A phase 2b randomised trial of the candidate malaria vaccines FP9 ME-TRAP and MVA ME-TRAP among children in Kenya

Abstract

Objective: The objective was to measure the efficacy of the vaccination regimen FFM ME-TRAP in preventing episodes of clinical malaria among children in a malaria endemic area. FFM ME-TRAP is sequential immunisation with two attenuated poxvirus vectors (FP9 and modified vaccinia virus Ankara), which both deliver the pre-erythrocytic malaria antigen construct multiple epitope-thrombospondin-related adhesion protein (ME-TRAP).

Design: The trial was randomised and double-blinded.

Setting: The setting was a rural, malaria-endemic area of coastal Kenya.

Participants: We vaccinated 405 healthy 1- to 6-year-old children.

Interventions: Participants were randomised to vaccination with either FFM ME-TRAP or control (rabies vaccine).

Outcome measures: Following antimalarial drug treatment children were seen weekly and whenever they were unwell during nine months of monitoring. The axillary temperature was measured, and blood films taken when febrile. The primary analysis was time to a parasitaemia of over 2,500 parasites/mul.

Results: The regime was moderately immunogenic, but the magnitude of T cell responses was lower than in previous studies. In intention to treat (ITT) analysis, time to first episode was shorter in the FFM ME-TRAP group. The cumulative incidence of febrile malaria was 52/190 (27%) for FFM ME-TRAP and 40/197 (20%) among controls (hazard ratio = 1.52). This was not statistically significant (95% confidence interval [CI] 1.0-2.3; p = 0.14 by log-rank). A group of 346 children were vaccinated according to protocol (ATP). Among these children, the hazard ratio was 1.3 (95% CI 0.8-2.1; p = 0.55 by log-rank). When multiple malaria episodes were included in the analyses, the incidence rate ratios were 1.6 (95% CI 1.1-2.3); p = 0.017 for ITT, and 1.4 (95% CI 0.9-2.1); p = 0.16 for ATP. Haemoglobin and parasitaemia in cross-sectional surveys at 3 and 9 mo did not differ by treatment group. Among children vaccinated with FFM ME-TRAP, there was no correlation between immunogenicity and malaria incidence.

Conclusions: No protection was induced against febrile malaria by this vaccine regimen. Future field studies will require vaccinations with stronger immunogenicity in children living in malarious areas.

Conflict of interest statement

Competing Interests: AVSH is cofounder of and an equity holder in Oxxon Therapeutics, a company developing prime-boost therapeutic vaccines. No other authors have any conflicts of interest.

Figures

Figure 1. Trial Profile

After screening for eligibility, parents were invited to bring their children back to the dispensary for immunisation. Children were randomised on attending for vaccination. Of the 17 children who attended for the first, but not the final, vaccination, two had moved out of the area, and parents of the remaining 15 chose not to reattend. No severe adverse events were identified in these children. Before 9 mo monitoring was complete, eight children had moved out of the area.

Figure 2. Primary Analysis of Efficacy

The probability of remaining free of clinical malaria is plotted over the 9 mo of monitoring (the primary analysis). Numbers of children at risk are given below the Kaplan-Meier plots for ITT (top; p = 0.55) and ATP (bottom; p = 0.14). Both plots use an endpoint of over 2,500 parasites/μl and fever.

Figure 3. Secondary Analyses for Efficacy

The results from secondary analyses of malaria episodes are shown. These multiple analyses were generated by varying the case definition and the statistical methodology, and are shown for both ATP and ITT. The more rigorous case definition (over 2,500 parasites/μl and fever) is the first in each group of comparisons. Cox regression was used to estimate hazard ratios for time to first episode (A) and Poisson regression was used to estimate incidence rate ratios for the frequency of episodes (B). Models were adjusted for age, village, and ITN use. The two groups of three points to the right of each panel show the hazard ratios and incidence rate ratios for subgroups FFM ME-TRAP-vaccinated children. Participants were divided into tertiles based on either ex vivo or cultured ELISPOT responses. Hazard ratios and incidence rate ratios for each tertile relative to the control group are shown, using a case definition of parasitaemia over 2,500/μl and fever.

Figure 4. Immunogenicity

T cell responses to vaccination identified by both ex vivo and cultured ELISPOT are displayed over time. Median, 25th, and 75th quartile, 5th and 95th quartile, and outlying results are given by box and whisker plots. Data were available for 400 children at screening (i.e., prevaccination), for 379 children 7 d after the last vaccination, for 345 at 3 mo, and for 304 at 9 mo. T cell numbers were similar at baseline for ex vivo (p = 0.4) and cultured (p = 0.91) responses. Ex vivo responses were higher among FFM vaccinees at 1 wk (p < 0.001) and 9 mo (p = 0.015), as were cultured responses. Ex vivo responses did not significantly differ at 3 mo (p = 0.27), but cultured responses did (p < 0.001).