Adenovirus-5-Vectored P. falciparum Vaccine Expressing CSP and AMA1. Part B: Safety, Immunogenicity and Protective Efficacy of the CSP Component

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

Immunogenicity of a Prime-Boost Vaccine Containing the Circumsporozoite Proteins of Plasmodium vivax in Rodents

“…The results obtained with the mouse model have fueled a number of human trials with plasmid DNA, recombinant viruses, and, more recently, radiation-attenuated sporozoites as vaccine formulations. Unfortunately, in spite of the enthusiasm generated by the mouse model, T cell-based vaccines against preerythrocytic stages of malaria have provided sterile immunity against infection with P. falciparum to only a few vaccinated individuals to date (39)(40)(41)(42)(43)(44). The precise reason for this failure is not clear.…”

Identification of a Suppressor Mutation That Improves the Yields of Hexon-Modified Adenovirus Vectors

“…At the end of the 60-min incubation, virus was aspirated from the cells, and the cells were washed with phosphate-buffered saline (PBS), overlaid with 3 ml of prewarmed DMEM plus 10% FBS, and incubated in a 5% CO 2 incubator at either 32°C or 37°C. At various time points postinfection (24,48, and/or 72 h) the infected cells were scraped into 15-ml polypropylene tubes and frozen and thawed three times to lyse infected cells and release vector particles. The number of viral particles was measured by the FFU assay as follows.…”

“…Ad5 vectors can be grown to very high yields in bioreactors and can be purified efficiently with reasonable cost-of-goods estimates for vaccines. Adenovirus-based vectors are capable of generating robust and protective T cell and antibody responses in animal models (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), and clinical data conclusively show that Ad5 vectors can induce potent CD8 ϩ and CD4 ϩ T cell and antibody responses in vaccinated volunteers (18)(19)(20)(21)(22)(23)(24)(25). Most encouragingly, the protective capacity of a DNA prime-Ad5 boost regimen expressing two malaria antigens demonstrated sterile protection from malaria in 27% of test subjects (26).…”

Development of Vaccines Based on Adenoviral Vectors: A Review of Foreign Clinical Studies (Part 2)

“…На серонега-тивных и серопозитивных по отношению к Ad5 добровольцах были исследованы различные дозы и схемы введения вакцины. Согласно результа-там эксперимента, вакцина безопасна, хорошо переносится, вызывает иммунный ответ про-должительностью до 12 месяцев (иммунный от-вет был выше в группе с низкой дозой вакцины), как гуморальный, так и клеточный, но не обе-спечивает стерильную защиту [22,30]. В схеме с однократным внутримышечным введением вакцины уровень гуморального иммунного отве-та был низким, хотя клеточный иммунный ответ на антигены малярийного плазмодия наблюдал-ся у 56% испытуемых для CS-антигена и у 100% для АМА1.…”