Immunogenicity and Protection of a Recombinant Human Adenovirus Serotype 35-Based Malaria Vaccine againstPlasmodium yoeliiin Mice

Abstract

Given the promise of recombinant adenovirus type 5 (rAd5) as a malaria vaccine carrier in preclinical models, we evaluated the potency of rAd35 coding for Plasmodium yoelii circumsporozoite protein (rAd35PyCS). We chose rAd35 since a survey with serum samples from African subjects demonstrated that human Ad35 has a much lower seroprevalence of 20% and a much lower geometric mean neutralizing antibody titer (GMT) of 48 compared to Ad5 (seroprevalence, 85%; GMT, 1,261) in countries with a high malaria incidence. We also demonstrated that immunization with rAd35PyCS induced a dose-dependent and potent, CS-specific CD8 ؉ cellular and humoral immune response and conferred significant inhibition (92 to 94%) of liver infection upon high-dose sporozoite challenge. Furthermore, we showed that in mice carrying neutralizing antibody activity against Ad5, mimicking a human situation, CS-specific T-and B-cell responses were significantly dampened after rAd5PyCS vaccination, resulting in loss of inhibition of liver infection upon sporozoite challenge. In contrast, rAd35 vaccine was as potent in naive mice as in Ad5-preimmunized mice. Finally, we showed that heterologous rAd35-rAd5 prime-boost regimens were more potent than rAd35-rAd35 because of induction of anti-Ad35 antibodies after rAd35 priming. The latter data provide a further rationale for developing rAd prime-boost regimens but indicate that priming and boosting Ad vectors must be immunologically distinct and also should be distinct from Ad5. Collectively, the data presented warrant further development of rAd35-based vaccines against human malaria.

Impact of Recombinant Adenovirus Serotype 35 Priming versus Boosting of aPlasmodium falciparumProtein: Characterization of T- and B-Cell Responses to Liver-Stage Antigen 1

“…A possible explanation of our results is that the LSA-1 protein expression and the antigen processing upon immunization are not optimal for the induction of T-helper cells required to trigger anti-LSA-1 antibody responses, probably due to the modified sequence of the protein (24). In line with this hypothesis, it is noteworthy that a relatively high dose of rAd35 (10 10 VP) was required to induce significant T-cell responses, in contrast to our previous results with other rAd35 vectors where a 1-log-lower dose (10 9 VP) was sufficient to induce an optimal T-cell response (37,38,41). The heterologous vaccination regimens elicited a level of anti-LSA-1 IgG responses comparable to that seen for the protein vaccinations.…”

“…The absence of LSA-1-specific antibody responses in mice immunized with rAd35.LSA-1 was surprising, since rAd35 has been reported in other studies to induce antibody responses against the transgene expressed (37,38). A possible explanation of our results is that the LSA-1 protein expression and the antigen processing upon immunization are not optimal for the induction of T-helper cells required to trigger anti-LSA-1 antibody responses, probably due to the modified sequence of the protein (24).…”

Memory CD8 T cell responses exceeding a large but definable threshold provide long-term immunity to malaria

“…Protective CD8 T cell immunity against liver-stage Plasmodium infection has been demonstrated after vaccination of rodents with irradiated or genetically attenuated parasites and after subunit vaccination against liver-stage antigens (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Immunity in rodents can last for 6-12 months (3,4,7,13), but in several studies also seems to wane with time (7,(14)(15)(16).…”

Efficient antitumor effects of carrier cells loaded with a fiber-substituted conditionally replicating adenovirus on CAR-negative tumor cells

“…High seroprevalence against Ad5 in adults has been reported. 6,7 Second, Ads originally have strong tropism for the liver, resulting in high levels of liver accumulation of Ads after intravenous administration. Even after local injection into tumors, Ads are disseminated from the injected points, drained into blood circulation and accumulated in the liver.…”