Immune Responses in Macaques to a Prototype Recombinant Adenovirus Live Oral Human Papillomavirus 16 Vaccine

Abstract

Immunization with human papillomavirus (HPV) L1 virus-like particles (VLPs) prevents infection with HPV. However, the expense and logistical demands of current VLP vaccines will limit their widespread use in resource-limited settings, where most HPV-induced cervical cancer occurs. Live oral adenovirus vaccines have properties that are well-suited for use in such settings. We have described a live recombinant adenovirus vaccine prototype that produces abundant HPV16 L1 protein from the adenovirus major late transcriptional unit and directs the assembly of HPV16 VLPs in tissue culture. Recombinant-derived VLPs potently elicit neutralizing antibodies in mice. Here, we characterize the immune response to the recombinant after dual oral and intranasal immunization of pigtail macaques, in which the virus replicates as it would in immunized humans. The immunization of macaques induced vigorous humoral responses to adenovirus capsid and nonstructural proteins, although, surprisingly, not against HPV L1. In contrast, immunization elicited strong T-cell responses to HPV VLPs as well as adenovirus virions. T-cell responses arose immediately after the primary immunization and were boosted by a second immunization with recombinant virus. T-cell immunity contributes to protection against a wide variety of pathogens, including many viruses. The induction of a strong cellular response by the recombinant indicates that live adenovirus recombinants have potential as vaccines for those agents. These studies encourage and will inform the continued development of viable recombinant adenovirus vaccines.

Capsid display of a conserved human papillomavirus L2 peptide in the adenovirus 5 hexon protein: a candidate prophylactic hpv vaccine approach

“…Plaque purified recombinant viruses were amplified in 293 cells and were screened for RG-1 reactivity to detect the L2 epitope and with a CSP-specific monoclonal antibody to confirm loss of the allelic malaria epitope. All recombinant adenoviruses were plaque-purified and virus particles were prepared by CsCl density gradient centrifugation and quantified as described previously [ 56 ]. A control recombinant that displays an epitope derived from influenza virus A hemagglitinin (HA) was prepared similarly (C. Deal and G. Ketner, unpublished).…”

“…On the third and sixth day later, the cells were fed with 2.5 mL of agar medium. On day six, the agar medium contained neutral red and plaques were counted daily until their numbers became constant [ 56 , 63 ].…”

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

“…Incorporation of identical or distinct epitopes in multiple hexon HVRs or multiple capsid proteins is possible and may enhance the magnitude or breadth of an antibody response to capsid display recombinants. We and others have demonstrated induction of robust T-cell responses against antigens delivered by live adenovirus recombinants that express whole proteins as transgenes (17,18,36). Recombinants that both contain a transgene and display a relevant epitope on the capsid therefore might effectively induce both humoral and cellular immunity.…”

Novel viral vectors in infectious diseases

“…To fully exploit the advantages of a self‐amplifying vaccine, several groups have also examined the use of replication‐competent adenovirus vectors, which were administered by varying mucosal routes in permissive species (mice are not permissive for human or simian adenoviruses.) Unfortunately, results with regard to induction of humoral immunity were mixed or disappointing . One beneficial feature of replication‐deficient adenoviral vectors is the fact that the transgene is typically immuno‐dominant by default, as the lack of adenoviral gene expression precludes immune competition.…”