The development of next-generation SARS-CoV-2 vaccines with increased humoral and cellular immunogenicity and improved safety, durability, and thermostability is a high-priority goal for global public health.
Here, we introduce a next-generation SARS-CoV-2 vaccine candidate. We formulated SARS-CoV-2 spike protein ferritin nanoparticle adjuvanted with Army Liposome Formulation containing QS-21 into dissolvable microneedle patches. We (1) conducted the biophysical characterization of SpFN+ALFQ MNPs to probe their delivery performance and thermostability, (2) assessed the local and systemic innate responses, and (3) evaluated the humoral and cellular responses in systemic and mucosal compartments.
SpFN+ALFQ MNP successfully delivered SpFN and ALFQ to the same antigen-presenting cell rich skin microenvironments and maintained its immunogenicity at room temperature for at least a year. SpFN+ALFQ MNP induced a proinflammatory local immune microenvironment (i.e., upregulation of Th1-predominant cytokines and chemokines) without local and systemic reactogenicity. Immunization with SpFN+ALFQ MNP evoked strong humoral and cellular responses in systemic and mucosal compartments, with Th1 bias. SpFN+ALFQ MNP-elicited antibodies were cross-reactive and long-lived (at least 76 weeks) and effectively neutralized many SARS-CoV-2 variants of concern. SpFN+ALFQ MNP-induced systemic and pulmonary antigen-specific polyfunctional CD4+ and CD8+ T-cell responses with robust lytic activity. Importantly, SpFN+ALFQ MNP induced comparable antibody responses in young and aged mice.
Together, these unique safety, thermostability, and innate and adaptive immunity characteristics of SpFN+ALFQ MNP provide a strong foundation for the development of rapidly translatable next-generation vaccines leveraging ferritin nanoparticle antigens, ALFQ, and MNPs against SARS-CoV-2 and other emerging pathogens.
Department of Defense, National Institutes of Health
Vaccines and Immunotherapy (VAC)
Sanpreet Singh, Stephen C. Balmert, Saniya Mahendiratta et al.· Journal of Immunology· 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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