BACKGROUNDThe replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. METHODSWe performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. RESULTSNo serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants. CONCLUSIONSIn these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy.

Background: Controlled human malaria infection (CHMI) studies are a vital tool to accelerate vaccine and drug development. As CHMI trials are performed in a controlled environment, they allow unprecedented, detailed evaluation of parasite growth dynamics (PGD) and immunological responses. However, CHMI studies have not been routinely performed in malaria-endemic countries or used to investigate mechanisms of naturally-acquired immunity (NAI) to Plasmodium falciparum.Methods: We conducted an open-label, randomized CHMI pilot-study using aseptic, cryopreserved P. falciparum sporozoites (PfSPZ Challenge) to evaluate safety, infectivity and PGD in Kenyan adults with low to moderate prior exposure to P. falciparum (Pan African Clinical Trial Registry: PACTR20121100033272).Results: All participants developed blood-stage infection confirmed by quantitative polymerase chain reaction (qPCR). However one volunteer (110) remained asymptomatic and blood-film negative until day 21 post-injection of PfSPZ Challenge. This volunteer had a reduced parasite multiplication rate (PMR) (1.3) in comparison to the other 27 volunteers (median 11.1). A significant correlation was seen between PMR and screening anti-schizont Enzyme Linked Immunosorbent Assays (ELISA) OD (p = 0.044, R = −0.384) but not when volunteer 110 was excluded from the analysis (p = 0.112, R = −0.313).Conclusions: PfSPZ Challenge is safe and infectious in malaria-endemic populations and could be used to assess the efficacy of malaria vaccines and drugs in African populations. Whilst our findings are limited by sample size, our pilot study has demonstrated for the first time that NAI may impact on PMR post-CHMI in a detectable fashion, an important finding that should be evaluated in further CHMI studies.

Protective immunity to the liver stage of the malaria parasite can be conferred by vaccine-induced T cells, but no subunit vaccination approach based on cellular immunity has shown efficacy in field studies. We randomly allocated 121 healthy adult male volunteers in Kilifi, Kenya, to Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts vaccination with the recombinant viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara (MVA), both encoding the malaria peptide sequence ME-TRAP (the multiple epitope string and thrombospondin-related adhesion protein), or to vaccination with rabies vaccine as a control. We gave antimalarials to clear parasitemia and conducted PCR (polymerase chain reaction) analysis on blood samples three times a week to identify infection with the malaria parasite Plasmodium falciparum. On Cox regression, vaccination reduced the risk of infection by 67% [95% confidence interval (CI), 33 to 83%; P = 0.002] during 8 weeks of monitoring. T cell responses to TRAP peptides 21 to 30 were significantly associated with protection (hazard ratio, 0.24; 95% CI, 0.08 to 0.75; P = 0.016).

BackgroundControlled human malaria infection (CHMI) studies, in which healthy volunteers are infected with Plasmodium falciparum to assess the efficacy of novel malaria vaccines and drugs, have become a vital tool to accelerate vaccine and drug development. CHMI studies provide a cost-effective and expeditious way to circumvent the use of large-scale field efficacy studies to deselect intervention candidates. However, to date few modern CHMI studies have been performed in malaria-endemic countries.MethodsAn open-label, randomized pilot CHMI study was conducted using aseptic, purified, cryopreserved, infectious P. falciparum sporozoites (SPZ) (Sanaria® PfSPZ Challenge) administered intramuscularly (IM) to healthy Kenyan adults (n = 28) with varying degrees of prior exposure to P. falciparum. The purpose of the study was to establish the PfSPZ Challenge CHMI model in a Kenyan setting with the aim of increasing the international capacity for efficacy testing of malaria vaccines and drugs, and allowing earlier assessment of efficacy in a population for which interventions are being developed. This was part of the EDCTP-funded capacity development of the CHMI platform in Africa.DiscussionThis paper discusses in detail lessons learnt from conducting the first CHMI study in Kenya. Issues pertinent to the African setting, including community sensitization, consent and recruitment are considered. Detailed reasoning regarding the study design (for example, dose and route of administration of PfSPZ Challenge, criteria for grouping volunteers according to prior exposure to malaria and duration of follow-up post CHMI) are given and changes other centres may want to consider for future studies are suggested.ConclusionsPerforming CHMI studies in an African setting presents unique but surmountable challenges and offers great opportunity for acceleration of malaria vaccine and drug development. The reflections in this paper aim to aid other centres and partners intending to use the CHMI model in Africa.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0671-x) contains supplementary material, which is available to authorized users.

BackgroundHeterologous prime boost immunization with chimpanzee adenovirus 63 (ChAd63) and Modified vaccinia Virus Ankara (MVA) vectored vaccines is a strategy recently shown to be capable of inducing strong cell mediated responses against several antigens from the malaria parasite. ChAd63-MVA expressing the Plasmodium falciparum pre-erythrocytic antigen ME-TRAP (multiple epitope string with thrombospondin-related adhesion protein) is a leading malaria vaccine candidate, capable of inducing sterile protection in malaria naïve adults following controlled human malaria infection (CHMI).MethodologyWe conducted two Phase Ib dose escalation clinical trials assessing the safety and immunogenicity of ChAd63-MVA ME-TRAP in 46 healthy malaria exposed adults in two African countries with similar malaria transmission patterns.ResultsChAd63-MVA ME-TRAP was shown to be safe and immunogenic, inducing high-level T cell responses (median >1300 SFU/million PBMC).ConclusionsChAd63-MVA ME-TRAP is a safe and highly immunogenic vaccine regimen in adults with prior exposure to malaria. Further clinical trials to assess safety and immunogenicity in children and infants and protective efficacy in the field are now warranted.Trial RegistrationPactr.org PACTR2010020001771828 Pactr.org PACTR201008000221638 ClinicalTrials.gov NCT01373879 NCT01373879 ClinicalTrials.gov NCT01379430 NCT01379430