Showing posts with label HCV Vaccine. Show all posts
Showing posts with label HCV Vaccine. Show all posts

Thursday, June 7, 2012

International Patent Application Submitted Covering Vaccines for Influenza (Universal Vaccine), Hepatitis C

International Patent Application Submitted Covering Vaccines for Influenza (Universal Vaccine), Hepatitis C,

* Reuters is not responsible for the content in this press release.

Thu Jun 7, 2012 7:00am EDT

OSLO, NORWAY, Jun 07 (Marketwire) --
Bionor Pharma ASA (OSLO: BIONOR)

News Summary
The new patent filed 6 June aims to strengthen the Company's general
protection of its peptide based vaccine technology, including four
specific product patents:

-- Vacc-Flu is a universal influenza vaccine that researchers believe
could produce long lasting immunity, and be effective for all seasonal
variations of influenza A.

-- Vacc-HCV is a vaccine that may be effective both as a therapy and for
prevention of chronic liver infection. Hepatitis C (HCV) may lead to
liver failure and liver cancer.

-- Vacc-CMV is a vaccine for treating cytomegalovirus (CMV) infection,
which has been associated with inflammatory diseases as well as
aggravating various cancer forms such as brain tumors and prostate

-- Vacc-HPV is a vaccine for treating throat and vaginal cancer caused by
Human papillomavirus (HPV).

Bionor Pharma ASA (OSLO: BIONOR) announced today that it has
initiated the international patent process for further protection of the
Company's peptide vaccine technology platforms, and for the vaccine
candidates Vacc-Flu, Vacc-HCV, Vacc-CMV and Vacc-HPV. This new peptide
vaccine platform submission complements the two previously filed
technology platform patents covering peptide vaccines designed for
generation of antibody responses and peptide vaccines designed for
generating T-cell responses.

All the vaccine candidates are developed from conserved parts (proteins)
of the respective viruses. By applying the platform technology to modify
the peptides, the vaccines are shown to have significantly improved
immune response properties as compared to the corresponding unmodified
(native) peptides.

The new platform patent is also covering protection of the various
administration regimes connected to the vaccines. Preclinical research is
ongoing for both the influenza and the HCV vaccines.

About Vacc-Flu
Developing a "universal" influenza vaccine has been
difficult because influenza viruses undergo constant genetic mutation.
Vacc-Flu targets conserved regions, the "Achilles' Heels" that are common
to all known Influenza A viruses. The vaccine is designed to provide
long-term protection over several years, reducing deaths and related
illnesses caused by all current influenza A subtypes, as well as future
influenza viruses that may emerge and lead to an influenza pandemic.
Vacc-Flu has shown in animal studies to reduce serious flu symptoms by 25
percent over the standard flu vaccine.

"The benefits of a universal vaccine far outweigh the current seasonal
vaccine development approach," said Steen Kroyer, CEO, Bionor Pharma.
"The goal is to eliminate the need for researchers to develop annual
vaccines, a challenging process that requires manufacturers to operate on
a tight schedule to meet WHO recommendations."

The global market for an influenza vaccine is approximately 250 million
doses corresponding to annual sale of approximately $2 billion to $2.7
billion. Today's influenza vaccines are specific only for one season and
new vaccines have to be developed each year.

About Vacc-HCV
Bionor's therapeutic vaccine for hepatitis C, Vacc-HCV
aims to treat chronic HCV infection that affects the liver and may lead
to scarring and cirrhosis with liver failure or liver cancer in advanced

An estimated 150 million people are living with chronic hepatitis C and
between three and four million people become infected per year. Over
350,000 deaths annually are attributed to hepatitis C-related diseases.

Although new drugs are expected to enter the market, these treatments
will not be without side effects and treatment failures. This opens the
door to even better stand-alone therapy or combination therapies,
including a therapeutic vaccine.

About Vacc-CMV
Bionor's therapeutic CMV vaccine targets diseases
associated with cytomegalovirus (CMV) infection. Researchers believe that
CMV may not itself be the disease causing agent, but that it aggravates
disease by changing the environment, resulting in a weakened immune
system. Thus CMV may be a contributing factor to inflammatory diseases or
tumor growth. In a number of inflammatory diseases such as rheumatoid
arthritis, inflammatory bowel disease and psoriasis, active CMV infection
can be detected. In various cancer forms such as prostate, colon, breast
and brain cancer, CMV can be detected in the tumor but not in the nearby

Vacc-CMV will be developed as a therapeutic T-cell (killer cell) vaccine
for treatment of CMV positive patients with inflammatory diseases orancer.

About Vacc-HPV
The Human papillomavirus is made up of a group of DNA
viruses in the family Papillomaviridae that infect the skin and mucous
membranes causing genital warts, cervical cancer and a growing number of
throat cancer cases. Worldwide, cervical cancer remains the second most
common malignancy in women, and is a leading cause of cancer related
death for females in developing countries. Company researchers believe
Vacc-HPV will be a therapeutic T-cell (killer cell) vaccine aiming to
complement today's standard of care.

About Bionor Pharma ASA
Bionor Pharma is a leading vaccine company,
listed on the Oslo Stock Exchange. The Company's investments in
developing therapeutic vaccines exceed US$70 million.

Bionor's vaccines are based on the proprietary technology platform
developed following more than two decades of research on peptides. The
vaccines are designed to safely activate each person's immune system to
combat viral diseases. The Company's lead HIV vaccine, Vacc-4x, is being
investigated as a therapeutic vaccine, and has completed a phase 2b
randomized, multinational (USA and 4 European countries), double-blind,
placebo-controlled trial. It produced a statistically significant
reduction in viral load and viral load set point by killing of virus
producing cells.

Bionor's second therapeutic HIV vaccine, Vacc-C5, is developed to induce
antibodies to HIV that can reduce viral production (lowering the set
point) and the harmful hyperactivation of the immune system that leads to
AIDS. Recently, the clinical phase I/II study with Vacc-C5 was approved
by the Norwegian Clinical Board. Subsequent to the Vacc-C5 phase I/II
trial, Bionor intends to combine Vacc-4x with Vacc-C5, which could form
the basis for both a therapeutic and a preventative HIV vaccine.

The Company's innovative technology platform is also well suited to
develop vaccines for other viral diseases, including Influenza, HCV
(Hepatitis C), CMV (Cytomegalovirus) and HPV (Human papillomavirus).

More information about Bionor Pharma, its research and products, is
available at .

This information is subject of the disclosure requirements acc. to
Section 5-12 vphl
(Norwegian Securities Trading Act). Vacc-4x, Vacc-C5,
Vacc-Flu, Vacc-HCV, Vacc-CMV and Vacc-HPV are investigational treatments
that have not been approved for marketing by any regulatory authority.

Bionor Pharma ASA, Oslo: +47 23 01 09 60
Bionor Pharma laboratories: +47 35 90 85 00
Steen Kroyer
Birger Sorensen
EVP, Head of Vaccines

USA Contact:
David Sheon
202 422-6999

Copyright 2012, Marketwire, All rights reserved

Tuesday, April 3, 2012

Scripps Research Institute Scientists Find Promising Vaccine Targets on Hepatitis C Virus

Scripps Research Institute Scientists Find Promising Vaccine Targets on Hepatitis C Virus

LA JOLLA, CA – April 3, 2012 ­– A team led by scientists at The Scripps Research Institute has found antibodies that can prevent infection from widely differing strains of hepatitis C virus (HCV) in cell culture and animal models.

HCV’s very high rate of mutation normally helps it to evade its host’s immune system. The newly discovered antibodies, however, attach to sites on the viral envelope that seldom mutate. One of the new antibodies, AR4A, shows broader HCV neutralizing activity than any previously reported anti-HCV antibody.

“These antibodies attach to sites on the viral envelope that were previously unknown, but now represent promising targets for an HCV vaccine,” said Mansun Law, an assistant professor at Scripps Research. Law is the senior author of the new report, which appears online this week in the Proceedings of the National Academy of Sciences.

A Desperate Need
An effective HCV vaccine is desperately needed. The World Health Organization (WHO) estimates that the virus has established mostly silent infections in 130 to 170 million people worldwide—nearly 3 percent of the human population—and spreads to 3 to 4 million new people annually. HCV principally infects liver cells, and is thought to cause chronic, often-unnoticed liver inflammation, which eventually can lead to serious liver ailments. The virus already is responsible for about a quarter of annual US cases of liver cirrhosis and primary liver cancer, and it is the leading cause of liver transplants. In some developing countries, HCV prevalence is extremely high; studies suggest that in Egypt, as many as 22 percent of the population is infected—apparently due to poor screening of blood products and past re-use of syringes. Even in developed countries, HCV infections represent a looming public health crisis. In the United States and Europe, up to 14 million people are now HCV-positive, and each year an estimated 150,000 people are newly infected.

The current leading treatment for HCV infection involves a 12- to 36-week course of the immune-stimulating protein interferon-alpha, the antiviral drug ribavirin and HCV protease blocker. But it is not completely effective, and it causes significant adverse side effects—aside from being very expensive. To fully stamp out the HCV pandemic, especially in developing countries, scientists will have to develop a cheap preventive vaccine.

Yet an effective HCV vaccine has so far been elusive. The virus mutates very rapidly, and thus, antibodies raised against one isolate of HCV typically won’t protect against a subsequent HCV infection. Hospital samples of HCV suggest that the virus’s genes, and the proteins for which they code, are highly variable even within an individual patient.
“One of the big goals of HCV vaccine development has been to find an accessible spot on the virus that doesn’t change constantly,” said Law.

Searching for Vulnerabilities
To find such vulnerable spots, researchers sift through antibodies sampled from infected people and look for those antibodies that can neutralize a broad range of viral strains. The locations on the virus where those broadly neutralizing antibodies bind mark the vulnerable viral structures that can be used as the bases of a broadly effective, antibody-stimulating vaccine. Previous studies, including a 2008 study in Nature Medicine, for which Law was lead author, have found some broadly neutralizing HCV antibodies. But for the present study, Law and his colleagues used a more thorough approach, known as “exhaustive panning,” to see if they could find new and even more broadly neutralizing antibodies. “Exhaustive panning is a powerful technique for finding rare antibodies that might otherwise go undetected,” Law said.

HCV employs a complex of two envelope glycoproteins, E1 and E2, to grab and fuse with target cells. Erick Giang, a research assistant in Law’s lab, harvested this viral E1-E2 complex from HCV-producing cells in a lab dish and used it as “bait” for a panel of antibodies derived from the blood of a person with chronic HCV infection. The exhaustive panning technique involves exposing this bait protein to different anti-HCV antibodies in sequence, so that the known antibody-binding sites on the complex are progressively covered until only new ones are left.

In this way, Giang catalogued 73 new anti-HCV antibodies, which bind to five distinct “antigenic regions” on the E1-E2 complex. In standard cell culture tests of HCV-neutralizing ability, several of these antibodies showed an ability to neutralize infection by a wide range of HCV strains. One, AR4A, turned out to bind to an almost-unvarying spot on E1-E2 complex, close to the surface of the virus’s outer coat of fat molecules. AR4A showed significant neutralizing ability against all 22 HCV strains in a test panel—not only in tests in Law’s lab, but also in confirmatory tests at the University of Copenhagen.

The Broadest Neutralizing Activity Yet
The new antibody thus is more broadly protective than the previous top contender, AR3A, which Law described in his 2008 Nature Medicine paper. “This human antibody AR4A has the broadest HCV-neutralizing activity known to the field,” Law said.

Collaborating researchers at Rockefeller University, who recently engineered a line of HCV-infectable mice, showed that AR4A antibodies protected these mice from two widely different HCV strains. A combination of half-doses of AR3A and AR4A antibodies worked less well.
The next step for Law and his colleagues is to start making and testing prototype vaccines based on the vulnerable HCV binding sites that have been revealed by these antibody studies. The researchers also plan to use the new antibodies to study the structure and function of HCV proteins such as the all-important E1-E2 complex.

Anti-HCV antibodies such as AR4A and AR3A could have some therapeutic use, too. Although they wouldn’t be able to clear existing HCV infections and would be too expensive and difficult to use on a large population to prevent new infections, they could be useful in preventing new HCV liver infections in liver transplant patients. Such infections can spread from HCV reservoirs in the patient’s body to the newly transplanted liver tissue.

“Antibody-based treatment has worked extremely well for liver transplants to patients with hepatitis B virus, and we hope the new HCV antibodies can be just as helpful to HCV liver transplant patients,” Law said.

In addition to Law and Giang, contributors to the paper, “Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus,” were Marcus Dorner, Charles M. Rice, and Alexander Ploss of Rockefeller University in New York; Jannick C. Prentoe and Jens Bukh of the University of Copenhagen; Matthew J. Evans of the Mount Sinai School of Medicine; and Marlène Dreux and Dennis Burton at Scripps Research.
The Law laboratory’s research is supported by the National Institutes of Health.

About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neuroscience, and vaccine development, as well as for its insights into autoimmune, cardiovascular, and infectious disease. Headquartered in La Jolla, California, the institute also includes a campus in Jupiter, Florida, where scientists focus on drug discovery and technology development in addition to basic biomedical science. Scripps Research currently employs about 3,000 scientists, staff, postdoctoral fellows, and graduate students on its two campuses. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, is ranked among the top ten such programs in the nation. For more information, see
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For information:
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Tel: 858-784-8134
Fax: 858-784-8136


Wednesday, March 14, 2012

Hepatitis C Vaccine-Okairos Announces Initiation of Phase I/II Clinical Trial

Okairos Announces Initiation of Phase I/II Clinical Trial for Potential First-in-Class Hepatitis C Vaccine

BASEL, Switzerland --Business Wire)--
Okairos today announced the initiation of a Phase I/II clinical trial evaluating its vaccine against the hepatitis C virus (HCV). This is the first multi-center, double blinded, randomized, placebo-controlled trial of a vaccine to prevent HCV infection, and represents a major milestone in the collaboration between Okairos and the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the US National Institutes of Health (NIH). The NIH-funded trial will be conducted by co-principal investigators from Johns Hopkins University and the University of California San Francisco (UCSF).

The trial follows promising Phase I results that were recently published in Science Translational Medicine, showing that the vaccine had a good safety profile, was well tolerated, and that it stimulated a highly potent T-cell response in healthy volunteers. This Phase I/II trial will provide the opportunity to demonstrate the potential effectiveness of such an approach in protecting against chronic HCV infection, the leading cause of liver cancer.i

Dr Riccardo Cortese, Chief Executive Officer of Okairos, said: "This news represents many years of work in developing our technology platform and proving its utility in early clinical studies in HCV and other areas. We are very pleased to be part of this productive collaboration and look forward to initiating additional clinical programs from our platform in the near future."

The trial will enroll 350 subjects and will begin with an interim hase I analysis of safety and immunogenicity data in a subset of them. The primary endpoints of the overall study will measure the incidence of chronic HCV infection, as well as the safety and tolerability of the vaccine.

Dr Alfredo Nicosia, Chief Scientific Officer of Okairos, explained: "The history of vaccine research has primarily focused on stimulating antibody responses. We've unlocked the door to stimulating robust T-cell responses and will leverage this technology to combat important diseases such as HCV, respiratory syncytial virus (RSV) and influenza."

About hepatitis C virus (HCV)
Three per cent of the global population carries HCV, which affects the liver cells and is the leading cause of liver transplants in the US. Around 170 million people have the chronic form of the disease, which may lead to cirrhosis, liver failure, hepatocellular carcinoma and ultimately death. In the US and Western Europe around 150,000 new cases occur annually.ii Extensive variations of the virus present major challenges to the development of a vaccine - there is currently no vaccine for the prevention (prophylactic vaccine) of HCV infection.

About Okairos' HCV vaccine
Extensive preclinical experiments and studies of the interaction of the virus with the human immune system have highlighted the importance of T-cells in counteracting HCV. Okairos' HCV vaccine is based on a technology platform that uses proprietary, chimpanzee-derived adenovirus vectors to stimulate a robust T-cell response against selected antigens. Okairos' research has shown that it is able to stimulate robust T-cell responses that provide strong protection in preclinical non-human primate challenge models.

About Okairos
Okairos is a clinical-stage biopharmaceutical company, developing genetic vaccines for major infectious diseases - including malaria, hepatitis C, influenza, respiratory syncytial virus and cancer - using a novel proprietary technology. The company is headquartered in Basel, Switzerland and has laboratories in Rome and Naples, Italy.

Okairos' technology platform is centered on the development of new, potent adenovirus vectors to generate a pipeline of T-cell vaccines against a range of infectious diseases for which there is currently no effective vaccine. The company is also pursuing therapeutic vaccines to treat cancer.
The company's investors include BioMedInvest, Boehringer Ingelheim Venture Fund, LSP, Novartis Venture Funds and Versant Ventures.
For more information, visit


Former Merck Unit Works on First Vaccine for Hepatitis C

Former Merck Unit Works on First Vaccine for Hepatitis C
Source: Bloomberg
By Makiko Kitamura - Mar 14, 2012 4:00 AM ET

Okairos AG, a biotechnology business that Merck & Co. (MRK) sold to venture capital funds in 2007, is seeking to produce the first preventive vaccine for hepatitis C, challenging makers of treatments for the disease.

Okairos has begun a mid-stage study, funded by the U.S. National Institutes of Health, of a gene-based vaccine designed to stimulate the body’s immune system to prevent hepatitis C from taking hold, Chief Operating Officer Tom Woiwode said in a phone interview from the company’s Basel, Switzerland, headquarters.

No vaccine exists for hepatitis C, which affects as many as 170 million people globally, putting them at risk of developing liver cancer, according to the World Health Organization. The growing population of patients infected with the virus spurred Gilead Sciences Inc. (GILD)’s decision in November to buy experimental hepatitis C-treatment maker Pharmasset Inc. for $10.8 billion and Bristol-Myers Squibb Co. (BMY)’s acquisition in February of Inhibitex Inc. for $2.5 billion.

“This could change the landscape quite a bit,” said Les Funtleyder, a health-care strategist and portfolio manager at Miller Tabak & Co. in New York. “In theory, if you could vaccinate everyone, you’d need a lot less drug.” Funtleyder said he isn’t aware of any other preventive vaccines in development.

Disease Transmission
Okairos’s vaccine would target those who may be at risk of infection. The disease is most commonly transmitted through contaminated blood transfusions, organ transplants, contaminated syringes and needle-injected drug use, according to the WHO.

Most preventive vaccines stimulate the production of antibodies, molecules produced by the immune system as part of the body’s defenses. Development of Okarios’s vaccine was triggered by studies of patients with early-stage hepatitis C, of whom about 20 percent spontaneously clear the virus and avoid advancing to the chronic phase, Woiwode said.

Researchers have found those patients tend to have a strong response in the blood’s T cells, Woiwode said. Armed with that knowledge, Okairos developed technology that delivers genetic material to stimulate T cells, the white blood cells that help the body fight diseases.

This approach contrasts with most other vaccines, which stimulate an antibody response, Woiwode said.
“We’ve opened up a new path that will allow us to address a number of diseases, hepatitis C being the first one,” he said in the interview yesterday.

Even if a vaccine is approved, medicines are needed to treat patients already infected, Miller Tabak’s Funtleyder said.

Industry Projects
Merck and Vertex Pharmaceuticals Inc. (VRTX) won approval last year for the first new therapies for hepatitis C in almost a decade. Johnson & Johnson (JNJ), a partner in the Vertex drug, is also cooperating with Swedish drugmaker Medivir AB (MVIRB) on a hepatitis treatment. Basel-based Roche Holding AG (ROG) agreed in October to buy Anadys Pharmaceuticals Inc., another maker of experimental medicines for hepatitis C, for about $230 million.

Profectus Biosciences Inc., a Baltimore-based vaccine manufacturer, is also developing a drug that prevents patients with early-stage hepatitis C from advancing to the chronic stage. The company plans clinical trials of the product in 2013.

Investors in Okairos, which is also developing malaria, cancer and flu vaccines, include Boehringer Ingelheim Venture Fund, Life Sciences Partners, Novartis Venture Funds and Versant Ventures. The Swiss company has also received grants from the European Union and the Bill and Melinda Gates Foundation.
The company is in discussions with potential partners for marketing the vaccine, Woiwode said.
“I have no doubt that if this Phase 2 study is successful, there will be no shortage of interest to work with us to bring this to the market globally,” he said.

To contact the reporter on this story: Makiko Kitamura in London at
To contact the editor responsible for this story: Phil Serafino at

Sunday, February 19, 2012

A significant step forward in Hep-C prevention

Uploaded by on Feb 17, 2012
Thousands of Canadians are infected with Hepatitis C every year. Treatment can be expensive and isn't always effective. Many scientists are working on vaccines but few have had success. Until now. A Canadian team has made what's being called a significant step forward in Hep-C prevention.

Wednesday, February 15, 2012

U of A researchers move closer to discovering hepatitis vaccine

U of A researchers move closer to discovering hepatitis vaccine

By Jodie Sinnema,

John Law, research associate, is part of a team that has made a significant discovery in the search for a vaccine against hepatitis C at the University Hospital in Edmonton, Feb. 15, 2012.

Photograph by: Ed Kaiser,

EDMONTON - A University of Alberta research team is one step closer to discovering a vaccine for hepatitis C that appears to work against all the major strains of the disease.

Michael Houghton, a researcher at the Li Ka Shing Institute of Virology at the U of A, says his discovery was unexpected. That’s because there are six major strains of hepatitis C and hundreds more subtypes infecting 170 million people around the world. Hepatitis C is spread through contaminated blood and can be associated with needle-sharing, medical procedures involving unsterilized equipment, or blood transfusions.

Vaccines, made with the antibodies of specific strains, tend to only work against those specific disease types. Think, for instance, about the flu vaccine and how it covers only certain strains expected to circulate during a given flu season.

Houghton said new data from the U of A shows his vaccine, made from one strain of the hepatitis disease, produces antibodies that can neutralize all the hepatitis C types around the world.

“I think that’s great news for our efforts to develop a vaccine for hepatitis C,” said Houghton, a world-renowned expert in medical microbiology and immunology who discovered the hepatitis C virus in 1989. He presented his recent findings during Wednesday’s Canada Excellence Research Chairs Summit in Vancouver. “It’s a very unexpected result and it’s guiding us toward the development of a successful hepatitis vaccine.”

Such a vaccine was thought impossible and impractical, since hepatitis C is more heterogeneous — or has more varieties — than HIV.

“In the HIV field, for example, it’s been the Holy Grail for many years to try to elicit antibodies that can neutralize all the different types around the world,” Houghton said. He, then, has potentially discovered the Holy Grail for hepatitis C.

“I think it’s a very big step forward,” he said. “I’ve been working on the vaccine for 15 years (and) for so many years, the field felt that antibodies would be very restricted in their neutralizing ability, that you could only neutralize the same strain that the vaccine was derived from.”

His lab study defied that belief.

“It’s very encouraging that we can do it and really gives us a hope that an effective vaccine can be produced for hep C.”

John Law, Houghton’s research partner, said preliminary tests showed the vaccine blocked some strains from entering a person better than others, with success rates ranging from 40 per cent to 100 per cent. He said the effectiveness could be improved in clinical trials by playing with the dosage.

Houghton said while it would take five to seven years before such a vaccine could hit the market — it must be proven safe and effective in large clinical trials involving humans — he said the vaccine could also help those already infected with the disease. Of the millions who carry the infection, up to 20 per cent develop chronic illness, including cirrhosis of the liver.

A drug cocktail already on the market cures 70 per cent of those infected with hepatitis C, Houghton said. He said further research needs to determine if a combination of that antiviral with the new vaccine could increase the success rate.

“It may also be beneficial as a therapeutic vaccine,” he said. “That does deserve attention in the future.”

Dr. Lorne Tyrrell, a hepatitis expert and the Canadian Institutes of Health Research and GlaxoSmithKline chair in virology at the U of A, said if the vaccine proves effective, it will have a global impact. In Egypt, for instance, 10 per cent of the population carries hepatitis C.

“In many parts of the world, the antiviral therapy we currently have for hepatitis C is often out of the reach of most people’s affordability so having a (cheaper) vaccine that could be used to prevent the disease in those countries is particularly important,” Tyrrell said.

“There’s still a lot of work that needs to be done, but at least it’s a clue and an indication that we can develop a potential vaccine for hepatitis C.”
© Copyright (c) The Edmonton Journal

CTV Edmonton: Major Hepatitis C discovery

Click Here To View Video  

CTV Edmonton's health reporter Carmen Leibel talks to a U of A researcher who may have discovered the world first Hepatitis C vaccine.

Tuesday, January 10, 2012

Behind the Headlines-Experimental hepatitis C vaccine tested

Behind the Headlines provides an unbiased and evidence-based analysis of health stories that make the news.

Each day the NHS Choices team selects health stories that are making headlines.

These, along with the scientific articles behind the stories, are sent to Bazian, a leading provider of evidence-based healthcare information.

Bazian's clinicians and scientists analyse the research and produce impartial evidence-based assessments, which are edited and published by NHS Choices.

Experimental hepatitis C vaccine tested

“An early clinical trial of a hepatitis C vaccine has shown ‘promising’ results,”

This story is based on a clinical trial that tested the dosage and safety of a newly developed vaccine against the hepatitis C virus. Researchers developed a vaccine by inserting small pieces of DNA from a hepatitis C virus into a rare form of the virus that causes the common cold.

When faced with a vaccine like this, the body should mount an immune response and ‘remember’ the virus so that it can respond swiftly to any potential infections in the future. The researchers found that cells indicating immunity to the virus were present for a year in 41 healthy people who were vaccinated. This suggests that the immune system was prepared to respond if faced with the virus. None of the people involved with the study experienced significant side effects.

This was an early-stage clinical trial designed to test the safety of the vaccine rather than whether it could prevent infections. Extensive further research will now be needed to determine effectiveness, particularly whether or not it can prevent hepatitis C infections in real-life settings. Given the complexities of testing and development, it is likely to take many years before any such vaccine could enter clinical use.

Where did the story come from?

The study was carried out by researchers from the Universities of Oxford and Birmingham, and from institutions throughout Italy. The research was funded by the European Union, the UK Medical Research Council, the Wellcome Trust, the UK National Institute for Health Research and the US National Institutes of Health.

The study was published in the journal Science Translational Medicine.

The media reported on this study appropriately, with both the BBC and the Daily Mirror emphasising the early nature of the research and the fact that the possibility of a working vaccine is still several years away.

What kind of research was this?

This was a phase I clinical trial that tested the safety and tolerability of a new vaccine intended to prevent infection with the hepatitis C virus. The virus primarily affects the liver, causing inflammation and damage to the organ. It can lead to severe liver scarring (cirrhosis) and liver cancer. There are currently no vaccines available to protect against infection with hepatitis C, and treatments vary in effectiveness depending upon the specific strain of the virus causing the infection.

The Health Protection Agency estimates that more than 200,000 people have the disease in the UK, and that many carry the virus without knowing it. Approximately 20% of people infected with the virus have a natural immunity to it and will clear the virus within the first six months after infection, before the disease is considered to be chronic. Among those who develop chronic hepatitis C, most can clear the infection with the help of drugs, although not all respond to treatment and some remain chronically infected.

As a blood-borne virus, it is particularly common among intravenous (IV) drug users. The development of an effective vaccine would be invaluable, as the World Health Organization estimates that around 130-170 million people around the world have chronic hepatitis C, and therefore could pass the infection on. Certain countries are also reported to have very high rates of hepatitis C, with around 22% of the Egyptian population having a chronic infection. Phase I clinical trials are conducted in small groups of healthy individuals, and are designed to test the safety and tolerability of new drugs and therapies. They are not designed to test the effectiveness of new treatments, although the results are used to determine the dosing regimen that should be used in future studies. Such small, early studies are required before larger, longer-term research can be conducted to assess the effectiveness of the therapy.

What did the research involve?

The researchers made the vaccine by inserting small pieces of DNA from the hepatitis C virus into a rare form of the virus that causes the common cold. They injected 41 healthy volunteers with the vaccine, and collected data on any side effects, as well as the scale and duration of the immune response. Two rounds of the vaccine were given – an initial priming dose and a subsequent boosting dose four weeks later.

They first conducted ‘dose-escalation’ studies to determine the size of vaccine dose that produced an optimal immune response. The researchers divided the volunteers into groups of four or five people, with each group being given a different dose of the vaccine. They assessed the immune response and tolerability of the vaccine at each of these increasing doses.

The researchers also assessed, in laboratory experiments, whether the immune responses would hold against different strains of the hepatitis C virus, including the strain most commonly affecting European IV drug users (a group that is at highest risk of hepatitis C infection in the UK). To do this they took a blood sample from the study participants, challenged the blood cells with proteins found in different strains of the virus, and analysed the immune response. This was done using laboratory tests. No participants were exposed to these viruses.

What were the basic results?

The researchers found that there were no serious side effects associated with the vaccine. They observed mild side effects that increased at higher doses, but they were short lived. The researchers determined an optimal dose for the vaccine, and found that the immune response elicited by this dose was similar to that seen in people who have a natural immunity to the hepatitis C virus. They were able to detect this immune response up to a year after vaccination. They found that the vaccine elicited an immune system response to multiple hepatitis C strains, including the strain that is most common to European IV drug users.

The immune response to this strain was, however, approximately only 20% of the response seen to the strain used in the vaccine. Despite this lower response level, this was still higher than the response seen in control subjects not given the vaccine. This indicates that the vaccine did in fact produce some immune response against a common European strain of the virus.

How did the researchers interpret the results?

The researchers say that this study indicates that the vaccine can induce a sustained immune response to the hepatitis C virus, and that further clinical studies into its use as a preventative and therapeutic agent are needed. The next step, they say, is to test it in a setting where exposure to the hepatitis C virus is common, such as in IV drug users, which could help test whether the immunisation is an effective vaccine.


This was a small, early-stage human study into a new vaccine against the hepatitis C virus. While such research is required to determine the safety profile of a new therapy, little information on the effectiveness of the vaccine can be gleaned from the study. Phase I clinical trials are designed to determine the optimal dose of a new therapy, and to assess the safety and tolerability of treatments. This study shows that the developed vaccine is well tolerated and safe to use, and the preliminary results indicate that the immune response may be similar to that of people with a natural immunity to the virus.

In addition to the small study size and the focus on safety and not effectiveness, there are other practical limitations to the study that should be considered before it is concluded that a preventative vaccine against hepatitis C will be available, even in the next several years: Further research is needed to determine whether the vaccine will be effective over a longer period than a year.

The researchers say that the specific strain of the hepatitis C virus used in the vaccine is common in the US, but that it is not the most common strain in the UK. This may limit how useful any future vaccine is in this country.

The researchers point out that there are difficulties surrounding the design and execution of future trials, as the virus is common to specific subgroups of people.

Future trials will need to be conducted in high-risk groups in whom the predominant virus strain is the same as the strain used to develop the vaccine.

All in all, this was an important initial study into the development of a vaccine against a virus that is difficult to detect and treat. As this was an early-stage study, it will be several years before it could potentially result in an available vaccine.

Links to the headlines

Hepatitis C vaccine: Oxford researchers' trial 'promising'. BBC News, January 5 2012

Hepatitis C vaccine hope after cold virus tests. Daily Mirror, January 5 2012

Links to the science

Barnes E, Folgori A, Capone S et al. Novel Adenovirus-Based Vaccines Induce Broad and Sustained T Cell Responses to HCV in Man. Science Translational Medicine, January 4 2012: Vol. 4, Issue 115, p115ra1

Wednesday, January 4, 2012

Hepatitis C vaccine: Oxford researchers' trial 'promising'

The scientists devised a vaccine which would target the "inner engine" rather than the surface

An early clinical trial of a hepatitis C vaccine has shown "promising" results, according to researchers at Oxford University.

Designing a vaccine has been difficult as the virus changes its appearance, making it hard to find something to target.

Writing in Science Translational Medicine, researchers say their trial on 41 patients shows it is possible.

The Hepatitis C Trust said the findings were very promising.

The virus can go unnoticed for years, but during this time it can cause considerable liver damage.

In the UK, up to 500,000 people may be infected with the virus. The World Health Organization believes the global figure could be as high as 170 million people.

It spreads through blood-to-blood contact such as sharing needles. While infection can be controlled with antiviral drugs, the Oxford University researchers say a vaccine "would be a major step forward".

Shifting target

They attempted to target the inner workings of the virus, rather than the variable surface markings.

While we are hopeful, it could be a long road to any vaccine that protects people against hepatitis C”

End Quote Prof Paul Klenerman Oxford University

One of the researchers, Prof Paul Klenerman, said: "That's where the engine of the virus is, where we may be able to successfully target many of the crucial pieces of machinery."

Cold viruses were modified with genetic material from the hepatitis C virus in order to prime the immune system to attack the hepatitis C virus.

The aim of the Phase I trial was to determine whether the treatment was safe and to help plan future trials.

Forty-one healthy patients were given the vaccine. Scientists said it produced a "very strong" immune response which lasted for at least a year and had no major side-effects.

Prof Klenerman said: "The immune responses we've seen are exciting and we are beginning the next stage of trials. While we are hopeful, it could be a long road to any vaccine that protects people against hepatitis C."

The next step will be to give the vaccine to people at-risk of hepatitis C infection to see whether it protects against the virus.

Charles Gore, chief executive of the Hepatitis C Trust, said: "This is very promising research.

"There has been rapid development in drugs to treat hepatitis C, but vaccine development has lagged behind. Yet, if we only treat existing infections, we will always be behind the curve.

"We badly need to improve prevention and this is an excellent step in that direction."

Monday, September 26, 2011

Seeking Drugs to Fight and Prevent HCV Infection

Compass Biotechnologies, Inc. Seeking Drugs to Fight and Prevent HCV Infection

EDMONTON, Sept. 26, 2011 -- CompassBiotech
Making Drugs to Combat Major Human Diseases

EDMONTON, Sept. 26, 2011 /PRNewswire/ - Compass (COBI:OB) is pleased to announce new research findings that it believes will alter the course of HCV vaccine development and other vaccines in general. Vaccine products continue to be the success story for pharmaceutical companies, with the world market for preventative vaccines in 2010 being $ 28 billion as compared to $26 billion in 2009, $24 billion in 2008 and $18.5 billion in 2007.

"The Hepatitis C Vaccine market potential for Compass is approximately US$2 billion, but with the development of a second anti HCV type product based on new scientific findings that augments to make a HCV vaccine even more potent, then this means that sales could jump to much higher levels. We would be the market leaders in this area "commented Garth Likes CEO.

New studies have contributed to the understanding of a previously unknown mechanism of antibody-mediated Hepatitis C Virus (HCV) neutralization and interference. It was found that while the human immune system produces neutralizing antibodies against HCV, a second interfering antibody is also created which stops the neutralizing antibodies from being totally effective or interacting and killing the HCV.

The findings suggest that, if this interfering mechanism operates in humans during HCV infection, and that neutralizing antibodies can be impeded by a second interfering antibody binding; then this may account for the persistence of HCV infection even in the presence of an abundance of neutralizing antibodies.

Dr. Joseph Sinkule, the President and COO of Compass stated "we are now working on an approach using peptide-blocking or single chain antibodies against HCV epitope-II to remove the restraints imposed by interfering antibodies to epitope-II. We believe this epitope blocking approach, combined with VLP immunization and the generation of neutralizing antibodies to epitope-I could result in cross-genotype neutralization - the holy grail of HCV vaccine development."

This new combination of vaccine plus use of developing anti-interference molecules will allow Compass to develop drugs which could provide a practical and targeted approach to the development of a more potent and broadly reactive hepatitis C therapeutic vaccine.
Further Technical Background:
The Company previously announced an exclusive worldwide license from the NIH regarding technology to make artificial virus-like particles (VLPs) made from expression of virus proteins or capsids, E1 and E2, which are structural proteins of the HCV virus. Thus Compass is making a VLP vaccine that will allow the body to make antibodies against the structural Hepatitis C proteins E1 and E2.

The Company's HCV VLPS have been used by numerous researchers as a model system to discover how the HCV virus infects the human liver cells and identifying potential mechanisms that might be used to prevent infection of the human cell by the virus. In the course of experimentation to identify antibodies that might neutralize or block HCV virus entry, investigators have identified neutralizing epitopes (sites) on the E2 protein that are directly implicated by several laboratories in virus neutralization and inhibition of infection.
The inventor of Compass' technology developed an HCV-LP-based model system for a systematic functional analysis of antiviral antibodies from patients with acute or chronic hepatitis C infection. They demonstrated that cellular HCV binding was specifically inhibited by antiviral antibodies isolated from serum of patients with acute or chronic hepatitis C infection in a dose-dependent manner. In other laboratories at the NIH, researchers used purified human immune globulins from HCV-positive patients, and similarly identified two antibody epitopes in the E2 protein of the HCV virus. It was shown that epitope-I was implicated in HCV neutralization whereas the binding of a non-neutralizing antibody to epitope-II disrupted virus neutralization mediated by antibody binding at epitope-I.

ABOUT COMPASS BIOTECHNOLOGIES INC. -Please visit our website for updated news and reports
Compass Biotechnologies, Inc. (COBI:OB) is a publically-traded specialty drug company with a mission to development and commercialization of drugs, peptides, and proteins to combat major human diseases. Compass Biotechnologies, Inc. (Compass) is working on two therapeutic platforms - recombinant biosimilars and biobetters, and combating viral hepatitis infection by developing drugs to treat existing disease and vaccines to prevent disease. Under an exclusive worldwide license from the National Institutes of Health (NIH), the Company has opportunities to develop HCV VLP vaccine products using patented technology to manufacture virus-like particles (VLPs).

Compass has previously announced an agreement with PanGen Biotech of Seoul, South Korea to provide Compass with a wide array of recombinant protein biosimilars manufactured in "CHO" cells, and a relationship with Arecor Ltd. of Cambridge, England to develop a biobetter, heat-stable formulation of the commercial hepatitis B vaccine. The Company is also pursuing a near-term revenue generation strategy by commercializing Compass' own brand of generic ribavirin (400 mg and 600 mg tablets) through collaboration with Aurobindo Pharmaceuticals and pegylated alpha interferon, the mainstays of anti-viral drug therapy used to treat hepatitis B and hepatitis C infections. The annual hepatitis market for the two drugs is estimated at over US$4 Billion.

Forward Looking Statements
This news release contains "forward-looking statements", as that term is defined in Section 27A of the United States Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Statements in this current report which are not purely historical are forward-looking statements and include any statements regarding beliefs, plans, expectations or intentions regarding the future. Actual results could differ from those projected in any forward-looking statements due to numerous factors. Such factors include, among others, the inherent uncertainty of financial estimates and projections, the competitive and regulatory environments, stock market conditions, unforeseen technical difficulties and our ongoing ability to operate a business and obtain financing. These forward-looking statements are made as of the date of this news release, and we assume no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements. Although we believe that our beliefs, plans, expectations and intentions contained in this current report are reasonable, there can be no assurance that such beliefs, plans, expectations or intentions will prove to be accurate. Investors should consult all of the information set forth herein and should also refer to the risk factors disclosure outlined in our quarterly reports on Form 10-Q and our other periodic reports filed from time-to-time with the Securities and Exchange Commission pursuant to the Securities Exchange Act.
SOURCE Compass Biotechnologies Inc.

Wednesday, August 17, 2011

Murdoch researchers attempt to thwart hep C virus

“Our project is using genetics to identify these escape patterns so we can create vaccines that take this ability of the virus to change, into account. That should mean a higher chance of success.”—Michaela Lucas. Image: iStock

Murdoch researchers attempt to thwart hep C virus

MURDOCH University researchers have begun a study to develop a new and innovative vaccine for the hepatitis C virus (HCV).

HCV affects 284,000 Australians, with up to 15,000 new infections every year. Up to 20 per cent of people with chronic hepatitis C develop cirrhosis of the liver.
Despite public health programs and anti-viral therapy, hepatitis C remains one of the most prevalent blood-borne infections in Australia.
Although 30 per cent of individuals can naturally clear the virus, the majority fail to eliminate HCV completely.

This discrepancy intrigues researchers.
“HCV may be amenable to a protective vaccine, since natural immunity does exist in the population,” says researcher Silvana Gaudieri.
“In fact, there are individuals who have been exposed to different HCV strains multiple times but who remain virus-free. These individuals may hold the key to unlocking the secret to obtaining a vaccine.”

By comparing individuals who have cleared the virus and those who have developed chronic hepatitis C, researchers hope to identify virus-specific T-cell responses.
However, the task is made more complicated by the fact that at least six strains of HCV exist. These strains, in turn, have different genetic profiles, with separate genotype variations.
“T-cell responses against one genotype may not be effective against another,” says Prof Gaudieri.

And then there is the added issue of viral adaptation.
T-cells recognise infected cells via a beacon comprised of part of the virus that has been digested in the cell and the human leucocyte antigen (HLA).
However, HCV is a highly mutable virus and can escape T-cell responses by mutating in the areas presented by the HLA molecule. In a sense the virus adapts to its host.
“Previous attempts to create a vaccine have been limited because like HIV, hepatitis C virus escapes our immune system by rapid changes of its genome and shape,” says researcher Michaela Lucas.

“Our project is using genetics to identify these escape patterns so we can create vaccines that take this ability of the virus to change, into account. That should mean a higher chance of success.”

The on-going research is funded by the National Health and Medical Research Foundation, Haemophilia Foundation of Australia and the McCusker Foundation.
Murdoch is represented by professors Michaela Lucas and Silvana Gaudieri, as well as PhD student Pooja Despande, with collaboration from Oxford University Prof Paul Klenerman and Dr Ellie Barnes.

Wednesday, August 3, 2011

New approach a step forward for hepatitis C vaccine

By Ben Hirschler

LONDON Wed Aug 3, 2011 5:27pm EDT

LONDON (Reuters) - French scientists have developed a novel hepatitis C vaccine that may offer the first effective way to prevent an infection that can cause chronic liver disease and cancer.

There is currently no available vaccine for hepatitis C, though some companies are developing so-called "therapeutic vaccines," which are designed to help patients who are already infected.

The latest experimental shot has been tested successfully on mice and monkeys, but not humans, and has been shown to activate a broad response from immune system proteins called neutralizing antibodies.

The antibodies fought off multiple variants of the hepatitis C virus in tests, suggesting the new vaccine should be effective even after the virus mutates, the researchers reported on Wednesday.

Neutralizing antibodies play a central role in most existing vaccines against other diseases, but harnessing them in hepatitis C has previously proved elusive. Work to date on therapeutic vaccines has focused on another immune system mechanism known as T-cells.

"For a preventative vaccine, neutralizing antibodies are absolutely essential, and for a therapeutic product they would also be a big advantage," David Klatzmann, a member of the research team, told Reuters.

About 130 million to 170 million people worldwide are chronically infected with hepatitis C virus, and more than 350,000 die from hepatitis C-related liver diseases each year, according to the World Health Organization.

Unlike hepatitis A or B, most people with hepatitis C develop chronic disease because their bodies are unable to get rid of the virus. The condition is spread by exposure to infected blood.

Interferon and ribavirin-based therapy has been the mainstay of treatment, although recently Vertex and Merck have both launched promising new medicines that are tipped to become multibillion-dollar-a-year sellers.

Commercial interest in hepatitis C vaccines has been more muted. French biotech company Transgene and Austria's Intercell are both testing therapeutic versions, but the main markets for a preventative shot would be in the developing world, which is less attractive for Big Pharma.

Commercial rights to the new vaccine are held by French start-up Epixis, which is being acquired by an undisclosed U.S. biotech company.

Epixis CEO Charlotte Dalba said she hoped that initial human trials of the vaccine could start in 2012, provided funding was in place.

The experimental vaccine uses virus-like particles, which resemble viruses but are non-infectious because they don't contain any viral genetic material. Details of its development were published in the journal Science Translational Medicine.

In an accompanying commentary, Ranjit Ray of Saint Louis University said the work to date on mice and macaque monkeys showed significant progress, though "many questions still remain."

SOURCE: Science Translational Medicine, August 3, 2011.


Friday, July 1, 2011

European Research Consortium wants to develop novel vaccination against hepatitis C

Innovative vaccines with nanotechnology
European Research Consortium wants to develop novel vaccination against hepatitis C
HCVAX is a European joint project that reaches out to develop a vaccine against hepatitis C based on nanotechnology. The German Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung, HZI) in Braunschweig and its department "Vaccinology and Applied Microbiology" is now a part of the transnational consortium with researchers from Germany, France and Switzerland.

More than 170 million people are infected with the hepatitis C virus (HCV) worldwide. Also in Europe this form of hepatitis is a big problem with three per cent of the population affected. The virus is transmitted in operations such as transplantations or by the re-use of syringes for drug usage. Anti-viral treatments are very expensive, have serious side effects and are only effective for some patients. Most of the patients carry the infection for the rest of their lives, with the threat of later developing liver cirrhosis and cancer. Certainly, the most effective way to combat hepatitis C would be a vaccine against the virus – but to date no efficacious vaccine exists.

"We will pursue a completely new approach to develop a HCV vaccine," says Prof. Carlos A. Guzmán, head of the Vaccinology Department at the HZI. With the help of innovative, biocompatible nanogels part of the genetic information of the virus is brought into the body by so-called "RNA replicons". The synthetic nanogels have a diameter of only a few nanometres and are composed of a biopolymer matrix. Immune cells will take up the nanogels with the genetic information and will produce harmless components of HCV. The immune cell then responds to those foreign structures and will generate memory cells: with this, the vaccination would be successful and from then on one would be protected against an infection with pathogen HCV.

By using novel drug amplifiers, so-called adjuvants, the immune response shall be more efficient and targeted. "The HZI has a long-standing expertise in this field. We will incorporate this knowledge into the project to develop more effective vaccines," says Guzmán. "We want to identify those adjuvants that are most eligible for a use in the nanogel composition. The targeted transport to certain defence cells shall guarantee an optimal immune response."

To exclude side effects, potential vaccine candidates have to be tested in several systems. Promising structures will then be selected for further clinical development.

The consortium consists of two companies, three academic institutions and one clinic. They combine their expertise on the field of nanotechnology, biochemistry, immunology, vaccine development and clinical research. "Beyond that we expect that these novel vaccination strategies can be expanded onto the clinical management of other diseases," says Guzmán.

Funding is granted for the next three years from the "EuroNanoMed Joint Transnational Initiative" of the European Union. The German Ministry for Research and Education is funding the project in Germany.

The Partners:

Federal Department of Economic Affairs (Eidgenössisches Volkswirtschaftsdepartement), Mittelhäusern, Switzerland (coordinator)

Medipol SA, Lausanne, Switzerland

Institut Pasteur, Paris, France

Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung GmbH), Braunschweig, Germany

EDI GmbH, Reutlingen, Germany

Hôpital Cochin, Paris, France

Monday, June 20, 2011

2011-Vaccination for Hepatitis C Virus

From Expert Review of Vaccines

Vaccination for Hepatitis C Virus

Closing in on an Evasive Target
John Halliday; Paul Klenerman; Eleanor Barnes
Posted: 06/20/2011; Expert Rev Vaccines. 2011;10(5):659-672. © 2011 Expert Reviews Ltd.

Hepatitis C virus (HCV) infects more than 170 million people globally and is a leading cause of liver cirrhosis, transplantation and hepatocellular carcinoma. Current gold-standard therapy often fails, has significant side effects in many cases and is expensive. No vaccine is currently available. The fact that a significant proportion of infected people spontaneously control HCV infection in the setting of an appropriate immune response suggests that a vaccine for HCV is a realistic goal. A comparative analysis of infected people with distinct clinical outcomes has enabled the characterization of many important innate and adaptive immune processes associated with viral control. It is clear that a successful HCV vaccine will need to exploit and enhance these natural immune defense mechanisms. New HCV vaccine approaches, including peptide, recombinant protein, DNA and vector-based vaccines, have recently reached Phase I/II human clinical trials. Some of these technologies have generated robust antiviral immunity in healthy volunteers and infected patients. The challenge now is to move forward into larger at-risk or infected populations to truly test efficacy.

Hepatitis C virus (HCV) infects more than 170 million people globally with another 3 million people newly infected each year.[1,2] Following acute infection, 20% of people eradicate the virus over weeks or months and are often asymptomatic. The remaining 80% of people will develop chronic disease, of whom approximately 20% will eventually develop liver cirrhosis and 1–5% will develop liver cancer.[3–5] HCV infection is now the leading cause for liver transplantation in the Western world. Disease prevalence varies by region, with the highest rates in parts of Asia and Africa where up to 20% of the population are infected.[6] The current treatment for HCV is pegylated interferon and ribavirin. This is expensive, prolonged, has an extensive side-effect profile and frequently fails. Clearly then, there is a real need for both a prophylactic vaccine that will prevent or attenuate primary infection, and also a therapeutic HCV vaccine that will increase cure rates of infected patients, and substantial progress has been made in this endeavor in recent years.
This article will first detail our current understanding of HCV infection, pathogenesis and treatment, and highlight the significant degree of viral diversity that presents a real challenge to vaccine development. Next we will review host–viral immune interactions and the broader challenges to the successful development of a vaccine. Finally, we will examine vaccine approaches that have reached human clinical trials and present our vision of this rapidly moving field for the future.

HCV Diversity: Implications for Vaccine Development
Studies based on the molecular evolution of African and Asian HCVs suggest that HCV first appeared over 1000 years ago.[7] Subsequently, HCV evolved in discrete geographical regions giving rise to six distinct genotypes (1–6). These genotypes share a genetic homology of approximately 80% and are further subdivided into more than 100 subtypes.[8,9] In recent decades there has been a global epidemic of a few subtypes (1a, 1b, 3a, 2a and 4a) associated with intravenous drug use (IVDU) and modern medical practice. The HCV genotype not only has relevance in relation to geographic distribution but more importantly in determining response to current medical therapy.[10]
HCV is a particularly fastidious virus and has only been demonstrated reproducibly to replicate in the hepatocytes of humans and chimpanzees. It is a ssRNA virus with an enveloped virion belonging to the family Flaviviridae.[11] The positive-sense RNA genome is 9600 nucleotides in length. A single HCV polyprotein comprised of 3011 amino acids is translated from the genome and subsequently cleaved by cellular and viral proteases into three structural proteins (core, E1 and E2) and seven nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B).[12,13] The envelope proteins mediate viral cell entry by binding to a number of cell surface receptors (e.g., low-density lipoprotein receptor, CD81, scavenger receptor B1 and claudin).[14]
HCV mutates at nearly one nucleotide per replication cycle as a consequence of the poor fidelity of the NS5B viral polymerase (which lacks proofreading function). This, in conjunction with a short viral half-life and rapid turnover (just a few hours), results in a high genetic variability. Consequently, many distinct but closely related HCV variants (known as quasispecies) are typically found in each infected individual.[15] It is estimated that HCV viral diversity is ten-times greater than that found in HIV infection and this clearly represents a significant challenge to successful vaccine development.

The Need for a Therapeutic HCV Vaccine
Current gold-standard therapy for HCV infection is weekly subcutaneous injections of pegylated interferon (PEG-IFN) combined with daily oral ribavirin for a period of 24 weeks for genotypes 2 and 3, and 48 weeks for genotypes 1 and 4. Therapy is fraught with significant side effects and leads to a sustained virological response (SVR; patients are negative for the virus by reverse transcription PCR 6 months after finishing therapy) in approximately 40–50% of patients with genotype 1 infection, 65–70% with genotype 3 and 80% of those with genotype 2. PEG-IFN and ribavirin treatment is also expensive and, at an average cost of approximately GB£7000 in the UK for a treatment course, is unaffordable in developing countries.[16]
Two viral protease inhibitors (telaprevir and boceprevir) are currently in Phase III clinical trials for HCV and more are in development. These drugs will need concomitant PEG-IFN/ribavirin therapy to avoid the rapid emergence of viral mutants and are currently only effective against genotype 1 infection. It is expected they will increase SVR rates following treatment to 70%.[17,18] Because these drugs will be used together with PEG-IFN/ribavirin, the cost of treatment will rise further and additional side effects, in particular skin rashes, can be anticipated. The cost of a 3-month course of protease inhibitor in the UK is currently predicted to be GB£18,000–22,000 [Vertex Pharmaceuticals, Pers. Comm.]. Many other direct antiviral therapies are in development but these are unlikely to reach clinical application in the next few years.

Interestingly, the SVR rate of individuals that are treated in the early phase of infection with IFN alone is very high (70–90%).[19] The reasons for this are not known but may relate to the fact that the infecting virus has not yet evolved to subvert the effects of IFN – or alternatively, that IFN therapy harnesses the host's robust natural immunity that is present in acute infection in a way that it is unable to do so once chronic infection is established. Similarly, it is plausible that a therapeutic vaccination strategy may prove more efficacious in early infection. In clinical practice, however, acute infection is frequently asymptomatic and patients usually do not present to clinicians until chronic infection is established.
Clearly, a therapeutic vaccine that increases SVR rates in chronic infection, or reduces the duration of therapy would represent a major step forward.

The Need for a Prophylactic HCV Vaccine
The need for a prophylactic HCV vaccine may be debated, since a change in social or cultural practices, such as the prevention of IVDU and the efficient screening of blood products and medical instruments worldwide would abort most new HCV infections. In practice, however, eradication through cultural change may be unachievable since the source of HCV infection is unclear (with no risk factors identified) in up to 20% of infected people, the prevention of IVDU has, to date, not been possible, and HCV is particularly prevalent in poorer countries where there is limited capacity for the financial investment required to reduce transmission during medical procedures.

Antiviral Host Immunity: Relevance to Vaccine Development
Following acute infection with HCV, approximately 20% of people will spontaneously clear the infection.[4] This is in stark contrast to HIV where infection inevitably persists. The distinct clinical outcomes that follow acute HCV infection allow comparative analysis of antiviral immunity between these clinical groups – this has been the major focus of many research groups over the last decade. Although the exact mechanisms behind successful viral clearance are still not yet fully elucidated, it appears that multiple components of the immune system, both innate and adaptive, play a crucial role in this process (Figure 1). A key observation is that strong, broad adaptive immune responses are detected during acute infection and these persist in those who resolve infection – whereas persistent infection is associated with a weak, frequently undetectable HCV-specific T-cell response.

Figure 1.
Viral–host immune interactions during acute and chronic HCV infection.
HCV: Hepatitis C virus; TCR: T-cell receptor.

Is there any evidence, then, that the induction of adaptive immune responses during acute-resolved infection protects the host from subsequent viral challenge? If so, a HCV vaccine that mimics these responses may well afford protection. Findings from early seminal work demonstrated that chimpanzees that had recovered from HCV infection could be reinfected with the same inoculum.[20,21] However, we now have evidence that both chimpanzees and humans who have previously cleared HCV are at least partially protected against reinfection in the majority of cases.[22–25] Rather than preventing acute infection with sterilizing immunity, typically this form of protective immunity works by preventing progression to chronic infection following repeat HCV exposure. These findings suggest that a vaccine that induces and exploits similar immunogenic responses may ultimately succeed in preventing chronic HCV infection. Since chronic infection, and not acute infection, is associated with significant morbidity and mortality, prevention of chronicity is an acceptable end point.

Anti-HCV-specific T-cell Responses
The HCV-specific T-cell response has been shown to play a crucial role in determining the outcome of primary HCV infection. First, comparative studies in man have demonstrated that a broad and sustained CD8+ and CD4+ T-cell response targeting multiple HCV regions is associated with spontaneous viral clearance. Conversely, a weak and narrowly targeted T-cell response is a hallmark of persistent infection.[26–30] Second, immunogenetic studies from single-source outbreaks and from mixed populations have shown a clear association between different HLA class I and II alleles and viral clearance.[31,32] Both HLA B27 and HLA A3 were shown to be protective against the development of chronic infection following an outbreak of HCV genotype 1b infection in Irish women in 1977. Third, evidence from the chimpanzee model has shown that once protective responses are induced, depletion of either CD4+ and CD8+ T cells leads to loss of control over repeated HCV challenge.[27,33]
In comparison to those who clear acute HCV infection, studies examining patients who develop chronic infection suggest that both the quality and quantity of their CD4+ and CD8+ T-cell responses are impaired.[34,35] It is not yet clear, however, to what extent this is a cause or a consequence of chronic infection. Proposed mechanisms by which the T-cell response is attenuated include:
  • Viral escape from T-cell recognition: T cells recognize short viral peptides (T-cell epitopes) bound in the groove of MHC molecules. In the presence of selective pressure driven by T cells, viral variation in T-cell epitopes that arise during viral replication may abrogate this recognition – so called 'viral escape'. To varying degrees, viral escape mutations may be associated with reduced viral fitness. T-cell escape in HCV infection has clearly been demonstrated such that many T-cell responses detected during chronic infection target a 'historical' epitope that is no longer found in circulating virus. However, in many cases T cells clearly do target autologous circulating virus – therefore, T-cell escape cannot fully explain the paucity of responses seen in chronic infection. This also means that therapeutic vaccination may be able to rescue responses that are still able to target the host's circulating virus;
  • T-cell exhaustion: chronic antigen stimulation results in a reduction in antigen-specific T-cell frequency and function. This concept was first recognized in murine models of chronic viral infection. T-cell exhaustion is now thought to play a role in chronic HCV infection.[36–39] The mechanisms underlying exhaustion are poorly understood, but include expression of inhibitory receptors such as the molecules programmed death receptor-1 and cytotoxic T-lymphocyte-associated protein 4, which mediate T-cell function.[40] These receptors are normally involved in self tolerance, but in the setting of chronic infections may be upregulated, presumably to evade immunopathology. One of the key suggestions from murine models of persistent viral infection is that repair of these 'defective' T-cell responses is most readily achieved in the setting of a lowered viral load. Thus, the idea of vaccination or immunomodulation as an adjunct to conventional antiviral therapy has recently emerged;
  • Regulatory immune cell subsets: Tregs (FOXP3+) that may actively suppress CD8+ and CD4+ T-cell responses are increased in chronic HCV infection. Indeed, the depletion of Treg activity does lead to a consistent boost in T-cell function during HCV infection.[41] This may well be a consequence of chronicity rather than a cause, but nevertheless it may serve to limit the efficacy of immunotherapy unless it is reversed;
  • Finally, the liver itself is thought to represent a tolerogenic environment. In evolutionary terms this would serve to protect the liver, which is constantly exposed to antigens via the portal tract, from chronic inflammation. Interestingly, in organ transplantation the liver is the only organ where HLA matching between donor and recipient is not required.[42] This observation raises the intriguing possibility that antiviral T cells primed in the periphery during vaccination may induce T cells that are of a 'superior' quality to those primed in the liver during natural infection.

Humoral Immunity Towards HCV
Circulating antibodies to HCV are usually detectable within 1–3 months of HCV infection[43] and appear to be an important component to viral control in early infection. There is a direct correlation between viral clearance during acute infection and the rapid induction of a high-titer of circulating cross-neutralizing antibodies.[44] However, neutralizing antibodies are also found in high titers in the majority of chronically infected patients and clearly, in these cases, are unable to control infection.[45] The envelope protein, which is the major target for HCV antibodies, displays some of the virus' highest levels of genetic heterogeneity. It is likely that variation between quasispecies in these envelope proteins allows the virus to evade host neutralizing antibodies.[46] This contrasts to other viruses such as the genetically stable hepatitis B virus in which persistent humoral immunity has allowed successful development of a preventative vaccine.
There are several other mechanisms by which HCV evades humoral immunity including direct cell-to-cell viral transfer,[47] induction of antibodies that interfere with neutralizing antibodies[46,48] and the shielding of neutralizing epitopes by glycosylation of defined amino acids of envelope glycoproteins.[49] For these reasons, it seems unlikely that an antibody-mediated vaccine in isolation will successfully induce sterilizing immunity, however, such a strategy may have an important role either as an adjunct with other approaches, or in attenuating the course of acute infection.

Innate Immunity
The fact that IFN-α forms the mainstay of treatment of HCV clearly demonstrates that innate immune cytokines can eradicate the virus. However, the mechanism of action of IFN is complicated, having both direct antiviral actions through the inhibition of protein kinase R and cellular protein production, and through diverse effects on immune cellular function. Although some early studies suggested that HCV-specific T-cell responses are enhanced by IFN,[50,51] more recently, this has been challenged in studies that show that HCV-specific T cells and total T-cell counts decline in peripheral blood as treatment proceeds.[52,53] The reasons for this decline are unclear, but if they reflect a true failure of T-cell production, rather than migration, then therapeutic T-cell vaccination strategies will need to overcome this.
Recent genome-wide association studies and candidate gene studies have further highlighted the crucial importance of innate immunity during HCV infection. These studies identified a cluster of seven host single-nucleotide genetic polymorphisms linked to IFN-λ3 (also known as IL-28B) that are important in determining both spontaneous viral clearance during acute infection and also the response to standard PEG-IFN/ribavirin therapy.[54–57] Individuals homozygous for the protective alleles have viral clearance rates following treatment that are approximately three-times higher than those of patients who are homozygotes for the risk allele.[56] As yet, the causal genetic variant has not yet been identified. These observations have created intense interest in the field, and the biological role of IFN-λ3 is currently under intense scrutiny. The mechanism by which IFN-λ3 acts during HCV infection is not yet fully elucidated, although this cytokine clearly has direct antiviral actions in vivo and readily inhibits HCV replication in hepatoma cells (Huh-7.5).[58]
A Phase II human study of IFN-λ3 for the treatment for HCV is currently underway,[201] and while it is not yet known if this cytokine administered to patients will be of benefit, it is already clear that HCV vaccine studies will need to stratify patients according to IFN-λ3 host genotype.

The Ideal Vaccine

The Requirements…
Based on the viral–host interactions of HCV infection, as delineated in the previous sections, there are three characteristic properties that are likely to be shared by successful preventive and therapeutic vaccine approaches alike:
  • These vaccines will need to deal with high levels of viral genetic diversity both between and within hosts – as such, vaccines that target relatively conserved viral regions will be required;
  • The 'magnitude' of antiviral immunity associated with viral control is not precisely defined. Nevertheless, it is likely that a robust, broad and functional T cell, and possibly also a humoral, immune response will be required;
  • Clearly, to be safe, a successful vaccine will need to eradicate HCV from the liver without inducing liver immunopathology. Human studies to date suggest that this is a realistic goal.

…and the Challenges

In addition to overcoming the diverse mechanisms by which HCV evades immune clearance, there are practical obstacles that have hindered the development of both a preventive and therapeutic HCV vaccine. HCV is highly fastidious and there is no readily accessible animal model of infection. In 2003, study of viral entry and antibody-mediated neutralization was enabled for the first time through the development of retroviral particles pseudotyped with HCV envelope glycoproteins.[59] It was not until 2005 that a successful tissue model of HCV infection was developed.[60] This model uses the human hepatoma cell line Huh-7 and a unique viral variant capable of ongoing viral replication. This discovery allowed researchers to characterize the viral life cycle and viral–host interactions during infection for the first time. Transgenic mice expressing human MHC class I molecules have been used for specific HCV epitope analysis. Severe combined immunodeficieny (SCID) mouse models with chimeric human livers have been used to evaluate in vivo effects of antibodies to envelope glycoproteins.[61]

To date, the only immunocompetent animal model for the pathogenesis or immune control of viral infection is the chimpanzee. This model has proved very useful in the preclinical phases of vaccine development since the immune mechanisms associated with viral control are broadly similar. For example, a study by Folgori was clearly able to demonstrate a reduction in HCV viremia, associated with the induction of robust immunity, using a small number of animals.[62] This study subsequently facilitated the use of adenoviral vector technology in human trials. However, there are practical, financial and, for some, ethical limitations in using these animals for research.[63] As a result, the small number of chimpanzees that can be used in HCV studies may limit the power of any conclusions that can be drawn.

Designing clinical studies in humans to evaluate a prophylactic vaccine is also challenging since the incidence of HCV infection in developed countries is relatively low other than in intravenous drug-using populations – targeting this patient group raises its own set of ethical and practical difficulties.[64] Large studies in developing countries where the incidence may be higher raises logistical difficulties. Assessing the efficacy of a prophylactic HCV vaccine will require large numbers of patients and careful follow-up, since acute infection is often asymptomatic. Furthermore, it is possible that a prophylactic vaccine may be unable to achieve sterilizing immunity. However, a vaccine that led to an attenuated course of acute infection associated with viral clearance may be sufficient to ultimately prevent chronic infection, as has been suggested by studies in the chimpanzee model.[62] In addition, this has study design implications; careful consideration must be given to the timing of IFN therapy during primary infection, in the context of a clinical study that is assessing vaccine efficacy. In theory, the vaccine may facilitate viral clearance weeks after current guidelines suggest IFN treatment should be given.

Vaccine Approaches: Current Status
Over the last decade numerous HCV vaccine approaches have been assessed in mice and primates. Only a small fraction of animal HCV vaccine studies have progressed to human trials. The majority of these trials have evaluated potential therapeutic vaccines in HCV-infected patients. A smaller number have assessed vaccines in healthy volunteers; either with the aim of developing a prophylactic HCV vaccine or as a bridge to evaluating vaccine in HCV-infected patients.
The question as to which HCV antigen a vaccine should target is a key one. The envelope region, which is essential for viral cell entry, may seem the obvious target for a prophylactic HCV antibody-inducing vaccine – but as discussed previously, the major antigenic determinants of the envelope protein are hypervariable both between, and within, infected individuals. Chimpanzee data have demonstrated that the induction of HCV envelope antibodies will afford protection with challenge with homologous viral strains only.[65] This view has been recently challenged using collated chimpanzee data that have demonstrated protection from heterologous viral strains (both genotype-1a),[66,67] and cross-genotype neutralizing antibodies have been demonstrated using a SCID mouse model transplanted with human hepatocytes.[68] A prophylactic vaccine that induces anti-envelope immunity and attenuates the course of primary infection either alone, or in combination with other approaches, remains an attractive goal.
The HCV core protein might seem the obvious candidate for a therapeutic T-cell vaccine, since this is the most highly conserved region of the translated HCV genome both within, and between, different HCV genotypes. However, studies have shown that the core protein can interfere with innate and adaptive anti-HCV immune responses.[69,70] Furthermore, our own data suggests that in persistent infection, anticore T-cell responses are frequently detected in the absence of viral escape, suggesting that these responses in particular are unable to control viral replication.[71] Many core-based DNA vaccines have been tested in small animal models, and clearly robust anticore cellular responses can be generated. However, a heterologous prime–boost (plasmid-encoding DNA, boost with recombinant protein) vaccination strategy in chimpanzees vaccinated with core, E1, E2 and NS3 failed to induce any anticore responses.[72]
For these reasons, the most recent strategies have focused on inducing T-cell responses to the NS HCV antigens, which are genetically conserved compared with the HCV envelope, and which are known to contain multiple CD4+ and CD8+ T-cell epitopes.[73]
Four main vaccine strategies have been investigated in human clinical studies: recombinant protein vaccines, peptide vaccines, DNA vaccines and vector vaccines. The advantages and limitations of each of these approaches, in combination with a summary of human trials in HCV vaccine development, will be outlined in the following sections.

Recombinant Protein Vaccines
The use of recombinant proteins as potential vaccine candidates assumes that inducing an immune response to a limited number of viral epitopes is sufficient to develop protective immunity. The principle of this approach is to isolate the gene(s) encoding the appropriate protein and clone it in bacteria, yeast or mammalian cells. Recombinant proteins are prepared either from culture medium or transfected cells. While some recombinant proteins are sufficient in isolation to elicit a strong immune response, others require adjuvant therapy. Generally, protein-based approaches induce antibody and CD4+ T-cell responses.

Envelope Protein Vaccines
The hepatitis B vaccine was the first successful recombinant protein vaccine used in humans. This vaccine employs a conserved hepatitis B surface antigen and is effective in preventing hepatitis B infection through the production of antibodies. By contrast, the genetic variability of the HCV viral envelope, which is the main target for anti-HCV antibodies, makes such an approach for a HCV vaccine challenging. Nevertheless, recognition that the presence of pre-existing antibodies to HCV envelope proteins is associated with a better response to PEG-IFN therapy,[74] and that anti-envelope antibodies can lead to an attenuated course of primary infection,[75] has led to therapeutic and prophylactic vaccine studies, respectively, which aim to induce anti-envelope antibodies.

Prophylactic Vaccine
The only published clinical trial of a prophylactic vaccine for HCV utilized a recombinant E1/E2 heterodimer adjuvanted with adjuvant MF59C (an oil-in-water emulsion).[76] This placebo-controlled, dose-escalation Phase I study evaluated the vaccine in 60 healthy subjects. All subjects developed neutralizing antibodies and T-cell lymphocyte proliferation responses to E1/E2 and an inverse response to increasing amounts of antigen was noted. The vaccine was well tolerated. The study authors suggest that larger clinical trials to evaluate vaccine efficacy are indicated.

Therapeutic Vaccines
The first candidate therapeutic vaccine for HCV was administered to humans in 2003 (Table 1).[77,78] The vaccine consisted of a recombinant HCV-E1 protein in alum adjuvant. It was administered over 6 months via multiple injections to 20 healthy, and 34 chronically infected, treatment-naive patients. The vaccine induced HCV-specific antibody and T-cell responses in both patient groups (50 out of 54). Assessment of efficacy showed no change in HCV RNA levels but, in some subjects, improvements in liver histology were seen; a total of 24 HCV-infected patients underwent liver biopsies before and after vaccination. In nine of these patients there was histological improvement after 17 months. The observed increase in anti-E1 antibody levels correlated with improvement in liver histological scores and reduction in serum alanine transaminase levels (a measure of liver inflammation).
As a result, this work progressed to a placebo-controlled, multicenter trial (presented in abstract form in 2008[79]) that evaluated 122 patients who received four courses of six injections over 3 years. Humoral and cellular immune responses to the E1 protein were induced but vaccination did not prevent histological progression of liver disease.[79] Innogenetics, the company investigating this vaccine, ceased its program in 2008 and no further work has been published.

Core Proteins
Heat-killed yeast cells (Saccharomyces cervisiae) expressing conserved core–NS3 fusion protein have been trialed as a therapeutic vaccine candidate (GI5005).[80] In a Phase II, placebo-controlled trial, GI5005 was combined with standard therapy (PEG-IFN/ribavirin) in 66 chronic HCV-1 patients. The protocol consisted of a 12-week run-in of standard therapy, followed by weekly doses for 5 weeks followed by monthly doses for 2 months of GI5005 vaccine, administered subcutaneously. Prior nonresponders received 72 weeks of standard therapy while treatment-naive patients received 48 weeks. No data on immunological response have been published. The investigators report an increase in SVR rates in patients homozygous for the IFN-λ3 risk alleles.[81] Published peer-reviewed data are awaited.
A vaccine using conserved HCV core protein with an adjuvant composed of saponin, cholesterol and phospholipid, called ISCOMATRIX®, has been evaluated in a Phase I trial of 30 healthy volunteers.[82] The vaccine was safe and all eight volunteers who received the highest dose (50 µg) developed a specific humoral response to the core protein. However, HCV-specific CD8+ T cells could only be detected in two patients. Further studies are planned by the same investigators to evaluate this approach as a therapeutic vaccine in HCV-infected patients.

Peptide Vaccines
Like recombinant protein vaccines, peptide-based vaccines are well tolerated (Table 2). They induce HCV-specific T-cell immunity through the direct presentation of vaccine peptide to the T-cell receptor via HLA molecules. However, the major limitation of this approach is that peptide vaccines are HLA-specific and, as such, coverage will be restricted to a subset of the population. Additionally, HCV peptide vaccines to date have included only a handful of peptides – and the breadth of the induced T-cell response may be insufficient to control infection. In addition, some peptides may potentially induce tolerance of effector cells or Treg cells rather than inducing immunity.[83]

IC41 is a peptide vaccine currently in clinical development. It consists of five synthetic peptides from core, NS3 and NS4 proteins that are conserved across HCV genotypes 1 and 2, combined with the adjuvant poly-L-arginine. The peptides include three CD4+ T-cell and five HLA A2-restricted CD8+ T-cell HCV epitopes. In a Phase II, double-blind study, this vaccine was administered subcutaneously to 36 HLA A2 patients with genotype 1 chronic HCV infection who had previously been nonresponsive to PEG-IFN/ribavirin and compared with 24 controls.[84] The vaccine was well tolerated with no serious adverse events. Weak HCV-specific T-cell proliferative and IFN-γ enzyme-linked immunosorbent spot (ELISpot) responses were observed in 67 and 42% of patients, respectively. Three responders with the strongest IFN-γ-secreting T-cell response had a transient decline in serum RNA (>1 log). A subsequent Phase II study combined IC41 with PEG-IFN/ribavirin therapy in 35 patients with HCV genotype 1 infection. T-cell responses were observed in 73% of vaccinated patients and associated with higher rates of viral clearance.[85] The lack of an unvaccinated control arm makes it difficult to draw any significant conclusion regarding vaccine efficacy.

More recently, biweekly intradermal IC41 administration was found to induce stronger T-cell responses compared with the original monthly subcutaneous injection approach.[86] This optimized vaccine schedule has been tested in 50 patients with chronic hepatitis C. A significant decline in viral load was observed after 4 months according to results currently presented in abstract form only.[87] Intercell AG (Austria, Vienna), the company developing IC41, recently announced plans for a Phase II trial to begin in 2011 that will combine IC41 with nitazoxanide (a new broad-spectrum antiviral drug[88,89]) in 60 treatment-naive genotype-1-infected HCV patients.

In 2009, a peptide derived from HCV core region (C35–44) was evaluated in a Phase I, dose-escalation, Japanese study of 26 patients (23 nonresponders to PEG-IFN/ribavirin and three who had declined standard therapy).[90] A series of six biweekly subcutaneous injections was sufficient to induce peripheral peptide-specific CD8+ activity in 15 out of 25 patients (measured with ELISpot) and 12 injections augmented peptide-specific IgG production. A greater than 30% improvement in alanine transaminase was observed in seven out of 24 patients and two patients had a >1 log reduction in viral load. Further evaluation with a Phase II study is under consideration.

Another Japanese study adopted a 'personalized' peptide vaccine approach. In this study, 12 patients with HCV-1b, who had previously failed PEG-IFN/ribavirin therapy, were administered four CD8+ A24 peptides in combination with Freund's adjuvant. Only those peptides that induced an immune response in each individual following the first vaccine dose were then administered fortnightly for another 14 vaccinations.[91] At the first assessment (following seven vaccine doses), the majority of patients had developed peptide-specific T-cell responses. A dose-dependent decrease in serum alanine transaminase and HCV RNA levels was observed in five and three patients, respectively.

A novel method of peptide delivery using autologous monocyte-derived dendritic cells was recently explored in a small Australian study.[92] Dendritic cells were first harvested and then loaded and activated ex vivo with HLA A2 1-restricted T-cell epitopes. Six patients chronically infected with HCV who had previously failed PEG-IFN/ribavirin therapy received the vaccine. All patients developed weak de novo HCV-specific CD8+ T-cell responses (measured by IFN-γ ELISpot assays). The authors hypothesize that T-cell responses induced to viral epitopes not included in the vaccine may have been caused by epitope spreading. There was no change in viral load or anti-HCV core antibody levels and T-cell responses were not sustained.
Finally, a Phase I, placebo-controlled trial assessing a virosome-based vaccine containing NS3 peptides has recently been completed but no data have been released.[202]

In summary, peptide-based vaccines are well tolerated and able to induce weak peptide-specific T-cell and humoral responses. Efficacy needs to be optimized, as trials show a significant reduction in viral load in only a few patients.

DNA Vaccines
In 2001, the first DNA vaccine was licensed for use to protect horses from West Nile virus.[93] Initial work in the decade leading up to this significant accomplishment demonstrated that injection of a plasmid containing a gene could effectively result in protein expression in vivo and subsequently induce a host immune response.[94–96] Substantial research efforts have been aimed at developing an effective hepatitis C DNA vaccine (Table 3).[97]

Unfortunately, the initial success observed with DNA vaccination-induced immunity in mice did not translate well into similar results in humans – probably, in part, because the efficacy of DNA uptake and gene expression decreases as the size of the immunized host grows.[98,99] Subsequently, several methods were developed to improve DNA delivery and hence immunogenicity. These methods include:
  • Biolistic technology (biological ballistic or 'gene gun'): tungsten particles are loaded with genetic material and, using a device known as a particle gun, fired at living plant cells.[100] This resulted in delivery of DNA into a proportion of plant cells. In 2000, a clinical trial using a gene gun for DNA vaccination against hepatitis B was performed with successful induction of protective humoral immunity as well as hepatitis B surface antigen-specific T-cell responses;[101]
  • Electroporation (EP): electrical impulses create transient pores in living cells and subsequently allow delivery of DNA across the cell membrane. The local damage to cell membranes is also thought to enhance the local inflammatory response.[102–104] EP, at least in mice, is said to enhance the immunogenic response by DNA vaccination tenfold. This method has been successfully used in DNA vaccine trials in prostate cancer and is currently under evaluation in a Phase I/II HCV trial.[105]
The first DNA-based vaccine to reach clinical trial for HCV infection did not employ either of these adjuvant vaccine delivery techniques. This Phase I trial based in Cuba evaluated a vaccine (CICGB-230) combining plasmid expressing HCV structural antigens (core/E1/E2) with recombinant core protein (Co.120).[106] A total of 15 patients with HCV genotype-1 infection who had previously failed PEG-IFN/ribavirin therapy received monthly intramuscular injections for 6 months. The vaccine was well tolerated. The T-cell response to the vaccine components (as well as NS3) was measured using ELISpot and proliferation assays 1 month following the final vaccine. Although low levels of T-cell immunity were observed in 11 patients, others showed a reduction in responses. Six patients developed weak de novo neutralizing antibody responses against heterologous viral pseudoparticles. Only one patient had a drop in viral load of >1 log10. In addition, the authors reported stabilization or improvement in liver histology, however, the absence of a control arm makes this finding difficult to interpret.

The second HCV DNA-based vaccine (ChronVac-C, Tripep) to reach human trials employed electroporation to enhance the immunogenicity of intramuscular injection of plasmid expressing HCV antigens NS3/4a. Extensive codon modification was undertaken to allow effective DNA expression and enhance in vivo T-cell responses. A total of 12, treatment-naive, genotype-1 HCV-infected patients with a low viral load (<800,000 IU/ml) received four monthly doses of DNA (three groups: 167, 500 and 1500 µg) in this Phase I/IIa clinical trial. Preliminary results from this trial were reported in 2009.[105] A total of 67% (four out of six) of patients who received the higher doses had reductions in viral load exceeding 0.5 log10 lasting for 2 to more than 10 weeks, with corresponding activation of T-cell responses in three of these patients. No severe adverse reactions were observed.

Vector Vaccines
The use of viral vectors for the delivery of HCV RNA is an appealing vaccine choice. Adenoviral vectors have shown to be potent inducers of HCV-specific T-cell responses in the chimpanzee model and to reduce peak HCV viremia during primary infection.[62] This approach may induce a broader range of viral epitopes than a peptide-based approach since the immunogen contained within the vaccine is not HLA restricted.
Modified vaccinia Ankara (MVA) is a highly attenuated poxvirus strain that has been used safely in several vaccine designs for conditions such as HIV, colorectal cancer, TB and melanoma. A therapeutic vaccine (TG4040) using MVA that expresses NS3/4/5B proteins has been evaluated for safety and immunogenicity in an open-label, multicenter, dose-escalation study (Table 4). Preliminary results were presented at the European Association for the Study of Liver Disease conference in 2009.[107] A total of 15 chronically infected HCV patients received three weekly injections, nine of whom received a fourth injection at 6 months. In six out of 15 patients, a decline in HCV viral load (0.5–1.4 log10) was observed in association with a significant CD8+ T-cell response. A Phase II trial using the vaccine in combination with standard treatment is planned.[203]

Adenovirus vectors are also being employed in a Phase I vaccine trial to deliver NS HCV proteins (NS3–5B) to 36 healthy volunteers.[204] The vaccine vectors are genetically modified so that they are unable to replicate and the polymerase activity of the NS proteins is inactivated to further enhance vaccine safety. To overcome the problem of pre-existing anti-adenoviral antibodies, which may limit vector efficacy, two adenoviral vectors to which humans are rarely exposed are used: Ad6 and a simian vector AdCh3. Early data from this trial were presented at the American Association for the Study of Liver Disease in 2009 where this approach was reported to be highly immunogenic in healthy volunteers following a single priming injection (Ad6).[73] Further studies are planned in HCV-infected patients.

Future Vaccine Approaches
Novel future vaccine approaches include virus-like particle (VLP)-based vaccines that have been successfully employed for viral infections such as hepatitis B.[108,109] A HCV VLP vaccine approach could facilitate delivery of neutralizing antibody- and core-specific T-cell epitopes in a single construct resembling mature HCV virions. In theory, the delivery of important antigenic determinants in this form rather than as linear recombinant protein or synthetic peptides could enhance immunity.
Additional strategies include molecules that induce innate immune responses, with secondary effects on adaptive responses (such as TLR-9 ligands[110]) that are either encoded within a vaccine construct or used as a vaccine adjuvant.

Expert Commentary
Progress in our understanding of HCV pathogenesis and the treatment of infected patients is remarkable given that HCV was discovered only 21 years ago. Nevertheless, current gold-standard therapy (IFN/ribavirin) is ineffective in 30–50% of patients depending on viral genotype. Direct antivirals (protease inhibitors) will be available in the clinic in the next 2 years. These will increase viral clearance rates in genotype-1 patients in particular. However, these novel agents will be given in combination with IFN/ribavirin, costs will be prohibitive in many countries, and treatment will remain ineffective in approximately 30% of patients overall. So, while the authors welcome the addition of these drugs to the anti-HCV therapeutic armory, a HCV vaccine that prevented or increased the cure rates when treating infected patients remains an attractive goal.

The challenges in developing a prophylactic and a therapeutic vaccine overlap but are not identical. The diversity of the HCV genome is a significant challenge to vaccine development and may be greater once chronic infection is established. Similarly, the ability of HCV to subvert and evade antiviral immunity increases over time. Indeed, a hallmark of chronic HCV infection is a weak and narrowly focused HCV-specific T-cell response. The challenge to developing a successful therapeutic vaccination strategy will be to safely recover these responses and to broadly target circulating viral strains.

The fact that a significant proportion of acutely infected patients spontaneously eradicate infection in association with robust antiviral immunity suggests that the development of a prophylactic vaccine is an attainable goal. The ability to compare hosts who spontaneously clear HCV infection with those who develop persistent disease has allowed characterization of many important innate and adaptive immune processes that determine outcome. Although a broad CD4+ and CD8+ T-cell response is clearly important in clearing infection, humoral and innate immune responses also play an important part in this complex and dynamic process, and a single 'correlate of protection' has not been defined. It is, however, clear that a successful prophylactic HCV vaccine will need to exploit and enhance these natural immune defense mechanisms. Some of the challenges to prophylactic HCV vaccine development are the assessment of efficacy in clinical studies. In Western countries with the infrastructure and finance needed to support large clinical trials, the 'HCV at-risk population' are those who abuse intravenous drugs, and assessment of this cohort is not easy.
Significant advances in genomics and proteomics in recent years have enabled a variety of new HCV vaccine approaches to reach clinical trials. Peptide, recombinant protein, DNA and vector-based vaccines have all been explored with varying degrees of success. Recombinant protein vaccines that induce anti-envelope antibody responses are unlikely to provide sterilizing immunity owing to the genetic variability of the HCV envelope region – but may yet play a role in attenuating the course of primary infection or serve as an adjunct to a T-cell-based vaccine. Peptide and protein-based T-cell vaccines have induced weak T-cell responses only – this approach is likely to only progress with the development of novel adjuvants. DNA vaccines with additional techniques to enhance delivery and immunogenicity show some promise and have been shown to decrease viral load in some chronically infected patients. Adenoviral vectors appear to be highly immunogenic in healthy volunteers and Phase II studies in at-risk populations are required to assess efficacy. The effects of these vectors in HCV-infected patients is not yet known.
Ultimately, since HCV infection can be cleared by an appropriate immune response – vaccination remains a realistic goal.

Five-year View
There are several promising vaccine trials currently recruiting patients that will undoubtedly further expand our understanding of the complex interplay of HCV and host immunity and our ability to modulate this in favor of the host. New therapeutic HCV vaccine approaches are likely to continue to be explored in combination with standard medical therapy rather than in isolation. The new directly acting viral protease inhibitors that will become available in the next few years will further influence this process. While these drugs will improve treatment outcomes for patients with HCV genotype-1 infection, their high cost will limit availability. Approaches for nongenotype-1 strains also need some consideration given the major genetic divergence of the six major genotypes and their distinct immunoreactivity.
Vaccines that produce substantial antiviral T-cell responses are being developed, but in the absence of a clear correlate of protection, efficacy will need to be demonstrated in well-designed clinical trials. The organization and monitoring of these is a substantial issue for the field, but moves to harmonize studies of at-risk and acutely infected cohorts might accelerate this process.