A Replicating Adenovirus Capsid Display Recombinant Elicits Antibodies against Plasmodium falciparum Sporozoites in Aotus nancymaae Monkeys
Karen KA., Deal C., Adams RJ., Nielsen C., Ward C., Espinosa DA., Xie J., Zavala F., Ketner G.
<jats:p>Decades of success with live adenovirus vaccines suggest that replication-competent recombinant adenoviruses (rAds) could serve as effective vectors for immunization against other pathogens. To explore the potential of a live rAd vaccine against malaria, we prepared a viable adenovirus 5 (Ad5) recombinant that displays a B-cell epitope from the circumsporozoite protein (CSP) of<jats:named-content content-type="genus-species">Plasmodium falciparum</jats:named-content>on the virion surface. The recombinant induced<jats:named-content content-type="genus-species">P. falciparum</jats:named-content>sporozoite-neutralizing antibodies in mice. Human adenoviruses do not replicate in mice. Therefore, to examine immunogenicity in a system in which, as in humans, the recombinant replicates, we constructed a similar recombinant in an adenovirus mutant that replicates in monkey cells and immunized four<jats:named-content content-type="genus-species">Aotus nancymaae</jats:named-content>monkeys. The recombinant replicated in the monkeys after intratracheal instillation, the first demonstration of replication of human adenoviruses in New World monkeys. Immunization elicited antibodies both to the<jats:named-content content-type="genus-species">Plasmodium</jats:named-content>epitope and the Ad5 vector. Antibodies from all four monkeys recognized CSP on intact parasites, and plasma from one monkey neutralized sporozoites<jats:italic>in vitro</jats:italic>and conferred partial protection against<jats:named-content content-type="genus-species">P. falciparum</jats:named-content>sporozoite infection after passive transfer to mice. Prior enteric inoculation of two animals with antigenically wild-type adenovirus primed a response to the subsequent intratracheal inoculation, suggesting a route to optimizing performance. A vaccine is not yet available against<jats:named-content content-type="genus-species">P. falciparum</jats:named-content>, which induces the deadliest form of malaria and kills approximately one million children each year. The live capsid display recombinant described here may constitute an early step in a critically needed novel approach to malaria immunization.</jats:p>