Human adenovirus 5-vectoredPlasmodium falciparumNMRC-M3V-Ad-PfCA vaccine encoding CSP and AMA1 is safe, well-tolerated and immunogenic but does not protect against controlled human malaria infection

Abstract

Background: In a prior study, a DNA prime / adenovirus boost vaccine (DNA/Ad) expressing P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1) (NMRC-M3V-D/Ad-PfCA Vaccine) induced 27% protection against controlled human malaria infection (CHMI). To investigate the contribution of DNA priming, we tested the efficacy of adenovirus vaccine alone (NMRC-M3V-Ad-PfCA ) in a Phase 1 clinical trial.Methodology/Principal Findings: The regimen was a single intramuscular injection with two non-replicating human serotype 5 adenovectors encoding CSP and AMA1, respectively. One x 1010 particle units of each construct were combined prior to administration. The regimen was safe and well-tolerated. Four weeks later, 18 study subjects received P. falciparum CHMI administered by mosquito bite. None were fully protected although one showed delayed onset of parasitemia. Antibody responses were low, with geometric mean CSP ELISA titer of 381 (range < 50–1626) and AMA1 ELISA of 4.95 µg/mL (range 0.2–38). Summed ex vivo IFN-γ ELISpot responses to overlapping peptides were robust, with geometric mean spot forming cells/million peripheral blood mononuclear cells [sfc/m] for CSP of 273 (range 38–2550) and for AMA1 of 1303 (range 435–4594). CD4+ and CD8+ T cell IFN-γ responses to CSP were positive by flow cytometry in 25% and 56% of the research subjects, respectively, and to AMA1 in 94% and 100%, respectively.Significance: In contrast to DNA/Ad, Ad alone did not protect against CHMI despite inducing broad, cell-mediated immunity, indicating that DNA priming is required for protection by the adenovirus-vectored vaccine. ClinicalTrials.gov Identifier: NCT00392015.

Sterile Immunity to Malaria after DNA Prime/Adenovirus Boost Immunization Is Associated with Effector Memory CD8+T Cells Targeting AMA1 Class I Epitopes

“…As PBMC after the Ad boost were limited, we also used PBMC collected after challenge, as the pool-specificity of T cell activities was maintained, even though magnitudes of response were reduced after CHMI, perhaps due to localization of circulating antigen-specific T cells into the liver (Figure S6) [26]). Only AMA1 15mer peptides could be tested due to PBMC limitations.…”

“…Detailed accounts of each clinical trial have been previously published [19], [26]. The vaccine constructs and CHMI used the 3D7 clone of P. falciparum .…”

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

“…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. После экспериментального зараже-ния малярией только один испытуемый проде-монстрировал задержку развития паразитемии [31]. Таким образом, применение аденовекторов для вакцинации оправдано лишь при использо-вании схемы прайм-буст вакцинации, что и было продемонстрировано в схеме, когда вакцину на основе аденовирусного вектора вводили после праймирования испытуемых ДНК-вакциной, не-сущей такие же антигены.…”

The March Toward Malaria Vaccines

“…57 However, like DNA plasmids, viral vectors used alone have failed to induce significant protection against CHMI by mosquito bite even when two or more antigens have been tested in combination. 58,59,97 …”