Why is there still no vaccine against hepatitis C and why is it so important to develop one?

According to the World Health Organization (WHO), 58 million people worldwide suffer from chronic hepatitis C virus (HCV) infection, and 1.5 million new infections occur every year. HCV, which primarily attacks the liver, can trigger both acute and chronic infections. About 70% of people infected with this pathogen develop chronic hepatitis C.

The disease progresses slowly over time, causing the liver to become hardened or scarred (liver fibrosis) leading to cirrhosis in about 15–30% of patients over the age of 20 to 30 years. When cirrhosis begins, the infection can progress to end-stage liver disease and liver cancer. An estimated 290,000 people worldwide died from hepatitis C in 2019.

HCV is spread mainly by direct contact with infected blood. There are conditions and practices that may increase the risk of exposure to the virus, such as sharing syringes, lack of access to health services or certain sexual practices. These factors increase prevalence in certain groups, including people who inject drugs, marginalized communities with limited access to health services, and men who have sex with men.

Very effective treatment…

Although there is no vaccine against HCV, there is a highly effective treatment based on so-called direct-acting antivirals (DAAs), which prevent replication of the virus. These DAAs can cure more than 95% of affected people. Based on this, WHO has proposed that hepatitis C will no longer be a public health problem by 2030. To achieve this, it has set a target of diagnosing 90% of infected people and treating 80% of them.

…but they don’t find many infected people

Because chronic hepatitis C may not cause symptoms for many years after the initial infection, more than 80% of infected people do not know they are infected and do not receive treatment. They suffer from liver damage for years and can transmit HCV to others.

The lack of adequate policies and programs for screening and early diagnosis of hepatitis C, especially in more vulnerable populations where the prevalence of the disease is high, represents a significant challenge in the fight against this infection. Additionally, DAA treatment has some limitations:

  1. 2% to 5% of patients taking the drug do not recover completely. Additionally, the virus may mutate and in some cases become resistant to these treatments, reducing their effectiveness.

  2. DAAs are expensive, which limits their availability, especially in developing countries and for at-risk populations, where access to the drugs may be more difficult.

  3. Even after successful treatment with these drugs, immunity against HCV does not develop. This means that a recovered person can get infected again if they come in contact with the virus again.

For all these reasons, it seems unlikely that WHO’s objectives can be accomplished at a global level through the use of DAAs alone. The production of a vaccine against HCV will help control its transmission, especially in high-risk populations. This would counteract the limitations of DAA treatment and therefore help achieve WHO’s goal of eliminating hepatitis C.

Why don’t we have a vaccine?

Although this virus has been known for more than thirty years, there are still several difficulties that have hindered the development of a vaccine. Among them are the following:

  1. HCV is a virus with a high ability to mutate. In its evolution it has given rise to eight genotypes, which differ by about 30% in their genetic sequence. Furthermore, these genotypes are divided into approximately 90 different subtypes, with 15% variation between them. The vaccine must protect against all genotypes and subtypes, which is not easy to achieve.

  2. HCV has two proteins on its surface, called E1 and E2, that work together to allow the virus to enter and infect liver cells. The immune response of patients is primarily directed against these two proteins. In this reaction, antibodies are produced that bind to the E1 and E2 proteins, and block the entry of the virus into cells. The problem is that these proteins are the parts of HCV that vary most between genotypes: they can take different shapes and acquire different natural modifications, such as binding of sugars. All this makes it harder for antibodies to recognize it, allowing HCV to enter cells. In a certain way, we can say that they “hide” themselves so as not to be recognized.

  3. There is a lack of sufficient laboratory animals to test the effectiveness of the vaccines. For example, HCV does not infect mice, one of the most commonly used models in research. This makes it difficult to obtain very valuable data that can be transferred to humans.

  4. Conducting clinical trials for HCV vaccines is not easy. The relatively low incidence of infection in many industrialized countries makes it necessary to conduct such tests in marginalized populations at high risk of contracting HCV or in high-prevalence areas, as is the case in developing countries.

  5. Funding for HCV vaccine research and development is also relatively lacking. This is probably related to the silent nature of the infection, the emergence of DAAs, and widespread access to treatment in developed countries.

Structure of the E1E2 complex bound to three antibodies.

because of hope

Although some vaccines against HCV are in development, the most advanced vaccines have not demonstrated sufficient efficacy, which is a disappointment.

However, it seems that this scenario may soon change, primarily because we now have more information about the immune response that protects against HCV, the mechanisms of virus escape from that response, and the structure of the E1 and E2 proteins. There is also the possibility of using mRNA technology, similar to how it has been successfully applied in the development of a vaccine against SARS-CoV-2.

This knowledge will allow more rational development of new vaccines. For example, the use of genetic engineering will make it easier to produce the most suitable forms of E1 and E2 proteins to stimulate the production of the best antibodies capable of preventing the entry of the virus into cells.

There is some consensus that an effective vaccine against HCV should stimulate two main branches of the immune response: humoral immunity, which is based on antibody-producing B lymphocytes, and cellular immunity, which primarily involves T lymphocytes. Which are capable of destroying cells. Infect and help B lymphocytes to produce antibodies. In this sense, a vaccine based on the E1 and E2 glycoproteins appears to be the best option, since it stimulates both branches. An important step in this direction is the recent determination of the molecular structure of the complex formed by the union of both proteins. There are many reasons to be optimistic.

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