Phase 1 trial of malaria transmission blocking vaccine candidates Pfs25 and Pvs25 formulated with montanide ISA 51

Abstract

Background: Pfs25 and Pvs25, surface proteins of mosquito stage of the malaria parasites P. falciparum and P. vivax, respectively, are leading candidates for vaccines preventing malaria transmission by mosquitoes. This single blinded, dose escalating, controlled Phase 1 study assessed the safety and immunogenicity of recombinant Pfs25 and Pvs25 formulated with Montanide ISA 51, a water-in-oil emulsion.

Methodology/principal findings: The trial was conducted at The Johns Hopkins Center for Immunization Research, Washington DC, USA, between May 16, 2005-April 30, 2007. The trial was designed to enroll 72 healthy male and non-pregnant female volunteers into 1 group to receive adjuvant control and 6 groups to receive escalating doses of the vaccines. Due to unexpected reactogenicity, the vaccination was halted and only 36 volunteers were enrolled into 4 groups: 3 groups of 10 volunteers each were immunized with 5 microg of Pfs25/ISA 51, 5 microg of Pvs25/ISA 51, or 20 microg of Pvs25/ISA 51, respectively. A fourth group of 6 volunteers received adjuvant control (PBS/ISA 51). Frequent local reactogenicity was observed. Systemic adverse events included two cases of erythema nodosum considered to be probably related to the combination of the antigen and the adjuvant. Significant antibody responses were detected in volunteers who completed the lowest scheduled doses of Pfs25/ISA 51. Serum anti-Pfs25 levels correlated with transmission blocking activity.

Conclusion/significance: It is feasible to induce transmission blocking immunity in humans using the Pfs25/ISA 51 vaccine, but these vaccines are unexpectedly reactogenic for further development. This is the first report that the formulation is associated with systemic adverse events including erythema nodosum.

Trial registration: ClinicalTrials.gov NCT00295581.

Figure 1. Participant Recruitment and Flow.

^a One volunteer withdrew consent; one lost to follow up; study discontinued prior to second vaccination of the 3 volunteers. ^b One withdrew consent; two were withdrawn due to local reactions (severe swelling and induration in one volunteer and severe swelling, induration, and pain in the other); two were ineligible due to previously undisclosed exclusion criteria (concurrent participation in another investigational drug trial and mental illness). ^c Two were withdrawn due to local reactions (severe swelling and induration in one volunteer and severe swelling, induration, tenderness, and pain in the other). ^d Two were withdrawn due to systemic adverse events (erythema nodosum).

Figure 2. Correlation of anti-Pfs25H antibody units with transmission blocking activity measured as percent reduction in oocysts per mosquito.

Sera or purified IgGs were tested in replica in various dilution. The non-linear equation: was used to fit the data, where variables Y and X are the percent reduction of oocyst number, and the ELISA units, respectively, the curve parameters were calculated as a  = 1.27 (95% CI 0.96–1.68) and b = 1093 (95% CI 682–1565).