Results from tandem Phase 1 studies evaluating the safety, reactogenicity and immunogenicity of the vaccine candidate antigen Plasmodium falciparum FVO merozoite surface protein-1 (MSP1(42)) administered intramuscularly with adjuvant system AS01.
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.


BACKGROUND
Clinical Trials NCT00666380.
Walter Reed Project, Kenya Medical Research Institute, Kisumu, Kenya.
Nekoye
N
Otsyula
Evelina
E
Angov
Elke
E
Bergmann-Leitner
Margaret
M
Koech
Farhat
F
Khan
Jason
J
Bennett
Lucas
L
Otieno
James
J
Cummings
Ben
B
Andagalu
Donna
D
Tosh
John
J
Waitumbi
Nancy
N
Richie
Meng
M
Shi
Lori
L
Miller
Walter
W
Otieno
Godfrey Allan
GA
Otieno
Lisa
L
Ware
Brent
B
House
Olivier
O
Godeaux
Marie-Claude
MC
Dubois
Bernhards
B
Ogutu
W Ripley
WR
Ballou
Lorraine
L
Soisson
Carter
C
Diggs
Joe
J
Cohen
Mark
M
Polhemus
D Gray
DG
Heppner
Christian F
CF
Ockenhouse
Michele D
MD
Spring
D000276:Adjuvants, Immunologic; D000328:Adult; D000913:Antibodies, Protozoan / Q000276:immunology*; D000917:Antibody Formation; D000953:Antigens, Protozoan / Q000276:immunology*; D003429:Cross Reactions / Q000276:immunology; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D016778:Malaria, Falciparum / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D008297:Male; D020066:Merozoite Surface Protein 1 / Q000276:immunology*; D010963:Plasmodium falciparum / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D020066:Merozoite Surface Protein 1