Induction of Robust Immunity Against Hepatitis C Virus Using Rationally Adjuvanted Microneedle Patches Integrating A Secreted Form of E1E2 Heterodimer 2259568
The preclinical development of a novel HCV vaccine candidate engineered by formulating a novel native-like secreted E1E2 immunogen and a well-established combinatorial adjuvant of QS-21 + 3D-(6-acyl) PHAD into unique microneedle patches (MNPs).
Abstract
Safe, effective, durable, and broadly deployable vaccines are needed for sustainable control of hepatitis C virus (HCV) that poses a significant global public health threat. We reported the preclinical development of a novel HCV vaccine candidate engineered by formulating a novel native-like secreted E1E2 immunogen and a well-established combinatorial adjuvant of QS-21 + 3D-(6-acyl) PHAD into our unique microneedle patches (MNPs).
In C57BL/6 mice, we evaluated (1) the local immunomodulation characteristics by RT-qPCR; (2) the local and systemic reactogenicity; (3) humoral responses by ELISA and pseudovirus neutralization; and (4) cellular responses by antigen-specific stimulation of isolated splenocytes, followed by intracellular cytokine staining and flow cytometry. Intramuscular vaccination (IM) was used as a benchmark group. In human skin explants, we studied the effect of MNP-delivered adjuvant on the subsets and phenotypes of skin-migratory dendritic cells by flow cytometry.
Our HCV vaccine efficiently and safely (with no systemic and local reactogenicity) engineered the skin immune system in mice to induce proinflammatory milieu at the vaccine-targeted tissues with increased Nlrp3, Ifng, and Cxcl10 expression. In human skin explants, our HCV vaccine stimulated the migration of highly immunostimulatory antigen-presenting cells, supported by enhanced expression of co-stimulatory molecules, such as CD86 and CD83. Skin immunization of mice with our HCV vaccine elicited improved humoral (higher binding and neutralizing antibodies with enhanced Th1-skewing) and cellular polyfunctional T-cells responses compared to IM immunization. The formulation preserved potency for 3 months at 40 °C, indicating thermostability.
Unique safety, shelf-stability, innate and adaptive immunogenicity advantages of MNP-based skin immunization would enable the development of clinically translatable and globally accessible HCV vaccines with rationally designed antigens and adjuvants.
Department of Dermatology, University of Pittsburgh
Vaccines and Immunotherapy (VAC)
The immunodominance hierarchy of influenza antigens remains a major obstacle in developing broadly protective vaccines. Current flu vaccines primarily elicit antibody responses against variable head regions of hemagglutinin (HA), leading to strain-specific immunity and limited cross-protection. Cyclic dinucleotides (CDNs), potent agonists of the stimulator of interferon genes (STING) pathway, have emerged as promising adjuvants that can enhance both humoral and cellular immunity. In this study, we sought to investigate the capacity of CDN nanoparticle formulations to overcome immunodominance in influenza vaccination by combining CDN nanoparticles with influenza antigens.
Female C57BL/6 mice were immunized subcutaneously twice, with a 4-week interval between doses. Each group received either inactivated influenza vaccine (IIV) or hemagglutinin (HA) subunit antigen formulated with or without CDN nanoparticles. Serum samples were collected at defined time points to quantify antigen-specific IgG responses by ELISA. At the study endpoint, draining lymph nodes (inguinal lymph nodes) were harvested to assess germinal center B cell responses by flow cytometry, while bone marrow samples were collected to evaluate the frequencies of long-lived plasma cells reactive to influenza antigens by ELISpot.
CDN nanoparticles not only enhanced the GC formation in draining lymph nodes, resulting in increased frequencies of stem-specific B cells within the GC, but also increased the frequencies of long-lived plasma cells (LLPCs) in the bone marrow. Consequently, serum antibody responses were broader and more durable.
CDN nanoparticle adjuvants broadened antibody specificity, enhanced germinal center reactions, and promoted durable long-lived plasma cell formation. This strategy overcomes the immunodominance of conventional vaccines and represents a promising approach for developing next-generation influenza vaccines with broader and longer-lasting protection.
NIH
Vaccines and Immunotherapy (VAC)
Lantian Lu, Yanying He, Alexander R. Maldeney et al.· Journal of Immunology· 0 citations
Melioidosis, an infectious disease caused by Burkholderia pseudomallei (Bp), is difficult to treat due to intrinsic antibiotic resistance, latency with subsequent recrudescence and a diverse non-specific symptomatology. A vaccine is needed to effectively control this disease burden around the globe. Here we tested the efficacy of a novel Bp vaccine containing hemolysin-coregulated protein (Hcp1), capsular polysaccharide (CPS)-CRM197 conjugate, and CpG using the Atomic Layering Thermostable Antigen and Adjuvant (ALTA®) platform.
C57BL/6 mice were vaccinated and the protective efficacy as well as immunological profiles were evaluated pre- and post-aerosol challenge with B. pseudomallei K96243 strain.
Each tested dose of Bp ALTA® formulation demonstrated protective efficacy (20-50%) over a non-vaccinated control. Mechanistically, the Bp ALTA® formulations increased Hcp1-directed IFN-gamma recall in splenocytes, and produced robust antibody response against the principal dominant antigen, CPS. High levels of anti-CPS antibodies were associated with significant decrease in bacterial burden in the lung.
The ALTA® platform, which has previously been shown to provide antigen thermostability, was utilized in this study for Bp vaccination achieving protective efficacy from a single-shot administration. Studies are ongoing to optimize the immunogenic potential and protective capacity of these novel formulations.
DTRA-JSTO
Vaccines and Immunotherapy (VAC)
Michael L. Davies, Taloria K. Wheeler, Sergei S. Biryukov 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
It is established that the vaccine formulation can effectively boost and redirect pre-existing immunity, offering a promising approach to overcome the limitations of natural exposure and protect at-risk individuals from diverse Pa infections.
D. R. Howlader, Sayan Das, Satabdi Biswas et al.· Infection and Immunity· 0 citations
It is demonstrated that antigenic clade-matching is likely critical for protection against H5N1 and suggest that currently stockpiled H5N1 vaccines may not protect against contemporary viruses.
E. Gary, Nicholas J. Tursi, Casey E. Hojecki et al.· Journal of Immunology· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
