Statistical analysis plan for the Malaria Vaccine Pilot Evaluation (MVPE)
The Malaria Vaccine Pilot Evaluation (MVPE) is a joint initiative of the World Health Organisation’s Department of Immunization, Vaccines and Biologicals, and the Global Malaria Programme, to evaluate the effectiveness of the RTS,S/AS01 malaria vaccine delivered through the routine immunisation services in Kenya, Malawi and Ghana, over 4 years. In the phase 3 trial of the vaccine conducted from 2009 to 2014, in children who received four vaccine doses (three primary doses and a fourth dose 18 months later), the incidence of uncomplicated malaria and of severe malaria were reduced by 39% and 32% respectively over 4 years of follow-up. For every 1000 children vaccinated with 4 doses, a total of 1774 cases of malaria and 40 hospital admissions due to malaria were averted over about 4 years1. A total of 19 cases of severe malaria were averted, cases which, without the enhanced access to care provided in the context of the trial, might have led to death. The vaccine therefore could have a substantial public health impact. The current vaccination schedules include three primary doses to be administered before 9 months of age and a fourth dose at about 2 years of age. This involves three to four additional vaccination visits than are currently recommended in this age range. The MVPE seeks to determine the impact realised in practice when the vaccine is introduced in areas of high to moderate malaria incidence in three countries with year-round malaria transmission. The programme will evaluate the safety of RTS,S/AS01 in routine use, the feasibility of administering four doses of the vaccine, and the impact of the vaccine at population level, using a cluster-randomized design. The vaccine is being introduced sub-nationally in pilot areas in each of the three countries, by the EPI programme. Within the pilot area in each country, districts (in Ghana), subcounties (in Kenya), and clusters of equivalent population (in Malawi), have been randomized to either introduce the vaccine in 2019 (implementation clusters), or to delay introduction until the initial introduction has been evaluated (comparison clusters). Thus, the evaluation will use a cluster-randomized design. Community reporters will document all deaths occurring in children under 5 years of age in the implementation and comparison clusters. Hospital surveillance is being established in sentinel hospitals in a subset of clusters to monitor the incidence of admission with malaria and other conditions. Vaccine administration will be delivered through, and monitored by, the Expanded Programme for Immunization (EPI) in each country and uptake of RTS,S/AS01RTS,S will also be measured independently through cluster-sample household surveys. The MVPE will determine whether the introduction of RTS,S/AS01RTS,S leads to a reduction in child deaths, and a reduction in the incidence of hospital admission with severe malaria, over the 4 years of the implementation programme (MVIP, Malaria Vaccine Implementation Programme). The MVPE also addresses three safety signals that were observed in the phase 3 trial but whose significance was unclear: an unexplained excess of meningitis cases in RTS,S/AS01 recipients, an excess in cerebral malaria cases among RTS,S/AS01 recipients who developed severe malaria and, among the relatively small number of deaths that occurred in the trial, an excess of deaths among girls who received RTS,S/AS01 compared to girls who did not receive RTS,S/AS01. The data to be collected over 4 years will inform a policy decision about wider use of RTS,S/AS01 as a means to reduce malaria morbidity and mortality, when provided in addition to existing malaria control measures. It is anticipated that sufficient data to assess the safety signals are likely to be available after the first 2 years of the evaluation. At that time, all available data would be reviewed, including outcomes related to safety of the vaccine in routine use (meningitis, cerebral malaria, mortality by gender, AEFI), the impact on severe malaria and all-cause mortality, coverage of the first 3 doses, preliminary data on administration of the 4th dose, and cost-effectiveness assessment. A recommendation about wider use of the vaccine might therefore be made before final impact data are available, recognizing that the impact in any setting will depend on coverage and timeliness of vaccination and the malaria burden, which may differ from those in the MVIP.