Vaccines against hepatitis C: a travel into neutralisation space

Abstract

Since studies performed nearly 50 years ago on patients with posttransfusion hepatitis indicated the existence of HCV as the cause of chronic liver disease, in discoveries recently recognised by the Nobel Prize, at least 25 million people have died from chronic sequelae of this insidious infection, including liver cirrhosis and hepatocellular carcinoma. Currently, at least 400 000 people die due to hepatitis Crelated diseases, annually, despite the availability of curative directacting antivirals. Further, there is no prophylactic vaccine against this virus to prevent the nearly 2 million new cases annually, of which 75% result in persistent lifelong infections that for most remain undiagnosed. In fact, only very few vaccine candidates have advanced to clinical trials; most recently a T cell based vaccine, despite induction of robust immune responses, failed to lower the chronicity rate following HCV exposure. This stands in contrast to the development of effective antibodybased vaccines against SARSCoV-2, less than 1 year after the first description of its associated disease COVID-19. Thus, it would be important to consider which molecular features unique to HCV virus neutralisation challenges vaccine efforts, and to seek solutions by the lessons learnt from COVID-19 to finally change the trajectory towards universal vaccination against HCV. In this issue of Gut, Bankwitz et al explored infectious cell culture systems to advance testing for broadly reactive neutralising antibodies (NtAb) against HCV in patients and in vaccine studies. The HCV populations infecting humans have extensive genetic heterogeneity, with genomes of strains of different major genotypes differing by about 30%, and with the apparent existence of an unlimited number of serotypes. Further, the virus has unique features of the surfaceexposed envelope proteins E1 and E2 targeted by NtAb, linked to the presence of hypervariable regions, glycosylation and sequence polymorphisms, as well as various host factors such as apolipoprotein E, which all contribute to an inherent resistance to NtAb. Another important aspect highlighted by the data obtained by Bankwitz et al is that virus genomesequence relatedness does not necessarily reflect shared neutralisation features, meaning that isolates of the same HCV subtype can have very different neutralisation against the same antibody and divergent isolates can have very similar neutralisation profiles. Combined with constant highrate HCV evolution to elude induced NtAb throughout infection by developing specific escape mutations, these features make it a great challenge to develop vaccine candidates inducing broadly protective NtAb responses. Further, such broad NtAb appear to be represented primarily by specific germline heavy chain variable (VH) genes, in particular the VH1-69. 9 It is key to have experimental tools to characterise such antibodies, and retroviral pseudoparticles expressing HCV E1/E2 and infectious culture (HCVcc) systems have been developed for the different genotypes of HCV. However, it is essential to use systems or virus variants which reflect the entire HCV neutralisation space, and such a feat is reported here by Bankwitz et al, using HCVcc variants representing each of six identified neutralisation clusters. This will make it possible to readily compare the broadness of the HCV NtAb induced by different envelope antigens in worldwide vaccine efforts. A huge challenge for the generation of an antibodybased HCV vaccine is that expressed recombinant envelope proteins might not constitute the native form found in virus particles. Thus if, for example, an mRNA vaccine approach, highly successful for SARSCoV-2, is applied, the translated HCV E1 and/or E2 proteins might not form the true viral envelope and thus be ineffective in inducing crossprotective NtAb. Therefore, it will be of critical importance to determine the envelope structure found in the virus particle or in envelope proteins expressed in various forms. In contrast to what has been found for the modified spike protein of SARSCoV-2, developed based on prior knowledge gained from research on other coronaviruses, it appears that it will require further knowledge to solve the challenge of expressing the HCV envelope proteins in appropriate forms. Thus, the HCV research community needs to figure out how to design envelope protein antigens that can be produced and presented, which better reflect the particleassociated envelope and that raise NtAb targeting conserved epitopes. For example, it might be possible to design modified HCV envelope antigens by point mutations or deletions that more effectively presents recognised binding structures and neutralisation epitopes. An alternative is the use of inactivated virus particles, successful in vaccines against other RNA viruses, but here it is a challenge to culture HCV to titres sufficiently high to be applicable for purification processes and vaccination. It is not clear that neutralisation features determined in vitro fully reflect in vivo neutralisation capacity. 16 This is particularly true if the HCVcc strains used in in vitro neutralisation assays have acquired cultureadaptive substitutions in the envelope proteins compared with the original patient isolate. Thus, it will be important to continue efforts to develop immunocompetent small animal models. 18 The only small animal model yielding robust infection is a human liver chimeric mice model relying on a severe combined immunodeficiency background, that although useful in demonstrating the passive immuneprophylaxis ability of NtAb, does not provide info on the adaptive immune induction. Chimpanzees, that were critical for the discovery of HCV and for initial vaccine efforts on showing efficacy of recombinant envelopebased vaccines, are out. Thus, the mission into the neutralisation space will have to be manned, and it will be critical to invest heavily in efforts to rapidly take vaccine candidates forward to testing in humans. Importantly, the WHO recently acknowledged that an HCV vaccine is of key importance for the elimination of HCV, combined with the use of available curative drugs to treat patients with chronic HCV infection. This will require renewed commitments from governments, funding agencies and vaccine producers. A successful HCV vaccine will most likely require induced humoral and cellular immune responses. Thus, it will be critical to bring together efforts to generate efficient B cell and T cell responses in HCV vaccine candidates. The study by Bankwitz et al permits exploration of the neutralisation space, highly relevant for the task of designing antibodybased vaccine Copenhagen Hepatitis C Program (COHEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark