Satisfactory safety and immunogenicity of MSP3 malaria vaccine candidate in Tanzanian children aged 12-24 months

John P A Lusingu, Samwel Gesase, Salum Msham, Filbert Francis, Martha Lemnge, Misago Seth, Samwel Sembuche, Acleus Rutta, Daniel Minja, Method D Segeja, Samuel Bosomprah, Simon Cousens, Ramadhani Noor, Roma Chilengi, Pierre Druilhe, John P A Lusingu, Samwel Gesase, Salum Msham, Filbert Francis, Martha Lemnge, Misago Seth, Samwel Sembuche, Acleus Rutta, Daniel Minja, Method D Segeja, Samuel Bosomprah, Simon Cousens, Ramadhani Noor, Roma Chilengi, Pierre Druilhe

Abstract

Background: Development and deployment of an effective malaria vaccine would complement existing malaria control measures. A blood stage malaria vaccine candidate, Merozoite Surface Protein-3 (MSP3), produced as a long synthetic peptide, has been shown to be safe in non-immune and semi-immune adults. A phase Ib dose-escalating study was conducted to assess the vaccine's safety and immunogenicity in children aged 12 to 24 months in Korogwe, Tanzania (ClinicalTrials.gov number: NCT00469651).

Methods: This was a double-blind, randomized, controlled, dose escalation phase Ib trial, in which children were given one of two different doses of the MSP3 antigen (15 microg or 30 microg) or a control vaccine (Engerix B). Children were randomly allocated either to the MSP3 candidate malaria vaccine or the control vaccine administered at a schedule of 0, 1, and 2 months. Immunization with lower and higher doses was staggered for safety reasons starting with the lower dose. The primary endpoint was safety and reactogenicity within 28 days post-vaccination. Blood samples were obtained at different time points to measure immunological responses. Results are presented up to 84 days post-vaccination.

Results: A total of 45 children were enrolled, 15 in each of the two MSP3 dose groups and 15 in the Engerix B group. There were no important differences in reactogenicity between the two MSP3 groups and Engerix B. Grade 3 adverse events were infrequent; only five were detected throughout the study, all of which were transient and resolved without sequelae. No serious adverse event reported was considered to be related to MSP3 vaccine. Both MSP3 dose regimens elicited strong cytophilic IgG responses (subclasses IgG1 and IgG3), the isotypes involved in the monocyte-dependant mechanism of Plasmodium falciparum parasite-killing. The titers reached are similar to those from African adults having reached a state of premunition. Furthermore, vaccination induced seroconversion in all vaccinees.

Conclusion: The MSP3 malaria vaccine candidate was safe, well tolerated and immunogenic in children aged 12-24 months living in a malaria endemic community. Given the vaccine's safety and its induction of cytophilic IgG responses, its efficacy against P. falciparum infection and disease needs to be evaluated in Phase 2 studies.

Figures

Figure 1
Figure 1
MSP3 Phase 1 trial flow diagram.
Figure 2
Figure 2
Haematology and biochemical safety parameters. Line with filled squares show children vaccinated with 15 μg MSP3, filled circles show children vaccinated with 30 μg MSP3 and filled triangles show children vaccinated with Engerix B. Error bars show 95% confidence interval.
Figure 3
Figure 3
Individual pattern of antibody responses to MSP3 by vaccination dose with respect to vaccine type. Squares show children vaccinated with 15 μg MSP3, triangles show children vaccinated with 30 μg MSP3 and circles show children vaccinated with Engerix B. Lines connect median values. Abscissas: days post vaccination and ordinates: Elisa titers.
Figure 4
Figure 4
The pattern of cytophilic to non-cytophilic ratio. Line with filled squares show children vaccinated with 15 μg MSP3, filled circle show children vaccinated with 30 μg MSP3 and filled triangle show children vaccinated with Engerix B. Error bars show 95% confidence interval.

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