Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice

Abstract

Adenovirus serotype 5 (Ad5) is one of the most widely used viral vectors and is known to generate potent T cell responses. While many previous studies have characterized Ad5-induced CD8 T cell responses, there is a relative lack of detailed studies that have analyzed CD4 T cells elicited by Ad5 vaccination. Here, we immunized mice with Ad5 vectors encoding lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) and examined GP-specific CD4 T cell responses elicited by Ad5 vectors and compared them to those induced by an acute LCMV infection. In contrast to LCMV infection, where balanced CD4 T helper 1 (Th1) and T follicular helper (Tfh) responses were induced, Ad5 immunization resulted in a significantly reduced frequency of Th1 cells. CD4 T cells elicited by Ad5 vectors expressed decreased levels of Th1 markers, such as Tim3, SLAM, T-bet, and Ly6C, had smaller amounts of cytotoxic molecules like granzyme B, and produced less interferon gamma than CD4 T cells induced by LCMV infection. This defective CD4 Th1 response appeared to be intrinsic for Ad5 vectors and not a reflection of comparing a nonreplicating vector to a live viral infection, since immunization with a DNA vector expressing LCMV-GP generated efficient CD4 Th1 responses. Analysis at early time points (day 3 or 4) after immunization with Ad5 vectors revealed a defect in the expression of CD25 (interleukin-2 [IL-2] receptor alpha chain) on Ad5-elicited CD4 T cells, and administration of exogenous IL-2 following Ad5 immunization partially restored CD4 Th1 responses. These results suggest that impairment of Th1 commitment after Ad5 immunization could be due to reduced IL-2-mediated signaling.IMPORTANCE During viral infection, generating balanced responses of Th1 and Tfh cells is important to induce effective cell-mediated responses and provide optimal help for antibody responses. In this study, to investigate vaccine-induced CD4 T cell responses, we characterized CD4 T cells after immunization with Ad5 vectors expressing LCMV-GP in mice. Ad5 vectors led to altered effector differentiation of LCMV GP-specific CD4 T cells compared to that during LCMV infection. CD4 T cells following Ad5 immunization exhibited impaired Th1 lineage commitment, generating significantly decreased Th1 responses than those induced by LCMV infection. Our results suggest that suboptimal IL-2 signaling possibly plays a role in reduced Th1 development following Ad5 immunization. KEYWORDS CD4 T cell responses, T helper 1 (Th1), T follicular helper (Tfh), adenovirus serotype 5, vaccination R ecombinant adenovirus (Ad) vectors are one of the most favorable vaccine platforms as they have certain potential advantages, such as strong immunogenicity, large transgene capacity, and good safety profile. Ad-based vaccine vectors can induce

Recombinant Human Adenovirus Type 5 Co-expressing RABV G and SFTSV Gn Induces Protective Immunity Against Rabies Virus and Severe Fever With Thrombocytopenia Syndrome Virus in Mice

“…The replication-deficient Ad5 vectors, which possess good ability in inducing antibody and T cell response (Lee et al, 2017), are ideal tools for veterinary vaccine design given the low anti-Ad5 immunity in animals. The recombinant Ad5 virus expressing capsid proteins of foot-and-mouth disease virus (FMDV), as the most successful recombinant vaccine against FMDV to date, elicits effective antibody responses in cattle and provides complete protection from challenge in swine and cattle (Sreenivasa et al, 2017).…”

Inclusion of the murine IgGκ signal peptide increases the cellular immunogenicity of a simian adenoviral vectored Plasmodium vivax multistage vaccine

“…Immunization with the SP-SAd36 regimen also resulted in increased frequencies of IL-2 secreting CD4+ T cells observed in response to all peptide pools of cPvCSP and cPvMSP1. This feature may represent a significant improvement for adenoviral vectors based on a recent study by Lee et al [13] which found that vaccination with an Ad5 recombinant vector induced significantly lower frequencies of antigen-specific CD4+ TH1 cells compared to acute infection, an effect attributed low IL-2 signaling [13]. The increased IL-2 production we observed also has the potential to improve the overall T cell immunogenicity, as IL-2 promotes proliferation and differentiation of naïve CD8+ T cells and the survival of antigen-experienced T cells [52].…”

“…Adenoviral vectored malaria vaccines have been able to improve the immunogenicity of protein-based vaccines [6–9] and induce protective Plasmodium -specific CD8+ T cells in pre-clinical and clinical studies [10–12], but low induction of CD4+ T cell suggests further improvements to adenoviral vectors should be investigated [11]. Recent studies examining the induction of CD4+ T cells following vaccination with an Ad5 vector have shown significantly lower frequencies of antigen-specific CD4+ T cells are induced when compared to acute infection, an effect that could be attributed to lower IL-2 signaling [13]. Increasing secretion or altering post-translational modifications of adenoviral transgene products might result in improved presentation of vaccine antigens to CD4+ T cells.…”

Oncolytic Adenovirus in Cancer Immunotherapy

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