective compared all-cause death and hospitalization rates at 0–7 days versus 22–28 days after each vaccine dose administered. Secondary objectives included comparing all-cause death and hospitalization between 8–14 days and 15–21 days versus 22–28 days after vaccination. For infants with a delayed second or third dose of vaccine, the risk of serious AEFI was estimated for the period to the following dose, or at 24 weeks of age, or death, whichever occurred first. Infants were enrolled at the time of their first dose of pentavalent and OPV vaccines and followed weekly until 4 weeks after their third dose of pentavalent vaccine. In addition to collecting information on illnesses, data were collected for subsequent hospitalizations and deaths through weekly contact with the infant’s family. The information was entered electronically at interview. An International Advisory Group provided technical input on the protocol and statistical plan, reviewed study progress during several field visits, and reviewed preliminary study findings. In addition to analysing the project as a cohort study, secondary analyses will also include a self-controlled case series. Implementation of the study occurred between September 2014 and May 2016. In total over 30 000 infants were enrolled and followed weekly until 4 weeks after the third dose of vaccine. Data collection is complete and data analysis is ongoing, with plans for publication.

GACVS acknowledged the quality of the study implementation, the completeness of the follow-up and the thorough and timely data collection system. The primary analysis showed no safety concerns. This study will help to better characterize factors associated with untoward events temporally related with vaccination early in life and will provide a robust empirical basis to illustrate the coincidental occurrence of serious AEFI and quantify the frequency with which those events can be expected.

Global Alignment of Immunization safety Assessment in pregnancy (GAIA) project

Vaccination during pregnancy offers mothers and their infants effective protection against infectious diseases. However, due to the heterogeneity in the definitions of terms used to assess vaccine safety, data collection methods and their presentation, comparing results across studies and settings presents challenges. Thus, the harmonization of terms, disease concepts and the use of standardized case definitions of key events related to safety monitoring of vaccines will facilitate comparability of outcomes across studies.

In 2014, WHO convened an expert consultation to a) review existing obstetrical and paediatric adverse event case definitions and guidance documents; b) prioritize terms for key events for continuous monitoring of vaccine safety in pregnancy; c) develop concept definitions for these events; and d) recommend a core data set of key terms of events to be collected when monitoring safety of vaccines used in pregnancy. The consultation also recommended developing a guidance document for data collection, analysis and presentation of safety data, tools for harmonized data collection, data sharing, and the use of health-care data sets to strengthen safety surveillance.

The Global Alignment of Immunization safety Assessment in pregnancy (GAIA) network was formed to help establish a global, common understanding of outcomes and approaches to monitoring safety of vaccines used in pregnancy with particular focus on LMICs. GAIA has prepared draft guidelines – “Guidelines for collection, analysis and presentation of safety data in clinical trials of vaccines in pregnant women” on prioritizing data to be collected in studies of the use of vaccines in pregnancy, and to assist their applicability in various geographical, cultural and resource settings, including LMICs. The intention is also to optimize the use of data obtained from participants in clinical trials by improving data accuracy and comparability.

The guidelines are intended for all entities involved in the planning, evaluation, and implementation of studies on vaccines used in pregnancy. However, they are not regulatory in nature, and are not intended to replace established or mandated processes of adverse event reporting. In their current form, applying all recommended standards may thus prove complex for some settings.

The guideline document emphasizes 5 aspects of data collection for pregnancy vaccine trials: (i) collection of background data; (ii) pre-vaccination screening data; (iii) vaccine- and immunization-related data; (iv) follow-up monitoring data (including birth-related and neonatal data); and (v) adverse event monitoring data (including maternal, fetal and infant). While it may not be practical to pre-define and solicit all possible clinical and laboratory outcomes, a core dataset should be collected in all vaccine trials in pregnancy, where feasible. Two levels of priority for data collection have been defined: priority 1– data considered important for the understanding of the trial results and/or required by national and/or international regulatory authorities; and priority 2 – data considered less important but helpful.

The guidelines prepared by GAIA were reviewed and discussed by the pregnancy subgroup of GACVS and at the IABS4 “Harmonized Safety Monitoring of Immunization in Pregnancy International Consensus Conference” in March 2016, following which they were revised. GACVS reviewed the revised version and agreed that a global concerted approach was needed towards harmonized safety data collection in vaccine trials in pregnancy.

The Committee considered the GAIA guidelines timely and useful and noted that they should provide for flexibility regarding core data collection requirements as data collection in certain settings may not be feasible. Challenges related to infrastructure, availability of background data, changes in background rates or clinical standards in various settings should also be acknowledged, including the fact that the presence of researchers will affect some pregnancy-related outcomes. GACVS also noted the possibility of updating these guidelines which may also be applicable for safety monitoring in the context of observational studies. Furthermore, to test and facilitate their implementation, the Committee stressed the need for field testing and review, the generation of practical tools for investigators, capacity-building/training and a dissemination strategy.

Dengue vaccine update

GACVS last reviewed dengue vaccines in June 20155 and considered the Phase III clinical trial and long-term safety data of the tetravalent dengue vaccine CYD-TDV (Dengvaxia, manufactured by Sanofi Pasteur). Short-term safety surveillance of common adverse events demonstrated that the vaccine is well-tolerated. However, GACVS noted particular safety concerns related to the observed risk of hospitalized and severe dengue among children aged 2–5 years during the third year following vaccination. GACVS also recommended monitoring the risk of severe dengue among individuals of all ages who are seronegative prior to immunization, as well as among immunocompromised and older individuals (>45 years of age).

In April 2016, SAGE published recommendations indicating who would benefit most from CYD-TDV vaccination and issued guidelines for post-licensure surveillance.6 In particular, SAGE recommended that countries considered introducing CYD-TDV only in geographical settings (national or subnational) with high endemicity, as indicated by seroprevalence of approximately >70% in the age group targeted for vaccination or other suitable epidemiologic markers. Pregnancy remains a contraindication.

To date, although licenced in several countries, CYD-TDV has been introduced to the public vaccination programmes of one country alone – the Philippines. Here, CYD-TDV vaccination is administered as part of a school-based programme targeting 4th grade children (aged 9–10 years) in 3 highly endemic regions. The first child in the Philippines was vaccinated in April 2016. Currently, approximately 247 820 children are immunized, with a planned total cohort of about 750 000. In this cohort AEFI are monitored through enhanced passive surveillance. All serious AEFI are investigated promptly and reviewed by an independent expert committee. Thus far, 518 AEFIs have been reported including 21 serious AEFIs with 2 deaths. Those included 2 anxiety reactions and 4 cases classified as consistent with a causal association to the vaccine that recovered.

GACVS noted the commitment of the Government of the Philippines, the community and the vaccine and health-care providers in implementing the dengue vaccination programme. The Philippines, as the first country to introduce CYD-TDV vaccination, will thus provide critical post-licensure AEFI surveillance data that will benefit and inform the global community and other jurisdictions.

Representatives of Sanofi Pasteur, the manufacturer of the CYD-TDV vaccine Dengvaxia, gave a presentation to GACVS in which they addressed the longer-term follow-up of hospitalized dengue among Phase III clinical trial participants. With follow-up occurring after 4 years since the first dose of vaccine, no consistent increase was observed in the relative risk of hospitalization or severe dengue in vaccinated individuals aged 9–16 years. However in the younger age group of 2–8 years, an increased relative risk (RR>1, not reaching significance) was observed that declined after 3 years since the first dose. Dengvaxia is not licensed for children aged <9 years.="">

Following the introduction of dengue vaccination programmes, GACVS recommends robust, ongoing surveillance with particular emphasis on establishing disease and vaccination history. This requires allocating resources specifically to vaccination registries and ensuring that cases of hospitalized dengue are confirmed in accordance with established case definition. This may be feasible at sentinel sites only. Existing and planned clinical efficacy trials should be evaluated in depth and include careful assessment of pre-immunization seropositivity in selected cohorts. Data from these trials will contribute to a greater understanding of the potential risk factors and underlying immunology of dengue infection and severe dengue post-vaccination.

Proof-of-concept study through multi-country collaboration

In 2011 WHO and partners published the Global Vaccine Safety Blueprint7 with the aim of optimizing the safety of vaccines through the effective use of pharmacovigilance principles and methods. An aspect of this was to enhance the capacity for vaccine safety assessment beyond basic pharmacovigilance in LMICs. The Global Vaccine Safety Initiative, jointly with PAHO and VACCINE.GRID,8 and through the WHO Secretariat, tested the development of a global network of hospital-based sentinel sites for vaccine safety signal verification and hypothesis testing in LMICs.

A demonstration project was conducted to assess the feasibility, quality and potential for sustainability of a multi-country collaboration for the evaluation of rare vaccine adverse events. The process of setting up the collaboration and conducting a study along with preliminary results were presented to GACVS and complemented by the perspective from one participating institution. A total of 25 hospitals in 16 countries participated in the demonstration project. The project assessed the capacity of the network to verify the known association of measles-containing vaccines and idiopathic thrombocytopenic purpura (ITP) as well as aseptic meningitis associated with the mumps component of some measles/mumps/rubella (MMR) vaccines. The study sites offered training, either in person or by webinars, on the study protocol and study tools and procedures for data collection, local analysis and sharing to a central analysis hub through a secure portal. Case validation was retrospective, based on computer records or log book searches. Following validation, the pooled analysis identified the known ITP association with measles vaccine and the expected association of aseptic meningitis with some MMR vaccines.

GACVS recognized the effort required to successfully perform this complex study. The demonstration project contributed to the development of expertise at many sites involving interested physicians and nurses with GACVS focusing on the questions of sustainability and lessons learned. It is important that the site-specific experience in study implementation, and the collection of quality data, is documented; this will help the conduct of future studies of rare serious health events related to vaccines. In order to accomplish this, WHO must maintain contact with the sites and further communicate with their respective governments to demonstrate the value of this enhanced vaccine safety capacity. Integration of these capacities into the national vaccine pharmacovigilance system would ensure country ownership and sustainability. Sustainability also depends on future funding mechanisms, buy-in from the countries involved and whether there are relevant studies to be conducted. To maintain this expertise, one possibility discussed was to expand beyond vaccine safety to other relevant vaccine studies such as surveillance of vaccine preventable diseases. Following the publication of results from this collaboration, the next steps will be for further work to be carried out on sustainability and identifying relevant future projects

1 See No. 41, 1999, pp. 337–338.

2 GACVS invited additional experts to present and discuss evidence related to particular topics. These experts included persons affiliated with: Bill & Melinda Gates Foundation, Seattle WA, USA; GAVI Alliance, Geneva, Switzerland; INCLEN Trust International, New Delhi, India; Erasmus University, Rotterdam, The Netherland; P-95 Heverlee, Belgium; St George’s University, London, United Kingdom; Department of Health, Manila, The Philippines; Cincinnati Children’s Hospital Medical Center, Cincinnati OH, USA; and Sanofi Pasteur, Lyon, France.

3 Bill & Melinda Gates Foundation. A report of the safety surveillance working group. Available at:, accessed June 2016.

4 The International Alliance for Biological Standardization.

5 See No. 34, 2015, pp. 421–423.

6 See No. 21, 2016, pp. 282–284.

7 WHO Global Vaccine Safety Blueprint. Available at, accessed June 2016.

8 See