Hepatitis C is a serious blood-borne disease that can cause severe liver damage and affects more than 2.5 million Americans. Although the disease can be treated, the treatment is not yet widely available and affordable for those who need it. With an estimated 66,700 new infections occurring in the United States each year, a hepatitis C vaccine would help eradicate the disease in the United States and elsewhere. Current knowledge of the natural history and greater variability of the hepatitis C virus means that the vaccine must be both comprehensively protective and durable. Is such a vaccine feasible? Here we outline the reasons for optimism despite the prevalence of hepatitis C variants that have thwarted previous vaccination attempts.
Hepatitis C variants: the greatest difficulty in developing a vaccine
The hepatitis C virus multiplies rapidly and generates high variability resulting in multiple strains and subtypes. There are currently eight globally recognized hepatitis C genotypes with an estimated 30% variance in nucleotide divergence between them (Figure 1). Each genotype also has several subtypes that can differ by up to 20%. For comparison, the hepatitis B virus, for which we have a vaccine, has an estimated 8% variance between genotypes. It’s also important to note that the hepatitis C virus can cause superinfection. In these cases, a person can be infected with several types or subtypes of the virus at the same time. There is evidence that infection with one strain does not protect against infection with another strain. This means that a vaccine against many different strains must be largely neutralizing at the same time.
reasons for optimism
Despite the challenges ahead, there is reason for optimism in the development of a hepatitis C vaccine. About 30% of people infected with the hepatitis C virus develop an effective immune response, protecting them from disease and the infection itself eliminated. Examination of these individuals reveals two major factors in their immune responses: they produce broadly neutralizing antibodies, and they exhibit robust and sustained T cell responses (Figure 2). Knowing how these people can control and eliminate the infection offers valuable insights for the development of a successful vaccine.
Considerations for a largely neutralizing vaccine
An effective hepatitis C vaccine must first generate broadly neutralizing antibodies and second, induce long-term memory T cells. In the antibody immune response, B cells can induce the production of largely neutralizing antibodies. These specialized antibodies are useful because they can recognize and block virus entry across multiple hepatitis C strains. In addition to these antibodies, it is also important that the vaccine elicit robust T-cell immune responses. When an adaptive cell-mediated response begins to take effect, the immune system releases two types of T cells: CD4+ helper cells, which prompt B cells to make antibodies, and cytotoxic CD8+ cells, which are already infected with the hepatitis C virus kill cells. T cells with persistent memory play an important role in clearing current hepatitis C infections and preventing reinfection. Fortunately, we can learn lessons from previous vaccines such as those against respiratory syncytial virus and Ebola virus that show that by understanding prefusion complexes and conserved epitopes, one can generate broadly neutralizing antibodies and strong T-cell responses.
Conserved T cell epitopes
One method that vaccines, such as the Ebola vaccine, use to stimulate the production of T cells is by targeting conserved epitopes. An epitope is a specific part on the surface of a virus to which T cells can bind and signal B cells to produce antibodies specific to hepatitis C antigen. Conserved epitopes are T-cell targets that are found in several hepatitis C strains and would allow the vaccine to work against a wide range of antigen variants (Figure 3). Studying the antigens of people who have spontaneously cleared the hepatitis C virus can provide clues as to which conserved epitopes might be most useful in eliciting the best T cell responses. This method was also an integral part of the development of a pan-genotypic COVID-19 vaccine.
The success of the respiratory syncytial virus vaccine provides insight into prefusion complexes and how they generate broadly neutralizing antibodies. In order to fuse with and infect liver cells, hepatitis C virus surface proteins must undergo a conformational change. Broadly neutralizing antibodies prevent viral infection by binding to epitopes on the surface proteins of the virus and blocking conformational change. Persisting of the virus in its pre-fusion state can then trigger the production of general neutralizing antibodies (Figure 4). A vaccine containing these prefusion antigens would produce large amounts of largely neutralizing antibodies that not only recognize conserved epitopes, but also bind to multiple targets on the virus’s surface proteins. Current research focuses on the AR4 epitope and how it can block the E1-E2 hepatitis C protein in its prefusion form to block the ability to fuse with liver cells (Link).
What methods of vaccine delivery are being considered?
The final consideration in developing a successful hepatitis C vaccine is the design of the vector. Several methods are currently being explored, some better suited for antibody immunity, while others are better suited for eliciting a cell-mediated immune response. One delivery option is to use mRNA as a vector. These types of vaccines use a lipid coating, or inactive viral envelope, to deliver viral RNA into cells and teach them how to make effective antibodies. Another approach is based on subunit vaccines, purified proteins or peptides in combination with effective adjuvants. Still others rely on viral vectors, such as the adeno-associated virus family, to deliver the antigens.
While we don’t know if these methods will be successful, current efforts are promising. In the meantime, we must rely on the implementation of programs such as Egypt’s 100 Million Healthy Lives initiative and expanding efforts to reduce the cost of hepatitis C drugs.