Why is there no cure for herpes yet

New research from Dr. Luis M. Schang and his group at the Baker Institute for Animal Health has identified a new mechanism that plays a role in controlling how the herpes virus alternates between dormant and active stages of infection.

The herpes virus causes cold sores and genital sores, as well as life-threatening infections in newborns, encephalitis and corneal blindness.

Treatment of the virus is difficult, because it hides out in nerve cells and emerges months or years later to reactivate the infection.

In Schang's group, Mi Yao Hu and Esteban Flores Cortes discovered that the virus switches between the "latent" stage and the "lytic" stage, in which it is actively replicating, depending on how tightly its DNA is packaged into bundles called chromatin.

Their findings are in a paper, "Chromatin Dynamics and the Transcriptional Competence of HSV-1 Genomes During Lytic Infections," which published Nov. 14 in PLOS Pathogens. Schang's group collaborated with scientists from the University of Alberta, Canada, and University College London (UCL).

"Any problem that herpes causes is because of reactivation from latency," Schang said. "That's the reason why antivirals cannot cure the infection and why so far it's been impossible to develop a vaccine. Latency and reactivation are a major focus for herpes virus research."

When the herpes virus enters a cell, the cell tries to protect itself by wrapping the viral DNA tightly around spool-like proteins called histones and condensing it into chromatin, which causes the virus to go dormant. But if the cells are unsuccessful, the chromatin is only loosely bundled, leaving the viral DNA accessible. The virus particles can then turn on their genes and replicate using the cell's machinery to start a lytic infection, causing disease.

Most researchers have focused on when and how individual genes on the herpes virus genome are turned on and off during infection to figure out how the virus switches between latent and lytic stages. In the new study, however, the group showed that the dynamics of the chromatin regulate whether the entire herpes virus genome is turned on, which must occur before any individual genes can be expressed. This new mechanism represents a previously overlooked way to regulate gene expression at the level of the entire viral chromosome.

With this new knowledge, researchers can further explore the interplay between the virus and host cells that determines whether viral DNA is expressed. Antiviral drugs to treat herpes have existed since the 1960s, but thus far a cure or an effective vaccine has been out of reach.

"Latency and gene regulation is a big problem because we do not know nearly enough about it," said Schang. "It's big black box in herpes biology."

The discovery opens up new directions for exploring how the virus reactivates after lying dormant. Herpes' ability to lay low has thwarted efforts to create effective vaccines or antiviral drugs that fully prevent or cure the infection.

Early efforts to produce a protein-based vaccine for herpes failed. But a new mRNA approach has outperformed the efficacy of the past vaccines in preclinical trials and is expected to be introduced in clinical trials in the second half of 2022, investigators say. This new approach for a prophylactic genital herpes vaccine showed great promise in early studies.1

Research into the mRNA herpes vaccine began long before the COVID-19 mRNA vaccines were developed, says Harvey M. Friedman, MD, professor of medicine/infectious diseases at the University of Pennsylvania Perelman School of Medicine.

“We’re pretty far along in the research,” he says. “We are using the mRNA technology in a vaccine effort for preventing genital herpes. It’s not, at this point, intended for a treatment.”

The vaccine, which was studied in mice and guinea pigs, showed exceptionally good prevention. “We’re hopeful it will make it into humans this year,” Friedman says. “Sometime in the summer of 2022 is our target.”

This vaccine is good news for everyone at risk of STIs. More than one out of 10 Americans, age 49 years and younger, are infected with genital herpes, says Sita Awasthi, PhD, associate research professor in the infectious disease division at Perelman School of Medicine.

“This is important for so many people who are devastated by the infection. It’s a step in the right direction,” she says. “Hopefully, it will be proven in clinical trials to be effective.”

The vaccine also might help reduce HIV infection, since herpes greatly increases a person’s risk of contracting HIV, Awasthi says.

Awasthi has worked in the field of herpes for two decades, including her earlier efforts with the protein-based vaccine research. “With the advancement in mRNA technology, we saw an opportunity,” she says. “The previous studies were with glycoprotein D vaccines, which did not prevent disease or infection. Scientists are conditioned to persist and figure out what our failures are to learn lessons from our failures. Based on all the lessons we’ve learned from past clinical trials and novel technology, we were led to this new mRNA vaccine design, which we started before the COVID-19 mRNA vaccines came out.”

The Phase I clinical trial to determine safety will enroll 80 to 100 people. “It takes a while to do those studies. It’s not a simple matter,” Friedman says. “Then, we’ll go into bigger studies with thousands of subjects to show that it works.”

These studies will take at least three to four years to complete, and a little longer than that to publish results.

Everyone would like the research to move as fast as possible, but it cannot match the speed of the COVID-19 mRNA vaccines because herpes is not as ubiquitous as the coronavirus.

“The difference is that when COVID came along, everyone was coming down with COVID, so it didn’t take long to prove there was a benefit to the vaccine,” Friedman explains. “With genital herpes, you might have to follow 1,000 people for a year, and there might be 20 to 40 people who will be infected; with COVID, it was hundreds who might get infected.”

It also will take longer to enroll subjects for the herpes vaccine. Potential participants most interested in a herpes vaccine might already be infected, but the vaccine is not being studied yet for treatment.

“We’re interested in a vaccine that could be used as a treatment, and we’re turning our attention to that now,” Friedman says. “The type of immune response you need to prevent an infection is likely different from what you need to treat an infection, so I don’t think the vaccine for prevention will be useful for treatment.”

The goal is to complete trials successfully and receive FDA approval to offer the vaccine to adults for prevention of genital herpes. “If we can expand the vaccine to oral herpes, we’ll work on that as well,” Friedman says. “If it works with adults, we’ll move to adolescents.”

Ideally, a new herpes vaccine could be administered to adolescents, as is the HPV vaccine. Since herpes does not change over time and remains stable, a full vaccine regimen could prove protective over a person’s lifetime.

“We’ll have to have some boosters built in, but it won’t be every one month or six months; we’re hoping every five years, but we don’t know that,” Friedman says. “We know, in animal models, the vaccine protection lasts for a long time in their life.”

The success of the COVID-19 mRNA vaccines has helped build confidence in this new approach to preventing herpes.

“We’re seeing the success of the mRNA vaccine, which was a brand new model, and we’re not seeing too many adverse reactions,” Awasthi says. “Seeing the mRNA vaccine being used safely in so many people in all age groups, from 5 years to 90 years old, it gives us a lot of confidence for the safety of this approach.”

The mRNA vaccine approach has a better chance of success than did the previous protein-based vaccines. “But there’s no guarantee,” Friedman says.

REFERENCE

1. Awasthi S, Friedman HM. An mRNA vaccine to prevent genital herpes. Transl Res 2021;S1931-5244(21) 00303-0.

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