Phase 1/2a Trial of Plasmodium vivax Malaria Vaccine Candidate VMP001/AS01B in Malaria-Naive Adults: Safety, Immunogenicity, and Efficacy

Abstract

BackgroundA vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use.MethodsWe conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15μg, 30μg, or 60μg respectively of VMP001, all formulated in 500μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls.ResultsThe vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period.SignificanceThis trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials.

Safety and Reproducibility of a Clinical Trial System Using Induced Blood Stage Plasmodium vivax Infection and Its Potential as a Model to Evaluate Malaria Transmission

“…Previous P . vivax challenges have utilized sporozoites produced by experimental infection of mosquitoes with blood from infected patients [15–17]. The P .…”

“…The P . vivax mosquito challenge system has the drawback of the risk of relapse due to the formation of hypnozoites that may not be easily eradicated despite primaquine therapy in subjects with certain CYP2D6 phenotypes [17,18]. …”

Vaccines to Accelerate Malaria Elimination and Eventual Eradication

“…Although relatively few P. vivax vaccine approaches have been tested in human clinical trials, a chimeric PvCSP protein (VMP001), developed by Walter Reed Army Institute of Research (WRAIR) and incorporating a truncated repeat region containing sequences from both the VK210 (type 1) and the VK247 (type 2) parasites has been evaluated in a single CHMI study. Although all volunteers immunized with VMP001/AS01 progressed to blood-stage parasitemia following challenge by infected mosquitoes, a significant delay in the median prepatency period was noted as compared to the infectivity controls (Bennett et al 2016). These results suggest that induced immune responses partially blocked hepatocyte invasion by sporozoites and/or emergence of merozoites from infected hepatocytes.…”

“…CHMI by mosquito bite challenge has been the most widely adopted, and provides a cost-effective, highly reproducible assessment of vaccine candidates for their efficacy against infection. Two groups have reported successful challenge with P. vivax -infected mosquitoes opening up the potential for much-needed research on P. vivax vaccines (Herrera et al 2009;Bennett et al 2016).…”

Rationale for Further Development of a Vaccine Based on the Circumsporozoite Protein of Plasmodium vivax

“…In addition, it resulted in a delay in patency in 59% of vaccinees. The vaccine did not induce sterile protection [8]. …”