Global Vaccine Safety

Global Advisory Committee on Vaccine Safety,
6-7 December 2017

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 37th meeting in Geneva, Switzerland, on 6-7 December 2017.2 The Committee examined 3 vaccine specific safety issues: progress with pharmacovigilance readiness for the RTS,S malaria vaccine pilot countries, and updates on the safety profiles of both rotavirus and dengue vaccines. It also reviewed 3 generic issues: the interrater reliability of the revised causality assessment algorithm for serious adverse events following immunization (AEFIs); guidance on prevention and management of immunization-triggered stress reactions; and harmonized approaches for the vigilance of vaccine and other interventions during pregnancy.

Vaccine pharmacovigilance readiness for malaria vaccine implementation

The pilot implementation plans for the RTS,S malaria vaccines in Kenya, Malawi and Ghana have continued to develop since the GACVS meeting in June 2017.3 In particular a tripartite agreement between PATH, GSK and WHO, in terms of roles and responsibilities, and a funding agreement with GAVI, UNITAID and the Global Fund to Fight AIDS, Tuberculosis and Malaria were signed. Plans for a joint regulatory review in the implementing countries for restricted use in pilots have also been devised. In addition, a programme advisory group has been established. It is anticipated that pilot introduction will start mid- to late-2018.

At the June 2017 meeting, GACVS endorsed 6 key indicators of readiness for vaccine pharmacovigilance (PV) for the implementing countries – to be in place 6 months prior to vaccine administration. These were i) a minimum of 10 AEFI reports per 100 000 surviving infants; ii) a functioning AEFI committee that meets regularly; iii) trained and resourced AEFI investigation teams; iv) safety communication plans evaluated and tested; v) an identified person within the Expanded Programme on Immunization (EPI) to oversee and ensure optimal reporting and training; and vi) methods for active surveillance of adverse events of special interest (AESIs) developed and data collection initiated.4 GACVS received progress updates from each country on PV readiness, as well as the results of meetings between the countries on establishing the scope and their methodology to monitor AESI.

In Kenya, reporting rates are close to the target, with plans in place for education sessions and guidance for health-care providers to achieve the target. Work is in progress to establish a national AEFI committee and implement training at the national level. One officer in the EPI programme will oversee safety; communication plans are currently being developed.

In Malawi, a national AEFI committee has been constituted and a reporting system developed. Training has led to an increase in reporting of AEFIs, and also covered causality assessment for national experts. Plans are in place to use the VigiFlow reporting software for adverse events developed by the WHO Programme for International Drug Monitoring as the national database and for vaccine safety data sharing in early 2018.

In Ghana, AEFI reporting rates have increased and initiatives are in place to further increase not only the rates, but also timeliness, so that reporting levels will be achieved in all regions of the country. Additional activities include sharing revised reporting forms, educational lectures and the development of job aids. A national AEFI committee is in place, and additional training is being planned for AEFI investigation. A communication plan is also being developed.

Joint meetings of the 3 countries have occurred through a web-based work group platform to help establish the AESI to be monitored. A total of 10 events have been selected and a surveillance manual is being prepared with appropriate reporting forms and assessment tools. Training will need to be conducted to enable surveillance to begin.

GACVS welcomed the progress achieved, but also recognized the challenges remaining in reaching PV readiness prior to RTS,S introduction, and in AESI surveillance, given how soon vaccinations will begin. GACVS emphasized the importance of each country continuing to rapidly progress PV readiness according to the indicators, in view of target introduction later in 2018. Although the target of AESI reporting starting 6 months prior to vaccine introduction may not be feasible, nonetheless, this should occur as soon as possible to allow comparisons between pilot areas randomized to receive RTS,S and corresponding control areas. Ascertainment of vaccination history of AESIs was also identified as an area that could be challenging. However, GACVS learned that additional resource will be available to register vaccination status in RTS,S pilot areas.

Rotavirus vaccine safety update

In December 2011, GACVS initially reviewed the safety of currently administered rotavirus vaccines.5 The Committee noted that both Rotateq and Rotarix vaccines had a good safety profile and that although they may be associated with an increased (up to 6-fold) risk of intussusception, the benefit of the vaccines outweighed the potential risk. In December 2013, GACVS reviewed additional data that had become available from Australia and the United States of America (USA).6 It noted that both countries confirmed a risk of intussusception following vaccine administration, particularly within the first 7 days after the first dose, although attributable risk estimates varied across studies. The Committee concluded that the benefits of the vaccine outweighed the small potential risk of intussusception (in the range of 1–2 cases per 100 000 first doses).7 GACVS also suggested that given possible population differences in the risk of intussusception, active surveillance should be undertaken in countries where rotavirus vaccines are being introduced to ensure that benefits and risks can continue to be assessed.

The GACVS session in December 2017 reviewed recent evidence on the impact of rotavirus vaccine, an updated Cochrane review on rotavirus vaccines and intussusception, and recent data from multicountry studies from sub-Saharan Africa and South Africa.

As regards vaccine impact, data from randomized controlled clinical trials (RCTs) showed that Rotarix, Rotateq, Rotasiil and Rotavac vaccines reduced severe rotavirus gastroenteritis by 52–94% after 1 year of follow-up. Overall, weak evidence from observational studies suggested that the introduction of Rotarix and Rotateq vaccines reduced diarrhoea-related deaths in children. While the effectiveness was lower in some low-income countries, the benefit was still large due to the high disease burden.

A systematic review was conducted to update a 2012 Cochrane systematic review8 regarding the efficacy and safety of rotavirus vaccines. This review included RCTs (low power, low bias); historical controls (low power, high risk of bias); case-control studies (high power, high risk of bias); cohort studies (high power, high risk of bias); and self-controlled case series (SCCS) (high power, unclear risk of bias). Data were insufficient to evaluate many of the new vaccine products. For those products with sufficient data, evidence from RCTs showed that there was no difference in incidence of serious adverse events in the use of Rotarix, Rotateq, Rotasiil, or Rotavac compared with placebo, up to 2 years after vaccination. There was conflicting evidence from different sources as to whether Rotarix or Rotateq was associated with an increased risk of intussusception. While RCTs of Rotarix and Rotateq found no association between intussusception and vaccination, SCCS studies suggested an increased risk in the weeks following vaccination.

In the African Intussusception Surveillance Network that was formally established in 2014, and included 7 countries using Rotarix (Ethiopia, Ghana, Kenya, Malawi, United Republic of Tanzania, Zambia and Zimbabwe), surveillance for intussusception (defined using Brighton case definition criteria) was conducted at 28 sentinel paediatric hospitals. Vaccination status was identified via vaccination card or medical/clinic record. The potential association between oral rotavirus vaccine and intussusception was analysed using an SCCS study, in which each of the 717 identified case-patients (aged 28–245 days) served as their own control (risk periods were 1–7 days, 8–21 days, and 1–21 days following each dose, while the control periods were the other time windows). No increased risk of intussusception was identified after either dose 1 or 2.

Post-marketing monitoring is also ongoing in South Africa, where an SCCS study (using the same methods as described above) is being conducted among >300 case-patients aged 28–275 days. Thus far, no risk following the first dose, and a small risk (approximately 2-fold) in the first 7 days following the second dose, have been identified, but no overall increased risk 1–21 days following the second dose. Enrolment is ongoing.

While the reason behind the difference in potential risk of intussusception in different countries is not clear, hypotheses include: differences in age at vaccination; differences in effectiveness of vaccine (e.g. lower effectiveness may be associated with lower risk of intussusception); concurrent use of inactivated polio vaccine (IPV) versus oral poliovirus vaccine (OPV) (e.g. concurrent use of OPV may reduce both effectiveness of the rotavirus vaccine and risk of intussusception); and the “trigger” hypothesis (that vaccination could potentially trigger intussusception in a susceptible individual who may have developed intussusception later in the absence of vaccination). The Committee suggested that future follow-up studies continue to assess these variables. In addition, as countries transition from OPV to IPV, studies evaluating both effectiveness and risk of intussusception should be considered. Countries should also continue to assess risk of new vaccines as they are licensed and introduced. Overall, the Committee continues to be reassured that the benefit of rotavirus vaccination in preventing severe diarrhoea is greater than the small potential risk of intussusception identified in most, but not all post-licensure studies.

Dengue vaccine safety update

The WHO Global Advisory Committee on Vaccine Safety has been following the development of a tetravalent recombinant live dengue virus vaccine for the past 5 years.9,10,11,12. The most advanced product, CYD-TDV by Sanofi-Pasteur (Dengvaxia) is a yellow fever vaccine virus backbone vector that expresses envelope proteins of dengue viruses type 1 to 4 yellow fever vaccine virus genetic backbones. During early clinical trials, no serious vaccine-related events had been documented among the recipients, and no excess cases of dengue fever or severe dengue attributable to the vaccine had been observed. Subsequent large-scale phase 3 trials, CYD14 in Asia (among subjects aged 2–14 years) and CYD15 in Latin America (among subjects aged 9–16 years) were conducted in over 20 000 vaccine recipients and 10 000 control subjects and demonstrated partial efficacy of the vaccine.

Dengvaxia received its first marketing authorizations in late 2015 and is currently available in several Asian and Latin American countries. This report briefly reviews the experience presented to GACVS during clinical trial development (now with >5 years of follow up), and discusses new evidence presented to WHO during the GACVS meeting in December 2017. These new data are based on the reanalysis of clinical trial data using a new test that retrospectively distinguished subjects with and without prior exposure to wild dengue virus.

Background

Dengue is an increasingly important disease worldwide. As outlined in the WHO position paper on dengue vaccines published in July 2016,13 the number of cases reported annually to WHO increased from 0.4 to 1.3 million during the decade 1996–2005, reaching 2.2 million in 2010 and 3.2 million in 2015. Based on mathematical modelling, the global annual incidence has been estimated at approximately 50–100 million symptomatic cases, predominantly in Asia, followed by Latin America and Africa. However clinical cases are likely to represent only about 25% of all dengue virus infections. In 2013 dengue was estimated to be responsible for approximately 3.2 million severe cases and 9000 deaths, the majority occurring in lower middle-income countries. GACVS recognized several challenges for the evaluation of the safety of dengue vaccines, particularly the follow-up time needed to monitor the theoretical risk of increased severe dengue following vaccination. Severe dengue cases represent a small percentage of all dengue infections and are more common on second exposure to wild dengue viruses.

In 2015, the Committee was presented with results from the third year of follow-up in the CYD14 trial conducted in Asia. The trial found that the risk of hospitalized dengue was significantly higher in the vaccinated group compared with the control group of age 2–5-years (relative risk (RR) = 7.45, 95% confidence interval (CI): 1.15, 313.80). This risk was not found to be elevated in older age groups. At the time, GACVS highlighted the importance of understanding potential factors, other than age, that may be associated with this increased relative risk of hospitalization and of severe dengue. Among them, understanding if a subject had been exposed to wild dengue virus prior to vaccination was deemed critical given the lower vaccine efficacy in participants who were serologically naïve, and the potential risk of immune enhancement among previously infected subjects.

Based on these results, GACVS noted that the excess cases of hospitalized dengue (in the age group 2–5 years) could be related to age, serostatus, or both. The plausible hypothesis proposed was that vaccination primes the immune system similarly to natural infection, and that after a period of protection following vaccination, immunity wanes. According to this hypothesis, among seronegative individuals, the response to the first natural infection following vaccination (and waning immunity) may act as a second infection, which has typically been associated with a higher risk of serious disease. In seropositive individuals, the response to the first natural infection following vaccination is as if it was a third or later infection and not associated with a higher risk of serious disease. As a result of available evidence, licensure was sought for children and adults aged ≥9 years. The Strategic Advisory Group of Experts (SAGE) on Immunization issued recommendations in April 2016 to introduce Dengvaxia in geographical settings (national or subnational) with high endemicity only, as indicated by seroprevalence of >70% in the age group targeted for vaccination.

In June 2016,4 GACVS was presented with the longer-term 4-year follow-up of hospitalized dengue among CYD14 and CYD15 clinical trial participants. While no consistent increase was observed in the risk of hospitalization or severe dengue in vaccinated individuals aged 9–16 years, in the younger age group of 2–8 years, an increased relative risk (not reaching significance) was observed in year 3 of follow-up that persisted during year 4 but was declining. GACVS recommended that existing and planned clinical efficacy trials should be evaluated in depth and include careful assessment of pre-immunization seropositivity in selected cohorts. These data would contribute to a greater understanding of the potential risk factors and underlying immunology of dengue infection and severe dengue post-vaccination.

Current status and new data

To date, the vaccine has been licensed in 19 countries and introduced in public immunization programmes in the Philippines and Brazil. Immunization began in the Philippines in April 2016 and GACVS was presented with the programme’s early post-market surveillance experience.4 The country had seen dramatic increases in cases since 2010 with >150 000 dengue episodes and approximately 1000 deaths annually. By the time of the meeting in June 2016,4 almost 250 000 children aged ≥9 years had been vaccinated.

As SAGE identified vaccine safety in the seronegative population as a research priority,6 Sanofi Pasteur has undertaken a case-cohort study using a dengue anti-NS1 IgG ELISA assay (NS1) on blood samples available from clinical trial participants at 13 months after the first dose (1 month following the third and last dose of vaccine administered during the clinical trials). The research assay is designed to differentiate between prior natural infection and vaccination. Based on these results, the company reanalysed the safety and efficacy according to this surrogate of serostatus as well as age at the time of vaccination.

Overall, vaccinated trial participants had a reduced risk of virologically-confirmed severe dengue and hospitalizations. The subset of trial participants who had not been exposed to dengue virus infection prior to vaccination (i.e. dengue-naïve, seronegative according to the NS1 assay) had a twice higher risk of more severe dengue and hospitalizations compared with unvaccinated participants, regardless of age. In contrast, those trial subjects, at any age, with evidence of a previous dengue infection (as determined by NS1 assay) experienced a reduced risk of severe dengue for the duration of the observation period.

Based on this new analysis, Sanofi Pasteur estimated the actual risks in the study population. In study subjects aged 2–16 years without prior dengue infection, data suggest modest efficacy (15–32%) of vaccine against symptomatic dengue until the second year of follow-up. Subsequently, starting during year 3, the risk of hospitalized and severe illness becomes higher than among controls. In practical terms, and within the population studied, these data suggest that during a 5-year follow-up, approximately 5 additional hospitalized dengue cases, or 2 additional severe dengue cases, per 1000 vaccinees with no previous dengue infection (i.e. dengue naïve subjects) could occur following vaccination, compared with unvaccinated seronegative children. Importantly, in the clinical trial population, all cases recovered and no deaths were observed. On the other hand, among children who had a prior dengue infection (i.e. seropositive) there was a reduction of 15 cases of hospitalized dengue and 4 cases of severe dengue per 1000 who were vaccinated for the same duration of follow-up.

Implications and assessment by GACVS

GACVS considered these new results as well as the clinical trial data and early post-market data submitted. Key issues included the validity of these findings, the subgroups to which they mostly apply, the magnitude of the risk, and implications, both for those subjects already vaccinated, and those not yet vaccinated. GACVS acknowledged that the vaccine is safe and efficacious in individuals who have had a primary infection with wild dengue preceding immunization, thus preventing a “second” and therefore more severe episode of dengue. GACVS noted that the increased risk of severe dengue among vaccinated individuals who are seronegative to dengue at the time of vaccination became apparent during the third year after receipt of the first vaccine dose irrespective of age. Thus, as post-licensure use started in the second quarter of 2016, an increase in the number of severe dengue cases among seronegative subjects would not occur before 2018 in Brazil and the Philippines – the 2 countries with early introduction of the vaccine.

The new data indicate that the increased risk of hospitalization (and severe disease) from dengue affects vaccinated subjects who are naïve to wild dengue infection prior to vaccination. This provides strong indication that previously identified excess risk among younger vaccine recipients in the Asian study reflected a confounding association between age and exposure to wild dengue virus. Thus it appears that history of exposure to wild dengue, rather than age, predicts the risk of severe disease among vaccine recipients. This also corroborates prior hypotheses suggesting that immune priming from natural or other stimulation such as immunization with the dengue vaccine can lead to a higher risk of severe dengue disease on secondary exposure to wild dengue viruses.

GACVS recognizes that the vaccine has, to date, been administered to a large majority of subjects among populations where exposure to dengue virus is high and therefore most vaccine recipients are seropositive to wild dengue. Notable is that the clinical data presented by Sanofi Pasteur also showed that, even among seronegative population, the number that would experience untoward severe dengue is likely to be <1%, and that with proper clinical care, more serious consequences can be prevented in most instances.

As a result, GACVS recommends that Dengvaxia should not be administered to individuals who have not been previously infected with wild dengue virus. Data are not currently available to allow an analysis of the risk according to the number of vaccine doses received by subjects seronegative at baseline. It is therefore not possible to determine if incomplete vaccination would lead seronegative subjects to a higher or lower risk of severe dengue as compared to seronegative subjects who have received the full 3-dose course.

In order to minimize untoward consequences for dengue-naïve vaccinated subjects, GACVS recommends ensuring the enhancement of measures that reduce exposure to dengue infection among populations where the vaccine has already been administered. For vaccine recipients who present with clinical symptoms compatible with dengue virus infection, access to medical care should be expedited to allow for proper evaluation, identification, and management of severe forms of the disease.

Interrater reliability of causality assessment for serious adverse events following immunization

An adverse event following immunization (AEFI) is defined as any untoward medical occurrence following immunization which does not necessarily have a causal relationship to the vaccine. The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, symptom or disease. Based on the advice from GACVS to review the causality assessment system, WHO commissioned a group of experts to develop a methodology and tools to assist health-care personnel in the assessment of causality of an adverse event and use of a vaccine. The causality assessment (CA) methodology and tool developed included an eligibility component for the assessment that reviews the diagnosis associated with the event and identifies the administered vaccines; a checklist that systematically guides users to gather available information to feed a decision algorithm; and a decision support algorithm that assists the assessors to arrive at a classification of the individual AEFI (manual classification). This revised methodology was endorsed by GACVS at its meeting in June 2012.14 A causality assessment manual and AEFI causality assessment software were developed (electronic classification). Final classification generated by the process includes 4 categories in which the event is either: (1) consistent; (2) inconsistent; (3) indeterminate with respect of causal association; or (4) unclassifiable. Feedback obtained from end users of this methodology included the importance of conducting a validation study regarding the interrater agreement of the classification.

To address this concern, an interrater study of causality assessment for serious AEFIs was conducted in April 2017 to evaluate the reliability (i.e. the degree to which an assessment tool produces consistent results between country evaluators) of the methodology and to compare the manual AEFI causality assessment method with the electronic method. The study was conducted using serious AEFI cases from India and Zimbabwe. Each country had 2 assessing teams and each team had 4 persons with expertise in paediatrics, epidemiology, pharmacovigilance and public health

During the GACVS meeting in December 2017, members were presented with the methods and findings from the interrater study as well as proposed changes to the worksheets and manual. Overall, there was a good concordance of ratings with >80% agreement on cases between experts from both countries and >80% agreement between experts from the same countries using the manual or the electronic methods. Based on the data obtained from this study, it was concluded that the methodology was reliable and the electronic AEFI CA methodology was a suitable process for CA at country level and for comparison of the CA across countries. The CA appeared to be influenced by the quality of the case report and understanding of country specific processes of AEFI reporting, along with the experience of the assessors. A full scientific report is in preparation.

The results derived from the interrater study, as well as qualitative feedback from study participants, were used to further revise the worksheet and CA methodology by a GACVS working group. The Committee made several recommendations. To further refine the algorithm of the CA tool, GACVS recommended a systemic analysis of unclassifiable events; an analysis of the questions posed as part of the checklist to evaluate interrater agreement regarding the responses provided; the inclusion of additional AEFIs, such as seizures; and inclusion of additional evidence, if available, in the CA to support a potential causal association of an AEFI with vaccination. Based on the qualitative analysis from the evaluation exercise GACVS also provided suggestions to clarify some aspects of the methodology and supporting guidance documents. The Committee looked forward to the publication and online availability of the revised AEFI causality assessment manual; the updating of the AEFI causality assessment software with the revised inputs; and the translation into additional UN languages of both the manual and electronic tools.

Guidance on prevention and management of immunization-triggered stress responses

During its December 2015 meeting, GACVS was presented with literature and mainstream and social media reports from several countries where clusters of anxiety-related reactions following immunization affected immunization programmes had drawn negative attention from the media and public.15 Following the meeting, GACVS convened an expert working group to explore and understand the etiology of such events and their characteristics, and prepare a guidance document that would help guide public health efforts and programme managers and immunization staff in prevention and management.

The expert working group systematically reviewed the available literature along with information gathered from social media, and used the findings to initiate discussion with subject experts. The group prepared a draft guidance document aimed to equip immunization programme managers and health-care providers at local, regional and national levels with the knowledge to manage both individual and clusters of such events. The emphasis was to obtain clarity on the spectrum of anxiety-related manifestations, including their epidemiology and associated risk factors, and to better understand the context of their occurrence. The objective was to produce a document providing a framework and guidance to understand, prevent, diagnose and manage such events; to explain the context of their occurrence; to clarify the reporting mechanisms and the communication approaches when such events occur; and to identify research gaps and strategies to move forward.

GACVS was presented with a draft manual for programme managers to prevent, identify and respond to stress related events associated with immunization. During discussions, it was clarified that the term, “immunization anxiety related reaction” did not capture the spectrum of such events. A new term, “Immunization Triggered Stress Response” (ITSR) was therefore proposed which incorporates all events that manifest just prior to, during, or after immunization. ITSR can be subcategorized to peri-immunization stress response, post-immunization stress response and other disorders or syndromes that can occur post-immunization, such as the occurrence of anxiety, fear, phobia with immunization, and associated anxiety disorders including “needle phobias” and conversion disorders. Complex syndromes that may have a stress component are also considered in possible relation to immunization and outlined in the document in a biopsychosocial context.

GACVS discussed the proposed terminologies and the classification. It was clear that further research is still needed to better understand the rate of occurence of such events, their relationship to age and mechanisms of occurence. There is a need to link ITSR with pain mitigation and pain management following injections. Better guidance to prevent stress-related events is needed, particularly for parents, vaccinators and health-care providers to address the needs of older children, adolescents and adults prior to vaccination. The exploitation of ITSR by anti-vaccine groups was also mentioned. To avoid mismanagement, screening to differentiate between ITSR and actual vaccine reactions, such as anaphylaxis, is critical; incorporating this into training materials for health-care providers will be helpful. GACVS recommended that the manual be circulated for consultation to relevant stakeholders and that training materials be developed to accompany the new document.

Harmonized approaches for the vigilance of interventions during pregnancy

In 2013, GACVS examined the safety of the increasing number of vaccines intended for pregnant women as well as inadvertent vaccinations in pregnancy.16 The difficulty of differentiating the risks of pregnancy from the risks of interventions on pregnancy outcomes was noted. Given the limited amount of clinical trial data on pregnant women, risks should be closely assessed through enhanced pharmacovigilance in the post-licensure phase and in different geographical settings.

Several promising vaccines to protect mothers and infants in the first few weeks of life before infant vaccination are being developed. Safety monitoring of vaccines administered during pregnancy will require enhanced vigilance mechanisms and standardized case definitions of key events in pregnant women and newborns. In June 2016, GACVS reviewed the work conducted by the Global Alignment of Immunization Safety assessment in pregnancy (GAIA) project, and considered important not only the need for good health data, but also compatibility with the longstanding and established use of terminology coding underpinning disease monitoring (the International Classification of Diseases – ICD) or drug regulation (the Medical Dictionary for Regulatory Activities – MedDRA). The Committee also suggested that assessment of applicability of the case definition in different settings with limited health-care services be conducted. Immunization, however, is only one of many medical interventions during pregnancy and early childhood. Adequate vigilance requires that harmonization of methods be compatible with the work of other stakeholders including several WHO programmes.

During the meeting GACVS was informed of a stakeholders meeting on maternal interventions vigilance that took place in Geneva, 20–21 November 2017. The objectives of the meeting were to review current methods to monitor outcomes of maternal immunization and other interventions, with a particular focus on vigilance; assess available methodologies and identify where harmonization is needed; assess the global applicability of vigilance methodologies for maternal immunization and other interventions; and propose coordination mechanisms to support vigilance harmonization across programmes and partners working on improving pregnancy and early childhood health events. The stakeholders invited included WHO Collaborating Centres in pharmacovigilance, technical agencies with an interest in immunization in pregnancy;17 academic experts from all WHO regions;18 and regulatory experts with an interest in pregnancy interventions.19 Discussions addressed global applicability of vigilance methodologies for maternal health interventions during pregnancy. Several situations were highlighted that will affect the quantity and quality of data available; for example, during clinical research, there is likely to be a higher possibility of a specific diagnosis, compared with public health surveillance, where diagnoses may be based on minimal requirements. Likewise, weak civil registration systems can prevent the identification of vital events. It was therefore proposed that harmonized sets of data be collected so that studies and evaluations of the health of pregnant women can be developed. These sets should be tailored according to study characteristics, ranging from minimal to optimal infrastructure and clinical conditions.

GACVS noted the similar data needs for both clinical surveillance and public health vigilance, and that data coding and data systems should be usable for both purposes. The Committee agreed that minimal data elements will need to be assessed for their availability in different settings and for different types of studies. The November meeting has already resulted in plans for the GAIA definitions to be considered by those working on updating and refining ICD 11 as part of the ICD’s rolling programme for updating terms. ICD updates consider stakeholders, including obstetrics and gynaecology services, an essential part of the work in promoting ownership and use of ICD coding.

GACVS noted that as part of developing a roadmap for improving maternal, neonatal and child health programmes and assessments of vaccine safety in pregnancy, a WHO interdepartmental task force will be established to address harmonization of coding and data systems. The task force will include several stakeholders, including WHO regional and country offices and service providers. The aim of such a task force, over the next few years, is to establish a common platform to assess pregnancy related outcomes for any intervention delivered to women during pregnancy. GACVS welcomed this initiative and indicated that joint efforts to enhance access to quality data on pregnancy outcomes will benefit the broad community of stakeholders working to improve the health of mothers and their infants.


1 See No. 41, 1999, pp. 337–338.

2 GACVS invited additional experts to present and discuss evidence related to specific topics. These experts included persons affiliated with: The INCLEN Trust International, New Delhi, India; Centers for Disease Control and Prevention, Atlanta GA, USA; Food and Drugs Authority, Accra, Ghana; Women’s and Children’s Hospital, Adelaide, Australia; University of the Witwatersrand, Johannesburg, South Africa; University of Guelph, Canada; Pharmacy and Poisons Board, Nairobi, Kenya; Medicines Control Authority, Harare, Zimbabwe; Pharmacy, Medicines and Poisons Board, Lilongwe, Malawi; The Cochrane Collaboration, Oxford, United Kingdom; Sanofi Pasteur, Lyon, France.

3 See No. 8, 2017, pp. 393–396.

4 See No. 28, 2017, pp. 393–396.

5 See No. 06, 2012, pp. 54–56.

6 See No. 07, 2014, pp. 57–58.

7 See http://www.who.int/vaccine_safety/initiative/tools/Rotavirus_vaccine__rates_information_sheet.pdf?ua=1.

8 Soares-Wiser et al. Vaccines for preventing rotavirus diarrhoea: vaccines in use. http://www.cochrane.org/CD008521/INFECTN_vaccines-for-preventing-rotavirus-diarrhoea-vaccines-in-use

9 See No. 06, 2013, pp. 68–69.

10 See No. 04, 2015, pp. 17–18.

11 See No. 34, 2015, pp. 421–423.

12 See No. 28/29, 2016, pp. 346–347.

13 See No. 30, 2016, pp. 349–364.

14 See No. 30, 2012, pp. 284–286.

15 See No. 03, 2016, pp. 21–23.

16 Global Advisory Committee on Vaccine Safety. Safety of Immunization during Pregnancy. A review of the evidence. World Health Organization, 2014. Available at: http://www.who.int/vaccine_safety/publications/safety_pregnancy_nov2014.pdf, accessed December 2017.

17 PATH, Brighton Collaboration, GAPPS, the US Centers for Disease Control and Prevention, INCLEN, INDEPTH, IMPRINT, CROWNE, IABS.

18 University of Witwatersrand, South Africa; Washington State University, USA; University of Washington, USA; Baylor College, USA; Johns Hopkins Bloomberg School of Public Health, USA; Makere University, Uganda; London School of Hygiene and Tropical Medicine, UK; Monash University, Australia; University of Alberta, Canada; University of Utrecht, the Netherlands; Liverpool School of Tropical Medicine, UK

19 US Food and Drug Administration, industry umbrella organizations and the the Council for International Organizations of Medical Sciences.