Designing a therapeutic hepatitis B vaccine to circumvent immune tolerance

• Published in: Human vaccines & immunotherapeutics Vol. 16; no. 2; pp. 251 - 268
• Main Authors: Whitacre, DC, Peters, CJ, Sureau, C, Nio, K, Li, F, Su, L, Jones, JE, Isogawa, M, Sallberg, M, Frelin, L, Peterson, DL, Milich, DR
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01-01-2020; Taylor & Francis Group
• Subjects: Hbv; immune tolerance; Medicin och hälsovetenskap; neutralizing antibody; pres1; Research Paper; therapeutic vaccine; therapeutic vaccine; neutralizing antibody; immune tolerance; Hbv; pres1
• ISSN: 2164-5515; 2164-554X; 2164-554X
• DOI: 10.1080/21645515.2019.1689745

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.