Human adenovirus 5-vectored Plasmodium falciparum NMRC-M3V-Ad-PfCA vaccine encoding CSP and AMA1 is safe, well-tolerated and immunogenic but does not protect against controlled human malaria infection

Cindy Tamminga*, Martha Sedegah, Santina Maiolatesi, Charlotte Fedders, Sharina Reyes, Anatalio Reyes, Carlos Vasquez, Yolanda Alcorta, Ilin Chuang, Michele Spring, Michael Kavanaugh, Harini Ganeshan, Jun Huang, Maria Belmonte, Esteban Abot, Arnel Belmonte, Joglenna Banania, Fouzia Farooq, Jittawadee Murphy, Jack KomisarNancy O. Richie, Jason Bennett, Keith Limbach, Noelle Bpatterson, Joseph T. Bruder, Meng Shi, Edward Miller, Sheetij Dutta, Carter Diggs, Lorraine A. Soisson, Michael R. Hollingdale, Judith E. Epstein, Thomas L. Richie

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Background: In a priorstudy.a DNA prime/adenovirus boost vaccine (DNA/Ad) expressing P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1) (NMRC-M3V-D/Ad-PfCA Vaccine) induced 27% protection against controlled human malaria infection (CHMI). To investigate the contribution of DNA priming, we tested the efficacy of adenovirus vaccine alone (NMRC-M3V-Ad-PfCA) in a Phase 1 clinical trial. Methodology/Principal Findings: The regimen was a single intramuscular injection with two non-replicating human serotype 5 adenovectors encoding CSP and AMA1, respectively. An amount of 1 × 1010 particle units of each construct were combined prior to administration. The regimen was safe and well-tolerated. Four weeks later, 18 study subjects received P. falciparum CHMI administered by mosquito bite. None were fully protected although one showed delayed onset of parasitemia. Antibody responses were low, with geometric mean CSP ELISA titer of 381 (range < 50-1626) and AMA1 ELISA of 4.95 (xg/mL (range 0.2-38). Summed ex vivo IFN-/ELISpot responses to overlapping peptides were robust, with geometric mean spot forming cells/million peripheral blood mononuclear cells [sfc/m] for CSP of 273 (range 38-2550) and for AMA1 of 1303 (range 435-4594). CD4+ and CD8 +T cell IFN-γ responses to CSP were positive by flow cytometry in 25% and 56% of the research subjects, respectively, and to AMA1 in 94% and 100%, respectively. Significance: In contrast to DNA/Ad, Ad alone did not protect against CHMI despite inducing broad, cell-mediated immunity, indicating that DNA priming is required for protection by the adenovirus-vectored vaccine. ClinicalTrials.gov Identifier: NCT00392015.

Original languageEnglish
Pages (from-to)2165-2177
Number of pages13
JournalHuman Vaccines and Immunotherapeutics
Volume9
Issue number10
DOIs
StatePublished - Oct 2013
Externally publishedYes

Keywords

  • Adenovirus
  • Antibody
  • Efficacy
  • Malaria
  • T cells
  • Vaccine

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