Browsing by Author "Nohara, Junsuke"
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Item Open Access Conjugation of HIV-1 envelope to hepatitis B surface antigen alters vaccine responses in rhesus macaques.(NPJ vaccines, 2023-11) Nettere, Danielle; Unnithan, Shakthi; Rodgers, Nicole; Nohara, Junsuke; Cray, Paul; Berry, Madison; Jones, Caroline; Armand, Lawrence; Li, Shuk Hang; Berendam, Stella J; Fouda, Genevieve G; Cain, Derek W; Spence, Taylor N; Granek, Joshua A; Davenport, Clemontina A; Edwards, Robert J; Wiehe, Kevin; Van Rompay, Koen KA; Moody, M Anthony; Permar, Sallie R; Pollara, JustinAn effective HIV-1 vaccine remains a critical unmet need for ending the AIDS epidemic. Vaccine trials conducted to date have suggested the need to increase the durability and functionality of vaccine-elicited antibodies to improve efficacy. We hypothesized that a conjugate vaccine based on the learned response to immunization with hepatitis B virus could be utilized to expand T cell help and improve antibody production against HIV-1. To test this, we developed an innovative conjugate vaccine regimen that used a modified vaccinia virus Ankara (MVA) co-expressing HIV-1 envelope (Env) and the hepatitis B virus surface antigen (HBsAg) as a prime, followed by two Env-HBsAg conjugate protein boosts. We compared the immunogenicity of this conjugate regimen to matched HIV-1 Env-only vaccines in two groups of 5 juvenile rhesus macaques previously immunized with hepatitis B vaccines in infancy. We found expansion of both HIV-1 and HBsAg-specific circulating T follicular helper cells and elevated serum levels of CXCL13, a marker for germinal center activity, after boosting with HBsAg-Env conjugate antigens in comparison to Env alone. The conjugate vaccine elicited higher levels of antibodies binding to select HIV Env antigens, but we did not observe significant improvement in antibody functionality, durability, maturation, or B cell clonal expansion. These data suggests that conjugate vaccination can engage both HIV-1 Env and HBsAg specific T cell help and modify antibody responses at early time points, but more research is needed to understand how to leverage this strategy to improve the durability and efficacy of next-generation HIV vaccines.Item Open Access Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques.(Frontiers in immunology, 2023-01) Tuyishime, Marina; Spreng, Rachel L; Hueber, Brady; Nohara, Junsuke; Goodman, Derrick; Chan, Cliburn; Barfield, Richard; Beck, Whitney E; Jha, Shalini; Asdell, Stephanie; Wiehe, Kevin; He, Max M; Easterhoff, David; Conley, Haleigh E; Hoxie, Taylor; Gurley, Thaddeus; Jones, Caroline; Adhikary, Nihar Deb; Villinger, Francois; Thomas, Rasmi; Denny, Thomas N; Moody, Michael Anthony; Tomaras, Georgia D; Pollara, Justin; Reeves, R Keith; Ferrari, GuidoRhesus macaques (RMs) are a common pre-clinical model used to test HIV vaccine efficacy and passive immunization strategies. Yet, it remains unclear to what extent the Fc-Fc receptor (FcR) interactions impacting antiviral activities of antibodies in RMs recapitulate those in humans. Here, we evaluated the FcR-related functionality of natural killer cells (NKs) from peripheral blood of uninfected humans and RMs to identify intra- and inter-species variation. NKs were screened for FcγRIIIa (human) and FcγRIII (RM) genotypes (FcγRIII(a)), receptor signaling, and antibody-dependent cellular cytotoxicity (ADCC), the latter mediated by a cocktail of monoclonal IgG1 antibodies with human or RM Fc. FcγRIII(a) genetic polymorphisms alone did not explain differences in NK effector functionality in either species cohort. Using the same parameters, hierarchical clustering separated each species into two clusters. Importantly, in principal components analyses, ADCC magnitude, NK contribution to ADCC, FcγRIII(a) cell-surface expression, and frequency of phosphorylated CD3ζ NK cells all contributed similarly to the first principal component within each species, demonstrating the importance of measuring multiple facets of NK cell function. Although ADCC potency was similar between species, we detected significant differences in frequencies of NK cells and pCD3ζ+ cells, level of cell-surface FcγRIII(a) expression, and NK-mediated ADCC (P<0.001), indicating that a combination of Fc-FcR parameters contribute to overall inter-species functional differences. These data strongly support the importance of multi-parameter analyses of Fc-FcR NK-mediated functions when evaluating efficacy of passive and active immunizations in pre- and clinical trials and identifying correlates of protection. The results also suggest that pre-screening animals for multiple FcR-mediated NK function would ensure even distribution of animals among treatment groups in future preclinical trials.