HCV Amino Acid Mutations and Chronic Inflammation Hindering Vaccine Development

Offersgaard et al. state that overcoming HCV immune escape mechanisms requires rational vaccine design based on the molecular understanding of viral features and host protective immunity. SARS-CoV-2 undergoes amino acid mutations resulting in reduced efficacy of antiviral immunity induced by the RNA-based COVID-19 vaccine. Unlike SARS-CoV-2, amino acid mutations within the structural proteins of HCV cause altered antiviral immune responsiveness and troublesome persistent chronic inflammation.

The positive rate of anti-HCV antibodies among general blood donors in Japan is 1-2%, and based on this positive rate, the number of HCV-infected people in Japan is thought to be approximately 1.5 million. In the United States, approximately 4 million people (1.6% of the total population) are anti-HCV antibody-positive, and it is believed that there are 170 million HCV-infected persons worldwide. Especially in Mongolia, Egypt, Bolivia, etc., it is said that more than 10% of the total population of each country is an HCV carrier.

Hepatitis C vaccine, which seems to be the most effective prophylaxis against HCV infection, has not been put into practical use yet. Various specific antibodies against HCV proteins are produced in the blood of patients with chronic hepatitis C. However, due to the diversity of the HCV genome and the susceptibility to amino acid mutations in the envelope protein region, it is difficult to produce neutralizing antibodies against HCV. In addition, T cell responses are induced in association with HCV infection. However, compared with, for example, hepatitis B, cell-mediated immunity specific to HCV is thought to be induced more difficultly. Due to these factors, HCV escapes from the immune surveillance system of the host, and it is believed that persistent infection is established at a high rate in HCV-infected persons. Therefore, unlike hepatitis A and hepatitis B, hepatitis C is less likely to become fulminant, and symptoms such as jaundice are mild. HCV-infected patients have no subjective symptoms, chronic inflammation persists, and there are many cases in which abnormal liver function is indicated for the first time from the results of blood tests.

Basic medical research conducted worldwide has not developed a vaccine capable of simultaneously inducing both the neutralizing antibodies and cell-mediated immunity required to prevent HCV infection and development of hepatitis C. In a study using this novel system, Japanese research team has been investigating the in vivo anti-HCV immune response in a small primate model, the common marmoset, inoculated with inactivated HCV particles together with a novel adjuvant, K3-SPG. Research results using common marmosets revealed that both neutralizing antibodies and cell-mediated immunity, which are effective in preventing HCV infection, can be efficiently induced. Currently, techniques for large-scale synthesis of inactivated HCV particles and vaccination protocols are being refined and optimized. In the future, clinical research aimed at early practical application of HCV vaccine is desired.

Experiences gained on the cumbersome path toward an HCV vaccine might inform vaccine development for vaccine targeting viruses that cause other emerging infectious diseases.

We do not have potential conflicts of interest.

Report from Doctor specializing in cancer care

Published in Science on April 11, 2023 by Kyoto@takumaH