Adenovirus particles that display the Plasmodium falciparum circumsporozoite protein NANP repeat induce sporozoite-neutralizing antibodies in mice

Abstract

Adenovirus particles can be engineered to display exogenous peptides on their surfaces by modification of viral capsid proteins, and particles that display pathogen-derived peptides can induce protective immunity. We constructed viable recombinant adenoviruses that display B-cell epitopes from the Plasmodium falciparum circumsporozoite protein (PfCSP) in the major adenovirus capsid protein, hexon. Recombinants induced high-titer antibodies against CSP when injected intraperitoneally into mice. Serum obtained from immunized mice recognized both recombinant PfCSP protein and P. falciparum sporozoites, and neutralized P. falciparum sporozoites in vitro. Replicating adenovirus vaccines have provided economical protection against adenovirus disease for over three decades. The recombinants described here may provide a path to an affordable malaria vaccine in the developing world.

A Replicating Adenovirus Capsid Display Recombinant Elicits Antibodies against Plasmodium falciparum Sporozoites in Aotus nancymaae Monkeys

“…Ad5hr-NVDP is a viable recombinant that displays the P. falciparum CSP epitope NANPNVDP(NANP) 4 in hypervariable region 1 (HVR1) of hexon (11). Ad5hr-FFIG is a viable Ad5 recombinant that expresses green fluorescent protein from the major late transcriptional unit derived from Ad5-FFIG (20).…”

“…This repeat is conserved in all P. falciparum isolates (7) and is the immunodominant B-cell epitope of CSP (8). Antibody to the NANP repeat is sufficient to confer protection in animal models (9)(10)(11)(12), and protection by the most advanced malaria vaccine candidate, RTS,S, is correlated with antibody responses to the repeat region (13,14). However, no candidate vaccine yet induces high-level, durable protection against sporozoite infection (15,16), and an urgent need for novel malaria immunization strategies remains.…”

“…Adenoviruses that display exogenous epitopes on the surfaces of their capsids (capsid display recombinants) are potently immunogenic in mice (10)(11)(12)17). Capsid display recombinants that expressed either the central repeat B-cell epitope (NANP) 5 or a combined B-and T-cell epitope NANPNVDP(NANP) 4 induced high-titer P. falciparum CSP antibodies, and serum from (NANP) 5 -immunized mice (the only ones examined) neutralized sporozoites in an in vitro assay (11).…”

“…Capsid display recombinants that expressed either the central repeat B-cell epitope (NANP) 5 or a combined B-and T-cell epitope NANPNVDP(NANP) 4 induced high-titer P. falciparum CSP antibodies, and serum from (NANP) 5 -immunized mice (the only ones examined) neutralized sporozoites in an in vitro assay (11). However, human adenoviruses do not replicate in mice, and immunological responses to capsid display recombinants in mice are not likely to accurately predict responses to the recombinants as they replicate in humans.…”

Synergism/complementarity of recombinant adenoviral vectors and other vaccination platforms during induction of protective immunity against malaria

“…For malaria prevention also, Palma et al (2011) constructed a recombinant HAd5V expressing two different B cell epitopes of P. falciparum CSP within the hexon protein. Different from all others studies cited here, these two recombinant vectors were replicative.…”