Vaccination with an Adenoviral Vector That Encodes and Displays a Retroviral Antigen Induces Improved Neutralizing Antibody and CD4⁺T-Cell Responses and Confers Enhanced Protection

Abstract

We present a new type of adenoviral vector that both encodes and displays a vaccine antigen on the capsid, thus combining in itself gene-based and protein vaccination; this vector resulted in an improved vaccination outcome in the Friend virus (FV) model. For presentation of the envelope protein gp70 of Friend murine leukemia virus on the adenoviral capsid, gp70 was fused to the adenovirus capsid protein IX. When compared to vaccination with conventional FV Env-and Gag-encoding adenoviral vectors, vaccination with the adenoviral vector that encodes and displays pIX-gp70 combined with an FV Gag-encoding vector resulted in significantly improved protection against systemic FV challenge infection, with highly controlled viral loads in plasma and spleen. This improved protection correlated with improved neutralizing antibody titers and stronger CD4 ؉ T-cell responses. Using a vector that displays gp70 without encoding it, we found that while the antigen display on the capsid alone was sufficient to induce high levels of binding antibodies, in vivo expression was necessary for the induction of neutralizing antibodies. This new type of adenovirus-based vaccine could be a valuable tool for vaccination.Adenoviruses have been a focus of interest as vaccine vectors for more than a decade and have been tested in various preclinical and clinical studies for vaccination against viral and bacterial infections (reviewed in reference 38). This interest is based on the ability of adenoviral vectors to induce high antibody titers and robust cytotoxic T-lymphocyte (CTL) responses and on the high immunogenicity of the vector, which might have an adjuvant effect on vaccination (17). Adenoviral vectors have also been extensively evaluated for immunization against HIV (reviewed in reference 1), where they were used either alone or in combination with plasmid DNA or protein in prime-boost immunizations. However, vaccination with adenoviral vectors against HIV showed no effectiveness in a large phase IIb study (4), but it is conceivable that the observed lack of effectiveness was due to the choice of vaccine antigen rather than the vector itself, as the vaccine relied exclusively on the induction of CTL responses, and the outcome was unexpected given previous results from studies in nonhuman primates (33,42). The findings of the phase IIb study brought about a shift of focus from the CTL response to a more balanced immune response, including neutralizing antibodies, that is now expected to be necessary for protection from HIV infection.Apart from adenoviral vectors that encode vaccine antigens, there have also been approaches to modify adenoviral capsid proteins to include antigenic epitopes. These were mostly inserted into external loops of the hexon protein (5,22,25,26,43), which is the main component of the adenovirus capsid, but also other components of the capsid, such as fiber, protein IX, and penton base, have been evaluated (22). These studies showed that incorporation of single epitopes into capsid proteins of adenovirus leads ...

Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus

“…Small numbers of allotypically marked EF4.1 TCRβ-transgenic CD4 + T cells were transferred into wild-type (WT) C57BL/6 (B6) recipients and primed either by infection with Friend virus (FV) or by immunization with a human Adenovirus 5 (Ad5)-based vector expressing F-MLV gp70 (Ad5.pIX-gp70) (Bayer et al., 2010). FV is a retroviral complex of F-MLV and spleen focus-forming virus (SFFV) that causes chronic infection in B6 mice (Hasenkrug and Chesebro, 1997, Tsuji-Kawahara et al., 2013), whereas the Ad5.pIX-gp70 vaccine vector is replication defective (Bayer et al., 2010). Microarray-based comparison of EF4.1 env-reactive CD4 + T cells primed by Ad5.pIX-gp70 indicated elevated transcription of CTL-related genes, in comparison with T cells primed by FV (Thorborn et al., 2014).…”

Codelivery of the Chemokine CCL3 by an Adenovirus-Based Vaccine Improves Protection from Retrovirus Infection

“…We demonstrated in those experiments the advantage of heterologous prime-boost combinations (2) and generated a new type of adenoviral vector that displays vaccine antigens on the virus capsid, which induced increased CD4 ϩ T cell and neutralizing antibody responses, resulting in improved immune protection (3).…”

Viral vectors as vaccine platforms: deployment in sight

“…This has prompted the development of alternative serotypes of adenovirus not circulating in human populations such that the prevalence of neutralizing antibodies is low [17,18]. One strategy is the identification and development of rare human serotypes such as AdHu35 [19], AdHu28 [20], or modification of the AdHu5 capsid [21,22]. Adenoviruses isolated from chimpanzees (AdC) have also been well characterized and developed as vectors.…”