Open Access Research

Results from tandem Phase 1 studies evaluating the safety, reactogenicity and immunogenicity of the vaccine candidate antigen Plasmodium falciparum FVO merozoite surface protein-1 (MSP142) administered intramuscularly with adjuvant system AS01

Nekoye Otsyula1, Evelina Angov2, Elke Bergmann-Leitner2, Margaret Koech1, Farhat Khan2, Jason Bennett2, Lucas Otieno1, James Cummings2, Ben Andagalu1, Donna Tosh2, John Waitumbi1, Nancy Richie2, Meng Shi2, Lori Miller2, Walter Otieno1, Godfrey Allan Otieno1, Lisa Ware2, Brent House2, Olivier Godeaux3, Marie-Claude Dubois3, Bernhards Ogutu1, W Ripley Ballou3, Lorraine Soisson4, Carter Diggs4, Joe Cohen3, Mark Polhemus2, D Gray Heppner2, Christian F Ockenhouse2* and Michele D Spring2

Author Affiliations

1 Walter Reed Project, Kenya Medical Research Institute, Kisumu, Kenya

2 Malaria Vaccine Branch, Walter Reed Army Institute of Research, 2460 Linden Lane, Bldg #503, Silver Spring, USA

3 GlaxoSmithKline Biologicals, Rue de l’Institut 89, Rixensart, Belgium

4 US Agency for International Development, 1300 Pennsylvania Avenue, Washington DC, 20523, USA

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Malaria Journal 2013, 12:29  doi:10.1186/1475-2875-12-29

Published: 23 January 2013

Abstract

Background

The development of an asexual blood stage vaccine against Plasmodium falciparum malaria based on the major merozoite surface protein-1 (MSP1) antigen is founded on the protective efficacy observed in preclinical studies and induction of invasion and growth inhibitory antibody responses. The 42 kDa C-terminus of MSP1 has been developed as the recombinant protein vaccine antigen, and the 3D7 allotype, formulated with the Adjuvant System AS02A, has been evaluated extensively in human clinical trials. In preclinical rabbit studies, the FVO allele of MSP142 has been shown to have improved immunogenicity over the 3D7 allele, in terms of antibody titres as well as growth inhibitory activity of antibodies against both the heterologous 3D7 and homologous FVO parasites.

Methods

Two Phase 1 clinical studies were conducted to examine the safety, reactogenicity and immunogenicity of the FVO allele of MSP142 in the adjuvant system AS01 administered intramuscularly at 0-, 1-, and 2-months: one in the USA and, after evaluation of safety data results, one in Western Kenya. The US study was an open-label, dose escalation study of 10 and 50 μg doses of MSP142 in 26 adults, while the Kenya study, evaluating 30 volunteers, was a double-blind, randomized study of only the 50 μg dose with a rabies vaccine comparator.

Results

In these studies it was demonstrated that this vaccine formulation has an acceptable safety profile and is immunogenic in malaria-naïve and malaria-experienced populations. High titres of anti-MSP1 antibodies were induced in both study populations, although there was a limited number of volunteers whose serum demonstrated significant inhibition of blood-stage parasites as measured by growth inhibition assay. In the US volunteers, the antibodies generated exhibited better cross-reactivity to heterologous MSP1 alleles than a MSP1-based vaccine (3D7 allele) previously tested at both study sites.

Conclusions

Given that the primary effector mechanism for blood stage vaccine targets is humoral, the antibody responses demonstrated to this vaccine candidate, both quantitative (total antibody titres) and qualitative (functional antibodies inhibiting parasite growth) warrant further consideration of its application in endemic settings.

Trial registrations

Clinical Trials NCT00666380

Keywords:
Malaria; Vaccine; Merozoite surface protein-1; Plasmodium