Virosome-Formulated Plasmodium falciparum AMA-1 &amp; CSP Derived Peptides as Malaria Vaccine: Randomized Phase 1b Trial in Semi-Immune Adults &amp; Children

Patrick Georges Cech,Claudia Daubenberger,Nicole Westerfeld,Mwanajaa Shomari Abdallah,Sabine Alexandra Stoffel,Gerd Pluschke,Ester Barnabas Machunda,Maxmillian Mpina,Salim Abdulla,Thomas Aebi,Blaise Genton,Marcel Tanner,Rinaldo Zurbriggen,Ruth D Ellis

doi:10.1371/journal.pone.0022273

Abstract

BackgroundThis trial was conducted to evaluate the safety and immunogenicity of two virosome formulated malaria peptidomimetics derived from Plasmodium falciparum AMA-1 and CSP in malaria semi-immune adults and children.MethodsThe design was a prospective randomized, double-blind, controlled, age-deescalating study with two immunizations. 10 adults and 40 children (aged 5–9 years) living in a malaria endemic area were immunized with PEV3B or virosomal influenza vaccine Inflexal®V on day 0 and 90.ResultsNo serious or severe adverse events (AEs) related to the vaccines were observed. The only local solicited AE reported was pain at injection site, which affected more children in the Inflexal®V group compared to the PEV3B group (p = 0.014). In the PEV3B group, IgG ELISA endpoint titers specific for the AMA-1 and CSP peptide antigens were significantly higher for most time points compared to the Inflexal®V control group. Across all time points after first immunization the average ratio of endpoint titers to baseline values in PEV3B subjects ranged from 4 to 15 in adults and from 4 to 66 in children. As an exploratory outcome, we found that the incidence rate of clinical malaria episodes in children vaccinees was half the rate of the control children between study days 30 and 365 (0.0035 episodes per day at risk for PEV3B vs. 0.0069 for Inflexal®V; RR = 0.50 [95%-CI: 0.29–0.88], p = 0.02).ConclusionThese findings provide a strong basis for the further development of multivalent virosomal malaria peptide vaccines.Trial RegistrationClinicalTrials.gov NCT00513669

Highlights

The development of an effective malaria vaccine is regarded as one cornerstone in the fight against this deadly disease and to achieve its eventual elimination [1]
The circumsporozoite protein (CSP), the major surface protein of the P. falciparum sporozoite, has been the focus of numerous efforts to develop a pre-erythrocyte vaccine that aims at prevention of hepatocyte invasion by sporozoites [5]
To rule out that recorded anti-malaria antibody titer increases are caused by cross-reactive immune responses to influenza antigens, the small number of subjects immunized with the comparator influenza vaccine was sufficient

Summary

Introduction

The development of an effective malaria vaccine is regarded as one cornerstone in the fight against this deadly disease and to achieve its eventual elimination [1]. The apical membrane antigen 1 (AMA1), is essential for erythrocyte invasion of P. falciparum [11,12,13] It is localized within the apical complex and translocated to the merozoite surface before invasion of erythrocytes commences. A cyclized synthetic peptide of 49 amino acids (named AMA49-C1 as PE conjugate), comprising residues 446–490 of the semi-conserved loop I of domain III has been shown to induce asexual blood stage parasite growth inhibitory antibodies [17]. This trial was conducted to evaluate the safety and immunogenicity of two virosome formulated malaria peptidomimetics derived from Plasmodium falciparum AMA-1 and CSP in malaria semi-immune adults and children

Objectives

Methods

Results

Conclusion