Single‐dose immunogenicity and protective efficacy of simian adenoviral vectors against Plasmodium berghei

Abstract

Simian adenoviral vectors (SAd) offer an attractive alternative to standard human adenovirus serotype 5 (AdH5) subunit vaccination, due to pre-existing immunity affecting vaccine performance. We have used a mouse model of liver-stage malaria to test the efficiency of three chimpanzee-origin adenoviral vectors, AdC6, AdC7 and AdC9 containing ME.TRAP as an insert. AdC7 and AdC9 elicited strong immunogenicity (*20% of CD8 + T cells in spleen), equivalent to or outperforming AdH5 and inducing sterile protection in 92% (C9), 83% (H5 and C7) and 67% (C6) of the mice, providing the first evidence of single-dose protection to Plasmodium berghei. Protection was afforded by the SAd despite high levels of pre-existing immunity to AdH5. Phenotypic analysis showed that all adenoviral vectors (Ad) elicited CD8 + T cell responses with an effector memory T cell (T EM ) phenotype. By contrast, vaccination with poxviral vectors did not confer protection to P. berghei and induced a predominantly CD8 + central memory T cell (T CM ) response. Multifunctional CD8 + T cell responses (co-expressing IFN-c, TNF-a and IL-2) were also induced by the Ad in higher percentages than the poxviral vectors. Our data suggest that T EM cells are important as a first line of defense against fast-replicating pathogens such as murine Plasmodium and demonstrate the potential of replication-defective SAd as future malaria vaccines for humans.

Assessment of Chimpanzee Adenovirus Serotype 63 Neutralizing Antibodies Prior to Evaluation of a Candidate Malaria Vaccine Regimen Based on Viral Vectors

“…Recently, the issue of preexisting anti-vector immunity has been addressed through the development of new vectors based on serotypes to which the human population is less exposed, including those of chimpanzee origin (9,(14)(15)(16). Chimpanzee adenoviral vectors have been shown to be highly immuno-genic in animal models (17,18) and recently in clinical malarial vaccine trials (1,2).…”

4-1BBL Enhances CD8+ T Cell Responses Induced by Vectored Vaccines in Mice but Fails to Improve Immunogenicity in Rhesus Macaques

“…CD8 + T cells play an essential role in control of liver-stage malaria and the dominant epitope from P.berghei CS antigen (Pb9), expressed in our antigen TIP, alone can mediate protection in Balb/c mice [41], [42]. To determine whether an increase in Pb9-specific cells by coexpression of 4-1BBL would reflect in an increase in protection, mice were challenged with a lethal dose of P.berghei and monitored for development of blood-stage malaria.…”

“…Due to low levels of immunogenicity induced by DNA vaccination, immune response were measured in the spleen after two doses of DNA administered two weeks apart. To correspond to the peak in immunogenicity after viral vector vaccination [41], immune responses were measured in the spleen approximately 1 week after MVA and 2 weeks after HAdV5 vaccination.…”

Plasmodium vivax malaria vaccines: Why are we where we are?

“…Therefore, it will be very interesting to see recombinant adenoviruses and MVA entering the arena as a pre-erythrocytic, blood-stage, or transmission blocking vaccines. Such platforms have demonstrated an unparalleled ability to stimulate both, antibody and T-cell responses in pre-clinical and clinical studies for P. falciparum , while keeping a good safety profile 20 , 21 , 57 , 58 . Other platforms of great interest that would certainly make a substantial addition to the vaccine pipeline are the antigens delivered as particle vaccines, such as virus-like particles (VLPs) and RTS, S-like vaccines for P. vivax , which could enhance efficacy in comparison to a protein-based vaccine.…”