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

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.

Figure 1

Subject flow chart for Phase 1 study in the USA.

Figure 2

Subject flow chart for Phase 1 study in Kenya.

Figure 3

Antibody titres to MSP1₄₂ FVO by ELISA. Log ELISA OD 1.0 titres are reported as the geomean and 95% confidence intervals (CIs). Hatched line and filled-in squares are Kenyan subjects receiving 50 μg MSP1₄₂ FVO/AS01, hatched lines and triangles are Kenyan subjects receiving rabies vaccine, solid lines and filled in circles are US subjects receiving 10 μg MSP1₄₂ FVO/AS01 and solid line with open diamond are US subjects receiving 50 μg MSP1₄₂ FVO/AS01. X axis is day of study and Y axis is dilution reporting an OD =1.0 of MSP1₄₂ specific antibody. Plate antigen was the WRAIR E. coli expressed recombinant protein, MSP1₄₂ FVO.

Figure 4

Results of serum GIA for 10 μg and 50 μg MSP1₄₂ (FVO)/AS01 vaccine in malaria-naïve adults. Percent parasite growth inhibition against P. falciparum FVO clone parasites from the US MSP1₄₂ FVO/AS01 study. The net percent growth inhibition of pre-and post third immunization sera obtained for 10 μg and 50 μg MSP1₄₂/AS01 dose subjects is shown tested at 20% (v/v, final). Dashed horizontal lines indicate the median response, while the filled bars indicate the 25 and 75% quartiles. Individual responses are represented as either filled circles for the 10 μg or filled squares for the 50 μg dose subjects. P value calculated from two-tailed t-test.

Figure 5

Results of serum GIA against Plasmodium falciparum FVO parasites for subjects receiving rabies vaccine and the 50 μg MSP1₄₂ (FVO)/AS01 vaccines in both Phase 1 studies. Percent parasite growth inhibition against the P. falciparum FVO clone parasites, comparing serum antibody responses obtained from Kenyan adults and US naïve subjects immunized with the 50 μg dose of MSP1₄₂ FVO/AS01. Left panel are the day 0 and post third immunization, day 70, responses from Kenya adults either receiving the rabies comparator control vaccine or the 50 μg dose of MSP1₄₂ FVO/AS01. Right panel are the net percent growth inhibitory responses for the US subjects receiving the 50 μg dose of MSP1₄₂ FVO/AS01. Dashed horizontal lines indicate median responses, while the filled lines indicate the 25 and 75% quartiles. Individual responses are represented as either filled circles for the Kenyan adults receiving the rabies vaccine, filled triangles for the Kenyan adults receiving the MSP1₄₂ FVO/AS01 vaccine or filled gray squares for the US naïve subjects receiving the 50 μg dose MSP1₄₂ FVO/AS01.

Figure 6

Allele specific antibody titres to 50 μg MSP1₄₂ (FVO)/AS01 vs 50 μg MSP1₄₂ (3D7)/AS02 post third immunization. Comparison of MSP1₄₂ allele specific antibody responses induced by immunization with 50 μg MSP1₄₂ 3D7/AS02 and MSP1₄₂ FVO/AS01. Log ELISA OD 1.0 titres are reported as the median and 25 and 75% quartile antibody response. Hatched boxes indicate the antigen specific antibody responses induced by the MSP1₄₂ 3D7/AS02 vaccine, a study conducted at WRAIR in 2001 (reference 7), and open boxes indicate the responses induced by the MSP1₄₂ FVO/AS01 vaccine. Plate antigens were the WRAIR E. coli expressed recombinant proteins, MSP1₄₂ 3D7, FVO and CAMP alleles. P values are calculated from two-tailed t-tests.