We’ll soon have tools to protect infants against RSV. Can we put them to good use?

When scientists, physicians, and public health officials discuss RSV, the talk almost always turns to babies.

This ubiquitous infection can leave small children, especially infants, struggling to breathe. It petrifies parents. When RSV season hits, children’s hospitals are slammed by a surge in sick baby admissions.

Though scientists have worked for decades to devise tools — primarily vaccines — to protect against respiratory syncytial virus, they have done so without success. Until now.

An impressive number of vaccines and monoclonal antibody products are racing toward the end of the development pipeline, with two products aimed at protecting children expected to receive approval from the Food and Drug Administration by autumn. One, a maternal vaccine developed by Pfizer, received a recommendation last week from FDA’s vaccine advisory committee.

But there are sizable hurdles standing in the way of the implementation of these products, hurdles that could see the promise they offer squandered because of bureaucracy, health systems that don’t interact with one another, and steep price tags.

The medical professionals who care for the kids who struggle to breathe when they contract this pernicious virus are ecstatic they may soon have tools to prevent these infections, both for children and for older adults. They are also well aware of the challenges ahead, and are deeply worried those challenges may stand in the way of effective use of the vaccines.

“So it is wonderful to have these new tools that are an approach that will decrease disease and prevent kids, adults, pregnant women, elderly cancer patients from coming in the hospital and potentially prevent them from dying of this very common virus,” said Janet Englund, a pediatric infectious diseases specialist at Seattle Children’s Hospital who has been involved in RSV research for decades. “But if we don’t get them implemented, if we don’t use these tools, if we don’t get acceptance that RSV can be a spectacularly bad disease in young babies, then our work will not be that important.”

A number of the experts STAT interviewed for this article have either conducted studies for or have consulted with companies developing RSV vaccines or antibodies, and they readily disclosed those ties when asked by STAT. Some of this work has been remunerated; some of it has taken the form of unpaid consulting. But all of these people are emotionally invested in trying to prevent severe RSV infections with vaccines and other products.

The experts on federal government advisory committees quoted in this article must recuse themselves if they have any conflicts of interest related to a product under consideration.

RSV is so ubiquitous that by age 2, every child will have been infected at least once. They — we — go on to be reinfected multiple times over the course of a lifetime. For the majority of people who aren’t really young or fairly old, the infection is a nasty cold. But for humans at either end of the age spectrum, RSV infection can lead to hospitalization and even death.

The Centers for Disease Control and Prevention estimates that RSV kills between 100 and 300 children a year in this country — in the range of and some years more than the pediatric death toll of influenza. Globally, RSV is the No. 2 killer of children under the age of 1. (Malaria is No. 1.) In the United States, it is the most common cause of hospitalization of infants.

Soon, the country will have both a maternal vaccine that arms fetuses in utero with antibodies for the first months of life and an after-birth injection that will give infants antibodies to protect them from severe disease in their first year, if both, as expected, are approved by the FDA.

The antibody injection, nirsevimab, was developed by AstraZeneca and Sanofi; the latter is bringing it to market in the United States. It has been approved for use in the European Union and the United Kingdom, where it is marketed under the name Beyfortus.

Data from a trial presented at a scientific conference earlier this month showed an 83% reduction in hospitalizations for RSV-related lower respiratory tract infections, and a 76% reduction in very severe lower respiratory infections in babies who received nirsevimab compared to babies who did not.

The aforementioned Pfizer vaccine, which goes by the provisional name Abrysvo, is designed to take advantage of a phenomenon known as passive immunity — vaccinating people near the end of a pregnancy prompts them to generate antibodies that pass through the placenta to the fetus. Those babies are born with RSV antibodies already on board. A Phase 3 clinical trial showed a vaccine efficacy of 82% at 90 days after birth and 69% at 180 days when the goal was to prevent severe, lower respiratory tract illness in newborns and infants that required medical attention.

Up until now, the only tool to protect young babies has been an antibody therapy known as palivizumab. Sold as Synagis by AstraZeneca, the treatment requires monthly shots, the wholesale cost for which is $1,800, according to Elsevier Health. Given that price tag, it is used only in the highest-risk infants; about 2% of babies in the U.S. get it. But high-risk infants aren’t the only ones who end up in hospital with RSV. Healthy, full-term babies make up about 80% of children who are hospitalized for RSV.

Nirsevimab, which Sanofi hopes will get broad use, is a long-lasting formulation of antibodies that is given in a single shot; it will be substantially cheaper than palivizumab. But it’s unlikely to be cheap. A subcommittee of the Advisory Committee on Immunization Practices, which advises CDC on vaccination policy, has already expressed deep concern about the economics of giving this product to a broad swath of newborns.

A cost-effectiveness analysis done by CDC and University of Michigan experts was conducted assuming a per-dose cost of $300. Though Sanofi will not currently say what it plans to charge for nirsevimab in the U.S., the ACIP maternal and pediatric RSV work group believes the price might be $500 for newborns, and between $600 and $1,000 for high-risk children in their second year of life. Dosing is based on weight; the bigger the baby, the larger the dose, the higher the cost.

Sarah Long, a professor of pediatrics at Drexel University College of Medicine, chairs the RSV maternal and pediatric work group. At an ACIP meeting in February, she indicated the work group is torn over whether to recommend use of nirsevimab, if Sanofi sets such a high price.

“There was a sense that at the cost of $200, $300, this would be a go,” Long told the full committee. “And there was considerable trepidation for anything more than that.”

Sanofi knows there are concerns about where its price point will fall. “This is a monoclonal that we want to be treated like a vaccine,” Jon Heinrichs, global head of innovation and emerging sciences for Sanofi’s vaccines division, told STAT in an interview earlier this year. “So to make it available to the broad population, it needs to be priced in a similar way as a vaccine course would be.”

Merck is developing a competing monoclonal antibody, clesrovimab; it is in a Phase 3 clinical trial. If it succeeds, the competition could create downward pressure on the pricing of these products, said Ruth Karron, a professor in the department of international health at Johns Hopkins Bloomberg School of Public Health.

Beyond the issue of cost, nirsevimab faces other hurdles to get into broad use. Sanofi may want nirsevimab to be used like a vaccine, but it is not one. And that will create all kinds of deployment headaches.

Here is one of them: 53.6% of children in the United States are eligible to get their vaccinations through a CDC program called Vaccines for Children. VFC ensures that kids whose parents don’t have health insurance or who are underinsured can get vaccinated for free. American Indian or Alaska Native children are also eligible.

But VFC doesn’t cover drugs. Whether the per-dose cost is $200, $300, or $500, if nirsevimab isn’t included in VFC, babies from lower socioeconomic backgrounds may not be able to get this injection.

“To be equitable, it’s really got to be made available to all children. Because the burden of RSV is generally highest on disadvantaged kids, whether they’re Alaska native, Black or Hispanic, or just poor,” said Andrew Pavia, chief of the division of pediatric infectious diseases at the University of Utah, and director of hospital epidemiology, at Primary Children’s Medical Center in Salt Lake City.

It’s clear that policymakers are trying to figure out if there’s a work-around to resolve this dilemma. “I’m sure that there is a lot of discussion in a lot of offices about this,” Englund said. But it isn’t yet apparent if this circle can be squared.

Sean O’Leary, who chairs the American Academy of Pediatrics committee that updates the association’s bible on infectious diseases, “The Red Book,” sees myriad other difficulties ahead.

“No one’s really sure what would happen in [medical] practices if it was classified as something other than a vaccine. We don’t have a precedent for that,” O’Leary, who is the AAP’s non-voting representative on the ACIP, said at the February meeting.

As currently envisaged, babies born close to or during RSV season would get nirsevimab at birth. Babies are already given a birth dose of hepatitis B vaccine in this way. But most delivery hospitals don’t take part in VFC, said O’Leary, a professor of pediatrics at the University of Colorado School of Medicine and a pediatric infectious diseases specialist at Children’s Hospital Colorado. So even if nirsevimab is covered by VFC, they would not be able to get supplies through the program.

Many of these hospitals get paid a bundled fee to deliver a baby. The hepatitis B vaccine may not be covered in that fee, but at about $26 a dose, it’s not a make-or-break issue. “They can eat the cost, essentially,” he told STAT in an interview. “[Nirsevimab] becomes a much bigger deal for them to buy. And what I’ve heard from colleagues who are in hospital administration and neonatology who are making these decisions is they suspect that a lot of these hospitals will say: ‘Well, let’s give that in the pediatrician’s office because it’s going to be too hard to do it here.’ So the hospitals essentially may end up putting this on the pediatrician’s office, who may or may not be stocking the product themselves,” he said.

If that happens, it will create other challenges. In many pediatricians’ offices, medical assistants administer vaccinations. But in some states — like Washington — medical assistants are barred from administering biological products like nirsevimab. “There’s much interest and concern about the path forward,” said Englund, who is also a professor of pediatrics at the University of Washington.

Then there’s the fact that for non-VFC patients, pediatricians have to purchase products like these in advance, and then bill an insurance company after administration. Buying vaccines is the second largest outlay pediatric practices have, after staffing costs, said O’Leary, who noted that administering vaccines is pretty much a break-even operation.

“Let’s say a pediatric practice sees 100 newborns every month … and this product costs the practice $300 [per child]. That’s $30,000 a month,” he said.

And the pending introduction of nirsevimab is coming at a time when Covid vaccines are hitting the commercial market; both Pfizer and Moderna have indicated their prices will rise once private insurers are paying and the federal government isn’t picking up the tab.

“Most of these [practices] are operating as small businesses with very narrow margins,” O’Leary said. “The more I talk to people about this, the more barriers I see.”

Yet another problem O’Leary and others worry about relates to the other approach to protecting infants, the Pfizer maternal RSV vaccine. That vaccine may be unique among the panoply of vaccines currently in use. It will be given to pregnant people not to protect them, but to arm the babies they’ll give birth to with antibodies that will pass across the placenta.

While the maternal antibodies eventually dissipate, it’s expected they will last long enough to protect babies in their first six months of life, when their tiny airways make them especially vulnerable to severe RSV disease, if they become infected.

Getting pregnant people to take vaccines can be a challenge. (More on this in a bit.) But Karron anticipates a different type of problem. She worries that parents who are keen to protect their babies against RSV will opt for a belt-and-suspender approach, effectively saying “Well, you know, if that RSV [vaccine] that I get during pregnancy is good, and nirsevimab is really good, then maybe we should do both.”

“When there are children in the world dying of RSV that can’t get these products, for healthy [full-]term children in the U.S. to get both is an absolute waste of resources,” said Karron, who is also director of the Hopkins Vaccine Initiative.

Preventing unnecessary duplication won’t be easy, said Helen Chu, an associate professor of medicine at the University of Washington who specializes in adult infectious diseases. A pregnant person’s medical records, including the vaccines they received, may not be accessible to pediatricians trying to decide whether an infant should be given nirsevimab some months later. “When you deliver your baby, oftentimes the link between what has happened during pregnancy and what is happening at birth is not happening in real time,” she said.

In terms of the vaccine itself, the evidence suggests it will prevent severe infections early in life, saving infants and their families from the trauma of hospitalization, and preventing hospitals from being overwhelmed during RSV season. Broad use could lead to 20,000 fewer hospitalizations a year in the United States in this age group, and as many as 322,000 fewer illnesses that require medical care, Bill Gruber, Pfizer’s senior vice president of vaccine clinical research and development, told STAT.

Barney Graham, whose work (with others) on how to design effective RSV vaccines led to a number of the products that are heading towards the market, said delaying a child’s first symptomatic RSV illness until later could have long-term health benefits. Severe RSV in infancy is linked to wheezing and sometimes the development of asthma later in childhood.

“If we can prevent severe disease during those first six months of life when the lung is still in development, then we are hoping that that improves overall lung health for a lifetime,” said Graham, a professor of medicine and microbiology, biochemistry, and immunology at Morehouse School of Medicine.

(Graham, who is one of the patent-holders for the process for stabilizing RVS’s F protein — a development that opened the door to effective and safe vaccines — stands to gain financially from sales of the first round of RSV vaccines. Even if the vaccines are blockbusters, “it’s in the tens of thousands of dollars range, not the tens of millions,” he said.)

As with nirsevimab, this vaccine will only reduce the burden of RSV if it is used. And pregnant people are often reluctant to be vaccinated. Public health officials struggle every year to persuade them to get a flu shot; convincing them to get vaccinated against Covid-19 has been an even tougher slog.

Polling done earlier this year by the Annenberg Public Policy Center at the University of Pennsylvania showed that only 53% of women of childbearing age thought flu shots were safe to receive during pregnancy; 17% felt that statement was false. The distrust was more pronounced when it came to Covid vaccines, with only 42% of women saying they were safe to get during pregnancy and 31% saying they were not.

Karron worries about what lies ahead here. “If you consider Tdap” — the tetanus, diphtheria, and pertussis vaccine — “and flu, which are the two vaccines that we routinely offer to pregnant women, the uptake is about … 50% to 60%,” she said. “If the goal is to protect all infants, 50% to 60% doesn’t hit it.”

Meanwhile, Englund fears that distrust of science will undermine the benefits RSV prevention products could confer. “The United States has a huge challenge right now, due to a lot of people with differing opinions about the utility of science, the utility of vaccines, and … who to believe about medical care in general,” she said.

A survey conducted by the CDC, the University of Iowa, and Rand Corp. underscores the validity of her fears. Of a group of people who were either currently pregnant or who had been pregnant in the previous 12 months, 63% were more or as worried about the potential side effects their babies might experience from an injection of RSV antibodies as they were about how sick their baby might become if infected with RSV.

Concerns about the safety of being vaccinated against RSV during pregnancy may be further fueled by the fact that GSK stopped work on a maternal RSV vaccine after seeing more preterm births among women who received the vaccine than those who got a placebo in a Phase 3 clinical trial. There were also more neonatal deaths in the vaccine arm, a phenomenon that was considered to be a result of the increased number of preterm births, according to a poster GSK presented at an RSV science conference earlier this year. (See abstract 126 here.) This imbalance in preterm births was more pronounced in some of the low- and middle-income countries where the GSK trial was being conducted, rather than high-income countries.

“Although we’ve seen this imbalance, the overall incidence of preterm birth is low in both groups and remains below the preterm birth background rates for the majority of the participating countries,” a GSK spokesperson said via email. “We are still investigating the cause of the safety signal and, currently, do not have a mechanistic explanation for it.”

Pfizer also saw more preterm births in the vaccine arm of its trial, but the difference was not statistically significant. Furthermore, the phenomenon was only seen in a narrow band of upper- and middle-income countries in the Pfizer trial, said Gruber, and was not seen in high-income countries like the United States. He noted that if the vaccine is approved, Pfizer will do post-marketing surveillance for preterm births among pregnant people who get the vaccine.

“But right now, the benefit risk in our view, and I think the FDA will likely concur with this … greatly favors the vaccine, despite this sort of unusual finding,” he said. “My expectation is that we’ll find that it’s a spurious finding, but we need to do the post-approval studies to document that.”

Gruber also noted Pfizer did not see an imbalance in neonatal deaths in its study. “In our case, we’re actually seeing fewer deaths —  fewer infant deaths, fewer deaths amongst prematures. Now the numbers get very small when we’re talking, thankfully, about deaths. But nonetheless, the point estimates are lower.”

Despite the fact that Pfizer’s data do not precisely mirror GSK’s, there are concerns that the latter’s problem could color perception of the former’s product. “I think that might lead to hesitation,” said Chu.

It clearly did for the Vaccines and Related Biological Products Advisory Committee, the FDA panel that last week recommended the agency approve the Pfizer vaccine. The panel voted 14 to 0 on the question of whether Pfizer’s efficacy data is persuasive, but it voted 10 to 4 when asked whether Pfizer’s data proved the vaccine was safe, with much of the discussion centering around the preterm birth question.

Cost may also be an issue with this vaccine. Pfizer isn’t currently saying what it plans to charge for the maternal vaccine, but a cost-effectiveness analysis the company submitted to the ACIP used $200 a dose as the price point for the company’s adult vaccine. The same issue that faces pediatricians — buy in advance, get paid back when doses go into arms — faces obstetricians. “If you just do the simple math, depending on how big these practices are, it can be in the tens of thousands of dollars as an outlay,” O’Leary said.

Additionally, it will be important to establish if the maternal RSV vaccine can be administered at the same time as other vaccines given during pregnancy without depressing the immune system’s response to one or the other — an issue that deeply concerned some members of the VRBPAC panel. A couple of studies — not done in pregnant people — have shown that when RSV vaccine is administered at the same time as a flu shot or a Tdap vaccine, lower antibody levels to influenza and to the pertussis component of Tdap are generated then compared to what happens when those vaccine are given on their own.

Hana El Sahly, the VRBPAC chair, questioned if this solution — the RSV vaccine — might not trigger problems with other viruses that pose a risk to pregnant people and their babies.

“From an implementation standpoint, what are we going to tell our OB-GYN colleagues to prioritize and are we confident that giving these vaccines together or in proximity that is closer than one month apart that we would not be negatively impacting the health of the mother and the child?” she asked.

Despite this broad array of challenges, people in pediatric health insist ways must be found to effectively deploy these products — both here and globally, where the burden of RSV is huge.

“So the question is how are we as a world going to figure out how to make these interventions available and affordable for the whole world and not just high-income countries?” Graham asked. “That’s what I am more concerned about. People in high-income countries can make that choice, but people in low-income countries can’t make the choice unless they somehow get access.”