It's probably an understatement to say that scientist and co-founder of 2015 startup Rational Vaccines Inc. (RVx) William Halford is not impressed by the current state of efforts aimed at treatment and prevention of the rapid spread of the herpes virus – neither the persistent use of subunit vaccine technology nor the lengthy FDA development timelines.

"The reality of the situation is that 4 billion people" worldwide have herpes, Halford said. The World Health Organization estimates roughly 3.7 billion with oral herpes (HSV-1) and roughly a half billion with genital herpes (HSV-2). In the U.S. alone, about 3 million people infected with HSV-2 suffer "high-level chronic disease," meaning their symptoms recur anywhere from three to 30 days per month. Existing treatment with antivirals such as acyclovir and Valtrex (valacyclovir have limited efficacy – primarily due to low reductions in viral shedding – and have done little to slow the spread of herpes.

The past two decades have seen the rise of glycoprotein subunit vaccines with mixed results – candidates from the likes of Chiron Inc., Glaxosmithkline plc and Vical Inc. all ended up failing in late-stage testing. Glycoprotein D-based subunit approaches from Genocea Biosciences Inc. (GEN-003) and Admedus Ltd. are still in the works, with both firms reporting reductions in viral shedding in phase II trials with their respective candidates this year. But Halford said the reductions seen to date with subunit vaccines are only a fraction of the efficacy possible when compared to a live, attenuated herpes vaccine. (See BioWorld Today, June 24, 2015, and April 1, 2016.)

Halford, who currently serves as an associate professor in the Department of Medical Microbiology & Immunology at Southern Illinois University, has been researching herpes since the early 1990s and said an engineered live vaccine candidate could affect reductions in viral shedding of 50-fold to 100-fold.

Live vaccines have worked wonders in global health care, targeting viral diseases ranging from smallpox to chickenpox. But it has long thought to be too dangerous to develop a live herpes virus vaccine. In the 1970s, that fear was predicated on the subsequently disproved link of HSV-2 to cervical cancer – human papillomavirus turned out to be the culprit – and later the worry was that patients would end up infected with herpes, concerns that weren't completely unfounded, given that a small number of patients receiving the live polio vaccine developed active disease.

But those vaccines were developed long before researchers were able to sequence genomes. "They were all developed before we had any other option," Halford said. "We just did the best we could with what we knew."

The subunit vaccine technology emerged as an effort to create a synthetic vaccine, the idea being that "you don't really need the whole infectious agent; you can just cut out a small piece and it should work just as well and be a whole lot safer," he said.

A nice idea. The problem, according to Halford, is that the new subunit approach was never tested head-to-head against a live vaccine. "So everyone assumed that synthetic vaccines will work as well as all those live vaccines," he said. "There's not a shred of evidence that that is true."

Halford's lab in 2011 published a preclinical study in PLOS One that pitted a glycoprotein D-2 subunit vaccine against a genetically engineered, live, attenuated virus. Only three of 45 mice receiving the subunit vaccine survived an overwhelming challenge of the vagina or eyes with wild-type HSV-2, compared to 114 of 115 mice immunized with the live vaccine. Mice in the live virus arm also shed an average of 125-fold less HSV-2 challenge per vagina relative to the subunit-immunized mice.

The reason for that sounds like a no-brainer. A subunit vaccine encodes for one glycoprotein; "you've sort of glossed over the fact that there are 74 other proteins," Halford said. A live vaccine is capable of what he calls "antigenic breadth," encoding for a suite of the HSV-2 genetic proteins.

Advancements in technology allowed Halford to genetically engineer a live vaccine to address the possibility of inducing active disease. Both the therapeutic and preventive vaccines in development – Theravax and Profavax, respectively – have been engineered with specific deletions within the ICP0 gene aimed at impairing the viral spread. ICP0 "is kind of like a gas pedal for the virus," Halford explained. "So we're chopping that out.

"Scientifically, that means we can make live vaccines as we did before, but we can do it even better with 21st century technology."

Nonetheless, it's an argument that has failed to sway the NIH, and Halford's frustration at the lack of funding is clear. "It's a perfectly simple idea that I've been putting forth, and for 10 years has been getting killed in the back room at the NIH," he said. On top of that, the FDA has been hesitant about live herpes vaccine development, at least while subunit vaccines remain in the clinical pipeline.

It became clear to Halford that if he wanted to advance the live, attenuated vaccine approach, he would have to look outside the traditional funding and regulatory mechanisms.

THE OTHER HALF OF THE STORY

Halford found an ally and RVx co-founder well outside the biopharma mainstream.

Agustin Fernandez is a movie and television producer – with both an Oscar and an Emmy to his name – and had a previous medical investment "that worked well for me," he said. "I knew someone suffering with herpes, and dove into researching as much as I could . . . looking at where to put my time and money." He discovered Halford's research and blog.

"It made sense to me, what [Halford] was saying," he added. "All these live viral vaccines have always worked, and now we can attenuate it for safety. These subunit vaccines are failing forever.

"So it was a personal passion combined with the fact that this was the only guy making sense in the field."

Fernandez, who serves as RVx's CEO, also brings a different perspective. "If I have any other strength . . . it's that I'm not hindered by any of the rules. I'm coming at it with a clean slate. So it's a lot easier to see from that point of view."

That view helped Halford figure out how to advance his herpes vaccine program. Fernandez "contacted me in 2011 and basically badgered me for six to nine months on why I couldn't take this vaccine forward," he said. "He basically gave me the other half of the story," namely the perspective of people with herpes who waiting for more effective treatments.

"Ultimately, that's how the company was formed," Halford said.

The founders raised a small amount – about $700,000 – to fund the first clinical trial, aimed primarily at testing the vaccine's safety. And they decided to go outside the U.S. to conduct the study. "I talked to the NIH and the FDA for 10 years; I know they're not budging," Halford said.

RVx chose St. Kitts in the Caribbean, with patients from the U.S. and U.K. flying to the island to participate in the phase I trial testing Theravax. The trial met its primary goal of establishing the safety and tolerability in patients who suffer with recurrent genital herpes caused by HSV-1 or HSV-2, which for Halford came as no surprise since "basically all the theoretical underpinnings that led scientists in the 1970s [to declare a live herpes vaccine too dangers] have been proven time and time again wrong."

RVx's clinical trials "was like putting the cherry on top of an ice cream sundae," he added.

Secondary measures asked patients, who were enrolled with self-reported recurrent genital herpes and screened for HSV-1 or HSV-2 antibodies, about their symptoms. All 17 participants who received the three-shot vaccination series indicated Theravax HSV-2 was more effective in reducing their genital herpes symptoms than antiviral drugs. On average, participants reported a 3.2-fold reduction in the number of herpes-symptomatic days per month relative to years of experience taking antiviral drugs.

"All patients had to go off antivirals," Halford said. "And all 17 said, 'Oh, this [vaccine] is better.'"

He said the goal at RVx is to get the vaccines to patients as quickly as possible. Given the phase I results, "I don't think money-raising is the rate-limiting factor," he said. The next step likely will be finding a home, which will undoubtedly be outside the U.S., where, in addition to the current FDA pushback, there involves a lengthy development process.

"Probably the highest priority for us as a company is to find a venue like St. Kitts where we can simply make this vaccine available," Halford said. "We are absolutely interested in finding a path to the global market, running another five to 10 clinical trials – there's really a lot more to herpes than genital herpes." RVx also has a prophylactic vaccine in the works as well as a diagnostic program.

"Our mission here is not to bash the FDA," he told BioWorld Today. "It just created a system so that, in 2016, it's simply not possible to develop a vaccine that works really well on a responsible time frame."

It's an issue "we need to revisit," he added. "There are a lot of diseases like AIDS that are potentially vaccine preventable. We have to untie people's hands."