RTS,S introduction

At the December 2014 GACVS meeting, the manufacturer of RTS,S vaccine (GSK Biologicals) presented the post-booster results from the Phase 3 multicentre clinical trial. Those results had shown 2 safety signals, meningitis and febrile convulsions, recently published,¹³ which had already been observed after the primary dose.^{14, 15} Febrile convulsive seizures are a clearly identified adverse reaction in the 7 days following primary vaccination among subjects aged 5–17 months. Febrile seizures are also observed within 7 days after the booster dose irrespective of age at primary vaccination. All the febrile convulsions occurring within 7 days post vaccination resolved, without long term adverse outcomes reported to date. Meningitis cases occurred substantially more frequently in the groups that received RTS,S/AS01, especially in the older age group (5–17 months). The cases, however, are of varying etiologies, show no significant evidence of temporal clustering after vaccination and there is currently no clear causative relationship. The committee considered that meningitis should therefore be regarded as a potential signal which requires further assessment post-licensure. GACVS also reviewed safety data from a randomized control trial of 200 known HIV-positive children aged 6–17 weeks. There was a higher frequency of pneumonia in the RTS,S/AS01 group over the first 30 days after vaccination, although this difference was not statistically significant. At month 14, frequencies of pneumonia were very similar in both groups. So far, no safety signal has been detected in HIV-positive children.

A malaria vaccine GACVS sub-group has further developed guidance on post-licensure safety surveillance for the RTS,S/AS01 vaccine. Several adverse events of special interest have been considered, including meningitis, convulsive seizures, autoimmune disorders and those studied during the introduction of another inactivated vaccine (meningococcal A conjugate MenAfriVac) in sub-Saharan Africa through sentinel monitoring.¹⁶ With respect to evaluating the meningitis safety signal, GACVS acknowledges that it will be necessary to propose case definitions and investigation procedures adapted to the health-care resources available in the sites where early RTS,S introduction would take place. It would be desirable that those early introduction sites be selected based on their ability to promptly identify cases compatible with meningitis and conduct proper investigation, including etiological diagnosis.

Several African experts in autoimmunity were consulted to consider the feasibility and need for studies of auto-immune disorders following RTS,S/AS01 introduction. This concern was raised out of theoretical considerations related to the use of AS01, a potent new adjuvant, although there is currently no evidence in experimental or human situations suggesting AS01 could be a trigger for autoimmune disorders. The experts highlighted the numerous practical constraints linked to the establishment of adequate surveillance since there are relatively few diagnosed paediatric autoimmune diseases in sub-Saharan Africa and their epidemiology is largely undetermined. They also noted that data from experimental models show no evidence that AS01 triggers immune reactions away from the injection site. GACVS agreed that initially the guidance document would not address monitoring of autoimmune disorders. This could be revised in case a signal is identified from passive safety surveillance of RTS,S or from the study and monitoring of other vaccines using the same adjuvant.

GACVS recommended that the guidance document be completed with more detailed protocols for studies written later, if RTS, S/AS01 is introduced and suitable study sites identified.

¹³ RTS,S partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 2015 (EPUB) PMID:25913272

¹⁴ See No. 4, 2015, pp. 18-20.

¹⁵ RTS,S clinical trial partnership. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N Engl J Med 2011;365:1863-75.

¹⁶ Ouandaogo CR, Yaméogo TM, Diomandé FVK et al. Adverse events following mass vaccination campaigns during first introduction of a meningococcal A conjugate vaccine in Burkina Faso, 2010. Vaccine 2012; 30 Suppl 2:B46-51.

Full report of GACVS meeting of 10-11 June 2015, published in the WHO Weekly Epidemiological Record of 17 July 2015

This session continued the June 2014 discussion on preparedness for malaria vaccine introduction.⁶ The safety and efficacy data from the phase 3 multicentre trial of the RTS,S/A01 vaccine (GSK Biologicals) in 11 centres in Africa were reviewed. A total of 8922 children aged 5–17 months and 6537 infants aged 6–12 weeks were randomised 1-1-1 to receive 3 doses of RTS,S/AS01 (at 0, 1, 2 months) and a booster (at 20 months), or 3 doses of RTS,S/AS01 and a non-malaria comparator vaccine, or 4 doses of comparator vaccines (rabies or meningococcus C). The children have been followed up to a median of 48 months post dose 1 for the 5–17 month-old group and a median of 38 months for the 6–12 week-old group for safety monitoring. Two safety signals were noted that had already been published in interim analyses following the primary course at 0, 1, 2 months. The first was an increased risk of febrile convulsions within 7 days of vaccination and the second was a signal of a possible increased risk of meningitis (with no clear evidence of temporal clustering after vaccination). The company also presented a risk management plan and a post-approval monitoring plan. For the latter, it is planned to establish cohort event monitoring at a number of sites in Africa. This method would be used to collect background rates for adverse events of particular interest and malaria incidence data from a cohort of about 40 000 children in advance of vaccine introduction. Subsequently, event monitoring would continue following the introduction of the vaccine. In addition, during the study period, hospital-based surveillance would be used to identify severe adverse events of interest after vaccination . As well as for febrile convulsions and meningitis, the study would monitor for potential immune mediated diseases (PIMD). GACVS noted that while the planned post-licensure studies would enable further characterization of the febrile convulsion risk, and compare meningitis rates before and after vaccine introduction (although this may be affected by meningitis epidemics), these studies would be unlikely to identify potential risks associated with very rare diseases such as certain PIMDs unless those risks were large.

Following the company’s presentation, GACVS considered progress on the development of guidance by WHO on post-licensure safety surveillance for the RTS,S/AS01 malaria vaccine in special studies. The proposed approach is to study the signals identified during clinical trials and lists the events of interest for post-licensure surveillance. It also summarizes possible designs and settings for special studies of those outcomes of interest. GACVS discussed the potential difficulties in accurately identifying rates of febrile seizures without active follow-up as they are transient and may not always present to health-care facilities. As the febrile seizure risk has already been identified and quantified in pre-licensure clinical trials (and is statistically significant in self-controlled case series secondary analysis), prioritization of limited post-licensure study resources towards more severe outcomes may be appropriate. For certain outcomes, efficiency might be garnered by planned meta-analysis of pre- and post-licensure data collected using similar protocols.

Guidance on monitoring adverse events of special interest should be tailored to take into account the resources and infrastructure expected to be available in early introducer countries, maximizing synergies when possible. For example, in the case of meningitis, there is a well-established surveillance network in the meningitis belt countries that could provide reliable case validation, if RTS,S vaccination status could also be ascertained. To facilitate application of the guidance, protocols for each condition of interest should be developed jointly with clinicians and epidemiologists active in the countries under consideration. For PIMDs in particular, GACVS is concerned that many countries which will introduce malaria vaccine have insufficient capacity for identifying the majority of those events. It is recommended that a consultation be organized with experts from implementing countries to further consider what could (and could not) be identified and properly studied.

GACVS also highlighted that, as with the introduction of other vaccines, it is essential to allow for spontaneous reporting of any safety concern associated with the vaccine. This will mean reviewing existing vaccine safety monitoring systems and planning developments in order to improve upon available tools and ensure awareness of those involved with malaria vaccination. It also implies that those countries should have sufficient capacity in place to investigate cases of serious adverse events and have access to independent experts in order to assess the causal relationship between those events and administration of the vaccine.

⁶See No. 29, 2014, pp. 331–332.

Full report of GACVS meeting of 3-4 December 2014, published in the WHO Weekly Epidemiological Record of 23 January 2015

The most recent WHO malaria mortality estimate is 627 000 deaths for the year 2012. While this represents an estimated 42% reduction in global malaria mortality rates since 2000 in association with a large scaling up of WHO recommended preventive, diagnostic and treatment measures, there remains a need for additional preventive measures including vaccines. As one candidate malaria vaccine has reached the regulatory evaluation stage, GACVS considered the need for post-licensure safety assessment for when malaria vaccines become available for public use.

GACVS considers that the development of recommendations for post-licensure safety assessment of malaria vaccines is an important preparatory step, in order to provide early implementing sites with sufficient time for planning, training and improving or developing surveillance systems. Early identification of sites would also have the benefit of allowing the establishment of active surveillance for events of special interest, thereby providing background rates for those events prior to vaccine introduction. GACVS noted that the safety guidance would be developed alongside effectiveness and impact guidance and that it was important to ensure harmonisation with this guidance, as it is likely that studies could be designed to examine the impact of both safety and effectiveness. GACVS also noted the guidance was intended for use by the public sector of implementing countries to assist them to conduct independent studies and be prepared to assess data obtained by the manufacturer.

GACVS discussed the principal elements of such recommendations and suggested that the main components should cover on-going strengthening of routine systems for reporting adverse events following immunization (AEFIs), stimulated passive reporting in selected settings, such as health demographic surveillance system sites and active follow-up for specific events of interest using suitable epidemiological designs – such as case control, self-controlled case series and cohort event monitoring – to enable testing of hypotheses and quantification of risks. These components would allow detection and evaluation of signals for rare unexpected events as well as assessment of events of interest from clinical trials – in particular febrile convulsions and meningitis. It was noted that it is important that lessons are learnt from the experience in Africa of safety studies for meningococcal serogroup A vaccine introduction, but that a key difference was that the vaccine would probably be introduced with a routine schedule rather than through large mass campaigns. It was also noted that it is important that the guidance balances the need for high quality studies with what is feasible in the settings where these studies are likely to be done. This includes, for example, use of case definitions adapted to local clinical practice. Further discussion focused on the importance of considering rare but serious events and possible mechanisms for following up vaccine recipients such as diary cards, issuing of mobile telephones or identifying patients through hospital admissions. It is expected that a guidance document will be available in mid-2015.

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