Controlled Human Malaria Infection of Healthy Adults With Lifelong Malaria Exposure to Assess Safety, Immunogenicity, and Efficacy of the Asexual Blood Stage Malaria Vaccine Candidate GMZ2

Abstract

Background: GMZ2 is a recombinant malaria vaccine inducing immune responses against Plasmodium falciparum (Pf) merozoite surface protein-3 and glutamate-rich protein. We used standardized controlled human malaria infection (CHMI) to assess the efficacy of this asexual blood-stage vaccine.

Methods: We vaccinated 50 healthy, adult volunteers with lifelong exposure to Pf 3 times, at 4-week intervals, with 30 or 100 µg GMZ2 formulated in CAF01, a liposome-based adjuvant; 100 µg GMZ2, formulated in Alhydrogel; or a control vaccine (Verorab). Approximately 13 weeks after the last vaccination, 35/50 volunteers underwent CHMI by direct venous inoculation of 3200 Pf sporozoites (Sanaria® PfSPZ Challenge).

Results: Adverse events were similarly distributed between GMZ2 and control vaccinees. Baseline-corrected anti-GMZ2 antibody concentrations 4 weeks after the last vaccination were higher in all 3 GMZ2-vaccinated arms, compared to the control group. All GMZ2 formulations induced similar antibody levels. CHMI resulted in 29/34 (85%) volunteers with Pf parasitemia and 15/34 (44%) with malaria (parasitemia and symptoms). The proportion of participants with malaria (2/5 control, 6/10 GMZ2-Alhydrogel, 2/8 30 µg GMZ2-CAF01, and 5/11 100 µg GMZ2-CAF01) and the time it took them to develop malaria were similar in all groups. Baseline, vaccine-specific antibody concentrations were associated with protection against malaria.

Conclusions: GMZ2 is well tolerated and immunogenic in lifelong-Pf-exposed adults from Gabon, with similar antibody responses regardless of formulation. CHMI showed no protective effect of prior vaccination with GMZ2, although baseline, vaccine-specific antibody concentrations were associated with protection. CHMI with the PfSPZ Challenge is a potent new tool to validate asexual, blood-stage malaria vaccines in Africa.

Clinical trials registration: Pan-African Clinical Trials: PACTR201503001038304.

Keywords: Plasmodium falciparum; clinical trial; controlled human malaria infection; malaria vaccine.

Figure 1.

Study flow diagram. Abbreviation: CHMI, controlled human malaria infection; Vac, vaccination.

Figure 2.

Kaplan-Meier plot. A, The time to malaria treatment in control is shown in light blue, GMZ2-Alhydrogel in dark blue, 30 µg GMZ2-CAF01 in light green, and 100 µg GMZ2-CAF01 in dark green for vaccinated volunteers. B, The time to malaria treatment with anti-GMZ2 immunoglobin G concentration at baseline above the median is shown in dark blue, and below the median is in light blue.

Figure 3.

Parasitemia over time. Parasitemia was measured by quantitative, polymerase chain reaction. Data until treatment with an antimalarial (either due to symptoms or at the end of the 35-day follow-up period) are shown. Volunteers who developed malaria are shown in dark blue, those with controlled parasitemia at low levels without symptoms are in light blue, and those who were fully protected are in green. There was 1 volunteer of Group B who had non-NF54 submicroscopic parasitemia over the complete CHMI period and was considered protected (green). Abbreviations: CHMI, controlled human malaria infection; DVI, direct venous inoculation.

Figure 4.

Vaccine-specific IgG over time. The increase of IgG from baseline to 4 weeks following the last vaccination (Day 84) is shown. The numbers indicate baseline-corrected fold-increase over control vaccine on Day 84 (95% confidence interval). Note the large range of IgG at baseline. Volunteers who developed malaria are shown in dark blue, those with controlled parasitemia at low levels without symptoms are in light blue, those who were fully protected are in green, and those who did not undergo CHMI are in gray. Abbreviations: aGLURP, anti-glutamate rich protein IgG; aGMZ2, anti-GMZ2 IgG; aMSP3, anti-merozoite protein-3 IgG; CHMI, controlled human malaria infection; IgG, immunoglobin G. *Indicates pooled Group D and E estimates. Bolded values: statistically significant change.