DNA Prime/Adenovirus Boost Malaria Vaccine Encoding P. falciparum CSP and AMA1 Induces Sterile Protection Associated with Cell-Mediated Immunity

Chuang, Ilin, Sedegah, Martha, Cicatelli, Susan, Spring, Michele, Polhemus, Mark, Tamminga, Cindy, Patterson, Noelle, Guerrero, Melanie, Bennett, Jason W., McGrath, Shannon, Ganeshan, Harini, Belmonte, Maria, Farooq, Fouzia, Abot, Esteban, Banania, Jo Glenna, Huang, Jun, Newcomer, Rhonda, Rein, Lisa, Litilit, Dianne, Richie, Nancy O., Wood, Chloe, Murphy, Jittawadee, Sauerwein, Robert, Hermsen, Cornelus C., McCoy, Andrea J., Kamau, Edwin, Cummings, James, Komisar, Jack, Sutamihardja, Awalludin, Shi, Meng, Epstein, Judith E., Maiolatesi, Santina, Tosh, Donna, Limbach, Keith, Angov, Evelina, Bergmann-Leitner, Elke, Bruder, Joseph T., Doolan, Denise L., King, C. Richter, Carucci, Daniel, Dutta, Sheetij, Soisson, Lorraine, Diggs, Carter, Hollingdale, Michael R., Ockenhouse, Christian F., and Richie, Thomas L. (2013) DNA Prime/Adenovirus Boost Malaria Vaccine Encoding P. falciparum CSP and AMA1 Induces Sterile Protection Associated with Cell-Mediated Immunity. PLoS ONE, 8 (2). e55571. pp. 1-15.

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Background: Gene-based vaccination using prime/boost regimens protects animals and humans against malaria, inducing cell-mediated responses that in animal models target liver stage malaria parasites. We tested a DNA prime/adenovirus boost malaria vaccine in a Phase 1 clinical trial with controlled human malaria infection.

Methodology/Principal Findings: The vaccine regimen was three monthly doses of two DNA plasmids (DNA) followed four months later by a single boost with two non-replicating human serotype 5 adenovirus vectors (Ad). The constructs encoded genes expressing P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). The regimen was safe and well-tolerated, with mostly mild adverse events that occurred at the site of injection. Only one AE (diarrhea), possibly related to immunization, was severe (Grade 3), preventing daily activities. Four weeks after the Ad boost, 15 study subjects were challenged with P. falciparum sporozoites by mosquito bite, and four (27%) were sterilely protected. Antibody responses by ELISA rose after Ad boost but were low (CSP geometric mean titer 210, range 44–817; AMA1 geometric mean micrograms/milliliter 11.9, range 1.5–102) and were not associated with protection. Ex vivo IFN-γ ELISpot responses after Ad boost were modest (CSP geometric mean spot forming cells/million peripheral blood mononuclear cells 86, range 13–408; AMA1 348, range 88–1270) and were highest in three protected subjects. ELISpot responses to AMA1 were significantly associated with protection (p = 0.019). Flow cytometry identified predominant IFN-γ mono-secreting CD8+ T cell responses in three protected subjects. No subjects with high pre-existing anti-Ad5 neutralizing antibodies were protected but the association was not statistically significant.

Significance: The DNA/Ad regimen provided the highest sterile immunity achieved against malaria following immunization with a gene-based subunit vaccine (27%). Protection was associated with cell-mediated immunity to AMA1, with CSP probably contributing. Substituting a low seroprevalence vector for Ad5 and supplementing CSP/AMA1 with additional antigens may improve protection.

Item ID: 41429
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 "Development of Adenovirus-Vectored Malaria Vaccines" 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, MIRP work unit number 62787A 870 F 1432
Date Deposited: 23 Mar 2016 04:28
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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