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Hepatitis C Vaccination: History
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Subjects: Allergy
Contributor: Robert Gish

The hepatitis C virus (HCV) is a common cause of chronic liver disease and liver cancer worldwide. Despite advances in curative therapies for HCV, the incidence of new infections is not decreasing at the expected rate to hit the World Health Organization (WHO) target for the elimination of HCV by 2030. In fact, there are still more new cases of infection in the United States and worldwide than are being cured. The reasons for the rise in new cases include poor access to care and the opioid epidemic. The clinical burden of HCV requires a multimodal approach to eradicating the infection. Vaccination would be an excellent tool to prevent incidence of new infections; however, the genetic diversity of HCV and its ability to generate quasispecies within an infected host make creating a broadly reactive vaccine difficult. Multiple vaccine candidates have been identified, but to date, there has not been a target that has led to a broadly reactive vaccine, though several of the candidates are promising. Additionally, the virus is very difficult to culture and testing candidates in humans or chimpanzees is ethically challenging. Despite the multiple barriers to creating a vaccine, vaccination still represents an important tool in the fight against HCV. 

  • hepatitis C virus
  • vaccination
  • chronic liver disease
  • direct acting anti-virals (DAAs)

1. Introduction

The hepatitis C virus (HCV) is one of the most common causes of chronic liver disease, cirrhosis, liver transplant, and liver cancer worldwide, and is also a systemic infection with effects on many organ systems and quality of life. Acute infection with HCV generally becomes a chronic condition, with up to 75% of patients remaining HCV ribonucleic acid (RNA) positive, and thus often leads to liver disease-related morbidity and mortality [1]. Since the 1980s, the prevalence of new HCV infections has decreased in some countries, but due to a multitude of factors, the incidence is rising in other countries and blunting the change in prevalence. With the advent of the direct-acting antiviral (DAAs) therapies, the treatment and cure of chronic HCV has significantly improved [1].
Despite improvements in screening, treatment, and linkage to care for at-risk populations, a majority of people with chronic hepatitis C (CHC) have not been tested or treated in most countries [2]; the exceptions are global leaders such as Egypt and Georgia where screening and linkage to care is at very high levels. Several theories have been postulated as to why this is the case, but regardless of the reasons, it is abundantly clear that preventive strategies would augment the efforts to manage the burden caused by HCV. A vaccine for HCV would be an ideal preventive solution to add to the arsenal; however, due to the genetic diversity of the virus and an incomplete understanding of the body’s immune response to the virus, vaccine development continues to be in experimental stages.

2. Clinical Need for Hepatitis C Virus Vaccine

Worldwide, roughly 100 million people have been infected with HCV (i.e., anti-HCV positive) at an annual incidence of 3–4 million/year, along with an estimated 71 million people thought to have CHC (i.e., HCV RNA positive) [1][3]. The prevalence of HCV varies greatly from region to region, with the eastern Mediterranean region having the highest prevalence, at 2.3%, and the western Pacific region having the lowest prevalence, at 0.5% [1]. In contrast to the United States Preventive Services Task Force (USPSTF) recommendations for universal HCV screening of all asymptomatic adults aged 18 to 79 years, countries with limited resources to HCV screening are at increased risk of sequelae from undiagnosed CHC due to the delays in diagnosis and receiving care. Additionally, data from the Centers for Disease Control and Prevention (CDC), which has tracked the incidence of acute HCV in the US since 1982, show that while acute infections in the US have decreased from the peak in 1989 to a nadir in 2010, there has been a disturbing trend of increasing cases since 2010 [1]. For example, the CDC estimates there has been a 4-fold increase in cases from 2010 to 2017: from roughly 11,800 cases of acute HCV in 2010 to 44,700 cases in 2017 [1]. The increase in cases has been linked to an ongoing opioid epidemic in the US, as persons who inject drugs (PWID) were found to have a much higher incidence of HCV infection, especially young adults [4][5]. The increased incidence and prevalence among PWID is not limited to the US, as shown in a systemic review that estimated that 52.3% of PWID have been exposed to HCV based on anti-HCV antibodies [6]. Data on the prevalence of HCV by HCV RNA was lacking in most countries, but of the countries that provided data, the lowest prevalence was noted in sub-Saharan Africa among PWID, and this was still listed at roughly 21.8% [6]. As more developing countries report data on PWID, it is apparent that this is a very high-risk group for CHC around the world.
The treatment of CHC has changed drastically within the last decade with the advent of DAAs, leading to a significant reduction in the use of ribavirin and an almost complete discontinuation of interferon. The vast majority of patients are treated with the newest DAA regimens, which are well tolerated and allow patients to achieve sustained virologic response (SVR) in excess of 98% [7]. Although management of CHC has become easier than ever before, there are still several considerations that highlight the utility of HCV prevention. For instance, increased usage of DAA therapy can lead to the development of viral resistance to current regimens, especially as resistance to treatment regimens has been documented during clinical trials [8]. Furthermore, liver disease can progress in a subset of patients, and some patients are still at risk for hepatocellular carcinoma (HCC) even with cure of CHC [9][10][11][12]. In addition, the specter of reinfection continues to follow those patients who are still deemed at high-risk for HCV infections, such as PWID, as treatment with DAAs has not been shown to give lasting immunity to HCV [13][14]. Access to treatment is another barrier to curative therapy [15]; several reports attest to the inability of patients to get treatment covered by public or private insurances in the US [15][16].
Given the current clinical burden of HCV infections, the World Health Organization’s (WHO) goal of a 90% reduction of HCV infections by 2030 is in jeopardy of not being achieved [1]. Therefore prevention, via vaccination, would be an ideal alternative to treatment in order to achieve this goal. Indeed, mathematical models have shown that a vaccine with even as little as 30% efficacy would still reduce the clinical burden of disease significantly [17][18][19][20].

3. Limitations of Models for Hepatitis C Virus Vaccination

The development of an HCV vaccination has proven to be a difficult task not only due to complex HCV virology that makes identifying a universal target for antibodies elusive, but also because of limited appropriate preclinical animal models. While humans are the natural reservoir of HCV, human and even chimpanzee experimental conditions for a vaccine are ethically challenging. Many animal studies use chimeric humanized mouse models and HCV analogues from the Hepacivirus genus, which are attempted simulations of the actual human-HCV relationship [21].

4. Future Directions

The development of a broadly reactive HCV vaccine has progressed significantly in the last decade with multiple trials in both animal and human models. Unfortunately, there are still significant limitations in vaccine development as noted by the fact that all the above studies are still in early phases. An effective vaccine will likely need to integrate both an antibody response as well as a robust T-cell response, but to do this, a better understanding of the underlying mechanisms of how immune cells mediate short- and long-term protection is necessary. In addition, technological advancements—including usage of computational strategies such as computer-generated HCV virus vaccine sequences to elicit a cross-reactive T-cell response, which has been shown to be effective [22]—have not yet reached widespread use or study. Testing effective vaccines remains a challenge, and some experts have suggested that taking a small group of human volunteers to design a human infection model might be a useful and necessary next step [23]. Other experts have also noted that the overall public image of HCV is that it affects marginalized communities only, which has led to decreased interest, as evidenced by lack of funding. One Lancet article noted that in 2019 there were 39 human clinical trials for HIV vaccines whereas there were only 2 human clinical trials for HCV [24]. This suggests that more public education on the widespread nature of HCV and its implication to public health is also necessary to more quickly allow the science to progress. While many obstacles remain, the current research offers a hint on how to approach building a vaccine for HCV to augment the other available treatment strategies.

This entry is adapted from the peer-reviewed paper 10.3390/pathogens10121619

References

  1. World Health Organization. Global Hepatitis Report. 2017. Available online: http://apps.who.int/iris/bitstream/10665/204370/1/WHO_HIS_SDS_2015.23_eng.pdf (accessed on 19 October 2021).
  2. Bailey, J.R.; Barnes, E.; Cox, A.L. Approaches, progress, and challenges to hepatitis C vaccine development. Gastroenterology 2019, 156, 418–430.
  3. Messina, J.P.; Humphreys, I.; Flaxman, A.; Brown, A.; Cooke, G.; Pybus, O.; Barnes, E. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology 2015, 61, 77–87.
  4. Zibbell, J.E.; Asher, A.K.; Patel, R.C.; Kupronis, B.; Iqbal, K.; Ward, J.W.; Holtzman, D. Increases in acute hepatitis C virus infection related to a growing opioid epidemic and associated injection drug use, United States, 2004 to 2014. Am. J. Public Health 2018, 108, 175–181.
  5. Suryaprasad, A.G.; White, J.Z.; Xu, F.; Eichler, B.-A.; Hamilton, J.; Patel, A.; Hamdounia, S.B.; Church, D.R.; Barton, K.; Fisher, C.; et al. Emerging epidemic of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, 2006–2012. Clin. Infect. Dis. 2014, 59, 1411–1419.
  6. Degenhardt, L.; Peacock, A.; Colledge, S.; Leung, J.; Grebely, J.; Vickerman, P.; Stone, J.; Cunningham, E.B.; Trickey, A.; Dumchev, K.; et al. Global prevalence of injecting drug use and sociodemographic characteristics and prevalence of HIV, HBV, and HCV in people who inject drugs: A multistage systematic review. Lancet Glob. Health 2017, 5, e1192–e1207.
  7. American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Available online: https://www.hcvguidelines.org/ (accessed on 2 July 2021).
  8. Franco, S.; Tural, C.; Nevot, M.; Molto, J.; Rockstroh, J.K.; Clotet, B.; Martinez, M.A. Detection of a sexually transmitted hepatitis C virus protease inhibitor-resistance variant in a human immunodeficiency virus–infected homosexual man. Gastroenterology 2014, 147, 599–601.e1.
  9. Poynard, T.; Moussalli, J.; Munteanu, M.; Thabut, D.; Lebray, P.; Rudler, M.; Ngo, Y.; Thibault, V.; Mkada, H.; Charlotte, F.; et al. Slow regression of liver fibrosis presumed by repeated biomarkers after virological cure in patients with chronic hepatitis C. J. Hepatol. 2013, 59, 675–683.
  10. Poynard, T.; McHutchison, J.; Manns, M.; Trepo, C.; Lindsay, K.; Goodman, Z.; Ling, M.; Albrecht, J. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterol. 2002, 122, 1303–1313.
  11. Maylin, S.; Martinot–Peignoux, M.; Moucari, R.; Boyer, N.; Ripault, M.; Cazals–Hatem, D.; Giuily, N.; Castelnau, C.; Cardoso, A.C.; Asselah, T.; et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology 2008, 135, 821–829.
  12. Aleman, S.; Rahbin, N.; Weiland, O.; Davidsdottir, L.; Hedenstierna, M.; Rose, N.; Verbaan, H.; Stal, P.; Carlsson, T.; Norrgren, H.; et al. A risk for hepatocellular carcinoma persists long-term after sustained virologic response in patients with hepatitis C–associated liver cirrhosis. Clin. Infect. Dis. 2013, 57, 230–236.
  13. Midgard, H.; Bjøro, B.; Mæland, A.; Konopski, Z.; Kileng, H.; Damås, J.K.; Paulsen, J.; Heggelund, L.; Sandvei, P.K.; Ringstad, J.O.; et al. Hepatitis C reinfection after sustained virological response. J. Hepatol. 2016, 64, 1020–1026.
  14. Martinello, M.; Grebely, J.; Petoumenos, K.; Gane, E.; Hellard, M.; Shaw, D.; Sasadeusz, J.; Applegate, T.L.; Dore, G.J.; Matthews, G.V. HCV reinfection incidence among individuals treated for recent infection. J. Viral Hepat. 2016, 24, 359–370.
  15. Millman, A.J.; Ntiri-Reid, B.; Irvin, R.; Kaufmann, M.H.; Aronsohn, A.; Duchin, J.S.; Scott, J.D.; Vellozzi, C. Barriers to treatment access for chronic hepatitis C virus infection: A case series. Top. Antivir. Med. 2017, 25, 110–113.
  16. Gowda, C.; Lott, S.; Grigorian, M.; Carbonari, D.; Saine, M.E.; Trooskin, S.; Roy, A.J.; Kostman, J.R.; Urick, P.; Re, V.L. Absolute insurer denial of direct-acting antiviral therapy for hepatitis C: A national specialty pharmacy cohort study. Open Forum Infect. Dis. 2018, 5, ofy076.
  17. Hahn, J.A.; Wylie, D.; Dill, J.; Sanchez, M.S.; Lloyd-Smith, J.O.; Page, K.; Getz, W.M. Potential impact of vaccination on the hepatitis C virus epidemic in injection drug users. Epidemics 2009, 1, 47–57.
  18. Scott, N.; McBryde, E.; Vickerman, P.; Martin, N.K.; Stone, J.; Drummer, H.; Hellard, M. The role of a hepatitis C virus vaccine: Modelling the benefits alongside direct-acting antiviral treatments. BMC Med. 2015, 13, 198.
  19. Stone, J.; Martin, N.K.; Hickman, M.; Hellard, M.; Scott, N.; McBryde, E.; Drummer, H.; Vickerman, P. The potential impact of a hepatitis C vaccine for people who inject drugs: Is a vaccine needed in the age of direct-acting antivirals? PLoS ONE 2016, 11, e0156213.
  20. Scott, N.; Wilson, D.P.; Thompson, A.J.; Barnes, E.; El-Sayed, M.; Benzaken, A.S.; Drummer, H.E.; Hellard, M.E. The case for a universal hepatitis C vaccine to achieve hepatitis C elimination. BMC Med. 2019, 17, 175.
  21. Duncan, J.D.; Urbanowicz, R.A.; Tarr, A.W.; Ball, J.K. Hepatitis C virus vaccine: Challenges and prospects. Vaccines 2020, 8, 90.
  22. Burke, K.P.; Munshaw, S.; Osburn, W.O.; Levine, J.; Liu, L.; Sidney, J.; Sette, A.; Ray, S.; Cox, A.L. Immunogenicity and cross-reactivity of a representative ancestral sequence in hepatitis C virus infection. J. Immunol. 2012, 188, 5177–5188.
  23. Hartlage, A.; Kapoor, A. Hepatitis C virus vaccine research: Time to put up or shutup. Viruses 2021, 13, 1596.
  24. Hepatology, T.L.G. The hunt for a vaccine for hepatitis C virus continues. Lancet Gastroenterol. Hepatol. 2021, 6, 253.
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