Hepatitis Vaccines

Scientists Discover How a Protein and Enzymes Enabling Hepatitis A Virus Replication

Karen McClorey Hackett — Fri, 08 Jul 2022 17:53:55 +0000

Reviewer:

While focusing on the viral replication cycle in the hepatitis A virus (HAV), UNC School of Medicine scientists recently discovered that replication requires specific interactions between the human protein ZCCHC14 and a group of enzymes called TENT4 poly(A) polymerases.

They also found that the oral compound RG7834 stopped replication at a critical step, making it impossible for the virus to infect liver cells.

These findings were published in the Proceedings of the National Academy of Sciences on July 7, 2022, and are the first to demonstrate an effective drug treatment against HAV in an animal model of the disease.

“Our research demonstrates that targeting this protein complex with an orally delivered, small-molecule therapeutic halts viral replication and reverses liver inflammation in a mouse model of hepatitis A, providing proof of principle for antiviral therapy and the means to stop the spread of hepatitis A in outbreak settings,” commented senior author Stanley M. Lemon, M.D., professor in the UNC Department of Medicine and UNC Department of Microbiology & Immunology, and member of the UNC Institute for Global Health and Infectious Diseases.

Dr. Lemon, who in the 1970s and 80s was part of a Walter Reed Army Medical Center research team that developed the first inactivated HAV vaccine administered to humans, said research on HAV tapered off after the vaccine became widely available in the mid-1990s.

The good news is HAV cases plummeted in the 2000s as vaccination rates skyrocketed.

Not everyone gets vaccinated, Lemon pointed out, and HAV can exist for long periods in the environment – such as on our hands and in food and water.

Several outbreaks have occurred over the past several years, including in San Diego in 2017, primarily driven by homelessness and illicit drug use, causing severe illness in about 600 people and killing 20.

In 2022, a small outbreak was linked to organic strawberries in multiple states, leading to about a dozen hospitalizations.

As of July 1, 2022, since the HAV outbreaks were first identified in 2016, 37 states reported 44,696 cases, hospitalizations (61%), and 423 related fatalities.

Symptoms include fever, abdominal pain, jaundice, nausea, loss of appetite, and a sense of taste.

Once sick, there is no treatment.

In 2013, Lemon and colleagues discovered that the hepatitis A virus changes dramatically inside the human liver.

The virus hijacks bits of the cell membrane as it leaves liver cells, cloaking itself from antibodies that would have otherwise quarantined the virus before it spread widely through the bloodstream.

This work was published in Nature and provided insight into how much researchers had yet to learn about this virus discovered 50 years ago and likely caused diseases dating back to ancient times.

Lemon’s lab led experiments to search for human proteins that HAV needs to replicate, and they found ZCCHC14 – a particular protein that interacts with zinc and binds to RNA.

“This was the tipping point for this current study,” Lemon said.

“We found ZCCHC14 binds very specifically to a certain part of HAV’s RNA, the molecule that contains the virus’s genetic information. And as a result of that binding, the virus can recruit TENT4 from the human cell.”

In normal human biology, TENT4 is part of an RNA-modification process during cell growth. Essentially, HAV hijacks TENT4 and uses it to replicate its own genome.

This work suggested that stopping TENT4 recruitment could stop viral replication and limit disease.

Lemon’s lab then tested the compound RG7834, which had previously been shown to actively block the Hepatitis B virus by targeting TENT4.

In the new PNAS paper, the researchers detailed the precise effects of oral RG7834 on HAV in liver and feces and how the virus’s ability to cause liver injury is dramatically diminished in mice that had been genetically modified to develop HAV infection and disease.

The research suggests the compound was safe at the dose used in this research and the acute timeframe of the study.

“This compound is a long way from human use,” Lemon said, “But it points the path to an effective way to treat a disease for which we have no treatment at all.”

The pharmaceutical company Hoffmann-La Roche developed RG7834 for use against chronic hepatitis B infections and tested it in humans in a phase 1 trial, but animal studies suggested it may be too toxic for use over long periods.

“The treatment for Hepatitis A would be short-term,” Lemon said, “and, more importantly, our group and others are working on compounds that would hit the same target without toxic effects.”

The hepatitis A vaccination is the best way to prevent HAV infection, says the CDC.

One dose of single-antigen hepatitis A vaccine has been shown to control outbreaks of hepatitis A.

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This research was a collaboration between the Lemon lab and the lab of Jason Whitmire, professor of genetics at the UNC School of Medicine. Lemon and Whitmire are members of the UNC Lineberger Comprehensive Cancer Center.

This work was supported by grants from the National Institute of Allergy and Infectious Diseases. In addition, the UNC Pathology Services Core and UNC High-Throughput Sequencing Facility were partially supported by a National Cancer Institute Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. No industry conflicts of interest were disclosed.

PrecisionVaccinations publishes fact-checked, research-based vaccine news curated for mobile readership.

Sub Title:

Hepatitis A outbreaks produced over 420 fatalities since 2016

References:

Scientists Discover Key to Hepatitis A Virus Replication, Show Drug Effectiveness

The ZCCHC14/TENT4 complex is required for hepatitis A virus RNA synthesis

Hepatitis Vaccines 2022

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Tuesday, July 12, 2022 - 21:00

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The U.K. Confirms Undefined Hepatitis Outbreak in Children

Karen McClorey Hackett — Tue, 12 Apr 2022 21:47:23 +0000

Reviewer:

Robert Carlson, MD

Holly Lutmer PharmD

The UK Health Security Agency (UKHSA) today announced doctors and scientists at the UK’s public health agencies are continuing to investigate 74 cases of hepatitis (liver inflammation) in children since January 2022.

Of these recent hepatitis cases, 49 are in England, 13 are in Scotland, and 12 are in Wales and Northern Ireland.

The number of confirmed cases in such a short time, combined with the geographical spread, is unusual.

For example, Scotland generally reports about 7 or 8 non-A to E hepatitis cases in children annually.

The UKHSA confirmed as of April 12, 2022, the usual viruses that cause infectious hepatitis (hepatitis A to E) have not been detected.

The clinical syndrome of currently identified cases is severe acute hepatitis with markedly elevated transaminases, sometimes preceded by gastrointestinal symptoms, in children up to 13 years.

Some cases have required transfer to specialist children’s liver units, and a small number of children have undergone liver transplantation.

Furthermore, none of the currently confirmed hepatitis cases in the UK has been COVID vaccinated.

This means there is no link to COVID-19 vaccination.

Dr. Meera Chand, Director of Clinical and Emerging Infections at UKHSA, commented in a related press statement, “We are working swiftly with the NHS and public health colleagues in Scotland, Wales, and Northern Ireland to investigate a wide range of possible factors which may be causing children to be admitted to hospital with liver inflammation known as hepatitis.”

“One of the possible causes that we are investigating is that this is linked to adenovirus infection.”

“However, we are thoroughly investigating other potential causes.”

“We are also calling on parents and guardians to be alert to the signs of hepatitis – including jaundice – and to contact a healthcare professional if they are concerned.”

Adenoviruses are a family of common viruses that usually cause mild illnesses, and most people recover without complications. While they don’t typically cause hepatitis, it is a known rare complication of the virus.

Adenoviruses are commonly passed from person to person through the respiratory route and by touching contaminated surfaces.

The most effective way to minimize the spread of adenoviruses is to practice good hand and respiratory hygiene and supervise thorough handwashing in younger children.

The UKHSA stated it is ‘working with partners, will continue to make the public aware of findings throughout the investigation.’

The U.S. CDC says hepatitis means inflammation of the liver and is often caused by a virus. The most common types of viral hepatitis are hepatitis A, B, and C.

And autoimmune hepatitis is a rare cause of long-term hepatitis in which the immune system attacks and damages the liver.

Since 2005, the epidemiology of viral hepatitis in the U.S. has changed substantially.

Decreases in hepatitis A incidence that occurred following the release of the hepatitis A vaccine in the late 1990s ended in 2016, when large person-to-person outbreaks of hepatitis A began in the ‘heartland’ states, such as Kentucky, Indiana, and West Virginia.

Hepatitis A accounts for over 100 million infections per year and tens of thousands of deaths, mainly due to fulminant liver failure, says the WHO.

And decreases in acute hepatitis B incidence that occurred after the release of the hepatitis B vaccine in the 1980s ceased in 2010.

Also, in 2010, decreases in acute hepatitis C incidence that were first observed in the 1990s began to reverse.

Rates of acute hepatitis C have most notably increased among people 20–49 years of age, American Indian/Alaska Native people, and non-Hispanic White people.

The shift in acute hepatitis B and hepatitis C incidence is most evident in jurisdictions disproportionately affected by the opioid crisis.

The CDC recently released updated hepatitis vaccination schedules for children and adults.

The latest hepatitis vaccine news is posted at PrecisionVaccinations.com/Hepatitis.

PrecsionVaccinations publishes fact-checked research-based news.

Updates: EU/EEA Member States can share information about suspected cases on the ECDC EpiPulse platform to facilitate the investigation.

Sub Title:

Scotland and UK report unusual rates of liver inflammation (hepatitis) in children

References:

Increase in hepatitis (liver inflammation) cases in children under investigation

CDC: Viral Hepatitis

Highlights from the Meeting of the Strategic Advisory Group of Experts (SAGE) on Immunization

Hepatitis Vaccines 2022

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health, vaccines, vaccinations, hepatitis, uk children, liver disease, covid, covid vaccines

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