A Vaccine for Chronic HCV
In this podcast, Andrea Cox, MD, PhD, discusses her team’s recent randomized controlled trial that examined the effectiveness of a vaccine regimen for preventing chronic hepatitis C virus infection.
Page K, Melia MT, Veenhuis RT, et al. Randomized trial of a vaccine regimen to prevent chronic HCV infection. New Engl J Med. 2021;384(6):541-549. doi:10.1056/NEJMoa2023345
Andrea Cox, MD, PhD, is the director of the Medical Scientist Training Program and a professor of medicine at Johns Hopkins University School of Medicine in Baltimore, Maryland.
Leigh Precopio: Hello everyone, and welcome to another installment of Podcasts360, your go‑to resource for medical news and clinical updates. I'm your moderator Leigh Precopio with Consultant360.
Chronic hepatitis C virus, or HCV, affects approximately 3.2 million adults in the United States and is the leading cause of chronic liver disease among other adverse outcomes. From the initial discovery of HCV in 1989, efforts have been underway to develop effective prevention methods and treatment options for those with chronic HCV infection.
Recently published research has sustained the momentum of the past several decades of research efforts, as the first preventative vaccine regimen was tested in a clinical trial.
Today I'm joined by one of the authors from this study, Andrea Cox, MD, PhD, who is the director of the Medical Scientist Training Program and a professor of medicine at Johns Hopkins University School of Medicine in Baltimore, Maryland.
Thank you for agreeing to speak with me today, Dr. Cox. Your study examined the effectiveness of a vaccine regimen to prevent chronic HCV infection in at‑risk adults. What prompted this study?
Andrea Cox: Hepatitis C virus infects about 71 million people in the world and is actually a major cause of death. It is the leading cause of liver cancer and liver failure in the United States, and it is a serious cause of illness in many.
There are many infections in the world that we've managed to reduce the number of people dying from them through treatments and vaccinations but hepatitis C mortality, meaning the number of people dying from it, has been increasing over time. It and other forms of viral hepatitis are gradually overtaking other causes of death. It is now one of the world's leading causes of death.
Leigh Precopio: What is the current standard of care for preventing HCV infection in at‑risk populations?
Andrea Cox: In individuals at-risk of hepatitis C virus infection, there is not much that we have to prevent it. We have, thanks to amazing work on the part of many researchers and clinicians, incredible treatments for hepatitis C. The problem is that we don't have an effective way of preventing new infections. So while those treatments are very important, diagnosing people with hepatitis C and getting them to treatment is key, we can't reduce the total number of people infected if for every person we treat a new person becomes infected.
What we have been seeing is the treatment for hepatitis C has increased dramatically. Unfortunately, infection rates also increased dramatically, particularly in the United States, in the first 10 years of 2000, so between 2000 and 2010.
At this point, the risk factors for hepatitis C, it is a blood‑borne illness, so the major risk factor for acquisition of infection is through injection drug use. There have been cases with contaminated medical equipment. It's very rarely transmitted through blood transfusion because the blood supply is so effectively screened, but there are many people who acquire hepatitis C in other countries through blood transfusions. It's possible to get it through tattooing or the sharing of razor blades or toothbrushes if those were used to brush the teeth of, tattoo, or shave someone with hepatitis C. We ask people to seek treatment for any forms of drug use they have. We ask people to not share razor blades or toothbrushes if they're infected.
We are trying to diagnose everyone because if we reduce the number of people who have the infection, of course, it's harder for them to spread to others.
It is, unfortunately, in the list of diseases for which we do not have a vaccine. Vaccines have been shown, time and again, as the most effective way to prevent infections and to prevent death from infections.
Leigh Precopio: The results of your study indicated that while there were no significant difference in the incidence of chronic HCV infection between the vaccine and placebo groups, the vaccine group had lower peak HCV RNA levels after infection, and T‑cell responses were found in 78% of the vaccine group participants. What is the importance of this finding?
Andrea Cox: It holds some promise. What we see in vaccines is that there are diseases against which vaccination is a little bit easier. Then there are diseases that are very hard. If you think about it, many of the diseases for which we do not have vaccines are those most adept at evading the human immune system. For example, HIV is one of the harder pathogens. There have been some efforts to generate a preventative HIV vaccine, but HIV is so good at evading the human immune response, as is evidenced by the fact that it becomes a chronic infection in those it infects almost uniformly.
In contrast, there are other infections where people are infected once, they control the infection, and then they have lifelong immunity. Those are probably the two ends of the spectrum with easy to get an immune response that protects, and hard to get an immune response that protects.
Hepatitis C is probably on the harder end of the spectrum because 3/4 of the people infected become persistently or chronically infected. It is quite adept at evading the human immune system. But unlike the previous trials in some other diseases and the HIV vaccine trials, for example, this vaccine did seem to pressure the virus in some way. It lowered the average peak level of virus detectable in individuals who were vaccinated compared to the peak level of virus in people who got the placebo.
That suggests that the vaccine did mount some pressure on the virus, and is a positive signal that we could study to enhance the vaccine to not just pressure the virus but to actually eradicate it. While we didn't see what we hoped, which is that vaccinated individuals would clear the hepatitis C virus from their bodies and not be chronically infected, we did see some evidence that the vaccine pressured.
We just need to amplify that pressure and hopefully generate vaccines that prevent chronic infection, because it's chronic infection that results in the vast majority of disease caused by hepatitis C virus.
Leigh Precopio: How do you hope the results of your study will impact the future of preventative medicine for HCV?
Andrea Cox: It's really important to realize that hepatitis C is, again, a major cause of illness throughout the world. Particularly in the United States we have big problems with this virus. We have made some strides in treatment. We'd like to see comparable strides in prevention. The study indicates that it is possible to generate a vaccine that modulates the course of hepatitis C. While we need to do better, designing more effective vaccines might enable us to create a vaccine that prevents new people from becoming infected. Then when we treat people, the total number of people infected will decrease, as will the number of people dying of liver cancer and liver failure.
If we look at hepatitis B virus, which is also a cause of liver cancer, in the countries that implemented widespread hepatitis B vaccination, we've seen dramatic decreases in the rates of liver cancer. Where hepatitis B is the major cause of liver cancer, for example, in Taiwan, universal vaccination reduced liver cancer rates.
My hope is that vaccination to prevent hepatitis C will prevent liver failure and liver cancer and death, but we can't give up hope. This is the first vaccine that we ever tested in people who are at risk for hepatitis C. And while it certainly would've been great to see the very first vaccine we ever tried be perfect, that's not how most things work. Most drugs that get made, there are improvements made to the drugs over time. We're certainly not treating many diseases in the way that we were treating diseases 50 years ago. Vaccine development is often iterative like that as well. Meaning, we get a vaccine, then we might make a better vaccine, then we might even make a better vaccine than that. The truth is that it's very rare for the very first thing you try to be as perfect as you can get.
The fact that there was some effect mediated by the vaccine gives us some hope that this is an achievable goal. We just need to continue to use what we've learned about this virus, this vaccine, as well as other vaccine platforms and strategies, such as those being used to combat COVID‑19. I think that those all provide promise and hope for an improved hepatitis C vaccine that will have a big impact on global mortality.
Leigh Precopio: What are some next steps for research on vaccines for HCV infection?
Andrea Cox: As I mentioned, we're employing some novel strategies, including possibly encoding the envelope protein of hepatitis C, which is the target of neutralizing antibodies. Encoding the envelope protein in an mRNA vaccine, such as those being used against COVID‑19, would be one option.
We're also investigating optimal strategies for inducing T‑cell responses as well as neutralizing antibody responses. For viruses that evade the human immune response and the antibodies, in particular, it's helpful to have a T‑cell component that comes in and helps to eradicate the infection if it slips past antibodies.
That is something that we're studying, how to optimize generation of good T‑cell responses against the virus as well. I think we'll see some ideally new vaccines be tested and ultimately advance to at‑risk patient populations with hopefully better results showing that they protect against chronic infection.
The only other thing maybe to note is that about half the people in the United States who have it are unaware that they have it. Everyone should be tested once. People who are at risk, like people who are injecting drugs, should be tested regularly for infection, because treatment is available, but if you don't know you have it, then you're not going to be able to seek treatment. That's a really important point. That's going to need to be used in conjunction with development of a preventative vaccine to achieve the goals we have for elimination of hepatitis.
The WHO set goals for global hepatitis elimination by the year 2030. Even before the pandemic, we were not on target to achieve those goals. The pandemic has certainly made achievement of those goals harder. The reality is that we are going to have to think about not just treating our way out of an epidemic but preventing new infections in order to achieve the WHO elimination goals.
There are a lot of studies that are now showing that, as I said, if you take someone out of the pool of infected people but someone new jumps in, you're not making any headway. That's what the data are showing. The rates of new infections are still so high that even the people who are treated can unfortunately be infected again. Even the same person can go back into the infected pool. We really do need to think about strategies to reduce the incidence of infection and not just ways to treat chronic infection, which, at this point, are very advanced and outstanding.
Leigh Precopio: Great. Thank you for taking the time to speak with me today.
Andrea Cox: Thank you for taking the time to ask these great questions about a really important infection that is not thought about as often as I think it probably should be. To improve human health and well‑being, this is something that we need to think about advancing.