Safety and Immunogenicity of a Recombinant Plasmodium falciparum AMA1 Malaria Vaccine Adjuvanted with Alhydrogel™, Montanide ISA 720 or AS02

Meta Roestenberg,Quirijn De Mast,Will Roeffen,Vanessa Walraven,Odile Leroy,Opokua Ofori-Anyinam,W Ripley Ballou,Ed Remarque,Joe Cohen,Karina Teelen,Erik De Jonge,Clemens H M Kocken,Stéphane Ascarateil,Søren Jepsen ,Alan W Thomas ,Melina Arnold ,Egeruan Babatunde Imoukhuede ,Bart W Faber ,Rick Hermsen ,Hildur E Blythman ,Marie-Claude Dubois ,André Van Der Ven ,Robert W Sauerwein

doi:10.1371/journal.pone.0003960

Abstract

Background Plasmodium falciparum Apical Membrane Antigen 1 (PfAMA1) is a candidate vaccine antigen expressed by merozoites and sporozoites. It plays a key role in red blood cell and hepatocyte invasion that can be blocked by antibodies.Methodology/Principal FindingsWe assessed the safety and immunogenicity of recombinant PfAMA1 in a dose-escalating, phase Ia trial. PfAMA1 FVO strain, produced in Pichia pastoris, was reconstituted at 10 µg and 50 µg doses with three different adjuvants, Alhydrogel™, Montanide ISA720 and AS02 Adjuvant System. Six randomised groups of healthy male volunteers, 8–10 volunteers each, were scheduled to receive three immunisations at 4-week intervals. Safety and immunogenicity data were collected over one year. Transient pain was the predominant injection site reaction (80–100%). Induration occurred in the Montanide 50 µg group, resulting in a sterile abscess in two volunteers. Systemic adverse events occurred mainly in the AS02 groups lasting for 1–2 days. Erythema was observed in 22% of Montanide and 59% of AS02 group volunteers. After the second dose, six volunteers in the AS02 group and one in the Montanide group who reported grade 3 erythema (>50 mm) were withdrawn as they met the stopping criteria. All adverse events resolved. There were no vaccine-related serious adverse events. Humoral responses were highest in the AS02 groups. Antibodies showed activity in an in vitro growth inhibition assay up to 80%. Upon stimulation with the vaccine, peripheral mononuclear cells from all groups proliferated and secreted IFNγ and IL-5 cytokines.Conclusions/SignificanceAll formulations showed distinct reactogenicity profiles. All formulations with PfAMA1 were immunogenic and induced functional antibodies.Trial RegistrationClinicaltrials.gov NCT00730782

Highlights

In sub-Saharan Africa the burden of death and disease from Plasmodium falciparum malaria is severe
Seven volunteers were excluded because they developed grade 3 erythema after the second immunisation; one in the Montanide 10 mg group, the other six in the AS02 groups
Most post immunisations adverse events were mild-to-moderate in intensity and have been seen previously with other vaccines[35,36,37,38,39,40]. Because this was the first time Pichia Pastoris produced FVO Plasmodium falciparum Apical Membrane Antigen 1 (PfAMA1) antigen was being given to humans, the occurrence of a grade 3 adverse event was a stopping criterium, which led to withdrawal of seven subjects post dose 2 for grade 3 (.50 mm) erythema

Summary

Introduction

In sub-Saharan Africa the burden of death and disease from Plasmodium falciparum malaria is severe. The MSP1 and AMA1 candidate vaccines are in early stage clinical development and efficacy trials will provide information to determine whether these antigens are suitable targets, and whether they can be deployed singly or as components of a multivalent malaria vaccine. Following an infected mosquito bite, P. falciparum sporozoites migrate to hepatocytes, each developing over a period of a week to release several thousand merozoites These initiate cyclical asexual blood stage development, producing merozoites that invade erythrocytes. Plasmodium falciparum Apical Membrane Antigen 1 (PfAMA1) is a candidate vaccine antigen expressed by merozoites and sporozoites It plays a key role in red blood cell and hepatocyte invasion that can be blocked by antibodies

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