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.

Viral Vector Malaria Vaccines Induce High-Level T Cell and Antibody Responses in West African Children and Infants

“…Furthermore, a novel methodology for more physiological and robust comparison between adult and pediatric T cell responses was developed and applied across several age de-escalating clinical studies. Our immunogenicity findings combined with the acceptable safety profile observed in these studies 40 show clear potential utility of this approach for immunization against malaria and other childhood illnesses where either antibodies or cellular immunity are relevant to protection, for example RSV 52 . Further studies are underway to assess optimal regimes for immunization with co-administration of WHO Expanded Program of Immunisation (EPI) vaccines and to determine efficacy against clinical and severe malaria in a cohort of infants and children in a region of high malaria transmission.…”

“…Primary outcomes of safety, reactogenicity, dose-finding, and preliminary cellular immunogenicity from this study are reported separately 40 . Baseline demographics of trial participants are shown in Table S1.…”

“…We report elsewhere ex vivo IFNγ ELISpot responses stratified by age and dose in group 1 and group median response data stratified by dose in groups 2, 3, and 4 40 . Peak ELISpot responses were compared between groups in these age de-escalation studies with those from previously published adult phase I trials in the United Kingdom 34 and The Gambia 32 .…”

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

“…Reactogenicity of the ChAd63 RH5 vector was similar to that seen with the same doses of ChAd63 vectored vaccines encoding the P. falciparum antigen multiepitope string-thrombospondin-related adhesion protein (ME-TRAP), circumsporozoite protein (CSP), MSP1, or AMA1 (36-39, 52, 54) or the P. vivax antigen Duffy-binding protein region II (PvDBP_RII) (43). The same vectors encoding ME-TRAP have similarly been safe following immunization of adults, children, and infants residing in malaria-endemic areas (41,42). Our data with ChAd63 RH5 add to the growing body of evidence that this simian adenovirus vector is safe for clinical use.…”

“…This heterologous prime-boost approach has shown antibody induction against difficult-to-express malaria antigens in numerous animal models, including nonhuman primates (32,34,35). These vectors, delivering antigens from P. falciparum, have now been shown to be safe and immunogenic for T cell and antibodies in healthy European and American adult volunteers (36)(37)(38)(39)(40), as well as African adults, children, and infants (41,42). More recently, similar adenovirus-poxvirus vectored vaccine technologies have been used to immunize humans against numerous other pathogens including P. vivax malaria (43), Ebola virus (44), hepatitis C virus (HCV) (45), respiratory syncytial virus (RSV) (46) and HIV-1 (47).…”