Phase Ia Clinical Evaluation of the Safety and Immunogenicity of the Plasmodium Falciparum Blood-Stage Antigen AMA1 in ChAd63 and MVA Vaccine Vectors

PLoS One. 2012;7(2):e31208. doi: 10.1371/journal.pone.0031208. Epub 2012 Feb 21.

Abstract

Background: Traditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, to date no such vaccine encoding a blood-stage antigen(s) alone has induced significant protective efficacy against erythrocytic-stage infection in a pre-specified primary endpoint of a Phase IIa/b clinical trial designed to assess vaccine efficacy. Cell-mediated responses, acting in conjunction with functional antibodies, may be necessary for immunity against blood-stage P. falciparum. The development of a vaccine that could induce both cell-mediated and humoral immune responses would enable important proof-of-concept efficacy studies to be undertaken to address this question.

Methodology: We conducted a Phase Ia, non-randomized clinical trial in 16 healthy, malaria-naïve adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines encoding two alleles (3D7 and FVO) of the P. falciparum blood-stage malaria antigen; apical membrane antigen 1 (AMA1). ChAd63-MVA AMA1 administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to both alleles 3D7 (median 2036 SFU/million PBMC) and FVO (median 1539 SFU/million PBMC), with a mixed CD4(+)/CD8(+) phenotype, as well as substantial AMA1-specific serum IgG responses (medians of 49 µg/mL and 41 µg/mL for 3D7 and FVO AMA1 respectively) that demonstrated growth inhibitory activity in vitro.

Conclusions: ChAd63-MVA is a safe and highly immunogenic delivery platform for both alleles of the AMA1 antigen in humans which warrants further efficacy testing. ChAd63-MVA is a promising heterologous prime-boost vaccine strategy that could be applied to numerous other diseases where strong cellular and humoral immune responses are required for protection.

Trial registration: ClinicalTrials.gov NCT01095055.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviruses, Simian / genetics*
  • Adolescent
  • Adult
  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Protozoan / immunology
  • Antigens, Protozoan / immunology*
  • Enzyme-Linked Immunospot Assay
  • Female
  • Genetic Vectors / genetics*
  • Humans
  • Immunization
  • Interferon-gamma / immunology
  • Life Cycle Stages
  • Malaria Vaccines / adverse effects*
  • Malaria Vaccines / immunology*
  • Malaria, Falciparum / immunology
  • Male
  • Middle Aged
  • Plasmodium falciparum / growth & development
  • Plasmodium falciparum / immunology*
  • T-Lymphocytes / immunology
  • Vaccinia virus / genetics*
  • Young Adult

Substances

  • Antibodies, Neutralizing
  • Antibodies, Protozoan
  • Antigens, Protozoan
  • Malaria Vaccines
  • Interferon-gamma

Associated data

  • ClinicalTrials.gov/NCT01095055