Safety and Immunogenicity of ChAd63/MVA Pfs25-IMX313 in a Phase I First-in-Human Trial

Abstract

BackgroundTransmission blocking vaccines targeting the sexual-stages of the malaria parasite could play a major role to achieve elimination and eradication of malaria. The Plasmodium falciparum Pfs25 protein (Pfs25) is the most clinically advanced candidate sexual-stage antigen. IMX313, a complement inhibitor C4b-binding protein that forms heptamers with the antigen fused to it, improve antibody responses. This is the first time that viral vectors have been used to induce antibodies in humans against an antigen that is expressed only in the mosquito vector.MethodsClinical trial looking at safety and immunogenicity of two recombinant viral vectored vaccines encoding Pfs25-IMX313 in healthy malaria-naive adults. Replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA), encoding Pfs25-IMX313, were delivered by the intramuscular route in a heterologous prime-boost regimen using an 8-week interval. Safety data and samples for immunogenicity assays were taken at various time-points.ResultsThe reactogenicity of the vaccines was similar to that seen in previous trials using the same viral vectors encoding other antigens. The vaccines were immunogenic and induced both antibody and T cell responses against Pfs25, but significant transmission reducing activity (TRA) was not observed in most volunteers by standard membrane feeding assay.ConclusionBoth vaccines were well tolerated and demonstrated a favorable safety profile in malaria-naive adults. However, the transmission reducing activity of the antibodies generated were weak, suggesting the need for an alternative vaccine formulation.Trial RegistrationClinicaltrials.gov NCT02532049.

Poor CD4+ T Cell Immunogenicity Limits Humoral Immunity to P. falciparum Transmission-Blocking Candidate Pfs25 in Humans

“…Murine Vaccine-Induced Abs Demonstrate Superior Transmission-Reducing Activity to Human BALB/c mice were primed (Day 0) with 1 × 10 8 infectious units (vp) of ChAd63-Pfs25-IMX313 and boosted 8 weeks later (day 56) with 1 × 10 7 plaque forming units (pfu) of MVA-Pfs25-IMX313, while the healthy UK adult volunteers enrolled into the VAC062 trial (ClinicalTrials.gov Identifier : NCT02532049) were primed with 5 × 10 10 vp ChAd63 Pfs25-IMX313 followed by either 1x10 8 pfu or 2x10 8 pfu MVA Pfs25-IMX313 boost (Groups 2B and 2C, respectively) (12). Sera were collected from both mice and human volunteers on days 72 (2 weeks post-boost) and magnitude of the anti-Pfs25 serum IgG Ab response was assessed by ELISA against Pfs25 recombinant protein.…”

“…We cannot rule out the idea that different Pfs25-directed vaccine approaches may have differing immunogenic potential, given the diverse range of immunogen designs, expression systems, formulations and immunization schedules. Although it is encouraging that vaccination of humans can induce transmission-blocking Abs targeting Pfs25 when delivered via viral vectors ( 12 ), it does seem likely, however, that boosting the immunogenicity of the Pfs25 via novel adjuvants, carrier proteins and nanoparticle or viral-particle formulations will be necessary to elicit robust titers of Pfs25-immunity in humans. In particular, it would be pertinent to consider formulations that contain CD4 + T cell epitopes and adjuvants that trigger pathways known to enhance Tfh cell differentiation, enabling them to guide an appropriate B cell response and achieve sufficient amount of high-quality Abs able to facilitate transmission blocking.…”

“…In total, twenty six volunteers were enrolled, with twenty four vaccinated as per protocol and twenty two completing follow-up. This was a Phase I open-label, dose escalation, first-in-human, non-randomized trial of the viral vectored vaccines ChAd63 Pfs25-IMX313 and MVA Pfs25-IMX313 given in a prime-boost regimen with an eight week interval ( 12 ). The study received ethical approval from the Oxfordshire Research Ethics Committee A in the UK (REC reference 15/SC/0237).…”

“…CFCA was performed as previously described ( 12 , 70 , 75 ), using a Biacore X100 instrument, a Biotin CAP chip, and X100 control and evaluation software (GE Lifesciences, UK). Briefly, CFCA was performed using serum samples isolated either from vaccinated mice or human subjects in Groups 2B and 2C with a range of Pfs25-specific IgG Ab responses as assessed by ELISA.…”

“…This C4 bp oligomerization domain has been shown to spontaneously form soluble heptameric structures when expressed in E. coli ( 11 ) and we have already demonstrated in mice that Pfs25 fused to IMX313 domain improved Ab responses over the same amount of monomeric antigen when expressed in ChAd63 and MVA viral vectors ( 10 ). Although this approach showed great promise in mice ( 10 ), relatively low anti-Pfs25 Ab titers were generated in humans in our Phase I First-in-Human clinical trial ( 12 ). In this study, the transmission reducing activity of the antibodies generated was weak, but both test vaccines were well tolerated and demonstrated a favourable safety profile in malaria-naive adults.…”