Prime and pull vaccine approach prevents genital herpes infection

Genital herpes is a lifelong infection. While available treatments can manage symptoms, they cannot cure the infection or prevent transmission. Now, Yale School of Medicine researchers have taken a significant step toward a genital herpes vaccine that in preclinical models prevented infection.

In a study published June 19 in Science Immunology, researchers evaluated a two-part vaccination against genital herpes. With the technique, the first part - a typical intramuscular injection like you would receive for a flu shot, for example - is followed by the introduction of nanoparticles to the vagina, where herpes infection occurs in women.

The idea is the initial injection "primes" the immune system while the second localized treatment "pulls" immune activity right to where infection takes place. This study extends the original "prime and pull" approach by developing a new nanoparticle that effectively induces local immunity.

We've found that, in preclinical experiments, this approach is a safe way to recruit the right immune cells in the right place to generate protective immunity."

Akiko Iwasaki, senior author, Sterling Professor of Immunobiology, Yale School of Medicine

A two-pronged vaccine for genital herpes immunity

Efforts to develop a genital herpes vaccine have uncovered a key limitation of typical intramuscular injections: They do not establish robust immune cell populations or antibodies against the herpes virus at the vaginal lining where the virus is introduced in women. This limits the extent of immune attack against the herpes virus.

To address this challenge, the Iwasaki lab has explored methods to "pull" an immune response to the vaginal lining. They first tested whether introducing chemokines - proteins that can direct immune cells - to the vagina could establish immunity there. That technique led to only partial protection against herpes as it did not engage necessary immune cells called B cells.

They then evaluated a DNA molecule that stimulates the immune system. While it did reduce the amount of virus at the vagina, it also caused inflammation.

So the researchers wondered if combining the two methods might yield the best of both worlds.

"We had these two really promising strategies in the lab, but each had some shortcoming," said Sachin Bhagchandani, a postdoc in Iwasaki's lab and lead author of the study. "So we set out to formulate a particle that could overcome those shortcomings."

Nanoparticles prevent herpes infection

The result of that work is BEACON (Bioactive Enhanced Adjuvant Chemokine Oligonucleotide Nanoparticles). The researchers made these nanoparticles by linking a piece of immunostimulating DNA to a chemokine.

"Sachin led this work, creating a nanoparticle that was stable and effective, which was no small feat," said Iwasaki, who is also a professor of dermatology and of epidemiology, as well as an investigator with the Howard Hughes Medical Institute.

For the study, the researchers first primed female mice with an intramuscular vaccination against the herpes virus and then applied BEACON and virus antigen intravaginally. They found that BEACON established strong immune cell and antibody responses against the herpes virus in the vaginal tissue and that it lasted long term, at least six months.

When exposed to the herpes virus, mice given the "prime and pull" treatment were highly resistant to infection: 80% displayed no signs of disease over six months. That's compared with just 40% of mice that received the intramuscular injection alone.

"That showed us that this approach could be profoundly impactful, establishing local immune responses for a significantly long period of time," said Bhagchandani.

Further, BEACON enabled the researchers to target the right cells for generating immunity, rather than broadly affecting all cells. This meant they needed less of the DNA molecule than they used in previous experiments, and this smaller amount prevented the development of inflammation.

"This formulation is quite remarkable in that way," said Iwasaki.

A vaccine for humans

The researchers are now evaluating whether this "prime and pull" method can be used to treat infection as well as prevent it. They're also thinking about what this might look like for people.

"We're collaborating with the Appel lab at Stanford to see if we can turn BEACON into translatable formulation, such as a vaginal suppository," said Bhagchandani. "We're also exploring a nasal approach wherein the 'pull' happens in the nose, which would allow this kind of treatment to work for men as well."

While further down the road, the researchers aim to test this method in human clinical trials, because ultimately, the goal is to develop a vaccine for humans.

"A lot of the suffering patients go through is not just physical; it's mental and societal," said Iwasaki. "But viruses are the same - whether it's the flu or Epstein-Barr virus or herpes simplex, it's not the person's fault that they caught it. And yet there's a lot of stigma. We hope that this kind of strategy will prevent diseases that affect people in a profound way."