DNA prime/Adenovirus boost malaria vaccine encoding P. falciparum CSP and AMA1 induces sterile protection associated with cell-mediated immunity
- PMID: 23457473
- PMCID: PMC3573028
- DOI: 10.1371/journal.pone.0055571
DNA prime/Adenovirus boost malaria vaccine encoding P. falciparum CSP and AMA1 induces sterile protection associated with cell-mediated immunity
Abstract
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.
Trial registration: ClinicalTrials.govNCT00870987.
Conflict of interest statement
Figures
Similar articles
-
A three-antigen Plasmodium falciparum DNA prime-Adenovirus boost malaria vaccine regimen is superior to a two-antigen regimen and protects against controlled human malaria infection in healthy malaria-naïve adults.PLoS One. 2021 Sep 8;16(9):e0256980. doi: 10.1371/journal.pone.0256980. eCollection 2021. PLoS One. 2021. PMID: 34495988 Free PMC article. Clinical Trial.
-
Sterile immunity to malaria after DNA prime/adenovirus boost immunization is associated with effector memory CD8+T cells targeting AMA1 class I epitopes.PLoS One. 2014 Sep 11;9(9):e106241. doi: 10.1371/journal.pone.0106241. eCollection 2014. PLoS One. 2014. PMID: 25211344 Free PMC article. Clinical Trial.
-
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.Hum Vaccin Immunother. 2013 Oct;9(10):2165-77. doi: 10.4161/hv.24941. Epub 2013 Jun 4. Hum Vaccin Immunother. 2013. PMID: 23899517 Free PMC article. Clinical Trial.
-
Prime-boost vectored malaria vaccines: progress and prospects.Hum Vaccin. 2010 Jan;6(1):78-83. doi: 10.4161/hv.6.1.10116. Epub 2010 Jan 18. Hum Vaccin. 2010. PMID: 20061802 Review.
-
Towards an RTS,S-based, multi-stage, multi-antigen vaccine against falciparum malaria: progress at the Walter Reed Army Institute of Research.Vaccine. 2005 Mar 18;23(17-18):2243-50. doi: 10.1016/j.vaccine.2005.01.142. Vaccine. 2005. PMID: 15755604 Review.
Cited by
-
High-Throughput Screening for the Prevalence of Neutralizing Antibodies against Human Adenovirus Serotype 5.Vaccines (Basel). 2024 Feb 1;12(2):155. doi: 10.3390/vaccines12020155. Vaccines (Basel). 2024. PMID: 38400138 Free PMC article.
-
Malaria Vaccines: Progress to Date.BioDrugs. 2023 Nov;37(6):737-756. doi: 10.1007/s40259-023-00623-4. Epub 2023 Sep 20. BioDrugs. 2023. PMID: 37728713 Free PMC article. Review.
-
Sporozoite immunization: innovative translational science to support the fight against malaria.Expert Rev Vaccines. 2023 Jan-Dec;22(1):964-1007. doi: 10.1080/14760584.2023.2245890. Epub 2023 Aug 11. Expert Rev Vaccines. 2023. PMID: 37571809 Free PMC article. Review.
-
Induction of antigen specific intrahepatic CD8+ T cell responses by a secreted heat shock protein based gp96-Ig-PfCA malaria vaccine.Front Immunol. 2023 Mar 28;14:1130054. doi: 10.3389/fimmu.2023.1130054. eCollection 2023. Front Immunol. 2023. PMID: 37056783 Free PMC article.
-
The Complexity of Interferon Signaling in Host Defense against Protozoan Parasite Infection.Pathogens. 2023 Feb 15;12(2):319. doi: 10.3390/pathogens12020319. Pathogens. 2023. PMID: 36839591 Free PMC article. Review.
References
-
- WHO (2011) World Malaria Report.
-
- PMI (2011) Fifth Annual Report to Congress.
-
- Clyde DF (1975) Immunization of man against falciparum and vivax malaria by use of attenuated sporozoites. Am J Trop Med Hyg 24: 397–401. - PubMed
-
- Roestenberg M, McCall M, Hopman J, Wiersma J, Luty AJ, et al. (2009) Protection against a malaria challenge by sporozoite inoculation. N Engl J Med 361: 468–477. - PubMed
-
- Roestenberg M, Teirlinck AC, McCall MB, Teelen K, Makamdop KN, et al. (2011) Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study. Lancet 377: 1770–1776. - PubMed
Publication types
MeSH terms
Substances
Associated data
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials