On the Precipice of the World’s First RSV Vaccine: What’s Taking So Long?

There’s a different respiratory virus making headlines this season. Respiratory syncytial virus (RSV) is a common respiratory virus that typically causes mild, coldlike symptoms. Although most people recover within 2 weeks, infants and older adults are susceptible to the worst of the infection.

Over the past few years, COVID-19– inspired preventive measures had the added benefit of reducing the incidence of other viruses like influenza and RSV. Now that practices such as masking and social distancing are falling out of favor, there has been an increase in other seasonal respiratory viruses.

RSV spiked early and violently this season, with infants under aged 6 months and adults older than 65 years experiencing severe and fatal infection. “We’ve actually had summer outbreaks of RSV in the past couple of years, which is very, very unusual” said Tina Q. Tan, MD, FAAP, FIDSA, FPIDS, a professor of pediatrics at Northwestern University’s Feinberg School of Medicine, medical director of the International Patient Services Program, co-director of the Pediatric Travel Medicine Clinic, and director of the International Adoptee Clinic at Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois.

The high rate of severe RSV infections is unprecedented, even in years before the public actively worked to lower disease transmission. The CDC reported¹ RSV hospitalizations for children up to aged 4 years peaked at 237.2 per 100,000 people, whereas hospitalizations in adults older than 65 years peaked at 17.6 per 100,000 people.

Overall hospitalizations this season peaked at 19.5 per 100,000 people. For reference, the previous high was a peak of 8.8 overall hospitalizations per 100,000 people, recorded during the 2019-2020 RSV season.

“It’s just been massively out of control this year.…People are acutely feeling it now due to the intensity of the peak,” said Iona M. Munjal, MD, director of clinical research and development at Pfizer.

Munjal explained that most children are exposed to RSV by age 5 years and easily clear the virus. Now, as schools and day cares begin to open post pandemic, large numbers of young children are experiencing severe RSV after being exposed to the virus for the first time.

RSV was first formally identified in the 1950s. Since then, Munjal said, there have not been elective solutions. “There is a single monoclonal [antibody] that you give to infants that is very, very costly, and it requires a monthly injection, so it’s only given to high-risk infants.”

There is another extended-duration monoclonal antibody completing phase 3 trials, which Tan called a “very promising development.” This monoclonal antibody would be for healthy preterm and term infants greater than 29 weeks gestation. If authorized, infants would receive a single dose of this monoclonal antibody prior to RSV season, and the dose would last the entire RSV season.

A high incidence rate of RSV does not mean other respiratory viruses have disappeared—quite the opposite, as fears of a confluence of RSV, influenza, and COVID-19, which some are calling a “tridemic,” are very real. “In addition to those 3 viruses,” said Tan, “there are other respiratory tract viruses that are also circulating that play into this mix.”

Unlike COVID-19 and flu, there is no approved vaccination to combat RSV. However, this may be about to change. The COVID-19 pandemic clearly demonstrated the rapidity with which an elective vaccine can be developed when there is a drastic unmet need. RSV has been circulating for decades longer than COVID-19, so why has it taken so long to get this close to the first authorized RSV vaccine?

According to Munjal, RSV is particularly elusive. “What’s really interesting about RSV is that it comes in, it changes its shape, and then it attaches to the human host cell,” she explained. “This shape change was something we didn’t know at first.”

Tan reiterated the challenging structure of the RSV organism. She said there are a few RSV vaccines that have successfully completed phase 3 clinical trials and will soon be submitted to the FDA for licensure.

Pfizer’s bivalent RSV prefusion vaccine candidate, RSVpreF or PF-06928316, accounts for the virus’ shape change. “We target the prefusion form of the virus,” said Munjal. The vaccine candidate is administered to pregnant people to help protect their infants from RSV after birth.

In December, Pfizer submitted, and the FDA accepted for priority review, a biologics license application (BLA) for RSVpreF for the prevention of RSC disease in older adults.

That we are finally on the precipice of the first approved RSV vaccine makes it easier to talk about this season’s high incidence, Munjal added. “I think that when you have solutions, people are more able to talk to the problem,” Munjal said, “because otherwise, it’s frustrating.”

Tan specifically noted that the Pfizer maternal vaccine is the most promising. “The pregnant [person] gets a dose of this vaccine,” she explained, adding that “data from the phase 3 trials show that [the vaccine] is 82% elective in preventing RSV lower tract disease in infants during the first 3 months of life. So it is very, very promising.”

There are other RSV vaccines on the horizon, albeit not as far along as the Pfizer maternal vaccine. “There are some RSV vaccines that are still in very early clinical trials,” said Tan. “These are intranasal RSV vaccines that will be used in children somewhere between 6 months and 24 months of age.”

Munjal said Pfizer is focused on maternal vaccination because of its safety and efficacy. “I’m a pediatrician. If I could prevent half of the babies coming into the hospital, I would,” she said. “Eight-two percent [efficacy] for me is a really, really amazing achievement for the vaccine. And we’re very excited.” Munjal also noted maternal vaccination ensures high levels of antibodies are passed to infants. “We found that in some cases, moms were passing more antibodies to the baby than they kept to themselves.…So relatively, they’re transferring a very, very high load of antibodies to the baby,” she said.

Respiratory viruses can be especially dangerous for pregnant people and their infants. Unfortunately, there has been an uptick in vaccine misinformation during the COVID-19 pandemic that could impact vaccinations among the most vulnerable populations.

“I think one of the biggest misconceptions is…that moms aren’t into taking vaccines,” said Munjal. “We’ve shown that in countries in which vaccines can be widely available, the uptick in the pregnant population is really quite good.” Munjal also emphasized that although the United States is experiencing a high rate of RSV in infants, these infections can be even more fatal in other nations. Therefore, the Pfizer RSV vaccine trials included participants across a number of other countries. “Outside of the United States, we have [data from] 17 other countries.…We thought it was equally important to gain data in those countries.”

As previously noted, older adults are also disproportionately likely to experience severe or fatal RSV disease progression. Munjal said that Pfizer plans to submit a BLA for both maternal and older adult populations. “The same dose that we give to pregnant women showed efficacy this year in older adults.”

The most common symptoms of RSV are congestion or runny nose, coughing, loss of appetite, fever or chills, sneezing, sore throat, and wheezing. Although these do overlap with COVID19 and flu symptoms, sneezing and wheezing specifically are unique to RSV.

The best way to know whether one is experiencing RSV, Tan said, is to get tested—especially if the infected person is a young child or older adult. “If you have someone presenting to you [who] is sick enough to seek medical care, you really need to test them to determine which one of these viruses, or ones of these viruses,” she said. Coinfection can occur and knowing how to treat these patients can be lifesaving.

In the past people experiencing symptoms of RSV would settle for simply calling it the common cold. But, Munjal pointed out, the severity of the COVID-19 pandemic has heightened our attention to respiratory viruses. “I think from a pediatric perspective, I’m always struck by how prevalent the virus is,” said Munjal, noting that “almost 100% of kids have this by age 2, so you don’t get away from RSV. It’s so prevalent and so contagious that almost everyone is exposed.”

Munjal also explained why RSV is so much deadlier for infants and young children: RSV causes a large volume of fluid to build up in the lungs. Although this is only mildly dangerous for adults, who have a large breathing tube, “babies are breathing through a breathing tube that’s the size of a straw.... [When] it completely fills up with fluid, you see them struggling to breathe,” said Munjal.

“Since the 1960s, you say, ‘Oh I know your baby has RSV, and there’s nothing I can do,’” Munjal explained. An RSV vaccine would certainly be beneficial on a global level, by significantly reducing the strain on hospital resources. But Munjal noted a vaccine is also about “that really, really impactful, patient-by-patient experience.…That’s the joy in this vaccine—you can finally say, ‘I have something to offer.’"