FDA approves first RSV vaccine, a long-sought scientific achievement

The Food and Drug Administration on Wednesday licensed the first-ever vaccine for respiratory syncytial virus, or RSV, completing an elusive quest that has been decades in the making. The product, GSK’s Arexvy, was approved for adults ages 60 and older.

GSK beat a crowded field of competitors to cross the finish line first. A vaccine that was developed by Pfizer and aimed at the same demographic is expected to be approved by the end of the month.

Phil Dormitzer, GSK’s senior vice president and global head of vaccines research and development, spoke of the sense of promise that many in the field of RSV research and prevention are currently feeling.

“There’s just the broad excitement of finally, after all these years, having good options emerging for RSV,” Dormitzer told STAT in an interview. “I guess also the triumph of the basic science — the fact that a very basic study … really changed the hunt for a vaccine and led to one or even more than one potential products coming forward to prevent RSV.”

The Centers for Disease Control and Prevention must recommend the vaccines before they can be pushed into the marketplace. That will likely happen after a CDC vaccine expert panel, the Advisory Committee on Immunization Practices, meets on June 21 and 22.

A vaccine to protect infants in their first six months of life — the age group at highest risk of being hospitalized with RSV — is expected to gain FDA approval later this year. Developed by Pfizer, it is designed to be given to pregnant people to generate antibodies that protect both the pregnant person and their newborn. Also up for approval soon is an antibody treatment, to be marketed in the U.S. by Sanofi, that would be given as an injection after birth or near the start of RSV season to protect in the first year of life.

In the United States, pediatric deaths from RSV are not common but the infection is the No. 1 cause of hospitalizations for children under the age of 1. Globally, however, it is the second leading cause of death in children under 1, after malaria.

The study paving the way for the development of these new tools involved the mapping of the crystal structure of what’s known as the F protein on the virus’ surface, the one that attaches to cells the virus invades. It was done by National Institutes of Health scientists who also figured out how to target the SARS-CoV-2 virus: Barney Graham, Jason McLellan, and Peter Kwong, among others. Graham is now at the Morehouse School of Medicine and McLellan is at the University of Texas at Austin; Kwong remains at the NIH.

Charting what the F protein looked like in its pre-fusion state was critical to creating vaccines that could trigger a safe and effective immune response through the production of antibodies that can neutralize the viral invader.

The safety issue was key. The work to develop effective RSV vaccines has been haunted by a clinical failure in the 1960s, when children who received an experimental vaccine in a trial experienced more severe disease than the children in the placebo arm. Two children, both under the age of 2, died.

That vaccine was made in a way that led to production of antibodies that targeted the post-fusion form of the F protein. This form of the RSV F protein does not induce production of neutralizing antibodies, which are important for controlling RSV infection and those post-fusion F antibodies failed to neutralize the virus. Analysis of lung tissue from the two toddlers who died showed that these infants had an abnormal inflammatory response to RSV that worsened the infection.

Graham and others spent years studying what went wrong with that early RSV vaccine. “We know how to put guardrails around that and avoid those kinds of things,” he said. (As one of the inventors of the process to fix the F protein in the pre-fusion state, Graham stands to earn royalties “to a certain capped amount” on the sale of vaccines that use this design.)

The risk of enhanced disease after vaccination in the 1967 trial was seen in children who had not previously been infected with RSV, experts explain. The vaccines in development today use a different design, one that includes the guardrails Graham spoke of. And older adults have decades of immunological experience with RSV viruses.

Phase 3 clinical trial data showed the GSK vaccine had an efficacy of 82.6% in preventing confirmed lower respiratory tract disease caused by RSV. The vaccine includes an adjuvant, a compound that boosts the response the vaccine triggers.

The GSK vaccine contains only one of the two RSV subtypes, RSV A. But studies conducted by the company showed that the vaccine is virtually equally protective against both RSV A and RSV B; the F protein on both is quite similar, Dormitzer said.

“Also, because older adults have all had RSV probably multiple times by the time they get [the vaccine], they’re primed against both A and B. So you’re able to get very solid boosting against both subtypes with a single adjuvanted F antigen,” he explained.

GSK is ready to start supplying the U.S. market for the upcoming RSV season, Dormitzer added. The company is also on the verge of getting full approval in Europe, and is seeking licensure in Japan, Canada, Australia, and other countries.

“The manufacturing is underway. And so we do not anticipate being supply constrained. We think we’ll be able to supply the demand starting in the fall … for the RSV season,” Dormitzer said.

RSV season has been unpredictable in the wake of the Covid-19 pandemic, though some experts believe RSV activity is moving back toward the seasonality seen in the pre-Covid days. In normal times, RSV season begins in about November, peaks in January, and ends in about April. But there was little transmission in 2020, when people were wearing masks and social distancing to avoid Covid. RSV returned abnormally early in 2021 — over the mid-to-late summer. An explosive season in 2022 in young children began in the late summer and early fall, peaking in November.

Experts who have eagerly awaited the advent of RSV vaccines acknowledge there is work to be done to persuade older adults and their doctors of the value of protection against this virus. The impact of the illness is well known in pediatric circles, but is far less recognized among adults; a lack of testing relegates RSV to the vague category of flu-like illnesses. All but the youngest of children have had RSV multiple times, but few of us would know with any certainty that this bad cold was caused by that bad virus.

In healthy adults, RSV generally manifests as a cold. But among older adults, adults with underlying heart or lung conditions, and people with weakened immune systems, the infection can descend into the lungs and trigger pneumonia.

The CDC estimates that in an average year among adults, RSV causes between 6,000 and 10,000 deaths, between 60,000 and 160,000 hospitalizations, and between 900,000 to 1.4 million medical encounters. Some experts, and the vaccine manufacturers, use slightly higher estimates.

Ann Falsey, an infectious diseases expert at the University of Rochester who specializes in RSV, said these numbers are likely low, because testing for RSV is not routine. In some places, testing is discouraged to save on costs, because there are no RSV antiviral drugs. The thinking is, she said: “If it’s not going to change your management, don’t test for it.”

Falsey recalled her colleagues’ surprise when RSV was added to multiplex tests that look for influenza and other respiratory viruses. “What is going on with RSV? Everybody has RSV,” she was told. Her reply? “Nothing’s going on with RSV. It’s always been there.”

Falsey and colleagues in Rochester did groundbreaking work in the late 1990s and early 2000s to try to capture the true extent of the disease burden caused by the virus, analyzing blood samples from older adults as well as swabbing their noses for virus. (Older adults don’t generate high levels of virus in their upper airways during RSV infection, making testing a challenge.)

“In our outpatient group, RSV was twice as common, but flu more frequently led to doctors visits and hospitalizations in healthy people,” she said. “And so, from our perspective, looking at the two illnesses, RSV was sort of a close second to flu.” Falsey has done unpaid consulting work for multiple companies working on RSV.

Though Arexvy’s approval is for adults 60 and older, it remains to be seen if the CDC will recommend it for that entire group. At an advisory committee meeting in February, members of a work group studying the adult vaccines that will soon come before ACIP indicated that at present, they don’t believe the vaccine would be cost-effective in people aged 60 to 64 and they would not recommend to the wider committee that it include people 60 to 64 in its recommendation for the use of the vaccine. (The group held the same position for the Pfizer RSV vaccine.)

If the CDC doesn’t recommend the vaccine for people in this age group, insurers will not be obliged to cover the costs, likely depressing uptake in people aged 60 to 64.

Falsey said that while healthy, active people in their early 60s may not need to be vaccinated, for others, the vaccine would offer important protection.

“[If] you’re out running marathons and biking 20 miles, and you’re not a smoker, you’ll probably do just fine with RSV. You won’t get terribly sick,” she said. “But there’s a lot of people in that age group that have underlying heart and lung disease. They have [chronic obstructive pulmonary disease]. They have heart failure. And those people are at markedly elevated risk for having a bad outcome.”