Safety and Immunogenicity of ChAd63 and MVA ME-TRAP in West African Children and Infants

Abstract

Malaria remains a significant global health burden and a vaccine would make a substantial contribution to malaria control. Chimpanzee Adenovirus 63 Modified Vaccinia Ankara Multiple epitope thrombospondin adhesion protein (ME-TRAP) and vaccination has shown significant efficacy against malaria sporozoite challenge in malaria-naive European volunteers and against malaria infection in Kenyan adults. Infants are the target age group for malaria vaccination; however, no studies have yet assessed T-cell responses in children and infants. We enrolled 138 Gambian and Burkinabe children in four different age-groups: 2-6 years old in The Gambia; 5-17 months old in Burkina Faso; 5-12 months old, and also 10 weeks old, in The Gambia; and evaluated the safety and immunogenicity of Chimpanzee Adenovirus 63 Modified Vaccinia Ankara ME-TRAP heterologous prime-boost immunization. The vaccines were well tolerated in all age groups with no vaccine-related serious adverse events. T-cell responses to vaccination peaked 7 days after boosting with Modified Vaccinia Ankara, with T-cell responses highest in 10 week-old infants. Heterologous prime-boost immunization with Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara ME-TRAP was well tolerated in infants and children, inducing strong T-cell responses. We identify an approach that induces potent T-cell responses in infants, which may be useful for preventing other infectious diseases requiring cellular immunity.

Figure 1

Participant flow chart for malaria vectored vaccine trials in Gambian and Burkinabe children and infants. (a) CONSORT flow chart for groups 1, 2, and 3 in The Gambia. (b) CONSORT flow chart for group 4 in Burkina Faso.

Figure 2

Immune responses following ChAd63/MVA ME-TRAP vaccinations in Gambian children. (a) Individual responses by dose of ChAd63 ME-TRAP 14 days after vaccination. Increases in response were significant in volunteers receiving 5 × 10¹⁰ vp i.m. compared with rabies vaccine (Groups 1d and 1e compared with 1c and 1f, P = 0.004, Kruskal–Wallis). Lines represent group median. (b) Individual responses 7 days after boosting with MVA ME-TRAP (day 63), responses among recipients of the higher dose of MVA (2 × 10⁸ pfu i.m.) increased significantly compared with rabies vaccination. Boosting with the lower dose of MVA (1 × 10⁸ pfu i.m.) also increased responses significantly in group 1a. There was no significant effect of priming or boosting dose on the magnitude of the ELISPOT response at day 63 (1a compared with 1b or 1d compared with 1e, two-tailed Mann–Whitney test). (c) Time course of median ELISPOT responses in 2–6 years old children receiving either ChAd63-MVA ME-TRAP or HDCRV. Abbreviations: ChAd63, chimpanzee adenovirus serotype63; ME-TRAP, multiple epitope–thrombospondin-related adhesion protein; MVA, modified vaccinia virus Ankara; pfu, plaque-forming units; vp, viral particles; i.m., intramuscularly; HDCRV, human diploid cell rabies vaccine. All comparisons between time points use Kruskal–Wallis with Dunn's multiple comparison test: *P < 0.05; **P < 0.01, ***P < 0.001.

Figure 3

Immune responses following ChAd63/MVA ME-TRAP vaccinations in Gambian and Burkinabe infants. (a) Time course of median ELISPOT responses in 5–12 months old. Only available data points are shown. (b) Time course of median ELISPOT responses in babies aged 10 weeks at first vaccination. Responses were significantly higher at day 21 after ChAd63 ME-TRAP vaccination in the group that received the higher dose (P = 0.002, group 3a compared with 3b, two-tailed Mann-Whitney test). (c) Time course of median ELISPOT responses among 28 children aged 5–17 months old in Burkina Faso. All received 5 × 10¹⁰ vp i.m. ChAd63 ME-TRAP followed by 1 × 10⁸ pfu i.m. MVA ME-TRAP 8 weeks later. Responses were significantly higher than preimmunization levels at D63 (P < 0.0001) and D243 (P < 0.05). Abbreviations: ChAd63, chimpanzee adenovirus serotype63; ME-TRAP, multiple epitope–thrombospondin-related adhesion protein; MVA, modified vaccinia virus Ankara; pfu, plaque-forming units; vp, viral particles; i.m., intramuscularly; HDCRV, human diploid cell rabies vaccine. All comparisons between time points use Kruskal–Wallis with Dunn's multiple comparison test: *P < 0.05; **P < 0.01; **P < 0.001.