Adenovirus-5-vectored P. falciparum vaccine expressing CSP and AMA1. Part B: safety, immunogenicity and protective efficacy of the CSP component

Tamminga, Cindy, Sedegah, Martha, Regis, David, Chuang, Ilin, Epstein, Judith E., Spring, Michele, Mendoza-Silveiras, Jose, McGrath, Shannon, Maiolatesi, Santina, Reyes, Sharina, Steinbeiss, Victoria, Fedders, Charlotte, Smith, Kathryn, House, Brent, Ganeshan, Harini, Lejano, Jennylynn, Abot, Esteban, Banania, Glenna J., Sayo, Renato, Farooq, Fouzia, Belmonte, Maria, Murphy, Jittawadee, Komisar, Jack, Williams, Jackie, Shi, Meng, Brambilla, Donald, Manohar, Nalini, Richie, Nancy O., Wood, Chloe, Limbach, Keith, Patterson, Noelle B., Bruder, Joseph T., Doolan, Denise L., King, C. Richter, Diggs, Carter, Soisson, Lorraine, Carucci, Daniel, Levine, Gail, Dutta, Sheetij, Hollingdale, Michael R., Ockenhouse, Christian F., and Richie, Thomas L. (2011) Adenovirus-5-vectored P. falciparum vaccine expressing CSP and AMA1. Part B: safety, immunogenicity and protective efficacy of the CSP component. PLoS ONE, 6 (10). e25868. pp. 1-20.

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Background: A protective malaria vaccine will likely need to elicit both cell-mediated and antibody responses. As adenovirus vaccine vectors induce both these responses in humans, a Phase 1/2a clinical trial was conducted to evaluate the efficacy of an adenovirus serotype 5-vectored malaria vaccine against sporozoite challenge.

Methodology/Principal Findings: NMRC-MV-Ad-PfC is an adenovirus vector encoding the Plasmodium falciparum 3D7 circumsporozoite protein (CSP). It is one component of a two-component vaccine NMRC-M3V-Ad-PfCA consisting of one adenovector encoding CSP and one encoding apical membrane antigen-1 (AMA1) that was evaluated for safety and immunogenicity in an earlier study (see companion paper, Sedegah et al). Fourteen Ad5 seropositive or negative adults received two doses of NMRC-MV-Ad-PfC sixteen weeks apart, at 1x1010 particle units per dose. The vaccine was safe and well tolerated. All volunteers developed positive ELISpot responses by 28 days after the first immunization (geometric mean 272 spot forming cells/million[sfc/m]) that declined during the following 16 weeks and increased after the second dose to levels that in most cases were less than the initial peak (geometric mean 119 sfc/m). CD8+ predominated over CD4+ responses, as in the first clinical trial. Antibody responses were poor and like ELISpot responses increased after the second immunization but did not exceed the initial peak. Pre-existing neutralizing antibodies (NAb) to Ad5 did not affect the immunogenicity of the first dose, but the fold increase in NAb induced by the first dose was significantly associated with poorer antibody responses after the second dose, while ELISpot responses remained unaffected. When challenged by the bite of P. falciparum-infected mosquitoes, two of 11 volunteers showed a delay in the time to patency compared to infectivity controls, but no volunteers were sterilely protected.

Significance: The NMRC-MV-Ad-PfC vaccine expressing CSP was safe and well tolerated given as two doses, but did not provide sterile protection.

Item ID: 41441
Item Type: Article (Research - C1)
ISSN: 1932-6203
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This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Funders: United States Agency for International Development (USAID), Congressionally Directed Medical Research Program (CDMRP), Military Infectious Research Program (MIRP)
Projects and Grants: USAID Grant GHA-P-00-03-00006-01, USAID Project Number 936-3118, CDMRP "Development of Recombinant Adenoviral-based Vaccines against Malaria" Grant #: W81XWH-05-2-0041
Date Deposited: 24 Mar 2016 03:54
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110799 Immunology not elsewhere classified @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 100%
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