Single-dose Immunogenicity and Protective Efficacy of Simian Adenoviral Vectors Against Plasmodium Berghei

Eur J Immunol. 2008 Mar;38(3):732-41. doi: 10.1002/eji.200737672.

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 ( approximately 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-gamma, TNF-alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviruses, Simian / genetics*
  • Animals
  • Antigens, CD / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cytokines / metabolism
  • Epitopes, B-Lymphocyte / immunology
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Genetic Vectors / genetics
  • Granzymes / metabolism
  • Injections, Intradermal
  • Interferon-gamma / metabolism
  • Malaria / immunology
  • Malaria / prevention & control*
  • Malaria Vaccines / administration & dosage
  • Malaria Vaccines / genetics
  • Malaria Vaccines / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Plasmodium berghei / immunology*
  • Poxviridae / genetics
  • Protozoan Proteins / genetics
  • Protozoan Proteins / immunology*
  • Spleen / cytology
  • Spleen / immunology
  • Spleen / metabolism
  • Survival Analysis
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Vaccines, DNA / administration & dosage
  • Vaccines, DNA / genetics
  • Vaccines, DNA / immunology

Substances

  • Antigens, CD
  • Cytokines
  • Epitopes, B-Lymphocyte
  • Epitopes, T-Lymphocyte
  • Malaria Vaccines
  • Protozoan Proteins
  • Vaccines, DNA
  • thrombospondin-related adhesive protein, protozoan
  • Interferon-gamma
  • Granzymes
  • Gzmb protein, mouse