As the monkeypox outbreak continues to grow, one thing seems abundantly clear. The global need for monkeypox vaccine outstrips the supply, and will likely continue to do so for quite some time.
Scientists at the National Institutes of Health are getting ready to explore a possible work-around. They are putting the finishing touches on the design of a clinical trial to assess two methods of stretching available doses of Jynneos, the only vaccine in the United States approved for vaccination against monkeypox.
They plan to test whether fractional dosing — using one-fifth of the regular amount of vaccine per person — would provide as much protection as the current regimen of two full doses of the vaccine given 28 days apart. They will also test whether using a single dose might be enough to protect against infection.
The first approach would allow roughly five times as many people to be vaccinated as the current licensed approach, and the latter would mean twice as many people could be vaccinated with existing vaccine supplies.
The answers the study will generate, hopefully by late November or early December, could significantly aid efforts to bring this unprecedented monkeypox outbreak under control. At this point more than 25,000 confirmed cases have been reported this year by more than 80 countries, with more than 6,600 of those cases having been detected in the United States.
“The questions that the folks at NIH are asking are very important questions,” Myron “Mike” Levine, a vaccines expert who is not involved in organizing the trial, told STAT. “Can we take the doses of [Jynneos] that we have now and can we immunize more people and maybe with one of the options faster, than if we used it at the dose that it’s now licensed to be used at?”
The current outbreak, the first outside of countries where the monkeypox virus is endemic in small forest animals, was first detected in mid-May in the United Kingdom. Health authorities there found four cases in gay, bisexual and other men who have sex with men who had not traveled to countries where monkeypox is endemic. In the weeks since, the virus has spread internationally, predominantly still in networks of men who have sex with men.
Demand for monkeypox vaccination surged when the federal government began to release doses of Jynneos — originally developed by the Danish vaccine maker Bavarian Nordic as a countermeasure against smallpox — to states and territories reporting monkeypox cases. Currently in this country, vaccine is being made available to people who are contacts of known cases, as well as men who are at high risk because of presumed exposure.
Though the Food and Drug Administration and the Centers for Disease Control and Prevention have stressed that the vaccine should be used as licensed — the two-dose regimen — several locations have announced they will only give first doses for now to try to give more at-risk people some protection. Others have said they’ll give single doses to some people who come forward to be immunized, but will only give second doses to men considered to be at high risk.
“There’s not a consistent message here. But it’s clear that some people are getting one dose now for six months or maybe longer,” said John Beigel, associate director for clinical research in the division of microbiology and infectious diseases at the National Institute of Allergy and Infectious Diseases, who is involved in designing the trial.
Beigel, who described the study earlier this week during a meeting organized by the World Health Organization to flesh out the research needed on monkeypox vaccine, said in an interview that the plan is to enroll 210 people in this three-arm trial. The study will be conducted over six to eight trial sites in the U.S., he said, and will start later this month or in the first half of September.
One-third of the subjects, the comparator arm, will receive two full doses of Jynneos given 28 days apart. A second group will get a single full dose of vaccine. The third group will also get two doses, given 28 days apart. But these doses will each be one-fifth of a full dose and the vaccine will be administered into the skin — intradermally — rather than into a muscle.
The study will not evaluate how protective the various regimens are. To generate vaccine efficacy estimates, much larger clinical trials involving thousands of participants would need to be conducted. Instead, the goal will be to study whether the two dose-sparing approaches generated antibody levels at least equal to what the two-dose regimen does. The study will also compare the tolerability and reactogenicity of giving the vaccine via the two different routes.
It’s long been known that intradermal vaccination, which involves slipping a small needle just under the top layer of the skin, can activate powerful immune responses, even using low doses of vaccine. But it’s a technique that isn’t commonly used, so vaccinators would need to be trained. And this approach can cause some short-term discomfort for vaccinees, Beigel said.
“Subcutaneous [administration] actually had more pain than the intradermal but intradermal had more itchiness and redness,” he said. “Realistically what we might be stuck with is to say … we can extend the vaccine supply five-fold, but we’re going to have to have people put up with more redness … and itchiness. And is that a tradeoff that people are willing to make?”
There is good reason to think fractional dosing will work. Vaccine manufacturers often err on the side of larger, not smaller, when they are conducting the initial dosing trials for new vaccines. Using dosages that are high enough to prove protection the first time round is more important than trying to figure out what the lowest effective dose might be.
Consider HPV vaccine. Originally licensed as a three-dose product, it is now given in two doses in some cases and earlier this year an expert panel that advises the WHO on vaccine policy concluded that one dose was sufficient for girls and women under the age of 20.
“There is lots of evidence, with viral and bacterial vaccines, that the vaccine that gets licensed is often much more than you need,” said Levine, associate dean for global health, vaccinology, and infectious diseases at the University of Maryland’s School of Medicine.
Fractional dosing in outbreak settings has been used effectively in the past. Several years ago when a large yellow fever outbreak in Angola and the Democratic Republic of the Congo nearly tapped out global supplies of yellow fever vaccine, the WHO recommended use of one-fifth doses.
Still, just because an approach has worked in some circumstances doesn’t mean it is assured to work in this situation, Levine cautioned. “Every vaccine is different. This is one of the important aspects of biologics: You take nothing for granted.”
Beigel is a little skeptical the one-dose approach will prove to be effective, even though there are data from a study in primates that showed they were protected from what should have been a fatal dose of monkeypox virus by a single dose of vaccine.
The animals were not fully protected, he said, noting they developed some pox lesions.
“It seems to keep monkeys alive, but it didn’t prevent the disease — or at least it didn’t prevent the disease entirely. So none of [this is] completely reassuring to me that one dose is going to be sufficient,” Beigel said.