Immunization with Hexon Modified Adenoviral Vectors Integrated with gp83 Epitope Provides Protection against Trypanosoma cruzi Infection

Abstract

Background Trypanosoma cruzi is the causative agent of Chagas disease. Chagas disease is an endemic infection that affects over 8 million people throughout Latin America and now has become a global challenge. The current pharmacological treatment of patients is unsuccessful in most cases, highly toxic, and no vaccines are available. The results of inadequate treatment could lead to heart failure resulting in death. Therefore, a vaccine that elicits neutralizing antibodies mediated by cell-mediated immune responses and protection against Chagas disease is necessary.Methodology/Principal FindingsThe “antigen capsid-incorporation” strategy is based upon the display of the T. cruzi epitope as an integral component of the adenovirus' capsid rather than an encoded transgene. This strategy is predicted to induce a robust humoral immune response to the presented antigen, similar to the response provoked by native Ad capsid proteins. The antigen chosen was T. cruzi gp83, a ligand that is used by T. cruzi to attach to host cells to initiate infection. The gp83 epitope, recognized by the neutralizing MAb 4A4, along with His6 were incorporated into the Ad serotype 5 (Ad5) vector to generate the vector Ad5-HVR1-gp83-18 (Ad5-gp83). This vector was evaluated by molecular and immunological analyses. Vectors were injected to elicit immune responses against gp83 in mouse models. Our findings indicate that mice immunized with the vector Ad5-gp83 and challenged with a lethal dose of T. cruzi trypomastigotes confer strong immunoprotection with significant reduction in parasitemia levels, increased survival rate and induction of neutralizing antibodies.Conclusions/SignificanceThis data demonstrates that immunization with adenovirus containing capsid-incorporated T. cruzi antigen elicits a significant anti-gp83-specific response in two different mouse models, and protection against T. cruzi infection by eliciting neutralizing antibodies mediated by cell-mediated immune responses, as evidenced by the production of several Ig isotypes. Taken together, these novel results show that the recombinant Ad5 presenting T. cruzi gp83 antigen is a useful candidate for the development of a vaccine against Chagas disease.

Genetic Adjuvantation of a Cell-Based Therapeutic Vaccine for Amelioration of Chagasic Cardiomyopathy

“…In the present study, analysis of the IgG subclasses from mice immunized with the adenoviral dendritic cell vaccine indicated that IgG1 was the dominant response in immunized BALB/c mice. In a previous study by Farrow et al (63), a strong IgG2b response induced by the Ad5-gp83 vaccine facilitated antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity in addition to eliciting neutralizing antibodies. Coordinated cellular (T H 1) and humoral (T H 2) responses are important for the effective clearance of intracellular pathogens by the adaptive immune system.…”

Development of novel vaccine vectors: Chimpanzee adenoviral vectors

“…A method termed as "antigen capsidincorporation" based on homologous recombination is efficient in capsid modification of Ads and is used in Ad-based vaccine development. [32][33][34][35] Chimpanzee Ad-based vaccines for infectious diseases As described above, AdC has many ideal features as a vaccine vector compared to other vaccine vectors even the AdHu5 vector. Though clinical trials based on the AdHu5 vector are still being conducted, increasing numbers of pre-clinical or clinical trials ( Table 2).…”

Development of Novel Adenoviral Vectors to Overcome Challenges Observed With HAdV-5–based Constructs

“…, capsid shielding, has been researched for both reduction of hexon HVR-antigen exposure as well as for HAdV-5 vector tropism retargeting. 80 , 81 , 82 However, unless fused to the amino terminus of pIX, the insertional size of shielding moieties is limited, and this approach has demonstrated to severely impact the manufacturability of such “shielded” and/or “re-targeted” vectors given the low yield of replication-deficient HAdV-5 vectors obtained. 83 Another strategy to shield the antigenic HAdV-5 vector sites is being investigated whereby coating of HAdV-5 capsids using diverse materials, like polymers and lipidic envelopes is attempted.…”