Abstract
BackgroundGene-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 FindingsThe 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.SignificanceThe 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 RegistrationClinicalTrials.govNCT00870987.
Highlights
According to the World Health Organization, malaria caused an estimated 216 million clinical cases and 655,000 deaths in 2011 [1], underscoring the urgent need for an effective vaccine [2]
While the immunological mechanisms underlying the high grade protection induced by these whole parasite vaccines remain unclear, animal studies demonstrate dependence on cell-mediated immunity (CMI), in particular cytotoxic CD8+ T cells [6,7] which release cytotoxins to lyse the malaria-infected hepatocyte or interferon gamma (IFN-c) to trigger nitric oxide production [8,9]
The study was conducted at the Walter Reed Army Institute of Research (WRAIR) Clinical Trials Center in accordance with: the principles described in the Nuremberg Code and the Belmont Report; all federal regulations regarding the protection of human participants as described in
Summary
According to the World Health Organization, malaria caused an estimated 216 million clinical cases and 655,000 deaths in 2011 [1], underscoring the urgent need for an effective vaccine [2]. Developing a vaccine should be feasible, based on evidence of durable sterile immunity induced in humans by the bites of Plasmodium falciparum-infected mosquitoes. In these models, sporozoites are injected into the human host but development is aborted in the liver by prior irradiation of the infected mosquitoes [3] or in the blood by co-administering a drug selectively active against blood stage parasites such as chloroquine [4,5]. 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
