GACVS evaluates information from multiple sources to assess vaccine safety. Standardizing, where possible in order to facilitate the assessment process and increase efficiency, was one of the recommendations of the recent 15-year review of GACVS.²⁹ The Committee has developed guidelines and a presentation template for reviewing the safety profile of new vaccines. The objective of this guidance document is to provide, for presenters, a framework that includes the essential safety information that GACVS requires in order to make an assessment of vaccine safety. It is acknow-ledged that safety data and issues may be diverse, and that presentations may need to be adapted accordingly. It is also recognized that while such a template may guide the presentation of safety data, such a document is not intended to replace existing documentation (such as the International Conference on Harmonisation Guideline for Good Clinical Practice) which details how clinical trials should be performed and what safety data should be collected.

For guidance in developing the template document, a subcommittee of GACVS has considered previous presentations. These include documents from the Advisory Committee for Immunization Practice (Guidance for Health Economics Studies) and the Council for International Organizations of Medical Sciences (CIOMS Guide to Active Vaccine Safety Surveillance).

The draft template is divided into 7 sections. Section 1 addresses the presenters and any conflicts of interest, an overview of product development, and the product characteristics. Section 2 is an Integrated Summary of Safety. Section 3 addresses the pre-licensure clinical trials; if possible these should be presented as a meta-analysis or collated studies. If there are a limited number of key trials, detailed description can be presented. Details, for example, would then focus specifically on the methodology and results that have led to the safety conclusions reached. Limitations should be specified. Section 4 covers the methodology and results from post-licensure trials and/or surveillance studies. Section 5 should detail the limitations of the pre- and post-licensure trials/studies, and should then detail any identified or potential risks. Section 6 details plans for future post-marketing studies or pharmacovigilance activities that will be conducted and include a summary of the product Risk Management Plans if one was developed. The final section includes supporting material such as lists of references, product labels, etc.

An accompanying draft document proposes guidance for preparing the session. Presenters will be identified, and invited by the WHO GACVS Secretariat 12 weeks prior to the planned session. Presentations and supporting documentation will be required 8 weeks prior to the session to allow time for review and comment of drafts. This presentation material will be reviewed by the WHO Secretariat and a GACVS committee member who will subsequently chair the relevant session at the time of the GACVS meeting. The presentation will be reviewed and 6 weeks prior to presentation will be returned to the presenter for points of clarification and to address any outstanding issues. The final presentation is required by the WHO Secretariat 4 weeks prior to presentation so that it can be provided to the committee members well in advance for their review.

Comments from the Committee included a suggestion to separate information gained from pre-licensure studies from those obtained through post-licensure studies. Clarifications on the information needed for novel adjuvants and information to be displayed in integrated safety summaries versus information from individual trials were also requested. GACVS also noted that the template requirements will not be met if clinical trials are not designed to generate this information. In some past presentations reviewed by GACVS, a lack of critical information prevented the Committee from reaching a definite conclusion on safety issues. The template will therefore help GACVS highlight areas of missing evidence more systematically. A revised version of the template and accompanying document will be produced based on the discussion at this meeting, and will be posted on the GACVS website after final endorsement.

²⁹ Asturias EJ, Wharton M, Pless R et al. Contributions and challenges for worldwide vaccine safety: The Global Advisory Committee on Vaccine Safety at 15 years. Vaccine. 2016;34(29):3342–3349.

Full report of GACVS meeting of 7-8 June 2017, published in the WHO Weekly Epidemiological Record of 14 July 2017

The Global Advisory Committee on Vaccine Safety is mandated to conduct risk–benefit assessment for immunization policies and procedures under consideration by WHO Member States and the Strategic Advisory Group of Experts (SAGE). In 2014, a review was conducted by current and former members of GACVS3 to assess the role of the Committee on immunization policy and its impact on global vaccine safety. The review included a quantitative and qualitative examination of contributions and explored the extent to which GACVS has been influential. Future challenges of GACVS and its mandate were also considered.

The 2014 review documented the productivity and influence of GACVS in supporting global safety efforts, including the publication of more than 100 reports, as well as statements and guidelines issued to inform public policies and respond to safety concerns. Challenges identified included the, often limited, evidence available for scientific assessment, along with difficulties in requesting further research on a specific topic, the need to incorporate review systems, such as GRADE – aimed at assessing intervention effectiveness but not always well suited to post-marketing vaccine safety questions (which usually require consideration of valuable post-licensure data) – and the challenge to support countries with more limited capacity to identify and assess safety signals. Moreover, the confidentiality of some of the evidence presented to GACVS and the need for enhanced transparency of processes presented additional challenges in the reporting of its work. A survey conducted in preparation of the review suggested that the audience of GACVS needs to be better articulated and defined, thus highlighting the need for a defined communications strategy. This is particularly exemplified by safety concerns that have been resolved at the scientific and policy levels, but still require public communication since many stakeholders may not have been sufficiently informed of the available evidence.

In discussing the recommendations, the Committee focused on 3 key areas: i) the need to apply a more formal systematic review methodology to the work of GACVS; ii) the need to direct more attention to the dissemination of GACVS products to the regulators, programme managers and policy-makers of low- and middle-income countries; and iii) the role of GACVS as an advocate and facilitator in bridging gaps in vaccine safety capacity globally.

The Committee discussed key areas for enhancing the review process. These included the mechanisms and resources required to strengthen the evidence-based approach for the work of GACVS, the need to improve the quality of evidence presented to the Committee, and improvements in how the methodology and outcomes can be developed (including increased capacity in low- and middle-income countries), presented and published. Transparency would be enhanced without compromising proprietary information or unpublished work. For example, access to unpublished and confidential reviews performed by regulatory agencies and/or national immunization technical advisory committees (NITAGs), could be requested on a limited basis.

With regard to communications, while meeting reports are published in the Weekly Epidemiological Record and made available online, along with statements on the WHO website, there is limited dissemination of the work of GACVS by other means. A mailing list of several thousand members is used; however, two thirds of members are from Europe and the Americas and large audiences from low- and middle-income countries are omitted. The Committee discussed several communication modalities including social media, unknown at the time GACVS was formed.

Finally, GACVS discussed the relationship of its work with the Global Vaccine Safety Initiative (GVSI) which aims to optimize the safety of vaccines through effective use of pharmacovigilance principles and methods, as well as helping to establish more effective safety monitoring in all countries. GACVS is a valuable resource for global vaccine safety and, while GVSI is relatively new, it has become a convening point for low- and middle-income countries and should have greater participation with GACVS. Recommendations included using GVSI to convene Member States to discuss global vaccine safety with GACVS representatives, and to identify priorities at all levels, from local to regional, including facilitating the formation of regional vaccine safety committees and passing urgent and important issues for review by GACVS. Advocacy by GACVS for GVSI activities could also be increased, to include, for example, GVSI helping to address some of the challenges identified by GACVS – GVSI being “closer” to the various players (that include not only countries, but also donor agencies and development partners).

Moving forward, GACVS will continue to explore advanced review methods, examine ways to improve communication of its products, and increase collaboration and capacity-building globally with a focus on low- and middle-income countries.

³ Asturias EJ, et al. Contributions and challenges for worldwide vaccine safety: The Global Advisory Committee on Vaccine Safety at 15 years. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.05.018

Full report of GACVS meeting of 30 November-1 December 2016, published in the WHO Weekly Epidemiological Record on 13 January 2017

On the occasion of its 15th anniversary, the Committee reviewed its accomplishments and reflected on new challenges in view of the evolving public health environment. The first GACVS meeting took place on 14–15 September 1999, and the Committee’s first report addressed macrophagic myofasciitis.⁷ Since then, the Committee has met regularly twice yearly and has also been convened by telephone conference more frequently when needed. The Committee’s regular reports are published soon after each meeting in the WHO Weekly Epidemiological Record, while urgent reports are posted separately on-line, and a compendium is available on the GACVS website maintained by WHO.⁸ Since its establishment the Committee has produced >100 reports related to vaccine safety issues. The role of the GACVS is primarily to assess risks related to vaccine use in order to assist policy-makers in identifying benefit and risks as part of evidence-based vaccination policies. GACVS risk assessments are regularly used by WHO advisory bodies, including the Strategic Advisory Group of Experts (SAGE), the Expert Committee on Biological Standards (ECBS) as well as regional technical advisory groups related to immunization.

In addition to its regular Committee reports, GACVS also issues statements in response to urgent vaccine safety issues. If required, the Committee can be convened urgently by conference call in order to respond to alerts of international significance. More recently, GACVS has also looked into capacity building aspects of global vaccine pharmacovigilance. The Committee has, in particular, provided advice on the development of the Global Vaccine Safety Blueprint⁹ – WHO’s strategy to optimize the safety of vaccines through effective use of pharmacovigilance principles and methods in all countries – and is now advising on the development of specific tools for vaccine safety monitoring, including the classification of AEFI, core data elements, and indicators for surveillance systems.

A total of 39 experts have served on GACVS to date, the current committee being composed of 15 members. Current and past members represent all WHO regions, although a majority (26) originate from industrialized countries in Europe, North America or Australia. They provide expertise in multiple fields related to vaccine safety including epidemiology, statistics, clinical medicine, pharmacology and toxicology, infectious diseases, public health, immunology, vaccinology, pathology, ethics and health product regulation. GACVS members, in addition to participating in bi-annual in-person meetings also contribute to the work of the Committee through various subgroups which develop statements on selected topics between regular meetings.

Perspectives were presented on the relevance of the work of the GACVS, including views from an immunization programme, a regulatory authority, a vaccine clinician, a vaccine communication expert, a pharmacovigilance collaborating centre, and a WHO advisory Committee. The discussion highlighted several specific examples where GACVS provided timely and useful guidance. Those have addressed some time-limited issues such as the risk of Bell’s palsy following intranasal vaccination in 2002,¹⁰ transmissible spongiform encephalopathy raised in 2004¹¹ and conjugate meningococcal vaccines and Guillain-Barre syndrome in 2005.¹² Other vaccines were reviewed and re-visited over time as new evidence accumulated or in response to new concerns. An example concerned the vaccine preservative thiomersal which was first discussed in 2002; additional reassuring evidence became available over time and a more comprehensive review was provided in preparation for the United Nations Environmental Program development of a global legally binding instrument on mercury, now known as the Minamata Convention on Mercury (2013).¹³ Similarly, evolving evidence related to the risk of intussusception associated with rotavirus vaccines has been continuously reviewed since 2005.¹⁴

The discussion highlighted the needs for an evolving approach in several domains. Particular considerations were given to: i) the evolving technical aspects of vaccine pharmacovigilance; ii) process issues related to GACVS operations; and iii) communication of GACVS findings. With respect to technical aspects, the main needs relate to the increasing number of new vaccine products that are becoming available for immunization programmes and their rapid availability for populations that are not served with robust safety monitoring systems. In some instances, some vaccines are specifically designed for rapid roll-out in parts of the world that report very few AEFIs and have not developed strong expertise for investigating specific concerns or actively monitoring them. This requires additional guidance from GACVS, not only in assessing available evidence but in identifying gaps in knowledge and proposing approaches that could be reasonably expected to answer the most pressing questions in those particular settings (e.g. the safety of meningococcal A conjugate vaccine used during pregnancy, as reviewed during this meeting). In addition, the methods by which vaccines are developed and produced is evolving, relying on newer technologies and processes. Likewise, individual susceptibility to vaccine reactions varies and new methodologies, including genomics, could potentially provide useful insights with respect to predisposing factors and ways to minimize such risks.

With respect to the GACVS process, the committee’s independence – including from the WHO secretariat – and high level of individual expertise are the main features that can maintain the credibility and impact of its advice. Participants also highlighted the need to maintain the highest possible standards with respect to the review of scientific evidence and adjusting with evolving methodologies. This implies a greater use of systematic and graded reviews when an association between a vaccine and a particular health event has been studied in many parts of the world. However this requirement will not affect most of GACVS’ work, since it has increasingly focused on accompanying the early post-licencing use of new vaccine products for which the scientific evidence is usually available from a limited number of sources. Throughout its existence, GACVS has operated through closed sessions. This confidential process was deemed necessary in order to ensure that all available data, including proprietary information, could be considered. Ensuring that Committee deliberations could be protected from undue influence was another consideration. In view of evolving standards relating to Committees of public importance, it was recommended that a transparency policy be developed with a view to providing more specific information on how conclusions were reached.

GACVS communication is currently directed to WHO technical audiences through the WHO Weekly Epidemiological Record and website. These audiences are immunization managers and policy makers in health ministries, regulatory authorities, professional organizations and immunization advisory groups in Ministries of Health. One GACVS initiative to reach out to broader audiences, and help counteract anti-immunization groups, was launched in 2003 through the creation of the Vaccine Safety Net. In order to assess information on vaccines publicly available on the internet, GACVS developed 4 categories of criteria for good information practices – regarding credibility, content, accessibility and design – to which sites providing information on vaccine safety should adhere. WHO evaluates websites for their adherence to these criteria and provides a list of resources in multiple languages. Vaccine safety communication, however, should be developed further and it was proposed that WHO examine approaches taken in other sciences where public risk is an important consideration, in order to develop and promote more effective practices.

The Committee concluded that although its work is well established and recognized, it was critical to remain mindful of current vulnerabilities. The evolving global vaccination landscape requires a continuous adjustment of methods and processes. A detailed report in preparation will provide a more comprehensive account of this analysis and propose a way forward to ensure that independent advice on vaccine safety issues for WHO remains relevant and timely.

⁷ See No. 41, 1999, pp. 338–340.

⁸ See http://www.who.int/vaccine_safety/committee/topics/en/

⁹ WHO 2012. Global Vaccine Safety Blueprint. WHO/IVB/12.07

¹⁰ See No. 47, 2002, p. 393.

¹¹ See No. 1, 2005, pp. 4–5.

¹² See No. 2, 2006, p. 18.

¹³ See http://www.who.int/vaccine_safety/committee/topics/thiomersal/en/

¹⁴ See http://www.who.int/vaccine_safety/committee/topics/rotavirus/en/

Full report of GACVS meeting of 11-12 June 2014, published in the WHO Weekly Epidemiological Record on 18 July 2014