Combination of Protein and Viral Vaccines Induces Potent Cellular and Humoral Immune Responses and Enhanced Protection from Murine Malaria Challenge

Abstract

The search for an efficacious vaccine against malaria is ongoing, and it is now widely believed that to confer protection a vaccine must induce very strong cellular and humoral immunity concurrently. We studied the immune response in mice immunized with the recombinant viral vaccines fowlpox strain FP9 and modified virus Ankara (MVA), a protein vaccine (CV-1866), or a combination of the two; all vaccines express parts of the same preerythrocytic malaria antigen, the Plasmodium berghei circumsporozoite protein (CSP). Mice were then challenged with P. berghei sporozoites to determine the protective efficacies of different vaccine regimens. Two immunizations with the protein vaccine CV-1866, based on the hepatitis B core antigen particle, induced strong humoral immunity to the repeat region of CSP that was weakly protective against sporozoite challenge. Prime-boost with the viral vector vaccines, FP9 followed by MVA, induced strong T-cell immunity to the CD8 ؉ epitope Pb9 and partially protected animals from challenge. Physically mixing CV-1866 with FP9 or MVA and then immunizing with the resultant combinations in a prime-boost regimen induced both cellular and humoral immunity and afforded substantially higher levels of protection (combination, 90%) than either vaccine alone (CV-1866, 12%; FP9/MVA, 37%). For diseases such as malaria in which different potent immune responses are required to protect against different stages, using combinations of partially effective vaccines may offer a more rapid route to achieving deployable levels of efficacy than individual vaccine strategies.

Phase I Safety and Immunogenicity Trial of Plasmodium vivax CS Derived Long Synthetic Peptides Adjuvanted with Montanide ISA 720 or Montanide ISA 51

“…Moreover, the trial indicated that although the peptide mixture as formulated did not appear to produce any synergism on immune responses, we expect an additive effect of cell-mediated immunity and antibodies, especially on their blocking activity on sporozoite invasion, which may be more effective than vaccination with individual peptides. [43][44][45] The peptide mixtures induced antibody titers to each peptide that were similar to those from our previous trial, in which volunteers were immunized with single peptides. This suggests that there is no detectable interference in the peptide mixture.…”

Prime-boost vectored malaria vaccines: Progress and prospects

“…We recently assessed in a pre-clinical P. berghei model in mice whether combined use of a protein-adjuvant based anti-sporozoite vaccine could add to the partial efficacy of a vectored vaccine against the liver-stage parasite. 46 The results were striking (Fig. 2).…”

“…Immunological analysis showed that the combination induced both the antibody response induced by the protein-adjuvant vaccine plus the T-cell response induced by the vectors. 46 Hence it appears that there can be synergistic efficacy with this approach, probably resulting from a substantial reduction in sporozoite number effected by the antibodies making it much easier for the T cells to clear a far smaller number of infected liver cells. Data of this type make a compelling case for assessing RTS,S and TRAP vectors together in humans.…”

Enhancing Blood-Stage Malaria Subunit Vaccine Immunogenicity in Rhesus Macaques by Combining Adenovirus, Poxvirus, and Protein-in-Adjuvant Vaccines

“…These murine studies also described further possible advantages of viral vectors in achieving consistent Ab priming, enhanced Ab avidity, and Th1-type IgG isotype skew. Data from the HIV-1 (32-36) and liver-stage malaria vaccine fields (37,38) also encourage efforts to combine adenoviral-vectored vaccines with protein vaccines.…”