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HCV Vaccine - Is it Possible ?
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Download the PDF here
Download the PDF here
Challenges Developing a Hepatitis C Vaccine
https://www.contagionlive.com/videos/challenges-developing-a-hepatitis-c-vaccine
Segment Description: Andrea L. Cox, MD, PhD, Professor of Medicine at Johns Hopkins University, discusses some of the challenges in developing a vaccine for hepatitis C and details the results of a vaccine trial.
Interview Transcript (modified slightly for readability):
Cox: Because hepatitis C doesn't replicate well in culture, including in animal cells, it's very difficult to make a live-attenuated or even a killed vaccine. So, the strategy employed here was to use viral vectors, specifically chimpanzee adenovirus 3 and modified vaccinia ankara, not capable of replicating but encoding Hepatitis C virus nonstructural proteins.
The point of the vaccine was to induce robust T cell responses not neutralizing antibodies because the envelope component of the virus isn't in the vaccine. And that was the strategy employed. The first vaccine was the chimpanzee adenovirus 3 given initially or placebo.
Then 8 weeks later, the second dose of placebo or the modified vaccinia Ankara, both chimpanzee adenovirus and modified vaccinia ankara, encoding the nonstructural proteins of Hep C.
This is the first ever trial that could look at efficacy of a Hepatitis C virus vaccine. We've not attempted in the past to test any vaccine against hepatitis C to see if it could modulate the course of disease.
Because the vaccine didn't contain envelope and wasn't predicted to induce neutralizing antibodies or reduce incidence, the primary outcome was to look at a reduction in the development of chronic infection. It's really chronic infection that mediates the vast majority, almost all, disease from hepatitis C. And the idea was that if we could reduce the risk upon exposure of the development of chronic infection that would have a big impact both on transmission of disease because people wouldn't remain persistently infected, and also would reduce the likelihood of developing disease at later stages.
The vaccines were well tolerated and did induce T cell responses, although less robustly then in healthy volunteers. The vaccine trial took place in people who are actively injecting drugs, and we're not certain if that patient population or other factors led to the slightly less robust responses seen, but in the end, there was a blunting of peak HCV RNA by about six-fold in vaccinees. We saw lower geometric mean peak HCV RNA levels, but finally, that did not result in either a reduction of incidence or in progression to chronic infection.
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"There are significant deficits in our tools for development of an HCV vaccine. Elucidating the mechanisms through which antigen-specific immune cell populations mediate long-term protection is an important goal. Vaccine strategies meant to overcome the enormous diversity of HCV must generate a broad immune response, capable of responding to abundant variations......On a practical level for all forms of vaccine development, a principal challenge "is the extraordinary genetic diversity of the virus. With 7 known genotypes and more than 80 subtypes, the genetic diversity of HCV exceeds that of human immunodeficiency virus-1," according to the authors....There is a lack of in vitro systems and immunocompetent small-animal models useful for determining whether vaccination induces protective immunity. Although a use of an HCV-like virus, the rat Hepacivirus, provides a new small-animal model for vaccine testing, this virus has limited sequence analogy to HCV.....The development of immunity to HCV in humans is complex and under broad investigation. However, decades of research have revealed that HCV-specific CD4+ helper T cells, CD8+ cytotoxic T cells, and antibodies all play a role in protection against persistent HCV infection, according to the authors, and vaccine strategies to induce all three adaptive immune responses are in development.
"A prophylactic HCV vaccine is an important part of a successful strategy for global control. Although development is not easy, the quest is a worthy challenge," the authors concluded."
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IFNL3-adjuvanted HCV DNA vaccine reduces regulatory T cell frequency and increases virus-specific T cell responses
February 20, 2020 Jnl of Hepatology
Pdf attached
We developed a DNA vaccine, GLS-6150, to prevent re-infection of patients with DAA-induced SVR and evaluated its safety and immunogenicity in individuals with chronic HCV infection.
Results
Severe adverse events or vaccine discontinuation were not reported. The IFN-γ spot-forming cells specific to NS3-NS5A were increased by GLS-6150. Both CD4+ and CD8+ T cells produced multiple cytokines. However, the frequency and phenotype of HCV-specific MHC-I dextramer+CD8+ T cells were not changed. Interestingly, the frequency of Treg cells, particularly activated Treg cells, was decreased by GLS-6150, as expected from previous reports that IFNL3 adjuvants decrease Treg cell frequency. Ex vivo IFN-λ3 treatment reduced Treg frequency in pre-vaccination peripheral blood mononuclear cells. Finally, Treg cell frequency inversely correlated with HCV-specific, IFN-γ-producing T cell responses in the study participants.
Conclusions
We demonstrate that GLS-6150 decreases Treg cell frequency and enhances HCV-specific T cell responses without significant side effects. A phase I clinical trial of GLS-6150 is currently underway in patients with DAA-induced SVR.
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Results of the First Prophylactic
Hepatitis C Virus Vaccine Efficacy Trial
http://www.natap.org/2019/IDWeek/IDWeek_86.htm
Results:
A total of 455 subjects received the prime-boost regimen or two doses of placebo, with 202 and 199 in the respective groups included in the according-to-protocol efficacy cohort. Overall incidence of infection was 14.1 infections per 100 person-years. There were no differences in development of chronic infection between vaccine and placebo arms, with 14 chronically infected subjects in each group. Specifically, the vaccine efficacy in preventing chronic infection was -0.53 (95% confidence interval [CI], -2.5 to 0.34). Of vaccinated subjects, 78% generated T cell responses to ≥1 vaccine-encoded HCV antigens. The vaccine was generally safe and well tolerated with no serious vaccine-related adverse events. There were more solicited reports of adverse events after either injection in the vaccine group (81%) than in the placebo group (59%), with the difference mainly due to injection-site reactions. Serious adverse events and deaths occurred with similar frequencies in the two groups.
Conclusion:
A randomized, placebo controlled, Phase I/II trial of a prime-boost vaccine to prevent chronic HCV infection was completed in an at-risk population, demonstrating the feasibility of conducting rigorous vaccine research in people who inject drugs. The regimen elicited robust immune responses without evident safety concerns, but did not provide protection against chronic HCV infection.
Cox and colleagues found no difference in the development of chronic infection between the vaccine and placebo arms, with 14 cases in each. The regimen's efficacy in preventing chronic infection was -0.53 (95% CI, -2.5 to 0.34).
However, the vaccine regimen blunted the peak HCV RNA level in recipients 1 month after vaccination compared with placebo - a statistically significant finding, Cox noted. In terms of immunogenicity, the vaccine regimen induced an immune response in 78% of recipients, which is a less robust response that what was observed in an earlier study of healthy volunteers, she said.
According to the researchers, there were no safety signals in the study, and the regimen was well-tolerated, with no serious vaccine-related adverse events.
"There remains a significant need for vaccine to interrupt transmission, and it will be critical for achieving WHO elimination goals," Cox said. "Testing vaccines in [people who inject drugs] is possible, but additional strategies will need to be considered - ideally, with information gained from this vaccine, informing future vaccine design."
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Approaches, Progress, and Challenges to Hepatitis C Vaccine Development
Gastroenterology - 2019 - Justin R. Bailey1 Eleanor Barnes2 Andrea L. Cox1
Pdf attached above
Future Directions
There are significant deficits in our tools for development of an HCV vaccine. Elucidating the mechanisms through which antigen-specific immune cell populations mediate long-term protection is an important goal. Vaccine strategies meant to overcome the enormous diversity of HCV must generate a broad immune response, capable of responding to abundant variations. Selecting antigens to maximize the induction of T-cell and antibody responses that elicit successful responses remains an active area of research. At least 4 types of HCV antigens have been proposed to maximize induction of robust and cross-protective responses: specific previously defined T-cell epitopes for inclusion, a single circulating HCV variant quadrivalent genotype 1a/1b/2a/3a VLP, and antigens generated computationally that minimize the degree of sequence dissimilarity between a vaccine strain and contemporary circulating viruses.
Going forward, successful control of HCV infection will most likely require a combination of large-scale screening to identify infected individuals, treatment of infected persons, and prevention and harm-reduction strategies for those who are uninfected and at risk. Although pharmaceutical companies have invested more in in drug development, vaccine development requires investment from sources beyond government and charitable foundations. A prophylactic HCV vaccine is an important part of a successful strategy for global control. Although development is not easy, the quest is a worthy challenge.
Risk factors for hepatitis C virus (HCV) infection vary, and there were an estimated 1.75 million new cases worldwide in 2015. The World Health Organization aims for a 90% reduction in new HCV infections by 2030. An HCV vaccine would prevent transmission, regardless of risk factors, and significantly reduce the global burden of HCV-associated disease. Barriers to development include virus diversity, limited models for testing vaccines, and our incomplete understanding of protective immune responses. Although highly effective vaccines could prevent infection altogether, immune responses that increase the rate of HCV clearance and prevent chronic infection may be sufficient to reduce disease burden. Adjuvant envelope or core protein and virus-vectored nonstructural antigen vaccines have been tested in healthy volunteers who are not at risk for HCV infection; viral vectors encoding nonstructural proteins are the only vaccine strategy to be tested in at-risk individuals. Despite development challenges, a prophylactic vaccine is necessary for global control of HCV.
The advent of all oral, interferon-sparing direct-acting antivirals (DAAs) that cure hepatitis C virus (HCV) infection has transformed treatment, particularly in high-income countries. Although DAAs have fueled optimism for global control, several limitations of treatment make development of a preventive vaccine necessary to achieve that goal. HCV infections are rarely symptomatic before the onset of advanced liver disease, and HCV screening is rare in most parts of the world, so most persons with HCV infection are not identified.
In addition, the cost of and practical aspects to delivering therapy result in only a subset of those diagnosed being treated. HCV treatment has been decreasing globally since its peak in 2015, as the HCV-infected people easiest to access have been treated, leaving those more difficult to access without treatment (John McHutchinson and Diana Brainard, Gilead Sciences, personal communication; 2018).
Some treated individuals have developed resistance to DAAs, and transmission of resistant HCV variants was documented in clinical trials before DAAs were even approved.
With expansion of treatment to patients less able to take medication reliably, antiviral resistance is likely to become more common. Furthermore, liver disease can progress and cancer can develop despite cure of the HCV infection in patients with cirrhosis. So, treatment does not eliminate all of the consequences of HCV infection and prevention of chronic infection offers significant advantages over treatment.
Despite increased cure rates with DAA, HCV elimination continues to be difficult due to reinfection. Immunity after effective treatment has been shown to be insufficient to prevent reinfection with HCV in individuals with ongoing risk of infection, including people who inject drugs (PWID), men having sex with men, and health care workers with frequent exposure to blood and bodily fluids.
Rates of reinfection in these populations vary, but are high when those most at risk of transmitting infection are treated, in part as a means to interrupt transmission. A recent study in PWID treated while actively injecting showed 6-month and 18-month reinfection rates of 12.6 and 17.1 per 100 person-years, respectively.
PWID, men who have sex with men, health care workers, infants born to HCV-infected mothers, and those living in the many countries with high HCV incidence would be expected to benefit from a preventive HCV vaccine. The effects of prophylactic vaccines with varying levels of efficacy and delivery strategies have been modeled.
Based on these models, high vaccination rates of high-risk seronegative PWID, even with a vaccine with only 30% efficacy, would have significant effects on transmission.
Global control will require annual rates of cure that are consistently and significantly higher than new HCV infection rates. Few countries are on target to eliminate HCV as a public health problem by 2030, the goal set by the World Health Organization in 2016, and nearly 60% of surveyed countries had more infections than cures in 2016.
Consequently, control is unlikely to occur without improved focus on and success in reducing the number of new HCV infections in addition to cure. An effective preventive vaccine would have a significant effects on HCV incidence and would provide a major advance toward global HCV control. However, there are barriers to development, including limitations to HCV culture systems, virus diversity, limited models, and at-risk populations for testing vaccines, and incomplete understanding of protective immune responses.
Feasibility of Traditional Approaches for HCV Vaccine Design
Generation of live-attenuated and inactivated whole virus vaccines has been effective against other viruses, but neither strategy is feasible for generating HCV vaccines. The inability to culture HCV (until recently) and ongoing limitations of HCV culture systems have posed challenges to production of a live-attenuated or inactivated whole HCV vaccine.
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Culture strains of HCV have adaptive mutations that increase replication efficiency in vitro with unknown effects on replication in humans. Live-attenuated vaccines against other viruses have been generated in 2 primary ways: by passage of virus in nonhuman primate cell lines in which natural variants can arise; these have reduced replication in human cells, and by genetic deletion or inactivation of virulence factors. However, HCV does not replicate at high levels in nonhuman primate cell lines and virulence factors for HCV have not been defined. Practical production aspects and the risk of causing HCV infection with live-attenuated vaccines limit their utility.
HCV Genetic Diversity
A principal challenge for HCV vaccine development is the extraordinary genetic diversity of the virus. With 7 known genotypes and more than 80 subtypes, the genetic diversity of HCV exceeds that of human immunodeficiency virus-1 (Figure 1). HCV strains from different genotypes differ, on average, at approximately 30% of their amino acids, whereas different subtypes within each genotype differ at an average of approximately 15% of their amino acids.
In addition to diversity among genotypes and subtypes, immune selection and the error-prone polymerase of the virus generate a diverse quasispecies of related but genetically distinct viral variants within each infected individual, presenting many opportunities for selection of viral variants with resistance to T-cell and antibody responses.
Several recent studies have demonstrated that antibody resistance can arise from mutations either within or distant from antibody binding epitopes, providing the virus with additional mechanisms of immune escape.
Trial Evaluating Experimental Hepatitis C Vaccine Concludes
May 29, 2019
https://www.niaid.nih.gov/news-events/trial-evaluating-experimental-hepatitis-c-vaccine-concludes
An experimental vaccine was not found to be effective at preventing chronic hepatitis C virus (HCV) infection in adults, according to results from a clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
The trial began in March 2012 at sites in California and Maryland; a site in New Mexico was added in September 2015. The Phase 1/2 clinical trial was evaluating whether the experimental prime-boost vaccine known as AdCh3NSmut1/MVA-NSmut was safe and could prevent chronic HCV infection-defined as persistent presence of HCV in the blood for six months after initial detection of infection.
The trial enrolled 548 participants ages 18 to 45 years with a recent history of injecting drugs. The participants were randomly assigned to receive the experimental vaccine (a dose of AdCh3NSmut1 followed by a dose of MVA-NSmut 56 days later) or two placebo doses 56 days apart. Investigators report that 14 of the 275 participants in the experimental vaccine group and 14 of the 273 participants in the placebo group became chronically infected with HCV. The results indicate that the candidate vaccine failed to offer increased protection against chronic HCV infection compared to placebo. No vaccine-related serious adverse events were reported. Seven participant deaths were reported during the clinical trial that were deemed not related to the experimental vaccine. Additional analyses of the trial data are ongoing.
If untreated, HCV infection can lead to chronic liver disease. People who inject drugs are at an increased risk for HCV infection because the virus can be transmitted by sharing needles, syringes, or other equipment to prepare or inject drugs. Antiviral drugs can now cure more than 95% of all treated patients with HCV infection. However, no vaccine exists currently to prevent HCV infection. Many people are unaware that they are infected and continue to unknowingly spread the virus. People who have been cured also can be re-infected if exposed again. An HCV vaccine would be an important public health tool to interrupt and control HCV spread and to protect high-risk populations, such as people who inject drugs.
NIAID continues to support HCV research and is hosting an HCV vaccine workshop on May 29, 2019, in Rockville, Maryland. At the meeting, NIAID scientific experts and outside collaborators will discuss plans for future HCV vaccine designs.
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