THE LINKED EPIDEMICS OF HEPATITIS C & INJECTION OPIOIDS

American Journal of Public Health Podcast

Jan 9, 2018

Hello and welcome to AJPH February 2018 podcast. This month we will be discussing the very worrisome epidemic of hepatitis C occurring in the United States. I first review with Professor Kimberly Page from the University of New Mexico how likely it is that, in a foreseeable future, the epidemic of hepatitis C could be controlled by a vaccine. Then the CDC epidemiologist Alice Asher explains why the epidemic is exacerbated by another epidemic of injection drug use, in particular of opioids, and why it is affecting young, non Hispanic white populations in the Appalachian region. And with Dr John Wong, clinical decision maker from Tufts University, we discuss how the availability of effective treatments may have transformed the prognosis of newly infected persons.

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Hepatitis C cross-genotype immunity and implications for vaccine development

Hepatitis C cross-genotype immunity and implications for vaccine development
Nazrul Islam, Mel Krajden, Jean Shoveller, Paul Gustafson, Mark Gilbert, Jason Wong, Mark W. Tyndall, Naveed Zafar Janjua & The BC-HTC Team

Received:31 May 2017

Accepted:02 August 2017

Published online:26 September 2017

Full Text Available online @ Scientific Reports 

Scientific Reports 7, Article number: 12326 (2017)

doi:10.1038/s41598-017-10190-8

Abstract

While about a quarter of individuals clear their primary hepatitis C (HCV) infections spontaneously, clearance (spontaneous or treatment-induced) does not confer sterilizing immunity against a future infection. Since successful treatment does not prevent future infections either, an effective vaccine is highly desirable in preventing HCV (re)infection. However, development of an effective vaccine has been complicated by the diversity of HCV genotypes, and complexities in HCV immunological responses. Smaller studies on humans and chimpanzees reported seemingly opposing results regarding cross-neutralizing antibodies. We report a lack of cross-genotype immunity in the largest cohort of people to date. In the adjusted Cox proportional hazards model, reinfection with a heterologous HCV genotype (adjusted Hazard Ratio [aHR]: 0.45, 95% CI: 0.25–0.84) was associated with a 55% lower likelihood of re-clearance. Among those who cleared their first infection spontaneously, the likelihood of re-clearance was 49% lower (aHR: 0.51, 95% CI: 0.27–0.94) when reinfected with a heterologous HCV genotype. These findings indicate that immunity against a particular HCV genotype does not offer expanded immunity to protect against subsequent infections with a different HCV genotype. A prophylactic HCV vaccine boosted with multiple HCV genotype may offer a broader and more effective protection.

Continue to article.....

HCV vaccines—back to the future?

Editorial
HCV vaccines—back to the future
Paul Klenerman

Received: 12 February 2017; Accepted: 15 February 2017; Published: 16 March 2017.

doi: 10.21037/aob.2017.02.01

Comment on: Yokokawa H, Higashino A, Suzuki S, et al. Induction of humoural and cellular immunity by immunisation with HCV particle vaccine in a non-human primate model. Gut 2016. [Epub ahead of print].

View Full Text Article Online

HCV is a huge global problem. Major advances have been made in recent years in the drug therapy for chronic HCV infection (1). If patients have access to such directly acting antiviral agents, there is a very high chance of cure in most settings, even in patients with advanced disease or with previous treatment failures. However, in order to effectively get on top of the epidemic, such therapy is likely only one weapon, as there is still a substantial amount of ongoing transmission and undiagnosed disease, often in populations that are hard to reach. Virologic cure through the new agents does not lead to host immunity, so approaches to prevention of new or repeat infections are still needed. For this reason, a vaccine for HCV still has an important place at the table (2,3).

The classical approach to vaccines has been to use either a live strain with attenuated pathogenicity—as in the case of smallpox vaccine—or to use a killed or inactivated vaccine. Both approaches have been very effective. Live strains—such as the yellow fever vaccine—produce long lasting immunity, and combine typically cellular immunity with humoral responses. While this is advantageous, for many pathogens there is no clear way of safely attenuating the virus, so the risks outweigh the benefits. Inactivated vaccines, for example the Salk polio vaccine, similar to the toxoids used for tetanus, induce a strong antibody response, although the induction of cytotoxic T cells is limited. In the end, the efficacy of the vaccine depends on the dominant form of protection. In the case of HBV vaccines, a recombinant protein approach is highly effective, as the levels of antibody generated are sufficient to provide robust immunity (4). Recombinant protein approaches mimic the killed vaccines in providing a non-replicating antigen, together with sufficient adjuvant to activate the innate immune responses needed for immunologic priming. For HBV the field is relatively well off as the antibodies represent a clear “correlate of protection”—i.e., their presence predicts efficacy (4). Unfortunately, we do not have very well defined correlates of protection in HCV infection, although there is a wealth of data that innate and adaptive immune responses are important, including a role for T cells. This includes studies of animal models, host immunogenetics, viral evolution and numerous correlative studies in acute and chronic disease, as well as challenge studies (5-7).

For HCV, there have been limited attempts to date to develop preventive vaccines, compared for example to HIV, and there are no simple live-attenuated avenues to explore (3,8,9). HCV is persistent, highly mutable, and difficult to grow in culture. It is also in many patients a relatively poor inducer of immune responses, partly because of its hepatotropism. In common with other complex infections such as HIV and malaria, a viral vector approach has been taken by a few groups, using HCV antigens expressed in the context of another virus, such as a poxvirus or adenovirus. This allows the immunogen to be presented in an optimal form to generate cellular immune responses, and in humans, adenoviral vectors have been shown to be quite effective at priming both CD4+ and CD8+ T cell responses (10,11). Currently a preventive HCV vaccine based on priming with a chimpanzee adenoviral vector expressing HCV non-structural proteins 3-5B, and boosting with a modified vaccinia Ankara (MVA) vector expressing the same proteins is in phase 2 trials in the USA (https://clinicaltrials.gov/ct2/show/NCT01436357).

Antibodies also have a role to play in protection against HCV, and in an ideal world a vaccine that induced a high-titre antibody response capable of blocking infection of a wide range of HCV strains—so-called broadly neutralising antibody (bNAbs)—would be very effective. Attempts have been made to generate antibodies using recombinant HCV envelope proteins, and bNAbs have been generated with this approach (12,13). However, high level production of these protein targets is not trivial and so this area is still open for development, including attempts to focus the antibody response on targets within envelope which are highly conserved and block infection (14).

On this background the recent study by Yokokama et al. in Gut is of interest as it combines new and old approaches to try and induce protective immunity against HCV (15). While it is not possible to routinely culture HCV, certain strains—notably JFH, first generated by Wakita, a co-author on the current study—can replicate in specific cell lines, and this technology has been further developed to allow different genotypes to be cultured (16). The authors were able to make high level stocks of a cell culture strain (HCVcc), purify it and then inactivate it using UV light for safe use as a vaccine. In order to improve its immunogenicity, they combined it with different adjuvants, one the classical album, and a second, based on stimulation by DNA motifs known as CpG presented in nano-particulate form. CpG motifs bind Toll like receptor 9 (TLR9) and induce strong innate immune activation, enhancing immunogenicity—in particular when presented in nanoparticulate form (17). They analysed immunogenicity of such a vaccine in mice and then in marmosets.

The study showed a number of important features. Animals receiving vaccinations using the alum based vaccine did generate some antibodies against HCV, although the levels of neutralisation were overall quite low. However, using the CpG based nanoparticle adjuvant K3-SPG, the same inactivated HCVcc preparation did induce neutralising antibody which was able to block infection. The levels of neutralisation in vitro reached around 60%, so blockade was not complete, but interestingly the sera did block infection by strains bearing envelopes from diverse genotypes, which would be an important attribute of any vaccine. There was also some evidence of T cell responses against components of the vaccine, capable of making interferon-gamma (IFNg). Analyses of marmoset T cell responses is difficult, so the overall levels of such responses are hard to gauge compared to human studies, but once again they were much more evident using the CpG based nanoparticle adjuvant K3-SPG. Induction of IFNg in response to HCV antigens does correlate with successful immune control of HCV in many human studies, was an important readout in the challenge studies performed previously using virally vectored vaccines, and remains the major measure immunogenicity in the development of HCV T cell vaccines in human trials (11).

This vaccine approach therefore is in many ways classical, but also relies heavily on the new adjuvant for its immunogenicity. The issue is to assess the potential for protection. This was not addressed in the marmoset model, although such animals can be infected with chimeric HCV/GBV-C viruses and that may be one possible approach (18). Additional pre-clinical models also include transgenic mouse strains which support HCV infection, some of which are immunologically intact (19). Given the lack of a clear correlate of protection, it would be very valuable to have more preclinical data before engaging in human studies. However, if it is possible to scale up and provide a highly robust safety profile for such a vaccine, immunogenicity studies in humans, followed by trials in populations at risk are really the only way to answer the question regarding protection. Possibly the blend of old and new approaches used in this study could pave the way for such future vaccines.

http://aob.amegroups.com/article/view/3718/4447

Hepatitis C mutations 'outrun' immune systems, lab study shows

Of Interest
Hep C virus exposed to attack
March 6, 2017
“We’re redirecting the focus of the immune response away from regions of the virus that generate antibodies that are not only ineffective, but which block the effectiveness of the desirable antibodies.
“It’s the first time this has been demonstrated in HCV that you can actually re-engineer the surface protein to generate a profoundly different immune response that is now cross-reactive and blocks the virus from entering cells.
“That gives us a lead that we can work with to produce a vaccine candidate that’s going to be amenable for a clinical trial.”
Continue reading..

Hepatitis C mutations 'outrun' immune systems, lab study shows

Study identifies mutations outside of traditional vaccine targets as barrier to vaccine development

Johns Hopkins Medicine
Unlike its viral cousins hepatitis A and B, hepatitis C virus (HCV) has eluded the development of a vaccine and infected more than 170 million people worldwide. Now, researchers at Johns Hopkins Medicine report that a novel laboratory tool that lets them find virus mutations faster and more efficiently than ever before has identified a biological mechanism that appears to play a big role in helping HCV evade both the natural immune system and vaccines.

For their study, described March 8 in PLOS Pathogens, the researchers used one of the largest libraries of naturally occurring HCV to rapidly sort out which mutations allow HCV to evade immune responses and found that mutations that occur outside of the viral sites typically targeted by such antibody responses play a major role in the virus' resistance.

"We think those mutations could account for the difficulty of making an effective vaccine," says Justin Bailey, M.D., Ph.D., assistant professor of medicine at the Johns Hopkins University School of Medicine.

All told, the researchers compiled a library of 113 HCV strains from 27 patients with HCV infections followed at The Johns Hopkins Hospital. The researchers then tested each strain of the virus for susceptibility to two potent and commonly used antibodies in vaccine development experiments for HCV, HC33.4 and AR4A.

Because natural HCVs do not thrive in the lab, the researchers first created pseudo-viruses using the contents and capsule of HIV, a virus that grows easily in the lab. Then, by placing surface proteins of each HCV virus onto these pseudoviruses, the researchers were able to efficiently infect human cells with the HCV strains in tissue culture.

One-third of the cells infected with each strain received treatment with HC33.4 antibodies, one-third received treatment with AR4A antibodies and a final third (the control group) received no treatment. The researchers then compared the level of infection in the treated cells against the untreated cells.

The investigators observed that HC33.4 and AR4A neutralized only 88 percent and 85.8 percent of the virus, respectively. "We discovered that there was a lot of naturally occurring resistance, meaning we may need to greatly expand the set of viruses we use to evaluate potential vaccines," says Ramy El-Diwany, a student at the Johns Hopkins University School of Medicine and first author of the study.

The team also found that the effectiveness of the antibodies varied, with some viral strains very inhibited by the antibodies and others hardly affected at all. To find out what was causing the variation, the researchers next tapped into the HCV genomes.

Using a program that compared the genetic sequences of each viral strain, the researchers were able to analyze which mutations conferred resistance to each strain of the virus. They found that despite wide-ranging levels of resistance to HC33.4 and AR4A, the areas that allow these antibodies to bind to the virus barely varied. The HC33.4 binding site mutated at only one location, for example, and the AR4A binding site was the same across all viral strains.

The researchers then expanded their search to the proteins on the surface of HCV. They found that while mutations in the binding site were not associated with resistance, other mutations in the surface proteins away from the binding site correlated with viruses that persisted despite antibody treatment.

"These are the mutations we believe may allow the viruses to avoid being blocked by antibodies altogether. If you think of it like a race, the antibody is trying to bind to the virus before it can enter the cell. We think this mutation may allow the virus to get into the cell before it even encounters the immune system," says Bailey.

HCV is spread from person to person through contact with the blood of an infected person. Some patients are able to fight off the infection naturally, but for 70 to 85 percent of people, the infection becomes chronic.

A new HCV infection is effectively treated with direct-acting antiviral drugs, but the researchers say a preventive vaccine is needed to control what they call an HCV pandemic because as many as 50 percent of people infected are unaware that they carry the virus, putting others at risk of infection. Treatment does not protect those at risk from future infection by HCV. "HCV is very unlikely to be eliminated by treatment alone," says El-Diwany.

Other researchers involved in this study include Valerie Cohen, Madeleine Mankowski, Lisa Wasilewski, Jilian Brady, Anna Snider, William Osburn and Stuart Ray of the Johns Hopkins University School of Medicine, and Ben Murrell of the University of California, San Diego.

PLOS Pathogens
Extra-epitopic hepatitis C virus polymorphisms confer resistance to broadly neutralizing antibodies by modulating binding to scavenger receptor B1

This research was funded by the National Institute of Allergy and Infectious Diseases Extramural Activities (1K08 AI102761, U19 AI088791), the National Institute of Drug Abuse (R37 DA013806), and the Johns Hopkins University Center for AIDS Research (1P30AI094189).

https://www.eurekalert.org/pub_releases/2017-03/jhm-hcm031417.php

Scientists uncover why Hepatitis C virus vaccine has been difficult to make

Scientists uncover why Hepatitis C virus vaccine has been difficult to make

LA JOLLA, CA -- Oct. 24, 2016 -- Researchers have been trying for decades to develop a vaccine against the globally endemic hepatitis C virus (HCV). Now scientists at The Scripps Research Institute (TSRI) have discovered one reason why success has so far been elusive.

Using a sophisticated array of techniques for mapping tiny molecular structures, the TSRI scientists analyzed a lab-made version of a key viral protein, which has been employed in some candidate HCV vaccines to induce the body's antibody response to the virus. The researchers found that the part of this protein meant as the prime target of the vaccine is surprisingly flexible. Presenting a wide variety of shapes to the immune system, it thus likely elicits a wide variety of antibodies, most of which cannot block viral infection.

"Because of that flexibility, using this particular protein in HCV vaccines may not be the best way to go," said co-senior author TSRI Associate Professor Mansun Law.

"We may want to engineer a version that is less flexible to get a better neutralizing response to the key target site and not so many off-target responses," said co-senior author Ian A. Wilson, TSRI's Hansen Professor of Structural Biology and a member of the Skaggs Institute for Chemical Biology at TSRI.

The report, published online ahead of print by the Proceedings of the National Academy of Sciences the week of October 24, 2016, is likely to lead to new and better HCV vaccine designs.

A Great Need

A working vaccine against this liver-infecting virus is needed desperately. HCV infection continues to be a global pandemic, affecting an estimated 130 to 150 million people worldwide and causing about 700,000 deaths annually from liver diseases including cancer. Although powerful antiviral drugs have been developed recently against HCV, their extremely high costs are far beyond the reach of the vast majority of people living with HCV infection. Moreover, antiviral treatment usually comes too late to prevent liver damage; HCV infection is notorious for its ability to smolder silently within, producing no obvious symptoms until decades have passed.

The Law and Wilson laboratories have been working together in recent years to study HCV's structure for clues to successful vaccine design. In 2013, for example, the team successfully mapped the atomic structure of the viral envelope protein E2, including the site where it binds to surface receptors on liver cells.

Because this receptor-binding site on E2 is crucial to HCV's ability to infect its hosts, it has an amino-acid sequence that is relatively invariant from strain to strain. The receptor-binding site is also relatively accessible to antibodies, and indeed many of the antibodies that have been found to neutralize a broad set of HCV strains do so by targeting this site.

For all these reasons, HCV's receptor-binding site has been considered an excellent target for a vaccine. But although candidate HCV vaccines mimicking the E2 protein have elicited high levels of antibodies against the receptor-binding site, these antibody responses--in both animal models and human clinical trials--have not been very effective at preventing HCV infection of liver cells in laboratory assays.

Enormous Flexibility

To understand why, the Law and Wilson laboratories teamed up with TSRI Associate Professor Andrew Ward and used electron microscopy and several other advanced structural analysis tools to take a closer look at HCV's E2 protein, in particular the dynamics of its receptor binding site. Their investigations focused on the "recombinant" form of the E2 protein, produced in the lab and therefore isolated from the rest of the virus. Recombinant E2 is a prime candidate for HCV vaccine design and is much easier to purify and study than E2 from whole virus particles.

One finding was that recombinant E2, probably due to its many strong disulfide bonds, has great structural stability, with an unusually high melting point of 85°C. However, the TSRI scientists also found evidence that, within this highly buttressed construction, the receptor binding site portion is extraordinarily loose and flexible in the recombinant protein.

"It adopts a very wide range of conformations," said study first author Leopold Kong, of TSRI at the time of the study, now at the National Institutes of Health.

Prior studies have shown that HCV's receptor binding site adopts a narrow range of conformations (shapes) when bound by virus-neutralizing antibodies. A vaccine that elicited high levels of antibodies against only these key conformations would in principle provide effective protection. But this study suggests that the E2 protein used in candidate vaccines displays far too many other binding-site conformations--and thus elicits antibodies that mostly do nothing to stop the actual virus.

Law and Wilson and their colleagues plan to follow up by studying E2 and its receptor binding site as they are presented on the surface of the actual virus. They also plan to design a new version of E2 or even an entirely different scaffold protein, on which the receptor binding site is stabilized in conformations that will elicit virus-neutralizing antibodies.

###

In addition to Law, Wilson, Ward and Kong, authors of the study, "Structural flexibility at a major conserved antibody target on hepatitis C virus E2 antigen," included Rameshwar U. Kadam, Erick Giang, Travis Nieusma, Fernando Garces and Netanel Tzarum, all of TSRI; and David E. Lee, Tong Liu, Virgil Woods and Sheng Li, of the University of California, San Diego.

Support for the study was provided by the National Institutes of Health (AI079031, AI123861, AI106005, AI123365, GM094586, AI117905, GM020501 and AI101436) and TSRI's Skaggs Institute for Chemical Biology.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists -- including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www.scripps.edu.

Credit: Illustration by Christina Corbaci and Leopold Kong

Trinity Scientists Homing in on New Hepatitis C Vaccine

Trinity Scientists Homing in on New Hepatitis C Vaccine

23 November 2015

Trinity researchers have just commenced a major new study to evaluate a new vaccine for the prevention of Hepatitis C infection in HIV patients, who are at increased risk of contracting the common infection.

Around 180 million people worldwide and an estimated 20,000 to 50,000 people in Ireland have Hepatitis C. It is a blood borne viral infection which is spread through direct contact with the blood of an infected individual and can lead to fibrosis (scarring of the liver), liver failure and cancer. Currently, there is no effective vaccine available for Hepatitis C and treatment is costly, often in the region of €50,000 per individual, lengthy, associated with side effects and is not 100% effective.

Numerous recent outbreaks of Hepatitis C in HIV-infected individuals internationally have highlighted the urgent need for a vaccine to prevent infection. HIV-infected individuals are at increased risk of Hepatitis C infection due to similar routes of acquisition. Hepatitis C infection also progresses more rapidly to liver damage in HIV-infected individuals. Approximately 20-30% of people with HIV are co-infected with Hepatitis C.

“A safe, affordable and effective vaccine for Hepatitis C would have a huge impact on combatting Hepatitis C given the multitude of people who are unaware of their diagnosis and represent a potential source for new infections,” said Dr Ciaran Bannan, a research fellow in Trinity College Dublin and the Department of GU Medicine and Infectious Diseases at St James’ Hospital who is leading the research with Professor Colm Bergin, Clinical Professor of Infectious Diseases, School of Medicine.

The study, which is the first phase-1 vaccine study in HIV infected people in Ireland, is also the first of a planned number of early intervention studies to be carried out in the Wellcome Trust-HRB Clinical Research Facility, a joint enterprise between Trinity College Dublin and St James’s Hospital.

The research team are evaluating the safety and the ability of a new vaccine to produce an immune response against Hepatitis C. Previous healthy volunteer studies in the University of Oxford have shown encouraging results. If effective, this vaccine could also be made available to other high risk groups such as intravenous drug users.

The study, which will run for 20 months, will follow 20 patients have in Dublin and St Gallen, Switzerland. Patients will be given two vaccines eight weeks apart and then followed closely to assess safety and the development of immune responses to Hepatitis C following vaccination. The vaccines being tested in this study are called AdCh3NSmut1 and MVA-NSmut and have been developed by ReiThera Srl and GlaxoSmithKline Biologicals SA.

This study is the result of collaboration between the University of Oxford, Kantonsspital, St. Gallen and GlaxoSmithKline Biologicals SA and has been funded by an EU Seventh Framework Program (FP7) grant.

http://www.tcd.ie/news_events/articles/trinity-scientists-homing-in-on-new-hepatitis-c-vaccine/6173#.VlYIv3arTrd

Hepatitis C Vaccine Safe In Humans, Study Finds

Study Link: Science Translational Medicine. 

Vaccine for Hepatitis C Inches Closer to Reality

By Randy Dotinga

HealthDay Reporter

WEDNESDAY, Nov. 5, 2014 (HealthDay News) -- An initial study suggests that a potential vaccine against hepatitis C, a liver disease that affects at least 130 million people worldwide, is safe in people.

The newly released findings are good news, said study co-author Dr. Ellie Barnes, a professor of hepatology and experimental medicine at the University of Oxford in England. 

The results indicate the vaccine can safely boost the immune system in a way that "targets multiple parts of the hepatitis C virus," she said. "We hope it will have the capacity to prevent people from being infected, and that's something we really need."

An estimated 1 percent of U.S. residents have chronic hepatitis C, which is usually transmitted through infected blood. In many people, the disease leads to scarring of the liver -- cirrhosis -- or liver cancer.

A powerful new drug called Sovaldi is expected to improve treatment of hepatitis C, but it costs $1,000 per day, or $84,000 for the typical 12-week course. Also, drugs like Sovaldi are least effective in patients with advanced liver disease and don't prevent reinfection, the study authors said.

Vaccines exist for two other types of hepatitis: A and B. But it's been difficult to create a vaccine to fight hepatitis C because the germs are sly when it comes to the immune system soldiers known as antibodies, Barnes said.

"They can put on a disguise and prevent antibodies from seeing them. What we're trying to do is develop a T-cell vaccine, which works by inducing T cells, a totally different part of the immune system," she explained.

Part of the vaccine works by sneaking into the body through a chimpanzee cold germ that human immune systems won't know to kill, Barnes said.

In the new study, a so-called phase I trial, researchers tested parts of the vaccine in 15 people. The researchers reported that the participants tolerated the vaccine well overall, with some mild or moderate side effects that largely resolved within 48 hours.

The study findings also suggest that the vaccine is achieving its goals on the immune system front. But two more stages of research, each in larger groups of people, are needed before the vaccine can be approved for use in the United States.

The second stage of research is already in progress, Barnes said, and results are expected in 2016. She declined to speculate how long it will take for the vaccine to become available if it works.

The vaccine will be targeted at people at high-risk for hepatitis C, not the population at large in Western countries where infection isn't widespread, Barnes said. High-risk groups include users of illegal injection drugs. Countries such as Egypt, where 20 percent of the population is thought to be infected, will need different strategies, Barnes said.

It's not clear how much the vaccine might cost, but Naglaa Shoukry, a hepatitis researcher and associate professor at the University of Montreal, said it shouldn't be "outrageously expensive."

Shoukry, who praised the new study, said drug companies don't make money off vaccines. "That's why they are usually hesitant to develop them," she said.

The study appears in the Nov. 5 issue of the journal Science Translational Medicine.

GSK hepatitis C shot shows promise, bodes well for Ebola vaccines
Source: Reuters - Wed, 5 Nov 2014 19:00 GMT
Author: Reuters

* Vaccine primes immune system to attack viruses

* Uses same science as Ebola shot being tested

By Kate Kelland

LONDON, Nov 5 (Reuters) - A new hepatitis C vaccine from GlaxoSmithKline based on the same technology as an experimental Ebola shot being fast-tracked through human trials has shown promise in early clinical tests, prompting strong and broad immune responses. 

Researchers testing the vaccine -- the first hepatitis C vaccine to reach second stage clinical trials -- said their results in a group of 15 healthy human volunteers showed it was very safe and well tolerated, and generated immune responses of a strength never seen before in a vaccine against this disease.

Continue reading @  Reuters 

Hepatitis C Vaccine Safe In Humans, Study Finds
Alexandra Sifferlin @acsifferlin
2:54 PM ET

Why there might be an HCV vaccine on the horizon

The first human clinical trial of a new hepatitis C vaccine shows that it’s safe in humans, says a study published in the journal Science Translational Medicine. 

The vaccine is currently undergoing testing in a Phase IIB study in both Baltimore and San Francisco among people who are intravenous drug users, one important mode of transmission for the disease. Results are expected in 2016...

Continue reading @ Time...

Inovio Therapeutic Vaccine for Hepatitis C Enters Phase I Clinical Trial

Inovio Pharmaceuticals Therapeutic Vaccine for Hepatitis C Enters Phase I Clinical Trial

Inovio is partnering with VGX International, its affiliate, in Korea

 

BLUE BELL, Pa., Oct. 21, 2013 /PRNewswire/ -- Inovio Pharmaceuticals, Inc. (NYSE MKT: INO) announced today that the safety, tolerability and immunogenicity of its therapeutic vaccine for hepatitis C (INO-8000/VGX-6150) will be studied in a phase I clinical trial in chronically HCV infected patients. Under a 2011 collaborative development agreement, Inovio's affiliate, VGX International Inc. (KSE: 011000), is fully funding and conducting the study at multiple sites in Korea. Inovio is also planning to evaluate this hepatitis C (HCV) vaccine in additional clinical studies in the U.S. beginning in 2014.

Dr. J. Joseph Kim, Inovio's President and CEO, said, "More effective antiviral drugs have changed the prognosis for patients with hepatitis C; however, treatment failures remain and combination with an immunotherapeutic approach could make the difference for many patients. In preclinical studies, Inovio's HCV immunotherapy has shown to generate powerful T cell responses in the liver, which could be important in clearing HCV-infected liver cells. We have already shown in published clinical studies that our vaccines generate best-in-class T-cell responses. In this study, the effects of Inovio's HCV immunotherapy will be directly tested in patients who have previously failed standard drug therapies. We look forward to entering the hepatitis C treatment arena, which is one of the fastest-developing markets in healthcare, with a projected value of $20 billion by the end of the decade."

This study is a multi-center, open-label, dose-escalating phase I trial in which 18 subjects will be divided into three groups and given four monthly vaccinations of 1 mg, 3 mg and 6 mg doses of VGX-6150, respectively. Individuals with chronic HCV who failed previous standard of care therapy with pegylated interferon and ribavirin or triple therapy with standard of care and direct-acting antiviral agents such as boceprevir or telaprevir will be enrolled. Both immunogenicity and virologic response will be evaluated in addition to the safety and tolerability of VGX-6150.

VGX-6150 is a SynCon® multi-antigen DNA vaccine covering hepatitis C virus (HCV) genotypes 1a and 1b and targeting HCV nonstructural proteins 3 (NS3) and 4A (NS4A) as well as NS4B and NS5A proteins. VGX-6150 also includes DNA encoding IL-28B to adjuvant the immune response. VGX-6150 will be administered with Inovio's proprietary CELLECTRA® delivery device.

About Hepatitis C

Hepatitis C is a contagious liver disease that ranges in severity from a mild illness lasting a few weeks to a serious, lifelong illness that attacks the liver. It results from infection with the hepatitis C virus (HCV), which is spread primarily through contact with the blood of an infected person. Hepatitis C can be either "acute" or "chronic." Acute hepatitis C virus infection is a short-term illness that occurs within the first six months after someone is exposed to the virus. For most people, acute infection leads to chronic infection, which can last a lifetime and lead to serious liver problems including cirrhosis (scarring of the liver) or liver cancer.

Currently there is no vaccine available for the prevention of hepatitis C infection. HCV mutation contributes to the difficulty in development of a prophylactic vaccine. The World Health Organization estimates that nearly 200 million people around the world are infected with hepatitis C, a prevalence of around 3.3% of the world's population. As many people are infected with HCV as are with HIV, the virus that causes AIDS. Without large scale efforts to contain the spread of HCV and treat infected populations, the death rate from hepatitis C will surpass that of AIDS in this century.

About INO-8000/VGX-6150

Inovio's SynCon® DNA vaccine, INO-8000, is coded to produce the antigens NS3/4A, NS4B, and NS5A of HCV genotypes 1a and 1b, the most difficult-to-treat genotypes. This broad spectrum of antigens targets HCV to create a higher probability to induce the desired therapeutic immune response. Our proprietary DNA vaccines are uniquely designed to enhance gene expression and antigen secretion, processing, and presentation through a proprietary combination of DNA, RNA, and codon optimization techniques as well as the use of patent protected IgE leader sequences. Our novel SynCon design is intended to provide broader protection against new mutations of a virus. Our CELLECTRA® electroporation device co-localizes vaccine delivery with the applied electric field and operates under more effective constant-current EP parameters. Together these next-generation technologies have generated levels of T-cells that are often orders of magnitude greater than competing technologies, including those using viral vectors and other facilitated delivery systems.

Under a co-development agreement signed between Inovio and VGX International in 2011, VGX International is funding the studies in Asia and has the commercialization right for the product (also known as VGX-6150) in Asia (excluding Japan).

About Inovio Pharmaceuticals, Inc.

Inovio is revolutionizing vaccines to prevent and treat today's cancers and challenging infectious diseases. Its SynCon® vaccines, in combination with its proprietary electroporation delivery, are generating best-in-class immune responses, with therapeutic T-cell responses exceeding other technologies in terms of magnitude, breadth, and response rate. Human data to date have shown a favorable safety profile. Inovio's lead vaccine, a therapeutic against HPV-caused pre-cancers and cancers, is in phase II. Other phase I and preclinical programs target prostate, breast, and lung cancers as well as HIV, influenza, malaria and hepatitis. Partners and collaborators include Roche, the University of Pennsylvania, Merck, NIH, HIV Vaccines Trial Network, National Cancer Institute, U.S. Military HIV Research Program, University of Southampton, US Dept. of Homeland Security, University of Manitoba and PATH Malaria Vaccine Initiative. More information is available at www.inovio.com.

Medivir refocuses hepatitis C vaccine research

Medivir refocuses hepatitis C vaccine research

Published on August 19, 2013 by Emma Rogers

Medivir AB announced on Thursday that it will exclusively focus its research on the development of its proprietary hepatitis C vaccine based on nucleotide inhibitors.

Medivir was previously working on the development of two hepatitis C vaccines: a nucleotide-based inhibitor vaccine and a vaccine with NS5A replication complex inhibitors. Medivir recently evaluated the climate of the competitive market and its projection for the future development of therapies for HCV infections and decided to end its NS5A program to focus its resources exclusively on the nucleotide-based inhibitor HCV.

“We remain very excited about our HCV nucleotide-based inhibitor program and the opportunity to develop a compound that could play an important role in interferon-free treatment,” Executive Vice President of Discovery Research at Medivir Richard Bethell said. “Given the attractive attributes of the nucleotide polymerase class and the scarcity of safe and effective inhibitors today’s decision to discontinue our NS5A program will enable us to focus our resources on our nucleotide-based polymerase program which is best placed to deliver an effective new medication for physicians and their patients.”

Hepatitis C is an infectious disease of the liver that claims the lives of approximately 350,000 people per year. Today approximately 150 million people are positive for Hepatitis C infections. The disease is a leading cause of chronic liver disease.

Medivir is a research-based pharmaceutical company that seeks to find solutions for infectious diseases. It currently has a Hepatitis C protease inhibitor vaccine in a Phase III clinical trial.

This story filed in Vaccine Development and tagged Hepatitis, vaccine development.
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Hepatitis C Virus Vaccines in the Era of New Direct-acting Antivirals

Expert Review of Gastroenterology and Hepatology

 

Hepatitis C Virus Vaccines in the Era of New Direct-acting Antivirals

Chao Shi, Alexander Ploss

Disclosures

Expert Rev Gastroenterol Hepatol. 2013;7(2):171-185.

Hepatitis C virus (HCV) infection is a major global health problem as it has a high propensity for establishing chronicity. Chronic HCV carriers are at risk of developing severe liver disease including fibrosis, cirrhosis and liver cancer. While treatment has considerably improved over the years, therapy is still only partially effective, and is plagued by side effects, which contribute to treatment failure and is expensive to manage. The drug development pipeline contains several compounds that hold promise to achieve the goal of a short and more tolerable therapy, and are also likely to improve treatment response rates. It remains to be seen, however, how potent antiviral drug cocktails will affect the hepatitis C burden worldwide. In resource-poor environments, considerable costs, inadequate infrastructure for medical supervision and distribution may diminish the impact of future therapies. Consequently, development of novel therapeutic and prophylactic strategies is imperative to contain HCV infection globally.

Read more @ Medscape

Prospects in HCV Treatment

Unmet Demands

HCV Vaccines

Current HCV Vaccine Research

Recent Progress in the Model Systems for Vaccine Studies

Adapting HCV to Infect Nonpermissive Species

Engineering the Hosts to Accommodate HCV

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Inovio to Initiate Clinical Trial for its Hepatitis C Therapeutic Vaccine (INO-8000) Later this Year

Inovio Pharmaceuticals to Initiate Clinical Trial for its Hepatitis C Therapeutic Vaccine (INO-8000) Later this Year

Phase I/IIa Trial Follows Preclinical Study Demonstrating for First Time that a Multi-Antigen HCV Vaccine Can Generate Potent T-Cell Response in Liver

Jan 9, 2013

BLUE BELL, Pa., Jan. 9, 2013 /PRNewswire/ -- Inovio Pharmaceuticals, Inc. (NYSE MKT: INO) and its development partner VGX International, Inc. (KSE: 011000) will move Inovio's hepatitis C (HCV) DNA vaccine into a phase I/IIa clinical trial by the end of 2013. This advancement is based on outstanding results of a preclinical study which demonstrated for the first time that a multi-antigen SynCon® HCV vaccine can generate robust T-cell responses not only in the blood but, more importantly, in the liver, an organ known to supress T-cell activity. VGX International is funding all preclinical and clinical development.

In preparation for entering clinical trials with its HCV vaccine (INO-8000), Inovio has completed manufacturing of its multi-antigen HCV vaccine and is performing IND (Investigational New Drug application)-enabling toxicity testing in animals. INO-8000 is a SynCon HCV therapeutic vaccine targeting NS3/4A, NS4B, and NS5A proteins of HCV. INO-8000 was designed with Inovio's SynCon process to broadly cover HCV genotypes 1a and 1b, the types that have been most difficult to treat with drug therapies.
  
It is estimated that more than 5 million people in the United States are infected with hepatitis C, and perhaps as many as 200 million around the world. This makes HCV one of the greatest public health threats of this century.

HCV vaccine research to date has mostly focused on one area of the virus (the NS3/4A proteins) to induce T-cell responses; however, there has been little research aimed at elucidating whether vaccines targeting proteins other than NS3/4A can induce potent T-cell responses within the liver. In this study, Inovio and its collaborators developed SynCon antigen constructs that targeted three other areas of the HCV virus (NS4B, NS5A and NS5B) and then demonstrated that each vaccine construct expressed its respective protein and that all three constructs induced potent HCV-specific T-cells in mice.

Prior research has also identified that a successful HCV vaccine must be able to induce not only strong HCV-specific T-cell responses that target several components of the virus but that these cells must migrate to the liver and remain activated. In this study, Inovio researchers observed in the liver not only NS4B-, NS5A- and NS5B-specific CD4+ and CD8+ (or killer T-cell) responses, but also a large pool of vaccine-specific T-cells. This pool of vaccine-specific T-cells was shown to be fully functional in an environment in which T-cell activity is usually suppressed. In fact, using a transient HCV infection model in mice, therapeutic immunization with INO-8000 was able to clear HCV antigens from the liver, demonstrating the therapeutic potential of this vaccine.
The pioneering preclinical research appears in the peer-reviewed journal Plos One in an article entitled: "Induction of Intrahepatic HCV NS4B, NS5A and NS5B Specific Cellular Immune Responses following Peripheral Immunization."

In addition to moving forward with INO-8000, Inovio has a long-standing partnership with ChronTech Pharma, which is developing its NS3/4A-based HCV DNA vaccine using Inovio's proprietary delivery technology. Interim results of ChronTech's open-label, randomized phase II trial are expected later in the first quarter of this year.
    
Dr. J. Joseph Kim, Inovio's President and CEO, said, "Inovio is a leader in developing therapeutic vaccines for HCV and HBV. The major hurdle to developing therapeutic vaccines for these ailments has been the inability to generate a functional T-cell response in the liver. The fact that our preclinical model demonstrated functional T-cells in the liver in this published study suggests that INO-8000 has the capacity to clear that hurdle. There have been important recent drug therapy advances for HCV; however, a safe and effective therapeutic vaccine could play a vital role in enhancing the potency of HCV treatments, especially for genotype 1, while achieving the desired goal of eliminating the use of interferon/ribavirin and their undesirable side effects."

About Hepatitis C and Inovio's SynCon® Vaccines
Hepatitis C is an infectious disease affecting primarily the liver, caused by the hepatitis C virus (HCV). The infection is often asymptomatic, but chronic infection can lead to liver failure or liver cancer. Approximately 80% of people who become infected with hepatitis C virus develop chronic infection.

The major obstacle to HCV vaccine development has been the extensive genetic variation between different strains and genotypes, and even the significant antigenic variation among virus within individual patients. In addition, the absence of a clearly defined protective immune response after natural infection has historically complicated the prospects of developing a vaccine against HCV infection.

However, unlike traditional vaccines constrained by the paradigm of matching a preventive or therapeutic vaccine to a single pathogen strain or strains, Inovio's SynCon vaccines are based on genetic code for a specific antigen from multiple strains of the target pathogen. Thus, while the SynCon antigens may not be perfectly (100%) matched to the pathogenic strains, they are designed to protect against multiple existing strains as well as changing strains of a virus. Extensive preclinical data has validated their ability to protect against many strains of a disease; initial human data for our influenza vaccine has also provided evidence of this capability.

About Inovio Pharmaceuticals, Inc.
Inovio is revolutionizing vaccines to prevent and treat today's cancers and challenging infectious diseases. Its SynCon vaccines are designed to provide universal cross-strain protection against known as well as newly emergent unmatched strains of pathogens such as influenza. These synthetic vaccines, in combination with Inovio's proprietary electroporation delivery, have been shown in humans to generate best-in-class immune responses with a favorable safety profile. Inovio's clinical programs include phase II studies for cervical dysplasia, leukemia and hepatitis C virus and phase I studies for influenza and HIV. Partners and collaborators include the University of Pennsylvania, Merck, ChronTech, National Cancer Institute, U.S. Military HIV Research Program, NIH, HIV Vaccines Trial Network, University of Southampton, US Dept. of Homeland Security, University of Manitoba and PATH Malaria Vaccine Initiative. More information is available at www.inovio.com.

This press release contains certain forward-looking statements relating to our business, including our plans to develop electroporation-based drug and gene delivery technologies and DNA vaccines and our capital resources. Actual events or results may differ from the expectations set forth herein as a result of a number of factors, including uncertainties inherent in pre-clinical studies, clinical trials and product development programs (including, but not limited to, the fact that pre-clinical and clinical results referenced in this release may not be indicative of results achievable in other trials or for other indications, that the studies or trials may not be successful or achieve the results desired, that pre-clinical studies and clinical trials may not commence or be completed in the time periods anticipated, that results from one study may not necessarily be reflected or supported by the results of other similar studies and that results from an animal study may not be indicative of results achievable in human studies), the availability of funding to support continuing research and studies in an effort to prove safety and efficacy of electroporation technology as a delivery mechanism or develop viable DNA vaccines, the adequacy of our capital resources, the availability or potential availability of alternative therapies or treatments for the conditions targeted by the company or its collaborators, including alternatives that may be more efficacious or cost-effective than any therapy or treatment that the company and its collaborators hope to develop, evaluation of potential opportunities, issues involving product liability, issues involving patents and whether they or licenses to them will provide the company with meaningful protection from others using the covered technologies, whether such proprietary rights are enforceable or defensible or infringe or allegedly infringe on rights of others or can withstand claims of invalidity and whether the company can finance or devote other significant resources that may be necessary to prosecute, protect or defend them, the level of corporate expenditures, assessments of the company's technology by potential corporate or other partners or collaborators, our ability to secure new partnerships and collaborations, capital market conditions, the impact of government healthcare proposals and other factors set forth in our Annual Report on Form 10-K for the year ended December 31, 2011, our Form 10-Q for the quarter ended September 30, 2012, and other regulatory filings from time to time. There can be no assurance that any product in Inovio's pipeline will be successfully developed or manufactured, that final results of clinical studies will be supportive of regulatory approvals required to market licensed products, or that any of the forward-looking information provided herein will be proven accurate.

CONTACTS:
Investors: Bernie Hertel, Inovio Pharmaceuticals, 858-410-3101, bhertel@inovio.com
Media: Jeff Richardson, Inovio Pharmaceuticals, 267-440-4211, jrichardson@inovio.com
(Logo: http://photos.prnewswire.com/prnh/20120131/LA44118LOGO)
SOURCE Inovio Pharmaceuticals, Inc.
 

Clinical Trial with Universal Vaccine Increases Response Rate of Subjects Generating Infection-Preventing Antibodies by 100% in Population Most at Risk for Flu Deaths

Clinical Trial with Universal Vaccine Increases Response Rate of Subjects Generating Infection-Preventing Antibodies by 100% in Population Most at Risk for Flu Deaths

Inovio Also Reports Completion of Enrollment for Phase II Hepatitis C Trial; Results Expected in 1Q 2013

BLUE BELL, Pa., Dec. 10, 2012 /PRNewswire/ -- Inovio Pharmaceuticals, Inc. (NYSE MKT: INO) reported interim results of a phase I trial that showed that a single dose of its H1N1 universal SynCon® flu vaccine followed with a dose of a seasonal flu vaccine generated protective immune responses in 40% of trial subjects compared with a 20% response rate in elderly patients who received the seasonal flu vaccine alone. This interim data is a significant step in developing a more effective flu vaccine for the most vulnerable segment of our population.

People over 65 years of age represent about 90% of annual influenza deaths in the US. Older people's immune systems typically mount much weaker protective immune responses to seasonal vaccines, often in only 10 to 20% of this population. In younger adults, the same flu vaccines generate protective immune responses in at least 65% of the vaccine recipients. Other approaches, such as the use of higher vaccine doses and novel adjuvants, have not significantly improved the seasonal vaccine's impact in the older population. Thus, there is a significant need for a new approach to provide better protection in this more vulnerable population.

With the vulnerability of the elderly in mind, this phase I study is evaluating the ability of Inovio's SynCon® vaccine alone, as well as in combination with the 2012 seasonal influenza vaccine, to generate protective levels of antigen-specific antibody immune responses in a greater proportion of the elderly population as well as to assess the potential for more universal protection against both matched and unmatched seasonal influenza strains.

In the trial, 50 healthy elderly patients have been divided into three groups: one group of 20 subjects received a two-dose regimen of Inovio's H1N1 universal SynCon® flu vaccine delivered using Inovio's proprietary CELLECTRA® intradermal electroporation device 16 weeks apart; a second group of 20 subjects received one dose of Inovio's SynCon® vaccine delivered using electroporation followed by a dose of seasonal flu vaccine 16 weeks later; a third group of 10 subjects received placebo delivered by electroporation followed by a dose of the seasonal flu vaccine 16 weeks later. The study's objectives are to assess the tolerability, safety, and immune responses of these different vaccination regimens. Today's interim results report on the last two arms in the influenza study. The phase I open label study is ongoing at the University of Manitoba in Winnipeg, Canada. See the clinical study protocol.

Serum samples from the vaccinated subjects were used to assess the generation of hemagglutination inhibition (HAI) titers meeting or exceeding a dilution of 1:40 to the current H1N1 seasonal flu strain (A/California/07/09). An HAI titer of 1:40 is the level recognized as a protective immune response against influenza in humans. Because of generally high HAI titer background rates to the A/California/07/09 strain, vaccine-specific, protective response rates were determined by assessing the number of patients in each group who had HAI titers greater than 1:40 and HAI titers at least 4-fold higher than the background value at the start of the trial. Vaccination with the H1N1 universal SynCon® flu vaccine followed with a dose of a seasonal flu vaccine generated protective immune responses in 40% (8 of 20) of trial subjects compared with a 20% (2 of 10) response rate in elderly patients who received the seasonal flu vaccine alone.

Dr. Gary P. Kobinger, Professor, University of Manitoba, and a principal investigator of this study, said, "These early results indicate the potential to significantly expand the protection of this at-risk population of elderly subjects against flu. With limited evidence of other innovations enhancing protection against influenza, this technology could potentially lead to a breakthrough vaccine."
Dr. J. Joseph Kim, Inovio's President and CEO, said, "Today's results provide evidence of the power of our DNA vaccine approach to generate protective antibodies in this vulnerable age group. They also show how our vaccines can increase the potency and coverage of existing therapies."
The need for a new vaccine approach that can stimulate a protective immune response in a greater proportion of people and a broader immune response that is capable of protecting against influenza strains not specifically matched to the strain(s) represented in the vaccine is even greater in the elderly population because they are most at risk for death and illnesses by influenza infection. In addition to improving the immune response and patient response rate against the matched seasonal strain in the older population, all patient serum samples will also be analyzed against other important H1N1 strains to assess the prime-boost regimen's ability to generate universal cross-strain protection and will be reported in 2013.

Inovio also reports that enrollment is complete for a phase II trial of a DNA vaccine for hepatitis C administered by Inovio's proprietary electroporation delivery technology. Researchers are currently analyzing levels of immune response and HCV viral load in trial subjects. Inovio will report preliminary results in the first quarter of 2013. The trial is being conducted by Inovio's partner, ChronTech Pharma AB.

About SynCon® Influenza Vaccines and this Clinical Trial Design
The strategy to combine an influenza DNA vaccine prime with a conventional seasonal vaccine boost is based on the idea that combining the different modalities of Inovio's SynCon® flu vaccine's ability to generate cross-protective antibody responses with the conventional seasonal flu vaccine in a prime-boost regimen could generate a stronger and broader antibody response in the elderly.
Inovio's SynCon® influenza vaccine approach provides "universality" within and across subtypes. Individual SynCon® DNA vaccine "constructs" are designed to provide broad cross-strain protection against existing and potential new strains of influenza within key branches (clades) of subtypes of greatest concern to humans, including H1N1, H3N2 and Type B as well as H5N1. Inovio combines multiple DNA constructs into a universal influenza vaccine potentially able to provide broad protection against the targeted subtypes. Such preemptive protection against new strains could be particularly important to the elderly.

About Inovio Pharmaceuticals, Inc.
Inovio is revolutionizing vaccines to prevent and treat today's cancers and challenging infectious diseases. Its SynCon® vaccines are designed to provide universal cross-strain protection against known as well as newly emergent unmatched strains of pathogens such as influenza. These synthetic vaccines, in combination with Inovio's proprietary electroporation delivery, have been shown in humans to generate best-in-class immune responses with a favorable safety profile. Inovio's clinical programs include phase II studies for cervical dysplasia, leukemia and hepatitis C virus and phase I studies for influenza and HIV. Partners and collaborators include the University of Pennsylvania, Merck, ChronTech, National Cancer Institute, U.S. Military HIV Research Program, NIH, HIV Vaccines Trial Network, University of Southampton, US Dept. of Homeland Security, University of Manitoba and PATH Malaria Vaccine Initiative. More information is available at www.inovio.com.
This press release contains certain forward-looking statements relating to our business, including our plans to develop electroporation-based drug and gene delivery technologies and DNA vaccines and our capital resources. Actual events or results may differ from the expectations set forth herein as a result of a number of factors, including uncertainties inherent in pre-clinical studies, clinical trials and product development programs (including, but not limited to, the fact that pre-clinical and clinical results referenced in this release may not be indicative of results achievable in other trials or for other indications, that the studies or trials may not be successful or achieve the results desired, that pre-clinical studies and clinical trials may not commence or be completed in the time periods anticipated, that results from one study may not necessarily be reflected or supported by the results of other similar studies and that results from an animal study may not be indicative of results achievable in human studies), the availability of funding to support continuing research and studies in an effort to prove safety and efficacy of electroporation technology as a delivery mechanism or develop viable DNA vaccines, the adequacy of our capital resources, the availability or potential availability of alternative therapies or treatments for the conditions targeted by the company or its collaborators, including alternatives that may be more efficacious or cost-effective than any therapy or treatment that the company and its collaborators hope to develop, evaluation of potential opportunities, issues involving product liability, issues involving patents and whether they or licenses to them will provide the company with meaningful protection from others using the covered technologies, whether such proprietary rights are enforceable or defensible or infringe or allegedly infringe on rights of others or can withstand claims of invalidity and whether the company can finance or devote other significant resources that may be necessary to prosecute, protect or defend them, the level of corporate expenditures, assessments of the company's technology by potential corporate or other partners or collaborators, our ability to secure new partnerships and collaborations, capital market conditions, the impact of government healthcare proposals and other factors set forth in our Annual Report on Form 10-K for the year ended December 31, 2011, our Form 10-Q for the quarter ended September 30, 2012, and other regulatory filings from time to time. There can be no assurance that any product in Inovio's pipeline will be successfully developed or manufactured, that final results of clinical studies will be supportive of regulatory approvals required to market licensed products, or that any of the forward-looking information provided herein will be proven accurate.

CONTACTS:
Investors: Bernie Hertel, Inovio Pharmaceuticals, 858-410-3101, bhertel@inovio.com
Media: Jeff Richardson, Inovio Pharmaceuticals, 267-440-4211, jrichardson@inovio.com

SOURCE Inovio Pharmaceuticals, Inc.

HCV In The News-Pharmaceuticals,HCV Vaccine,Liver Health And More

Hepatitis C In The News

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Liver Health

Common Antibiotics Pose a Risk of Severe Liver Injury in Older Patients

DGNews

OTTAWA, Ontario -- August 13, 2012 -- The commonly used broad-spectrum antibiotics moxifloxacin and levofloxacin are associated with an increased risk of severe liver injury in older people, according to a study published in the Canadian Medical Association Journal.

Both the European Medicines Agency (EMA) and Health Canada have issued warnings about the risk of liver injury from moxifloxacin, although there are few published studies on the safety of fluoroquinolones, especially related to liver damage.

Researchers examined the risk of acute liver injury in patients taking moxifloxacin compared with those taking other antibiotics commonly used to treat respiratory tract infections. They looked at 9 years of data from Ontario to identify people aged 66 years or older with no history of liver disease who were admitted to hospital for liver injury within 30 days after receiving a prescription for these antibiotics.

Excluding patients admitted for previous liver disease or recent hospitalisation, 144 patients were admitted for acute liver injury, with the median time from the dispensing of the antibiotic to admission to hospital being 9 days. Of the patients admitted for liver injury, 88 (61.1%) died.

"Compared with clarithromycin, moxifloxacin was associated with a more than 2-fold increased risk of admission to hospital for acute liver injury," wrote David Juurlink, MD, Institute for Clinical Evaluative Sciences, Toronto, Ontario, and colleagues. "Levofloxacin was also associated with a statistically significant, but lower risk of hepatotoxicity than…moxifloxacin."

The authors noted that, although these cases are serious, they are relatively rare, with about 6 cases for every 100 000 patients treated with the antibiotics.

The authors believe their findings are an important contribution to the evidence regarding the risks of these antibiotics.

"Despite recent regulatory warnings regarding the hepatic safety of moxifloxacin, there is a lack of controlled studies supporting the notion that moxifloxacin presents a particular risk relative to other broad-spectrum antibiotic agents and, in particular, to other fluoroquinolones," the authors wrote. "Although our results require confirmation in other settings, the findings suggest that both moxifloxacin and levofloxacin be considered for regulatory warnings regarding acute liver injury."

SOURCE: Canadian Medical Association Journal

Two Quinolones Linked to Liver Injury in Seniors (CME/CE)

8/13/2012 MedPage Today Gastroenterology

(MedPage Today) -- Two common fluoroquinolones were associated with a greater likelihood of hospitalization for idiosyncratic acute liver injury in older adults, Canadian researchers found.

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Curing Hepatitis C by Gregory T. Everson, M.D - Download Chapter Six

Chapter 6: The Future of HCV Treatment-Beyond Triple Therapy

Download PDF

Chapter six of the new book "Curing Hepatitis C" written by Gregory T. Everson, M.D. is available for downloading.

*Curing Hepatitis C will go on sale August 21, for more information or to pre-order the book click here.

Topics discussed in chapter six

• Status of Clinical Investigation into Future HCV Therapies
• Next Generation Triple Therapy
• Lambda interferon
• Inhibitors of NS3/4A protease
• Inhibitors of NS5B polymerase
• Inhibitors of NS5A protein
• Interferon-Free Regimens
• Mericitabine plus danoprevir
• Daclatasvir plus BMS-650032
• BI-201335 plus BI-207127 ± ribavirin
• GS-7977 plus ribavirin
• Genotype 1b versus 1a
• QUAD Therapy
• Daclatasvir plus BMS-650032 plus peginterferon/ribavirin
• Telaprevir plus VX-222 plus peginterferon/ribavirin
• Host-Acting Antivirals
• Cyclophyllin inhibitors
• Entry blockers
• Micro-RNA inhibitors
• Viral Resistance
• Concluding Remarks
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New Studies Investigate Boceprevir in Null Responders, Versus Telaprevir
Two studies presented at the European Association for the Study of the Liver (EASL)/International Liver Congress meeting in Barcelona, Spain, were the first to explore certain aspects of treatment with boceprevir. One study was the first to show the efficacy of boceprevir in the treatment of null responders with hepatitis C virus (HCV) infection. Another study addressed the absence of head-to-head clinical trials between boceprevir (Victrelis, Merck & Co.) and telaprevir (Incivek, Vertex Pharmaceuticals).
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HCV Vaccine

Major Breakthrough in Hepatitis C Vaccine Development

PRNewswire

Researchers at the Burnet Institute have solved a hepatitis C vaccine mystery which, once developed could be the first ever preventative vaccine for the virus.

Currently undergoing formal preclinical studies, the vaccine is the result of breakthrough work done by Associate Professor Heidi Drummer with her team from the Institute's Centre for Virology.

Hepatitis C affects around 200 million people around the world - a preventative vaccine has the potential to have a significant global health impact.

Associate Professor Drummer and her team have overcome a major hurdle in HCV vaccine research, developing a vaccine candidate that protects against a number of different HCV strains.

"Hepatitis C has a great ability to change its structure and evade the immune response. This makes vaccine development challenging," Associate Professor Drummer said.

"Our vaccine is unique as it contains only the most essential, conserved parts of the major viral surface protein, eliciting antibodies that prevent both closely and distantly related hepatitis C viruses from entering cells, thereby preventing infection."

Associate Professor Drummer unveiled the details about her HCV vaccine project at the prestigious Immunotherapeutics and Vaccine Summit (ImVacS) in Cambridge, Massachussets on August 13.

To arrange an interview with Associate Professor Heidi Drummer please contact: Catherine Somerville Media and Communications Officer Burnet Institute Tel: +61-(0)-422-043-498 or Email:

Read more here: http://www.sacbee.com/2012/08/13/4722020/major-breakthrough-in-hepatitis.html#storylink=cpy

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Big Pharma

New at NATAP

HCV Update Selected Highlights: key new HCV drugs, timelines & recent news developments

Currently approved are 2 protease inhibitors telaprevir & boceprevir. In phase 3 now are 4 drugs: 2 proteases TMC435 & BI1335; nucleotide GS7977; and NS5A BMS052. Also in phase 3 is Peg Lambda, a peginterferon that has showed in trials similar efficacy to current Peginterferons with little of the side effect. Phase 3 for these drugs should be finished in about one year with varying finish timelines between these drugs. Abbott is about to start phase 3 studies, they have 4 drugs in 3 classes: protease, NS5A, HCV polymerase nonnucleoside inhibitors (NNIs). Gilead has drugs in 4 classes: nucleotide, protease, HCV polymerase nonnucleoside inhibitors (NNIs), NS5A. BMS has drugs in 4 clases: NS5A, HCV polymerase nonnucleoside inhibitors (NNIs), nucleotide (trial just suspended, evaluating), protease; Roche/Genentech has drugs in 3 classes: protease, nuke, HCV polymerase nonnucleoside inhibitors (NNIs). Vertex has drugs in 3 classes: protease, nucleotide, HCV polymerase nonnucleoside inhibitors (NNIs). Merck has drugs in 2 classes: protease in development in addition to boceprevir, NS5A. Tibotec has protease TMC435 in phase 3 now with other drugs further back in development.
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Gilead: A Stock For The Future

Edited By Kate Boehme

Gilead Sciences (GILD) is a biopharmaceutical company involved in discovering, developing and commercializing medicines. Gilead's key areas of focus are HIV/AIDS, liver diseases - such as hepatitis B and C - and cardiovascular/metabolic and respiratory conditions. This company operates in North America, Asia Pacific, and Europe. Gilead is a leader in the biopharmaceutical industry, with a portfolio of 14 marketed products, as well as a growing pipeline of investigational drugs and 4,600 employees.

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Idenix To Forge Ahead On HCV Combo After Novartis' Departure

Thursday, August 09, 2012

Idenix Pharmaceuticals has been quite busy of late, on the fundraising front and elsewhere. A clinical-stage biotech with a market cap of nearly $900 million and no marketed products, the virology-focused firm has just exited a long-term collaboration with Novartis, raised $191 million in a registered direct offering, and previewed preclinical data for a hepatitis C candidate that it says appears to offer greater antiviral activity than any other clinical compound in its class.

Also of note, with IDX184, Idenix owns one of four nucleoside polymerase inhibitors still in clinical development for HCV, and that class widely is seen as the backbone for future combinations of all-oral, direct-acting antivirals that could transform a burgeoning market highlighted by millions of warehoused and potentially tens of millions of undiagnosed patients. The peak annual market for HCV drugs has been estimated as high as $20 billion worldwide, and Idenix, while trailing clear leader Gilead Sciences, is positioned as well or better than many more established and deep-pocketed companies racing to grab a significant chunk of that market.

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Roche Worker Sues For Whistleblowing & Firing

A former senior clinical program manager at the Genentech unit of Roche has filed a lawsuit against the drugmaker after claiming she suffered retaliation for effectively blowing the whistle on clinical trial practices that she alleged jeopardized patient safety.

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Drugs Companies Putting Profit Ahead of Medical Discoveries, Warn Scientists

Jeremy Laurance

(The Independent, London, August 8, 2012)

"The multi-billion pound pharmaceutical industry has spent the last decade developing new drugs which have produced little benefit and caused considerable harm, experts say...Counter to drug industry claims that the pipeline of new drugs is running dry, the number of new drugs being licensed each year has remained at between 15 and 25. But most involve minor tweaks to existing drugs, designed to grab a slice of an existing market rather than offering genuine therapeutic innovation. Independent reviews suggest that 85 to 90 per cent provide little benefit over existing treatments with some...causing serious side effects which led to their withdrawal."

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Liver Cancer

Celsion Corporation Reports Second Quarter 2012 Financial Results and Business Update
8/14/2012 8:53:39 AM

LAWRENCEVILLE, NJ--(Marketwire - August 14, 2012) - Celsion Corporation a leading oncology drug development company, today announced financial results for the second quarter ended June 30, 2012 and provided a business update including development progress with ThermoDox®, Celsion's proprietary heat-activated liposomal encapsulation of doxorubicin for the treatment of hepatocellular carcinoma (HCC), commonly referred to as primary liver cancer. ThermoDox® is currently being evaluated under a Special Protocol Assessment with the U.S. Food and Drug Administration (FDA) in a global, multi-center, randomized, pivotal Phase III trial (the HEAT Study) in patients with non-resectable primary liver cancer. The HEAT Study has been designated as a Priority Trial for liver cancer by the National Institutes of Health, has received Fast Track Designation from the FDA and has received Orphan Drug Designation in both the U.S. and Europe. ThermoDox® is also being evaluated in two Phase II trials for patients with recurrent chest wall breast cancer and colorectal liver metastases.

"Celsion has had a productive, if not pivotal, quarter in its development program for ThermoDox®, an investigational drug with the potential to provide a first line therapy for patients with HCC, the largest unmet need in oncology. Having successfully completed patient enrollment in the HEAT Study, secured a commercial supply agreement for ThermoDox® in China, entered into a $10 million loan agreement which strengthens our balance sheet well beyond data, and advanced several important collaborations with leading industry and academic players, we are well positioned for success," said Michael H. Tardugno, Celsion's President and Chief Executive Officer. "Our continued progress underscores the momentum and enthusiasm behind our ThermoDox® program, and its advancement toward the key clinical, regulatory and commercial milestones ahead. Among the most important of these near-term milestones, we look forward to top line results from the pivotal HEAT Study."

A total of 380 events of progression are required to reach the planned final analysis of the HEAT Study, which are projected to occur in late 2012. Top line results will be announced following review by the study's independent Data Monitoring Committee.

Mr. Tardugno added, "Beyond the HEAT Study, we are very encouraged by the progress being made with ThermoDox® in multiple indications using a variety of heat-based modalities in collaboration with some of the top names in science and healthcare, including Royal Philips Electronics, Oxford University and the University of Washington. These collaborations, along with our own clinical programs, we believe will bear out ThermoDox®'s significant clinical potential as it progresses through the commercialization process."

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Exeter Hospital Hepatitis C Outbreak

Lies, lack of reporting helped suspected hepatitis C infector slip through cracks

AP IMPACT: Med tech's arrest shows flaws in system
CONCORD, N.H. (AP) -- Radiology technician David Kwiatkowski was a few weeks into a temporary job at the University of Pittsburgh Medical Center-Presbyterian in 2008 when a co-worker accused him of lifting a syringe containing an addictive painkiller from an operating room and sticking it down his pants....

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Possible new hepatitis C infections in other states

In addition to the 31 patients he allegedly infected with hepatitis C in Exeter Hospital's cardiac catheterization laboratory, patients of at least two other hospitals where Kwiatkowski worked recently tested positive for hepatitis C. Positive test results were returned for a patient at Johns Hopkins Hospital in Baltimore, Md., but it's not clear ...
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Hep. C test results pending

Nearly 1,000 attend clinic after Exeter Hospital outbreak

By Aaron Sanborn

asanborn@seacoastonline.com

August 14, 2012 2:00 AM

STRATHAM — More than 900 people were tested on Friday and Saturday during the first state-run hepatitis C testing clinic at the Cooperative Middle School.

State officials said the first day of the clinic was rough, with long lines and delays, but the second day of the clinic went well.

"We got backed up for long periods of time on Friday. but we had no backups on Saturday," said Rick Cricenti, director of emergency management at the state Department of Health and Human Services.

Cricenti said as of Monday afternoon he had only received one written complaint about the two-day clinic, a letter from a recently formed patient advocacy group, The Patients Speak, on behalf of one of the patients that was tested over the two days. The complaints included long lines, lack of seating and a lack of privacy at the blood-draw stations.

On Friday, some patients were at the clinic for as long as three hours, according to Cricenti. By Saturday, most were out of the clinic in under an hour. Issues with long lines and lack of seating were remedied by Saturday.
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Unsafe Injections: More Preventive Action Needed, GAO Says
From Medscape Medical News
Emma Hitt, PhDAugust 13, 2012

The extent of unsafe injection practices may be underestimated because of a lack of proper documentation, according to a new report from the Government Accountability Office (GAO).

"Data on the extent and cost of blood-borne pathogen outbreaks related to unsafe injection practices in ambulatory care settings are limited and likely underestimate the full extent of such outbreaks," the authors write.

Two agencies, the Centers for Medicare and Medicaid Services (CMS) and the Centers for Disease Control and Prevention (CDC), both part of the Department of Health and Human Services (HHS), need to improve their efforts in this area, the report notes.

The CMS took steps to expand oversight of unsafe injection practices in ambulatory care settings in 2009 by requiring surveyors to use an Infection Control Surveyor Worksheet for documentation. However, the agency stopped collecting data from surveyor worksheets after fiscal year 2011.
"CMS may be undermining its efforts by stopping data collection after fiscal year 2011, in part because of concerns that the time and effort required in collecting the data placed a burden on surveyors," the report states.

The authors also suggest that the absence of comprehensive data underestimates outbreaks of blood-borne pathogens (hepatitis B and C) linked to a specific healthcare facility or clinician that uses unsafe injection practices.

Likewise, data from the CDC indicate that from 2001 through 2011, at least 18 outbreaks of viral hepatitis associated with unsafe injection practices in ambulatory settings, such as physician offices or ambulatory surgical centers, were reported.

Unsafe injection practices that led to outbreaks included syringe reuse, mishandling of medication vials, failure to prepare and store intravenous infusions under aseptic conditions, and medication preparation in a contaminated environment.

The GAO now recommends that HHS do the following: "(1) resume collecting data on unsafe injection practices that will permit continued monitoring of such practices, (2) use those data for continued monitoring of [ambulatory surgical centers], and (3) strengthen the targeting efforts of the One and Only Campaign for health care settings."

The One and Only Campaign is a program designed to educate both clinicians and patients about safe injection practices.

According to the report, HHS concurred with the above GAO recommendations and stated that the CMS intends to resume collection of the Infection Control Surveyor Worksheet data beginning in fiscal year 2013 for a state-stratified, randomly selected subset of ambulatory surgical centers surveyed in that year, and that the agency will repeat this sampling and data collection approximately every 3 years thereafter.

In addition, HHS said that the CDC supports targeting the outreach of the One and Only Campaign toward specific clinician groups and setting types, "though the agency further noted that broad outreach also remains critical as demonstrated by the wide variety of settings where blood-borne pathogen outbreaks and unsafe injection practices have been identified."
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HIV

CDC Recommendation: Dual Treatment to Curb Tide of Drug-Resistant Gonorrhea

Increasing fears about the emergence of antibiotic resistant gonorrhea in the U.S. have prompted new treatment and surveillance recommendations from the Centers for Disease Control and Prevention (CDC). Gail Bolan, director of the agency's Division of STD Prevention, called the move "a critical pre-emptive strike to preserve the last effective treatment option."

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Diabetes

Engineered Pancreatic Tissues Could Lead to Better Transplants for Diabetics

Released:8/14/2012 11:00 AM EDT
Source:American Technion Society

Newswise — Technion researchers have built pancreatic tissue with insulin-secreting cells, surrounded by a three-dimensional network of blood vessels. The engineered tissue could pave the way for improved tissue transplants to treat diabetes.

The tissue created by Professor Shulamit Levenberg of the Technion-Israel Institute of Technology and her colleagues has some significant advantages over traditional transplant material that has been harvested from healthy pancreatic tissue.

The insulin-producing cells survive longer in the engineered tissue, and produce more insulin and other essential hormones, Levenberg and colleagues said. When they transplanted the tissue into diabetic mice, the cells began functioning well enough to lower blood sugar levels in the mice.
Transplantation of islets, the pancreatic tissue that contains hormone-producing cells, is one therapy considered for people with type 1 diabetes, who produce little or no insulin because their islets are destroyed by their own immune systems. But as with many tissue and organ transplants, donors are scarce, and there is a strong possibility that the transplantation will fail.

The well-developed blood vessel network built into the engineered tissue is key to its success, the researchers concluded. The blood vessels encourage cell-to-cell communication, by secreting growth hormones and other molecules, that significantly improve the odds that transplanted tissue will survive and function normally.

The findings confirm that the blood vessel network “provides key survival signals to pancreatic, hormone-producing cells even in the absence of blood flow,” Levenberg and colleagues concluded in their study published in the journal PLoS One.

One reason transplants fail, Levenberg said, “is that the islets are usually transplanted without any accompanying blood vessels.” Until the islets begin to connect with a person’s own vascular system, they are vulnerable to starvation.

The 3-D system developed by the Technion researchers tackled this challenge by bringing together several different cell types to form a new transplantable tissue. Using a porous plastic material as the scaffold for the new tissue, the scientists seeded the scaffold with mouse islets, tiny blood vessel cells taken from human umbilical veins, and human foreskin cells that encouraged the blood vessels to develop a tube-like structure.

“The advantages provided by this type of environment are really profound,” said Xunrong Luo, an islet transplantation specialist at the Northwestern University Feinberg School of Medicine. She noted that the number of islets used to lower blood sugar levels in the mice was nearly half the number used in a typical islet transplant.

Islets grown in these rich, multicellular environments lived three times as long on average as islets grown by themselves, Levenberg and colleagues found.

The technology “is still far from tests in humans,” Levenberg said, but she noted that she and her colleagues are beginning to test the 3-D tissue scaffolds using human instead of mouse islets.
According to Northwestern’s Luo, the 3-D model demonstrated in the study “will have important and rapid clinical implications” if the same results can be replicated with human cells. “This model system also provides a good platform to study the details and mechanisms that underlie successful transplantation.”

The Technion-Israel Institute of Technology is a major source of the innovation and brainpower that drives the Israeli economy, and a key to Israel’s renown as the world’s “Start-Up Nation.” Its three Nobel Prize winners exemplify academic excellence. Technion people, ideas and inventions make immeasurable contributions to the world including life-saving medicine, sustainable energy, computer science, water conservation and nanotechnology.

American Technion Society (ATS) donors provide critical support for the Technion—more than $1.7 billion since its inception in 1940. Based in New York City, the ATS and its network of chapters across the U.S. provide funds for scholarships, fellowships, faculty recruitment and chairs, research, buildings, laboratories, classrooms and dormitories, and more.
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Around The World

China: Experts Call to Improve Monitoring of Organ Trade

Cao Yin

(China Daily, August 6, 2012)

"[A]bout 1.5 million Chinese need organ transplants every year, but only around 10,000 transplants are performed annually due to a lack of donors. The huge gap has led to a thriving illegal market for human organs, although the government has repeatedly pledged to improve regulations on organ transplants and increase the supply. China's central government issued its first national level regulations on human organ transplants in 2007, banning organizations and individuals from trading human organs...To increase the supply of legally harvested organs, Chinese health authorities are building an official network to facilitate organ donations."

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Just For Fun

Triple Hep C Therapy - Using Facebook Under The Influence
Establishing connections online is a highly beneficial experience to those who are newly diagnosed with hepatitis C. Although, when in the throes of HCV triple therapy it can be a challenge using a social site like Facebook.

To put it gently, comprehension is somewhat limited during therapy, additional side effects include fatigue, depression, anxiety, insomnia, spelling and impaired typing skills. The last two debilitating side effects have never been acknowledged in a peer-reviewed journal, but I'm thinking they should be.
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Healthy You

Hot Cocoa May Boost Seniors' Brain Power

By Kristina Fiore, Staff Writer, MedPage Today

Published: August 13, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Cocoa flavanols have shown some benefits for the heart, but they may also be good for cognitive function in older people, researchers found.

In a double-blind study, elderly patients with mild cognitive impairment who consumed high or moderate levels of cocoa flavanols for 2 months had significant improvements on certain cognitive assessment tests compared with those who took in only small amounts, Giovambattista Desideri, PhD, of the University of L'Aquila in Italy, and colleagues reported online in Hypertension.
"Although additional confirmatory studies are warranted, the findings...suggest that the regular dietary inclusion of flavanols could be one element of a dietary approach to the maintaining and improving not only cardiovascular health but also specifically brain health," they wrote.

Evidence suggests eating flavonoids, polyphenic compounds from plant-based foods, may confer cardiovascular benefits. Flavonols are a subclass of these compounds that are abundant in tea, grapes, red wine, apples, and cocoa products including chocolate.

So to assess whether cocoa flavanols could improve cognitive function in elderly patients with mild cognitive impairment (MCI), Desideri and colleagues assessed 90 elderly patients with MCI who were randomized to drink varying levels of a dairy-based cocoa containing flavanols per day for 8 weeks: 990 mg (high), 520 mg (intermediate), or 45 mg (low).

The researchers found that scores on the Mini Mental State Examination didn't change significantly in any of the groups ( P=0.13), a finding that was likely due to the low sensitivity of the test to detect small changes at the upper end of cognitive performance over time, they wrote.

There were, however, changes in the time required to complete Trail Making Tests A and B, with significantly greater improvements for those on high or intermediate doses of flavonols compared with those who had a low intake (P<0.05):

• High: -14.3 seconds for A, -29.2 seconds for B
• Intermediate: -8.8 seconds for A, -22.8 seconds for B
• Low: +1.1 second for A, +3.8 seconds for B

Scores on the verbal fluency test improved significantly for all groups, but, improvements were significantly greater for those who had a high versus low intake (P<0.05):

• High: +8.0 words per 60 seconds
• Intermediate: +5.1 words per 60 seconds
• Low: +1.2 words per 60 seconds

Also, the composite cognitive z-score significantly changed over the study period for the high and intermediate intake groups (P<0.0001), but did not change for those with the lowest intake, they reported.

Desideri and colleagues also observed improvements in several metabolic parameters, including blood pressure and insulin resistance, for those on high and intermediate doses of cocoa flavanols.
For blood pressure, the high flavanol group saw mean reductions of 10 mm Hg for systolic and 4.8 mm Hg for diastolic (P<0.0001) while the intermediate group saw a mean drop of 8.2 mm Hg for systolic and 3.4 mm Hg for diastolic pressures. There were no significant changes for those taking a low dose of flavanols.

Plasma glucose fell a mean 0.6 mmol/L for those in the highest group and by 0.5 mmol/L for those on the mid-level dose (P<0.0001) with no differences for low intake, and both the high and intermediate groups also had significant reductions in homeostasis model assessment–insulin resistance (HOMA-IR) scores (-1.7 and -0.9 points, respectively).

Changes in HOMA-IR were found to be the main determinant of changes in cognitive function, explaining about 40% of composite z-score variability through the study period, the researchers reported (P<0.0001).

Thus the effect on cognition appears to be mediated in part by improvement in insulin sensitivity, the researchers wrote.

They noted that there were no changes in cholesterol or triglycerides in any of the groups.
The study was limited because its short time-frame didn't allow for conclusions about the extent of cognitive benefits and their duration. Nor can it establish whether the observed benefits are a consequence of the cocoa itself or a secondary effect related to general improvements in cardiovascular function or health. Also, participants were in good health overall and without known cardiovascular disease, so the population may be representative of all subjects with MCI.
Still, the researchers concluded that the data "are suggestive of a possible clinical benefit derived from the regular dietary inclusion of cocoa flavanol-containing foods in subjects with MCI."
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