Feature

HCV Vaccine: Elegant Solution or Secondary Goal?

The quest for a hepatitis C virus vaccine has taken a back seat in the wake of ongoing breakthroughs in direct-acting antiviral therapies. The time, energy, resources and media attention invested in the vaccine effort have been greatly reduced. But some members of the clinical community said they believe that it would be unwise to entirely abandon the search for an HCV vaccine.

“You need multiple tools in the toolbox to eradicate a disease,” Andrea L. Cox, MD, PhD, associate professor of medicine, oncology, and immunology in the division of infectious diseases at Johns Hopkins University, told HCV Next in an interview. “Novel DAA therapies are highly effective, but we are not simply going to treat our way out of this epidemic.”

Andrea Cox

Andrea L. Cox

Beyond the current focus on treatment, a number of obstacles stand in the way of developing an effective HCV vaccine. One is the pangenotypic nature of the virus, which has made it an elusive target for vaccination.

Then there is the issue of delivering the vaccine to the people who need it.

“Once we have a vaccine, rolling it out to all those at risk will be challenging,” Cox said. She noted that the risk for HCV in hard-to-reach populations, ranging from injection drug users to those living in low-income countries in Asia and the Middle East, means a coordinated international effort will be required to eradicate HCV.

Amid anti-vaccination debates in childhood illnesses, dealing with groups and individuals who oppose vaccination represents another hurdle in the HCV realm. The subject of immunization has moved beyond the clinic into the political arena, so policy issues also are likely to come into play.

But a vaccine is absolutely essential, according to Cox and other experts such as Mark H. Kuniholm, PhD, research assistant professor in the department of epidemiology and population health at Albert Einstein College of Medicine in New York; Thomas F. Baumert, MD, professor of medicine, head of INSERM research unit U1110 and the Institute of Viral and Liver Diseases and hepatologist at the Center for Digestive Disease and Hepatology at the Strasbourg University Hospitals; and Georg M. Lauer, MD, PhD, assistant professor at Harvard Medical School and of the gastrointestinal unit at Massachusetts General Hospital.

“In the last 2 years, DAA therapies that are highly effective with very few side effects and few drug-drug interactions have hit the market,” Cox said. “It has been a major breakthrough. But early enthusiasm about those drugs entirely eliminating HCV alone has fallen by the wayside and reality has set in. It will take more than the drugs to eliminate HCV, which should be our ultimate goal.”

Motivation for a Vaccine

A few fundamental points exist in favor of ongoing vaccine research, even in the DAA era. Each of the experts interviewed by HCV Next voiced variations of the same arguments.

“The drugs are too expensive, even for many people in high-income countries,” Cox said. “So, of course, they are out of reach in low-resource settings. As effective as these drugs are, the economics will prohibit them from being as effective as they can be.”

Kuniholm also raised the question of whether treatment acts as prevention at the local and global levels. “The question is would a vaccine be a more appropriate intervention in these hard-to-reach places and populations,” he said. “It is something we should be considering strongly.”

“The drugs will not reach far enough to break the cycle of infection of new people,” Lauer added.

The next reason is the issue of reinfection. “Many injection drug users continue to engage in high-risk behaviors after effective treatment,” Cox said. “This increases the likelihood of reinfection. A vaccine could save us from treating these patients with multiple courses of therapy.”

Cox said shifting demographics among drug users is another argument in favor of a vaccine. “Widespread use of oxycodone is leading many people to heroin,” she said. “Young people in suburban and rural areas with fewer needle exchange and treatment centers are acquiring HCV. Identifying these HCV-infected populations, keeping them on treatment for 12 weeks, and preventing reinfection can pose a real challenge. A vaccine would help to solve this problem.”

Another concern is the limited response associated with novel DAAs, such as those patients with genotype 3 and cirrhosis. “There are still nonresponders to these drugs,” Baumert said. “We have not seen multidrug-resistant strains, but it is possible. A vaccine prevents this.”

Thomas Baumert

Thomas F. Baumert

The final major argument, put forth by Cox, is that HCV is a silent disease. “The majority of people who have HCV remain undiagnosed,” she said. “Despite broadened screening recommendations, people with this disease are often not seeking medical care. When they do present to care, there is often already a substantial amount of liver disease, or they are at high risk for [hepatocellular carcinoma]. We still can’t make a cirrhotic liver normal. Drugs do not reverse all the damage done. Many have argued that it would be better to prevent the infection in the first place than to wait to treat. I agree.”

Baumert agreed: “Indeed, many patients present with HCC, where treatment comes too late. Furthermore, most recent data show that despite treatment-induced cure, a substantial risk for HCC remains in patients with established fibrosis and cirrhosis.

“I believe a vaccine is the most elegant solutions to many of these problems,” he said.

Numbers Game

Although an optimal approach is, indeed, to chase multiple targets in the various genotypes of HCV with multiple vaccines, the financial realities of such an undertaking are another matter.

“As a society, we have to decide what proportion of money and resources should be earmarked for an HCV vaccine,” Kuniholm said. “I believe there should be continued money earmarked for vaccine research, including basic science in vaccines and immunology. However, we need to have a conversation about whether that proportion should shrink, and by how much.”

Infection rates support ongoing vaccine research, according to Kuniholm. “It is estimated that there are 3 million to 4 million new HCV infections each year globally,” he said. “Whether that can be sustainably brought down simply by DAA therapy remains to be seen.”

According to Baumert, there are 130 million to 185 million individuals who are currently infected. “With novel therapies, we are doing exciting work in a small fraction of patients,” he said. “It is difficult to control and eradicate a disease this way.”

For Kuniholm, there also is an ethical question at work. “Are we as a scientific community willing to drop millions of dollars of funding and so much time and energy publishing results on HCV vaccines because of the advent of DAAs?” he said. “This is a scientific workforce issue, but it is also an ethical and policy issue.”

Protective Immunity

The economic and policy discussions are essentially moot until a highly effective vaccine moves through clinical trials and hits the market. That particular finish line is still far away.

Swadling and colleagues conducted a study of a heterologous prime-boost vaccination strategy. The analysis included a replicative defective simian adenoviral vector (ChAd3) and modified vaccinia Ankara (MVA) vector encoding the NS3, NS4, NS5A and NS5B proteins of HCV genotype 1b. The patient population included healthy volunteers at no risk for HCV infection.

Results indicated that MVA optimally boosted HCV-specific T cells induced by ChAd3. Subsequently, CD4+ and CD8+ T cells targeting several HCV antigens were generated in the response. T-cell memory evolved with time as the heterologous MVA boost improved, according to the results.

“We have developed an HCV vaccine strategy, with durable, broad, sustained and balanced T-cell responses, characteristic of those associated with viral control, paving the way for the first efficacy studies of a prophylactic HCV vaccine,” they concluded.

“Adenoviruses derived from chimpanzees (ChAd) differ from human adenovirus primarily in hexon (surface) proteins, making Ab cross reactivity between vaccine adenoviruses and those to which humans have already been exposed low,” Cox said. “Our current focus is to use vectors to deliver viral antigens in a system that induces robust innate and adaptive immune responses.”

Utilizing this concept, Cox and other researchers at Johns Hopkins and the University of California at San Francisco, are currently conducting a double blind, randomized, placebo-controlled trial involving 344 active injection drug users aged 18 to 45 years. The aim of the trial is to assess the safety, induction of HCV specific immune responses, and efficacy of AdCh3NSmut1 and MVA-NSmut. Two injections are administered at 0 and 8 weeks. Clinicians will test HCV RNA on a monthly basis.

Despite the advances promised by these trials, there are still questions. “The T-cells involved are critical, but what qualities they need to have, what we need to target, and what parts of the immune system are involved remain unknown,” Lauer said. “Whenever we compare people who control and don’t control the same virus, we see more similarities than differences, especially in the critical early phase of infection. Defining what exactly is required for viral control presents a challenge for the immunology field overall.”

However, Lauer is hopeful about the efforts of Cox and colleagues. “No one has ever seen a T cell response this powerful in a vaccine,” he said. “Some of the vaccines we have seen for HIV have paled in comparison. This is the best we have.”

According to Lauer, the clinical community should be exploring different new vaccines. “It would be ideal if we were sure exactly what kind of immune response the vaccine needs to achieve,” he said. “But it is important that we have trials now that test certain vaccines. This will tell us whether we are going in the right direction.”

Georg Lauer

Georg M. Lauer

Another point to consider for HCV is that a vaccine inducing sterilizing immunity is not absolutely necessary because preventing chronic infection is the key goal, according to Lauer. “Acute HCV is not a major cause of morbidity,” he said. “People become only really sick from HCV and its consequences in chronic infection and thus it would be sufficient to have a T cell vaccine that prevents chronic disease.”

The Anti-Vaccination Movement

Ongoing opposition to vaccination is puzzling to most members of the clinical community.

“The data showing the link between the [measles, mumps and rubella] vaccine and autism were falsified,” Cox said. “The data were withdrawn. But people are still responding to these messages, even in industrialized nations. I wish we were beyond that stage, but we are not.”

The good news is that the anti-vaccination message may not be as applicable to HCV, according to Cox. “An HCV vaccine is much more feasible in adolescents,” she said, noting that fears of developmental disorders are not as great for vaccinations in this age group.

Lauer added that HCV is not an incredibly infectious disease. “If the virus appears, if you don’t have herd immunity, HCV won’t spread across the group rapidly,” he said. “For HCV, the key factor is that only a subpopulation is at risk and they need to receive the vaccine.”

Moving Forward

“At the beginning of the AIDS epidemic, Anthony Fauci said that we would have an HIV vaccine in 5 years,” Kuniholm said. “But that vaccine has not been developed. With so much attention on HCV right now, we need to make every effort to develop a vaccine.”

Mark Kuniholm

Mark  H. Kuniholm

Baumert was realistic about the obstacles to a successful HCV vaccine program. “The biggest challenge is the virus itself, with so many different genotypes and strains,” he said. The prevalence of genotypes 1 and 3 disease in North America vs. genotype 4 in many places in the Middle East could pose a huge logistical challenge. It is not yet clear whether a vaccine will be able to cross-protect against different genotypes.”

Lauer echoed this point. “Will we be able to offer broad protection for each particular population?” he said. “Can we get a vaccine that covers all? Or will there be vaccines for certain regions? These are big questions for which we don’t have answers.”

The clinical community need not look further than hepatitis B virus for evidence of these challenges, according to Cox. “We haven’t gotten rid of hepatitis B, and we have a good vaccine for that disease,” she said. “Rolling out a vaccine on a worldwide scale is expensive and requires ongoing, coordinated efforts.”

However, Cox highlighted improvements in liver cancer rates in places such as Taiwan after HBV vaccination of children. “I am not suggesting that it is easy, but I am suggesting that it is possible, and can be effective,” she said.

For Baumert, there is no question as to how the clinical community should proceed. “We absolutely need a vaccine if we want to globally eradicate HCV,” he said.

References:
Baumert TF, et al. J Hepatol. 2014;doi:10.1016/j.jhep.2014.09.009.
Day CL, et al. J Virol. 2002;76:12584-12595.
Grakoui A, et al. Science. 2003;302:659-662.
Shoukry NH, et al. J Exp Med. 2003;doi:10.1084/jem.20030239.
Swadling L, et al. Sci Transl Med. 2015;doi:10.1126/scitranslmed.3009185.
Thimme R, et al. Proc Natl Acad Sci USA. 2002;doi:10.1073/pnas.202608299.
Urbani S, et al. Hepatology. 2006;doi:10.1002/hep.21242.
van der Meer AJ, et al. JAMA. 2012;doi:10.1001/jama.2012.144878.
For more information:
Thomas F. Baumert, MD, can be reached at INSERM U1110, 3 Rue Koerbelé, F-67000 Strasbourg, France; email: Thomas.Baumert@unistra.fr.
Andrea L. Cox, MD, PhD, can be reached at 536 Rangos Building, 855 N. Wolfe St., Baltimore, MD 21205; email: acox@jhmi.edu.
Mark H. Kuniholm, PhD, can be reached at the Belfer Building, Room 1308C, 1300 Morris Park Ave., Bronx, NY 10461; email: mark.kuniholm@einstein.yu.edu.
Georg M. Lauer, MD, PhD, can be reached at Massachusetts General Hospital, Warren 1019A, Gastrointestinal Unit, 55 Fruit St. Boston, MA 02114; email: Glauer@Helix.MGH.Harvard.edu.

Disclosures: Baumert, Cox, Kuniholm and Lauer report no relevant financial disclosures.

The quest for a hepatitis C virus vaccine has taken a back seat in the wake of ongoing breakthroughs in direct-acting antiviral therapies. The time, energy, resources and media attention invested in the vaccine effort have been greatly reduced. But some members of the clinical community said they believe that it would be unwise to entirely abandon the search for an HCV vaccine.

“You need multiple tools in the toolbox to eradicate a disease,” Andrea L. Cox, MD, PhD, associate professor of medicine, oncology, and immunology in the division of infectious diseases at Johns Hopkins University, told HCV Next in an interview. “Novel DAA therapies are highly effective, but we are not simply going to treat our way out of this epidemic.”

Andrea Cox

Andrea L. Cox

Beyond the current focus on treatment, a number of obstacles stand in the way of developing an effective HCV vaccine. One is the pangenotypic nature of the virus, which has made it an elusive target for vaccination.

Then there is the issue of delivering the vaccine to the people who need it.

“Once we have a vaccine, rolling it out to all those at risk will be challenging,” Cox said. She noted that the risk for HCV in hard-to-reach populations, ranging from injection drug users to those living in low-income countries in Asia and the Middle East, means a coordinated international effort will be required to eradicate HCV.

Amid anti-vaccination debates in childhood illnesses, dealing with groups and individuals who oppose vaccination represents another hurdle in the HCV realm. The subject of immunization has moved beyond the clinic into the political arena, so policy issues also are likely to come into play.

But a vaccine is absolutely essential, according to Cox and other experts such as Mark H. Kuniholm, PhD, research assistant professor in the department of epidemiology and population health at Albert Einstein College of Medicine in New York; Thomas F. Baumert, MD, professor of medicine, head of INSERM research unit U1110 and the Institute of Viral and Liver Diseases and hepatologist at the Center for Digestive Disease and Hepatology at the Strasbourg University Hospitals; and Georg M. Lauer, MD, PhD, assistant professor at Harvard Medical School and of the gastrointestinal unit at Massachusetts General Hospital.

“In the last 2 years, DAA therapies that are highly effective with very few side effects and few drug-drug interactions have hit the market,” Cox said. “It has been a major breakthrough. But early enthusiasm about those drugs entirely eliminating HCV alone has fallen by the wayside and reality has set in. It will take more than the drugs to eliminate HCV, which should be our ultimate goal.”

Motivation for a Vaccine

A few fundamental points exist in favor of ongoing vaccine research, even in the DAA era. Each of the experts interviewed by HCV Next voiced variations of the same arguments.

“The drugs are too expensive, even for many people in high-income countries,” Cox said. “So, of course, they are out of reach in low-resource settings. As effective as these drugs are, the economics will prohibit them from being as effective as they can be.”

Kuniholm also raised the question of whether treatment acts as prevention at the local and global levels. “The question is would a vaccine be a more appropriate intervention in these hard-to-reach places and populations,” he said. “It is something we should be considering strongly.”

“The drugs will not reach far enough to break the cycle of infection of new people,” Lauer added.

The next reason is the issue of reinfection. “Many injection drug users continue to engage in high-risk behaviors after effective treatment,” Cox said. “This increases the likelihood of reinfection. A vaccine could save us from treating these patients with multiple courses of therapy.”

PAGE BREAK

Cox said shifting demographics among drug users is another argument in favor of a vaccine. “Widespread use of oxycodone is leading many people to heroin,” she said. “Young people in suburban and rural areas with fewer needle exchange and treatment centers are acquiring HCV. Identifying these HCV-infected populations, keeping them on treatment for 12 weeks, and preventing reinfection can pose a real challenge. A vaccine would help to solve this problem.”

Another concern is the limited response associated with novel DAAs, such as those patients with genotype 3 and cirrhosis. “There are still nonresponders to these drugs,” Baumert said. “We have not seen multidrug-resistant strains, but it is possible. A vaccine prevents this.”

Thomas Baumert

Thomas F. Baumert

The final major argument, put forth by Cox, is that HCV is a silent disease. “The majority of people who have HCV remain undiagnosed,” she said. “Despite broadened screening recommendations, people with this disease are often not seeking medical care. When they do present to care, there is often already a substantial amount of liver disease, or they are at high risk for [hepatocellular carcinoma]. We still can’t make a cirrhotic liver normal. Drugs do not reverse all the damage done. Many have argued that it would be better to prevent the infection in the first place than to wait to treat. I agree.”

Baumert agreed: “Indeed, many patients present with HCC, where treatment comes too late. Furthermore, most recent data show that despite treatment-induced cure, a substantial risk for HCC remains in patients with established fibrosis and cirrhosis.

“I believe a vaccine is the most elegant solutions to many of these problems,” he said.

Numbers Game

Although an optimal approach is, indeed, to chase multiple targets in the various genotypes of HCV with multiple vaccines, the financial realities of such an undertaking are another matter.

“As a society, we have to decide what proportion of money and resources should be earmarked for an HCV vaccine,” Kuniholm said. “I believe there should be continued money earmarked for vaccine research, including basic science in vaccines and immunology. However, we need to have a conversation about whether that proportion should shrink, and by how much.”

Infection rates support ongoing vaccine research, according to Kuniholm. “It is estimated that there are 3 million to 4 million new HCV infections each year globally,” he said. “Whether that can be sustainably brought down simply by DAA therapy remains to be seen.”

According to Baumert, there are 130 million to 185 million individuals who are currently infected. “With novel therapies, we are doing exciting work in a small fraction of patients,” he said. “It is difficult to control and eradicate a disease this way.”

For Kuniholm, there also is an ethical question at work. “Are we as a scientific community willing to drop millions of dollars of funding and so much time and energy publishing results on HCV vaccines because of the advent of DAAs?” he said. “This is a scientific workforce issue, but it is also an ethical and policy issue.”

Protective Immunity

The economic and policy discussions are essentially moot until a highly effective vaccine moves through clinical trials and hits the market. That particular finish line is still far away.

Swadling and colleagues conducted a study of a heterologous prime-boost vaccination strategy. The analysis included a replicative defective simian adenoviral vector (ChAd3) and modified vaccinia Ankara (MVA) vector encoding the NS3, NS4, NS5A and NS5B proteins of HCV genotype 1b. The patient population included healthy volunteers at no risk for HCV infection.

Results indicated that MVA optimally boosted HCV-specific T cells induced by ChAd3. Subsequently, CD4+ and CD8+ T cells targeting several HCV antigens were generated in the response. T-cell memory evolved with time as the heterologous MVA boost improved, according to the results.

PAGE BREAK

“We have developed an HCV vaccine strategy, with durable, broad, sustained and balanced T-cell responses, characteristic of those associated with viral control, paving the way for the first efficacy studies of a prophylactic HCV vaccine,” they concluded.

“Adenoviruses derived from chimpanzees (ChAd) differ from human adenovirus primarily in hexon (surface) proteins, making Ab cross reactivity between vaccine adenoviruses and those to which humans have already been exposed low,” Cox said. “Our current focus is to use vectors to deliver viral antigens in a system that induces robust innate and adaptive immune responses.”

Utilizing this concept, Cox and other researchers at Johns Hopkins and the University of California at San Francisco, are currently conducting a double blind, randomized, placebo-controlled trial involving 344 active injection drug users aged 18 to 45 years. The aim of the trial is to assess the safety, induction of HCV specific immune responses, and efficacy of AdCh3NSmut1 and MVA-NSmut. Two injections are administered at 0 and 8 weeks. Clinicians will test HCV RNA on a monthly basis.

Despite the advances promised by these trials, there are still questions. “The T-cells involved are critical, but what qualities they need to have, what we need to target, and what parts of the immune system are involved remain unknown,” Lauer said. “Whenever we compare people who control and don’t control the same virus, we see more similarities than differences, especially in the critical early phase of infection. Defining what exactly is required for viral control presents a challenge for the immunology field overall.”

However, Lauer is hopeful about the efforts of Cox and colleagues. “No one has ever seen a T cell response this powerful in a vaccine,” he said. “Some of the vaccines we have seen for HIV have paled in comparison. This is the best we have.”

According to Lauer, the clinical community should be exploring different new vaccines. “It would be ideal if we were sure exactly what kind of immune response the vaccine needs to achieve,” he said. “But it is important that we have trials now that test certain vaccines. This will tell us whether we are going in the right direction.”

Georg Lauer

Georg M. Lauer

Another point to consider for HCV is that a vaccine inducing sterilizing immunity is not absolutely necessary because preventing chronic infection is the key goal, according to Lauer. “Acute HCV is not a major cause of morbidity,” he said. “People become only really sick from HCV and its consequences in chronic infection and thus it would be sufficient to have a T cell vaccine that prevents chronic disease.”

The Anti-Vaccination Movement

Ongoing opposition to vaccination is puzzling to most members of the clinical community.

“The data showing the link between the [measles, mumps and rubella] vaccine and autism were falsified,” Cox said. “The data were withdrawn. But people are still responding to these messages, even in industrialized nations. I wish we were beyond that stage, but we are not.”

The good news is that the anti-vaccination message may not be as applicable to HCV, according to Cox. “An HCV vaccine is much more feasible in adolescents,” she said, noting that fears of developmental disorders are not as great for vaccinations in this age group.

Lauer added that HCV is not an incredibly infectious disease. “If the virus appears, if you don’t have herd immunity, HCV won’t spread across the group rapidly,” he said. “For HCV, the key factor is that only a subpopulation is at risk and they need to receive the vaccine.”

PAGE BREAK

Moving Forward

“At the beginning of the AIDS epidemic, Anthony Fauci said that we would have an HIV vaccine in 5 years,” Kuniholm said. “But that vaccine has not been developed. With so much attention on HCV right now, we need to make every effort to develop a vaccine.”

Mark Kuniholm

Mark  H. Kuniholm

Baumert was realistic about the obstacles to a successful HCV vaccine program. “The biggest challenge is the virus itself, with so many different genotypes and strains,” he said. The prevalence of genotypes 1 and 3 disease in North America vs. genotype 4 in many places in the Middle East could pose a huge logistical challenge. It is not yet clear whether a vaccine will be able to cross-protect against different genotypes.”

Lauer echoed this point. “Will we be able to offer broad protection for each particular population?” he said. “Can we get a vaccine that covers all? Or will there be vaccines for certain regions? These are big questions for which we don’t have answers.”

The clinical community need not look further than hepatitis B virus for evidence of these challenges, according to Cox. “We haven’t gotten rid of hepatitis B, and we have a good vaccine for that disease,” she said. “Rolling out a vaccine on a worldwide scale is expensive and requires ongoing, coordinated efforts.”

However, Cox highlighted improvements in liver cancer rates in places such as Taiwan after HBV vaccination of children. “I am not suggesting that it is easy, but I am suggesting that it is possible, and can be effective,” she said.

For Baumert, there is no question as to how the clinical community should proceed. “We absolutely need a vaccine if we want to globally eradicate HCV,” he said.

References:
Baumert TF, et al. J Hepatol. 2014;doi:10.1016/j.jhep.2014.09.009.
Day CL, et al. J Virol. 2002;76:12584-12595.
Grakoui A, et al. Science. 2003;302:659-662.
Shoukry NH, et al. J Exp Med. 2003;doi:10.1084/jem.20030239.
Swadling L, et al. Sci Transl Med. 2015;doi:10.1126/scitranslmed.3009185.
Thimme R, et al. Proc Natl Acad Sci USA. 2002;doi:10.1073/pnas.202608299.
Urbani S, et al. Hepatology. 2006;doi:10.1002/hep.21242.
van der Meer AJ, et al. JAMA. 2012;doi:10.1001/jama.2012.144878.
For more information:
Thomas F. Baumert, MD, can be reached at INSERM U1110, 3 Rue Koerbelé, F-67000 Strasbourg, France; email: Thomas.Baumert@unistra.fr.
Andrea L. Cox, MD, PhD, can be reached at 536 Rangos Building, 855 N. Wolfe St., Baltimore, MD 21205; email: acox@jhmi.edu.
Mark H. Kuniholm, PhD, can be reached at the Belfer Building, Room 1308C, 1300 Morris Park Ave., Bronx, NY 10461; email: mark.kuniholm@einstein.yu.edu.
Georg M. Lauer, MD, PhD, can be reached at Massachusetts General Hospital, Warren 1019A, Gastrointestinal Unit, 55 Fruit St. Boston, MA 02114; email: Glauer@Helix.MGH.Harvard.edu.

Disclosures: Baumert, Cox, Kuniholm and Lauer report no relevant financial disclosures.