Malaria transmission is in decline in some parts of Africa, partly due to the scaling up of control measures. If the goal of elimination is to be achieved, additional control measures including an effective and durable vaccine will be required. Studies utilising the prime-boost approach to deliver viral vectors encoding the pre-erythrocytic antigen ME-TRAP (multiple epitope thrombospondin-related adhesion protein) have shown promising safety, immunogenicity and efficacy in sporozoite challenge studies. More recently, a study in Kenyan adults, similar to that reported here, showed substantial efficacy against P. falciparum infection. One hundred and twenty healthy male volunteers, living in a malaria endemic area of Senegal were randomised to receive either the Chimpanzee adenovirus (ChAd63) ME-TRAP as prime vaccination, followed eight weeks later by modified vaccinia Ankara (MVA) also encoding ME-TRAP as booster, or two doses of anti-rabies vaccine as a comparator. Prior to follow-up, antimalarials were administered to clear parasitaemia and then participants were monitored by PCR for malaria infection for eight weeks. The primary endpoint was time-to-infection with P. falciparum malaria, determined by two consecutive positive PCR results. Secondary endpoints included adverse event reporting, measures of cellular and humoral immunogenicity and a meta-analysis of combined vaccine efficacy with the parallel study in Kenyan adults.We show that this pre-erythrocytic malaria vaccine is safe and induces significant immunogenicity, with a peak T-cell response at seven days after boosting of 932 Spot Forming Cells (SFC)/106 Peripheral Blood Mononuclear Cells(PBMC) compared to 57 SFC/ 106 PBMCs in the control group. However, a vaccine efficacy was not observed: 12 of 57 ME-TRAP vaccinees became PCR positive during the intensive monitoring period as compared to 13 of the 58 controls (P = 0.80). This trial confirms that vaccine efficacy against malaria infection in adults may be rapidly assessed using this efficient and cost-effective clinical trial design. Further efficacy evaluation of this vectored candidate vaccine approach in other malaria transmission settings and age-de-escalation into the main target age groups for a malaria vaccine is in progress.
BackgroundHeterologous prime-boost vaccination with chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) encoding multiple epitope string thrombospondin-related adhesion protein (ME-TRAP) has shown acceptable safety and promising immunogenicity in African adult and pediatric populations. If licensed, this vaccine could be given to infants receiving routine childhood immunizations. We therefore evaluated responses to ChAd63 MVA ME-TRAP when co-administered with routine Expanded Program on Immunization (EPI) vaccines.MethodsWe enrolled 65 Gambian infants and neonates, aged 16, 8, or 1 week at first vaccination and randomized them to receive either ME-TRAP and EPI vaccines or EPI vaccines only. Safety was assessed by the description of vaccine-related adverse events (AEs). Immunogenicity was evaluated using IFNγ enzyme-linked immunospot, whole-blood flow cytometry, and anti-TRAP IgG ELISA. Serology was performed to confirm all infants achieved protective titers to EPI vaccines.ResultsThe vaccines were well tolerated in all age groups with no vaccine-related serious AEs. High-level TRAP-specific IgG and T cell responses were generated after boosting with MVA. CD8+ T cell responses, previously found to correlate with protection, were induced in all groups. Antibody responses to EPI vaccines were not altered significantly.ConclusionMalaria vectored prime-boost vaccines co-administered with routine childhood immunizations were well tolerated. Potent humoral and cellular immunity induced by ChAd63 MVA ME-TRAP did not reduce the immunogenicity of co-administered EPI vaccines, supporting further evaluation of this regimen in infant populations.Clinical Trial RegistrationThe clinical trial was registered on (NCT02083887) and the Pan-African Clinical Trials Registry (PACTR201402000749217).
HighlightsAntibody dynamics and role in young the infants’ low susceptibility to febrile malaria were investigated.No evidence for association of antibody titres with clinical protection was found.Evidence for consistently low antibody titres in high and low transmission areas.Other antibodies, other antibody-mediated mechanisms or other protecting factors may be operating.
BackgroundRecent global estimates show thatP. falciparummalaria still constitutes an enormous public health concern. Chief amongst desirable interventions is an effective vaccine that could complement existing control measures. Heterologous prime-boost vaccinations involving chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara (MVA) encoding ME-TRAP have consistently shown acceptable safety, excellent immunogenicity and substantial efficacy in African adult and paediatric populations. When licensed, malaria vaccines would preferably be given to infants receiving routine childhood immunisations. Nevertheless, no studies have evaluated the interference of ChAd63/MVA ME-TRAP when co-administered with routine Expanded Programme Immunisation (EPI) vaccines.MethodsWe enrolled 65 Gambian infants and neonates in an age de-escalating fashion, priming at 4 months, 8 weeks or 1 week of age, and randomised them to vaccine or control (EPI vaccines only) arm. Safety was assessed by the description of vaccine-related adverse events ascertained through clinical assessments, biochemical and haematological tests. Immunogenicity was evaluated by IgG ELISA, interferon-gamma ELISPOT, intra-cellular cytokine staining and flow cytometry. Antibody testing was performed to assess any interference of the EPI vaccines with responses to ChAd63/MVA ME-TRAP.ResultsOverall, the vaccination regimes were well tolerated in all age groups with no vaccine-related serious adverse events. High level IgG and antigen-specific T cell responses were generated after boosting with MVA, with T cell responses highest in the infants 8 week old at priming dose. EPI vaccines retained unchanged antibody levels in all age groups.ConclusionsPotent humoral and cellular immunity induced by heterologous prime-boost immunisation with ChAd63 and MVA ME-TRAP did not interfere with the immunogenicity of co-administered routine EPI vaccines in infants and neonates. Potent T cell induction was again observed with the vectored malaria vaccines despite co-administration with EPI vaccines.
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