We evaluate the efficacy and immunogenicity of HIV clade A/E A244 envelope (Env) immunogens with the 23 amino acids of variable region 1 deleted (ΔV1) or retained (wild-type [WT]) in macaques. Only the ΔV1 regimen significantly reduces the risk of mucosal acquisition of clade C simian/human immunodeficiency virus (SHIV)1157(QNE)Y173H versus controls, providing 81% efficacy and leaving 10 of 12 immunized animals uninfected. ΔV1 vaccination induces higher systemic antibody-dependent cellular cytotoxicity (ADCC) targeting helical-V2 and anti-inflammatory myeloid cells, which, together with IL-17+NKp44+ innate lymphoid cells (ILCs) and systemic PD-1+ helper T cells, correlated with reduced infection risk. By contrast, WT immunization induces higher IL-15, CCR2+pDC, and gp70/V1V2-biased responses, which, along with mucosal IFN-γ+NKG2A-NKp44- ILCs, were associated with increased susceptibility. Ex vivo, ΔV1 gp120 reduced CCR5 expression on CD4+ T cells relative to WT gp120, consistent with the anti-inflammatory mucosal response by ΔV1-vaccine regimens in vivo. Thus, V1 deletion promotes an anti-inflammatory mucosal landscape less permissive to HIV seeding and dissemination following virus exposure.
Isabela Silva de Castro, Mohammad Arif Rahman, Massimiliano Bissa et al.· Cell Reports Medicine· 0 citations
ABSTRACT To identify strategies for augmenting vaccine immunogenicity, we compared a pox-protein prime-boost regimen comprising recombinant modified vaccinia virus Ankara and multimeric HIV-1 Env gp145, adjuvanted with Army Liposomal Formulation (ALF) either adsorbed to aluminum salt (ALFA) or formulated with the QS-21 saponin (ALFQ), in rhesus macaques. ALFQ promoted greater magnitude and more durable humoral and cellular immune responses than ALFA, which exhibits similar immunogenicity to aluminum-based adjuvants. Peak Env-specific CD4+ T cell responses assessed by intracellular cytokine staining were 10-fold greater with ALFQ, and CD8+ T cell responses were unexpectedly robust, averaging greater than 1%. ALFQ induced higher levels of several immunostimulatory cytokines in plasma, which correlated with adaptive immune responses. However, vaccination did not protect against heterologous intrarectal challenge with transmitted/founder SHIV-CH505. We provide evidence that CH505 Env may maintain a relatively closed conformation, rendering it less susceptible to targeting by Fc-mediated antibody functions. Overall, ALFQ is a promising adjuvant to improve antibody and T cell response magnitude. IMPORTANCE An effective and durable vaccine preventing HIV-1 acquisition is urgently needed to end the HIV-1 pandemic. To date, of the nine vaccine efficacy trials conducted in humans, only the RV144 vaccine trial demonstrated efficacy in reducing infections, although immune responses waned rapidly. We evaluated a modified HIV-1 vaccine regimen incorporating next-generation adjuvants to improve immune responses and vaccine efficacy in a gold standard, pre-clinical primate model. Adjuvanted protein boosting markedly increased antibody, T cell, and pro-inflammatory response magnitude. These data, combined with the adjuvant’s strong safety and immunogenicity track record in clinical trials, indicate that novel adjuvants represent a promising strategy for improving immune responses to protein immunogens. Future vaccine regimens against HIV-1 and other pathogens for which eliciting robust immunity has been difficult may benefit from incorporating these or related next-generation adjuvants. An effective and durable vaccine preventing HIV-1 acquisition is urgently needed to end the HIV-1 pandemic. To date, of the nine vaccine efficacy trials conducted in humans, only the RV144 vaccine trial demonstrated efficacy in reducing infections, although immune responses waned rapidly. We evaluated a modified HIV-1 vaccine regimen incorporating next-generation adjuvants to improve immune responses and vaccine efficacy in a gold standard, pre-clinical primate model. Adjuvanted protein boosting markedly increased antibody, T cell, and pro-inflammatory response magnitude. These data, combined with the adjuvant’s strong safety and immunogenicity track record in clinical trials, indicate that novel adjuvants represent a promising strategy for improving immune responses to protein immunogens. Future vaccine regimens against HIV-1 and other pathogens for which eliciting robust immunity has been difficult may benefit from incorporating these or related next-generation adjuvants.
Hannah A. D. King, C. Subra, Emily Tourtellott et al.· Journal of Virology· 0 citations
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