Phase 1 Trial of Malaria Transmission Blocking Vaccine Candidates Pfs25 and Pvs25 Formulated with Montanide ISA 51

Abstract

BackgroundPfs25 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 FindingsThe 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 µg of Pfs25/ISA 51, 5 µg of Pvs25/ISA 51, or 20 µg 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/SignificanceIt 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 RegistrationClinicalTrials.gov NCT00295581

Safety and skin delayed-type hypersensitivity response in vervet monkeys immunized with Leishmania donovani sonicate antigen delivered with adjuvants

“…Our safety report on MISA as an adjuvant for Leishmania vaccine differs from other studies that have associated this adjuvant with adverse reactions including swelling and erythema at the injection site observed within a few days following vaccination (PIERCE et al, 2010). Other studies have reported occasional unacceptable local reactogenicity in vaccines containing montanides (WU et al, 2008). It is likely that adverse reactions observed following immunizations with vaccines containing MISA may be a result of the immunizing antigen.…”

Safety and tolerability evaluation of the use of Montanide ISA™51 as vaccine adjuvant: A systematic review

“…However, it should be noted that 2 controlled studies on ISA 51-adjuvanted vaccines in healthy subjects were terminated prematurely due to unacceptable AEs. 40,43 The study of Wu et al was stopped after the 2 reported cases of erythema nodosum, which was not observed from other ISA 51-adjuvanted vaccine studies. The trial by Graham et al was stopped after 4 cases of sterile abscess, which was also reported by one subject who had erythema nodosum in the trial of Wu et al and by subjects in 2 other uncontrolled therapeutic vaccine studies in breast cancer patients.…”

“…None of the participants in the adjuvant control groups developed AEs above moderate. 43 The prophylactic vaccine trials performed by Atsmon et al, Herrera et al and Pialoux et al reported the number of AEs after each immunization 11,41,42 . For the trial of Pleguezuelos et al, only the number of systemic AEs that occurred after a single injection could be extracted.…”

Safety and immunogenicity of multi-antigen AMA1-based vaccines formulated with CoVaccine HT™ and Montanide ISA 51 in rhesus macaques

“…For Montanide ISA 51, though little to no reactogenicity has been reported in animal studies and in some human studies [41,50-52], other human studies have concluded that this adjuvant, with its current composition, might not be suitable for use in humans due to high reactogenicity [42,43]. …”