Hurdles to the Development of Effective HBV Immunotherapies and HCV Vaccines

Abstract

Chronic infections with HBV and HCV continue to be major public health problems, with hundreds of millions of people infected worldwide; this is despite the availability of both an effective prophylactic HBV vaccine for more than 3 decades and potent direct antivirals for HBV and, more recently, HCV infection. Consequently, development of HBV immunotherapies and prophylactic HCV vaccines remains extremely urgent, but limited funding and significant gaps in our understanding of the correlates of immune protection pose serious hurdles for the development of novel immune-based interventions. Here we discuss immunological questions related to HBV and HCV, some shared and some pertinent to only 1 of the viruses, that should be addressed for the rational design of HBV immunotherapies and HCV vaccines.

Keywords: T cell; antibodies; hepatitis-B; hepatitis-C; immune response; immunotherapy; research funding; vaccine.

Figure 1:

NIH research funding for HCV, HBV and HIV infection. Annual report of NIH funding, expressed as millions of dollars,(US) for research related to HIV (black bars), HCV (orange bars) and HBV (red bars) from 2012 to 2017.

Figure 2:

Risk of chronic Hepatitis B related to age. The risk of developing chronic HBV infection is strikingly age dependent.

Figure 3:

Natural evolution of chronic HBV infection in infants. The long-term course of chronic hepatitis B infection after infant exposure can be typically described in 3 different phases, characterized by different patterns of ALT elevation (green), HBV-DNA levels (grey), and the presence of HBe-Ag (red-line) or anti-HBe (blue).

Figure 4:

Viral diversity of three viruses: HIV, HBV amnd HCV. Phylogenetic trees for hepatitis B virus (HBV), human immunodeficiency virus (HIV), and hepatitis C virus (HCV) shown to the same scale in terms of nucleotide genetic distance, based on full-length genome nucleotide sequences. Sequences of representative strains for major genotypes were obtained from GenBank and aligned using ClustalX with minor manual adjustment, and then sites containing gaps were removed, resulting in an alignment of 3181 sites for HBV, 8316 sites for HIV, and 9198 sites for HCV. Maximum likelihood trees were inferred using PAUP* version 4b10, with the model (GTR+I+G in all three cases) and parameters selected by ModelTest 3.7 using the AIC criterion. Reproduced with friendly permission from Dr. Stuart Ray. (Figure 156-4 from Ray SC and Thomas DL. In: Bennett JE, Dolin R, and Blaser MJ (eds). Man-dell, Douglas, and Bennett's Principles and Practices of Infectious Diseases. 8th ed (updated). Churchill Livingstone Elsevier; 2015:1904-1927).