Reduced blood-stage malaria growth and immune correlates in humans following RH5 vaccination

Summary

Background

Development of an effective vaccine against the pathogenic blood-stage infection of human malaria has proved challenging, and no candidate vaccine has affected blood-stage parasitemia following controlled human malaria infection (CHMI) with blood-stage Plasmodium falciparum.

Methods

We undertook a phase I/IIa clinical trial in healthy adults in the United Kingdom of the RH5.1 recombinant protein vaccine, targeting the P. falciparum reticulocyte-binding protein homolog 5 (RH5), formulated in AS01 _B adjuvant. We assessed safety, immunogenicity, and efficacy against blood-stage CHMI. Trial registered at ClinicalTrials.gov, NCT02927145.

Findings

The RH5.1/AS01 _B formulation was administered using a range of RH5.1 protein vaccine doses (2, 10, and 50 μg) and was found to be safe and well tolerated. A regimen using a delayed and fractional third dose, in contrast to three doses given at monthly intervals, led to significantly improved antibody response longevity over ∼2 years of follow-up. Following primary and secondary CHMI of vaccinees with blood-stage P. falciparum, a significant reduction in parasite growth rate was observed, defining a milestone for the blood-stage malaria vaccine field. We show that growth inhibition activity measured in vitro using purified immunoglobulin G (IgG) antibody strongly correlates with in vivo reduction of the parasite growth rate and also identify other antibody feature sets by systems serology, including the plasma anti-RH5 IgA1 response, that are associated with challenge outcome.

Conclusions

Our data provide a new framework to guide rational design and delivery of next-generation vaccines to protect against malaria disease.

Funding

This study was supported by USAID, UK MRC, Wellcome Trust, NIAID, and the NIHR Oxford-BRC.

Graphical abstract

Highlights

• The RH5.1/AS01 _B vaccine is safe, well tolerated, and immunogenic in healthy adults

• A delayed fractional third dose significantly improves antibody response longevity

• In vivo blood-stage P. falciparum growth rate is significantly lower in vaccinees

• In vitro IgG-mediated growth inhibition activity is associated with challenge outcome

Context and significance

A highly effective vaccine against the human malaria parasite Plasmodium falciparum is urgently needed. One vaccine strategy aims to prevent parasite growth in the blood, protecting against clinical disease; however, this has proved exceptionally challenging. Here we show that a candidate vaccine (reticulocyte-binding protein homolog 5.1 [RH5.1]/AS01 _B) is safe in a phase I/IIa clinical trial and identify a vaccination regimen that improves the durability of the human antibody response, which is critical for long-term protection. Following experimental challenge of vaccinated adults with malaria, we observed that the vaccine could reduce parasite growth in the blood and identified immune responses that could predict how well the vaccine performs. These data will help guide the design of improved vaccines in the future.

Abstract

Minassian et al. report that the RH5.1/AS01 _B vaccine against blood-stage Plasmodium falciparum malaria is safe and immunogenic in a phase I/IIa clinical trial. They demonstrate a significantly reduced blood-stage parasite growth rate in vaccinees following controlled human malaria infection and identify that in vitro antibody-mediated growth inhibition activity is associated with challenge outcome.