Immunization with full-length Plasmodium falciparum merozoite surface protein 1 is safe and elicits functional cytophilic antibodies in a randomized first-in-human trial

Antje Blank,Anja Jäschke,Johannes Hüsing,Gerd Mikus,Thomas Giese,Hermann Bujard,Kirsten Heiss,Ernst Böhnlein,Walter E Haefeli,Michael Lanzer,Darrick Carter,Kristin Fürle,Monika Lehmann

doi:10.1038/s41541-020-0160-2

Abstract

A vaccine remains a priority in the global fight against malaria. Here, we report on a single-center, randomized, double-blind, placebo and adjuvant-controlled, dose escalation phase 1a safety and immunogenicity clinical trial of full-length Plasmodium falciparum merozoite surface protein 1 (MSP1) in combination with GLA-SE adjuvant. Thirty-two healthy volunteers were vaccinated at least three times with MSP1 plus adjuvant, adjuvant alone, or placebo (24:4:4) to evaluate the safety and immunogenicity. MSP1 was safe, well tolerated and immunogenic, with all vaccinees sero-converting independent of the dose. The MSP1-specific IgG and IgM titers persisted above levels found in malaria semi-immune humans for at least 6 months after the last immunization. The antibodies were variant- and strain-transcending and stimulated respiratory activity in granulocytes. Furthermore, full-length MSP1 induced memory T-cells. Our findings encourage challenge studies as the next step to evaluate the efficacy of full-length MSP1 as a vaccine candidate against falciparum malaria (EudraCT 2016-002463-33).

Highlights

In recent years, progress in global malaria control has stalled at~219 million clinical cases and 435,000 deaths annually following a decade of decreasing disease burden.[1]
Our study differs from previous clinical trials in that we vaccinated volunteers with full-length merozoite surface protein 1 (MSP1) instead of rather small MSP1 fragments
The rationale behind pursuing the development of MSP1 as a blood stage and as a pre-erythrocytic vaccine candidate in spite of discouraging results from two phase 2 challenge trials in humans,[46,47] is that the full-length MSP1 contains B-cell and Tcell epitopes not present in previous MSP1-based vaccine candidates,[32,40,48,49,50,51,52] which comprised merely the p42 fragment or composites made of conserved MSP1 domains.[46,47]

Summary

Introduction

Progress in global malaria control has stalled at. ~219 million clinical cases and 435,000 deaths annually following a decade of decreasing disease burden.[1] Apparently, the current intervention regimens, i.e., vector control and optimized drug treatment strategies,[2,3] are insufficient to achieve a sustainable, steady reduction in malaria incidence, and eventually an elimination of this infectious disease. A key priority is the development of a long-lasting, effective vaccine with a primary focus on the virulent and deadly form of malaria caused by the protozoan parasite Plasmodium falciparum.[4,5]. Great effort has been invested in the identification of protective antigens, previous vaccination strategies have generally been unsatisfactory and only the pre-erythrocytic vaccine RTS,S (MosquirixTM, GSK Bio), based on the P. falciparum circumsporozoite antigen, is under pilot implementation studies in three African countries.[8,9,10,11] its efficacy is moderate and short-lived (39% reduction in overall malaria incidence and 31.5% in life-threatening complications over a follow-up period of 48 months in children who received four injections12,13), possibly due to a decay in complement-fixing antibodies.[14]

Methods

Results

Conclusion