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Designing a therapeutic hepatitis B vaccine to circumvent immune tolerance.

ABSTRACT: An effective prophylactic hepatitis B virus (HBV) vaccine has long been available but is ineffective for chronic infection. The primary cause of chronic hepatitis B (CHB) and greatest impediment for a therapeutic vaccine is the direct and indirect effects of immune tolerance to HBV antigens. The resulting defective CD4⁺/CD8⁺ T cell response, poor cytokine production, insufficient neutralizing antibody (nAb) and poor response to HBsAg vaccination characterize CHB infection. The objective of this study was to develop virus-like-particles (VLPs) that elicit nAb to prevent viral spread and prime CD4⁺/CD8⁺ T cells to eradicate intracellular HBV. Eight neutralizing B cell epitopes from the envelope PreS1 region were consolidated onto a species-variant of the HBV core protein, the woodchuck hepatitis core antigen (WHcAg). PreS1-specific B cell epitopes were chosen because of preferential expression on HBV virions. Because WHcAg and HBcAg are not crossreactive at the B cell level and only partially cross-reactive at the CD4⁺/CD8⁺ T cell level, CD4⁺ T cells specific for WHcAg-unique T cell sites can provide cognate T-B cell help for anti-PreS1 Ab production that is not curtailed by immune tolerance. Immunization of immune tolerant HBV transgenic (Tg) mice with PreS1-WHc VLPs elicited levels of high titer anti-PreS1 nAbs equivalent to wildtype mice. Passive transfer of PreS1 nAbs into human-liver chimeric mice prevented acute infection and cleared serum HBV from mice previously infected with HBV in a model of CHB. At the T cell level, PreS1-WHc VLPs and hybrid WHcAg/HBcAg DNA immunogens elicited HBcAg-specific CD4⁺ Th and CD8⁺ CTL responses.

SUBMITTER: Whitacre DC

PROVIDER: S-EPMC7062423 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background & aimsInduction of potent, HBV-specific immune responses is crucial to control and finally cure HBV. The therapeutic hepatitis B vaccine TherVacB combines protein priming with a Modified Vaccinia virus Ankara (MVA)-vector boost to break immune tolerance in chronic HBV infection. Particulate protein and vector vaccine components, however, require a constant cooling chain for storage and transport, posing logistic and financial challenges to vaccine applications. We aimed to identify an optimal formulation to maintain stability and immunogenicity of the protein and vector components of the vaccine using a systematic approach.MethodsWe used stabilizing amino acid (SAA)-based formulations to stabilize HBsAg and HBV core particles (HBcAg), and the MVA-vector. We then investigated the effect of lyophilization and short- and long-term high-temperature storage on their integrity. Immunogenicity and safety of the formulated vaccine was validated in HBV-naïve and adeno-associated virus (AAV)-HBV-infected mice.ResultsIn vitro analysis proved the vaccine's stability against thermal stress during lyophilization and the long-term stability of SAA-formulated HBsAg, HBcAg and MVA during thermal stress at 40 °C for 3 months and at 25 °C for 12 months. Vaccination of HBV-naïve and AAV-HBV-infected mice demonstrated that the stabilized vaccine was well tolerated and able to brake immune tolerance established in AAV-HBV mice as efficiently as vaccine components constantly stored at 4 °C/-80 °C. Even after long-term exposure to elevated temperatures, stabilized TherVacB induced high titre HBV-specific antibodies and strong CD8+ T-cell responses, resulting in anti-HBs seroconversion and strong suppression of the virus in HBV-replicating mice.ConclusionSAA-formulation resulted in highly functional and thermostable HBsAg, HBcAg and MVA vaccine components. This will facilitate global vaccine application without the need for cooling chains and is important for the development of prophylactic as well as therapeutic vaccines supporting vaccination campaigns worldwide.Impact and implicationsTherapeutic vaccination is a promising therapeutic option for chronic hepatitis B that may enable its cure. However, its application requires functional cooling chains during transport and storage that can hardly be guaranteed in many countries with high demand. In this study, the authors developed thermostable vaccine components that are well tolerated and that induce immune responses and control the virus in preclinical mouse models, even after long-term exposure to high surrounding temperatures. This will lower costs and ease application of a therapeutic vaccine and thus be beneficial for the many people affected by hepatitis B around the world.

Project description:Blastomyces dermatitidis is a thermally dimorphic fungus that can cause serious and sometimes fatal infections, including blastomycosis. After spore inhalation, a pulmonary infection develops, which can be asymptomatic and have lethal effects, such as acute respiratory distress syndrome. Its most common extra-pulmonary sites are the central nervous system, bones, skin, and genito-urinary systems. Currently, no vaccine has been approved by the FDA to prevent this infection. In the study, a peptide-based vaccine was developed against blastomycosis by using subtractive proteomics and reverse vaccinology approaches. It focuses on mining the whole genome of B. dermatitidis, identifying potential therapeutic targets, and pinpointing potential epitopes for both B- and T-cells that are immunogenic, non-allergenic, non-toxic, and highly antigenic. Multi-epitope constructs were generated by incorporating appropriate linker sequences. A linker (EAAAK) was also added to incorporate an adjuvant sequence to increase immunological potential. The addition of adjuvants and linkers ultimately resulted in the formation of a vaccine construct in which the number of amino acids was 243 and the molecular weight was 26.18 kDa. The designed antigenic and non-allergenic vaccine constructs showed suitable physicochemical properties. The vaccine's structures were predicted, and further analysis verified their interactions with the human TLR-4 receptor through protein-protein docking. Additionally, MD simulation showed a potent interaction between prioritized vaccine-receptor complexes. Immune simulation predicted that the final vaccine injections resulted in significant immune responses for the T- and B-cell immune responses. Moreover, in silico cloning ensured a high expression possibility of the lead vaccine in the E. coli (K12) vector. This study offers an initiative for the development of effective vaccines against B. dermatitidis; however, it is necessary to validate the designed vaccine's immunogenicity experimentally.

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Designing a therapeutic hepatitis B vaccine to circumvent immune tolerance.

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