Abstract
BackgroundA 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 FindingsNMRC-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 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.SignificanceThe NMRC-MV-Ad-PfC vaccine expressing CSP was safe and well tolerated given as two doses, but did not provide sterile protection.Trial Registration ClinicalTrials.gov NCT00392015
Highlights
P. falciparum malaria causes 863,000 deaths and approximately 243 million cases annually and is a major infectious threat to nonimmune travelers to malaria-endemic areas[1]
Sterile protective immunity against malaria can be induced in animals or humans with radiation-attenuated sporozoites, delivered by mosquito bite, that invade hepatocytes, develop partially but are unable to transform into blood stage parasites [3,4,5]
Ethics The Trial Protocol for the clinical trial presented in this manuscript was approved by the National Naval Medical Center (NNMC), Naval Medical Research Center (NMRC) and Walter Reed Army Institute of Research Institutional Review Boards, in compliance with all applicable federal regulations governing the protection of human subjects
Summary
P. falciparum malaria causes 863,000 deaths and approximately 243 million cases annually and is a major infectious threat to nonimmune travelers to malaria-endemic areas[1]. Sterile protective immunity against malaria can be induced in animals or humans with radiation-attenuated sporozoites, delivered by mosquito bite, that invade hepatocytes, develop partially but are unable to transform into blood stage parasites [3,4,5]. Protection appears to be speciesbut not strain-specific, is sustained for at least nine months, and is probably dependent on cell-mediated immunity (CMI) against infected hepatocytes and antibodies against sporozoites [6,7,8,9,10]. This model of protective immunity provides a rationale for developing a vaccine inducing CMI targeting preerythrocytic stages. 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
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.