Update: The FDA and CDC have signed off on both the monoclonal antibody and the maternal vaccine.
On July 17, the FDA approved the monoclonal antibody injection, Beyfortus, for newborns and infants in their first RSV season and for children at risk of severe disease in their second RSV season, up to 24 months of age.
On Aug. 3, the CDC recommended that all babies born during the RSV season, or entering their first RSV season at age 8 months or younger, get one dose of the monoclonal antibody. Some children, those at increased risk of severe disease from RSV, also should get one dose before their second RSV season, up to 19 months of age.
The FDA approved Pfizer’s maternal vaccine, Abrysvo, on Aug. 21 for pregnant individuals at 32 to 36 weeks of gestation.
On Sept. 22, the CDC recommended Abrysvo for pregnant people at those stages of gestation on a seasonal basis, meaning they would get it if their babies would be born during the RSV season.
The CDC said either the monoclonal antibody or the maternal vaccine could be used to protect babies from serious illness from RSV. “Most infants will likely only need protection from either the maternal RSV vaccine or infant immunization, but not both,” the CDC said in a press release. “However, for example, if a baby is born less than two weeks after maternal immunization, then a doctor may recommend that the baby also receive the infant immunization.”
Nearly all children get sick from respiratory syncytial virus, or RSV, by the age of 2, and last year, there was a notable surge in RSV-associated hospitalizations. But the Food and Drug Administration is now considering approval of a vaccine and a monoclonal antibody aimed at protecting infants from this common virus. We’ll explain what we know so far about these medical products and the risks of RSV for young children.
RSV circulates in colder weather and causes a mild cold in most people. But infants and older adults can experience serious and dangerous illness. As we explained in a companion story, several potential vaccines for older adults are in the works, including one from Pfizer and another from GSK that could get a decision from the FDA in a few months.
Pfizer’s vaccine also has been administered to pregnant people in a clinical trial to determine whether the antibodies they develop in response to vaccination can then protect their babies up to 6 months of age. The company has applied for FDA approval for that use as well. Meanwhile, Sanofi and AstraZeneca have asked the FDA to approve a monoclonal antibody injection for newborns and infants, which, while not a vaccine, would act like one in preventively protecting babies from RSV illness.
As we’ve reported, children’s hospitals across the country were at full capacity last fall due to a spike in RSV infections. But scientists have been working on ways to prevent the illness for decades, and the current crop of candidates is due to scientific advances in 2013.
We don’t know if the products — both those for older adults and those for infants — will be approved by the FDA. But if they are, they could be available for the next RSV season this fall.
What is RSV illness in children, and why are these products being proposed now?
Nearly all children will get RSV, which typically circulates in the fall and winter, by the time they’re 2 years old, the Centers for Disease Control and Prevention says. While the virus causes cold-like symptoms, including runny nose, cough and fever, babies younger than 6 months old may only exhibit difficulty breathing, irritability and a reduction in activity or appetite.
Young and premature babies and infants with heart or lung disease, or weakened immune systems, are particularly susceptible to severe infection due to RSV. The virus is the leading cause of pneumonia and bronchiolitis — infection and inflammation of the lungs, respectively — in kids younger than 1, the CDC says.
The CDC estimates that 58,000 to 80,000 children under 5 years old are hospitalized each year because of RSV and that among every 100 babies under 6 months of age with RSV, 1 to 2 may need hospitalization. Deaths are “uncommon,” in the U.S. the CDC says, at an estimated 100 to 500 each year for kids under 5.
Worldwide, an estimated 45,700 babies up to 6 months of age died due to RSV in 2019, and more than 100,000 children up to age 5 died, according to a systematic analysis of hundreds of studies published in the Lancet. The researchers said that “more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries.”
As we explained in our story on the older adult vaccine candidates, the search for a safe and effective vaccine began many years ago. The field got off to a bad start when a trial testing an inactivated RSV vaccine for young children in the 1960s backfired. Instead of preventing infections or illnesses, the vaccine, which was made from killed virus, made infections worse. Vaccinated kids developed more severe disease than those who were unvaccinated when they were infected with RSV for the first time, and two infants died.
Nearly 50 years later, scientists had a breakthrough. In research published in the journal Science in 2013, they stabilized the pre-fusion form of the virus’s F protein — the protein the virus uses to enter human cells — and found that it sparked highly protective antibody responses in animals. The discovery came from a team at the National Institute of Allergy and Infectious Diseases, which is part of the National Institutes of Health.
Once the F protein fuses with cells, it changes into a post-fusion form, and targeting that post-fusion form, as some other vaccine candidates have done, produced a much lower immune response.
The vaccine and antibody candidates we’re seeing now target the pre-fusion F protein, building on that fundamental work by the NIH.
What are the potential vaccines for pregnant people?
In February, the FDA accepted Pfizer’s application for its maternal vaccine candidate.
The vaccine is the same formulation as Pfizer’s vaccine for older adults, but it would be given to pregnant people in order to pass antibodies on to babies to protect them from birth to at least 6 months of age. Pfizer expects a decision from the FDA in August.
“Starting immunization in the second trimester of pregnancy, protective antibodies are naturally passed from the mother’s circulation across the placenta and to the developing fetus,” Pfizer told us in an email. “Maternal immunization takes advantage of this natural process, resulting in infants having maternally derived protective antibodies at levels similar to or even higher than their mother.”
The vaccine is a protein subunit vaccine — like the hepatitis B and pertussis vaccines. It is made from pre-fusion F protein from RSV-A and RSV-B, subgroups of the virus; the pre-fusion F protein prompts an immune response but can’t cause RSV disease.
GSK also developed a protein subunit vaccine for older adults, and it was testing a nearly identical version for pregnant people. But in February 2022 GSK voluntarily stopped its clinical trials due to a safety signal: an imbalance in preterm births that it is investigating. (See below for more on this.) Unlike the older-adult version, the maternal vaccine doesn’t include an adjuvant, which boosts immune responses.
The older-adult vaccines are further along in the FDA approval pipeline. The FDA’s outside advisory group — the Vaccines and Related Biological Products Advisory Committee — has already met to discuss them.
What is the antibody for infants?
Sanofi and AstraZeneca have developed a monoclonal antibody, nirsevimab (pronounced nur-SEV-i-mab), to be administered as a single-dose shot to newborns or infants before their first RSV season to protect against RSV illness. The drug, which has the brand name Beyfortus, was already approved by the European Commission last fall.
Sanofi says it expects a decision from the FDA in the third quarter of this year.
Monoclonal antibodies are lab-produced antibody clones that mimic the actions of natural antibodies in preventing disease — in this case, nirsevimab targets the pre-fusion F protein of RSV.
“As a monoclonal antibody, nirsevimab does not require the activation of the immune system to help offer timely, rapid and direct protection against disease,” a Sanofi spokesperson told us.
Babies 11 pounds or more would receive the full 100 milligram dose, while smaller babies would receive a half dose.
There is another monoclonal antibody on the market to prevent RSV illness in infants, but it’s only recommended for some premature babies or high-risk children. The drug, palivizumab (pronounced pal-i-VIZ-oo-mab), with the brand name Synagis (SIN-uh-jis), is administered monthly during the RSV season, typically for five months. It was approved by the FDA in 1998, after a clinical trial showed a 55% risk reduction for RSV-associated hospitalization for infants who were born prematurely or children with chronic lung disease.
The idea of giving palivizumab to all infants “never had any real traction,” Dr. William Schaffner, medical director of the National Foundation for Infectious Diseases and also a professor of preventive medicine and infectious diseases at the Vanderbilt University School of Medicine, told us. The level of effectiveness of the drug is beneficial to high-risk children, but it “wasn’t sufficient,” particularly when the treatment required multiple injections, to give to all infants.
Preterm infants are also at the highest risk of developing bronchiolitis or a very severe RSV infection, he said.
Nirsevimab appears to be more effective in reducing hospitalization, even in full-term infants — more on this below — and only requires one injection. Schaffner noted that while the drug manufacturers hope nirsevimab will be offered universally to all infants, it remains to be seen what recommendations the CDC’s Advisory Committee on Immunization Practices and the American Academy of Pediatrics will make to pediatricians.
On Feb. 23, a maternal/pediatric RSV work group for the CDC’s ACIP presented its findings on nirsevimab, saying the work group would recommend the antibody for all infants in their first RSV season — at birth for those born in October to March and before the RSV season for other babies up to 8 months of age. A child’s first RSV infection is typically the worst.
In a child’s second RSV season, the work group favored recommending nirsevimab for high-risk children eligible for palivizumab, because it would be cost-effective. But the work group said it would need more time to consider which children would be at sufficiently high risk to receive the drug in their second season.
These recommendations are not the final word from the CDC, but rather feedback from the work group. If the FDA approves nirsevimab, the entire advisory committee will vote on these policy questions.
What do we know about the efficacy and safety of Pfizer’s vaccine?
The FDA’s advisory committee hasn’t discussed this vaccine; however, Pfizer’s Dr. Iona Munjal, senior director of vaccine research and development, presented data from a phase 3 clinical trial to the CDC’s ACIP on Feb. 23. (For more on the FDA approval process and clinical trial phases, see this graphic.)
The phase 3 study began in June 2020, enrolling nearly 7,400 pregnant participants in 18 countries, with half receiving the vaccine and half getting a placebo. Nearly all participants got the vaccine or placebo at 24 to 36 weeks gestation. The average age of the mothers was 29.
Among the infants, 7,128 continued with the study. About half were enrolled in the first year and are being followed for 24 months. The rest are followed for one year.
The study showed a vaccine efficacy of 81.8% against severe RSV-confirmed lower respiratory tract illness requiring a medical visit in the first 90 days after birth. Efficacy was 69.4% through 180 days after birth.
Efficacy is a measure of reduced risk for those receiving vaccination, compared with those who aren’t vaccinated.
Severe illness in the study was defined as at least one symptom including tachypnea, or rapid breathing; low blood oxygen; mechanical ventilation or supplemental oxygen therapy; or ICU admission for more than four hours or being unresponsive/unconscious.
There were 63 hospitalizations due to RSV up to 180 days after birth — 19 in the vaccine group and 44 in the placebo — for an efficacy in preventing hospitalization of 56.8%.
In terms of safety, Munjal said there were no serious adverse events deemed to be related to vaccination. Mothers reported common, mild or moderate vaccine side effects. Nearly 41% in the vaccine group reported pain at the injection site within a week of vaccination; nearly 27% reported muscle pain; 31% reported headache, which was slightly higher than the incidence in the placebo group.
There was no statistically significant difference between premature births, low birth weight or other reported events for infants within one month of birth. Premature births overall in the trial were low: A little over 5%, compared with a background rate of 10% of all births globally that are premature, Munjal said.
The few deaths and fetal losses among participants were unrelated to the study, as determined by the investigator leading the study and Pfizer. Munjal noted that an “external data monitoring committee” reviews all of the safety information in the trial and that any deaths associated with any respiratory illness are reviewed by an “external adjudication committee.” There was one maternal death in the vaccine group and zero in the placebo group. Fetal deaths and stillbirths were “rare” (10 in the vaccine group, eight in the placebo), Munjal said, and lower than background rates. There was one infant death associated with RSV illness, and it was in the placebo group.
In answering questions from ACIP members, Munjal said the trial had “a slightly more healthy population” than the general pregnant population at large, because participants self-selected. Therefore, there was a lower risk of prematurity. A screening ultrasound was required, and if congenital defects were detected, those pregnant people were excluded from the study.
The ACIP work group on RSV maternal/pediatric medical products will now consider the policy question of whether the Pfizer maternal vaccine should be recommended for all pregnant people at 24 to 36 weeks gestation. The work group will present its findings at a June meeting, and the full ACIP board could vote on such recommendations in October — if the vaccine is approved by the FDA by then.
Update, April 6: Pfizer’s phase 3 trial results were published in the New England Journal of Medicine on April 5.
Update, May 17: The FDA released its briefing document on the Pfizer vaccine in preparation for the May 18 meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee.
The briefing document said the “safety data appear generally favorable for vaccine administration,” but the FDA noted a “numerical imbalance of 1%” in premature births. FDA said the difference was not statistically significant but indicated the imbalance could be discussed by the advisory committee.
One premature birth was assessed to be “possibly related” to the vaccine. The infant had “a normal birth outcome and no complications,” the FDA said.
In the case of one infant death, due to complications of preterm birth, the FDA said it was “unable to exclude the possibility” that the prematurity and death were related to the vaccine.
The advisory committee will vote on whether the data support the safety and efficacy of the vaccine in preventing RSV-confirmed lower respiratory tract illness and severe cases of the illness. In terms of preventing all medically attended cases of RSV, the trial data found an efficacy of 51.3% at 180 days after birth.
Update, May 18: VRBPAC, the FDA advisory committee, voted unanimously, 14-0, that the data supported the effectiveness of the Pfizer maternal vaccine in preventing RSV lower respiratory tract disease and severe disease in babies from birth to age 6 months. The vote was 10-4 in favor of the data supporting the safety of the vaccine.
Those who voted no expressed concern about the data not providing enough certainty on whether the imbalance in preterm births was a safety issue. Dr. Paul A. Offit, a vaccine expert and pediatrician at the Children’s Hospital of Philadelphia, posed the question of whether the data was “adequate in terms of reassuring one that what was seen with GSK’s vaccine is not going to be seen here.” Offit said, “If you’re in any sense risking premature births with this vaccine, I think there’ll be a big price to pay, and so I guess I just don’t feel we have enough data to be reassuring.”
Others who voted yes said the difference in preterm births wasn’t statistically significant.
Dr. Jay M. Portnoy, a pediatrician at Kansas City’s Children’s Mercy Hospital, also talked about the dangers of RSV for very young infants. “So if I compare the very small risk of earlier birth with the almost certain risk of getting RSV and a very high risk of ending up in the hospital, I have to on balance say that the risk is much greater if we don’t give the vaccine then if we do, so that’s why I voted yes,” he said.
The FDA will now consider whether to approve the vaccine.
Update, Aug. 22: The FDA approved Pfizer’s vaccine, called Abrysvo, on Aug. 21. The FDA said the prescribing information will include a warning telling health care providers to administer the one-dose injection at 32 through 36 weeks of gestation in order to avoid a potential risk of preterm birth before 32 weeks. Because of the numerical imbalance in preterm births in the trial, the FDA said, “[t]he available data are insufficient to establish or exclude a causal relationship between preterm birth and Abrysvo.”
Births at 32 to 36 weeks are considered moderately or late preterm.
Pfizer will be required by the FDA to conduct additional studies to assess the potential risk of preterm birth as the vaccine is rolled out.
What about the safety and efficacy of the monoclonal antibody?
Results from phase 3 and 2b clinical trials of Sanofi and AstraZeneca’s monoclonal antibody nirsevimab were published in January in the Lancet Child & Adolescent Health journal.
The pooled results from those trials, which included infants born at 29 weeks through full term, showed 79.5% efficacy in preventing RSV lower respiratory tract illness requiring medical attention for up to five months, which would be one RSV season. (There were 19 such cases in the vaccine group and 51 in the placebo.) In the trials, vaccination lowered the risk of hospitalization by 77.3% and the risk of “very severe” RSV by 86%.
Updated phase 3 data, presented at an RSV international conference in Portugal in late February, showed efficacy rates above 76% for preventing each of those three outcomes. The phase 3 trial includes 3,012 infants in more than 20 countries born at 35 weeks gestation or more, with nearly 2,000 of them receiving nirsevimab and the rest getting a placebo. (See page 18.)
Trial results assessing the safety of nirsevimab were published in three articles in the New England Journal of Medicine in 2020 and 2022. For preterm, late preterm and full-term infants, reports of adverse events up to 360 days after the injection were similar between the treatment and placebo groups, and no serious adverse events, including a small number of deaths, were related to the trial, according to investigators.
There were no serious allergic reactions to the treatment. A few infants developed rashes that were considered to be related to the injections.
In assessing the use of nirsevimab compared with palivizumab for preterm infants or those with heart or lung disease, researchers concluded that the two drugs had a similar safety profile. They found that reported adverse events were “similar across treatment groups and cohorts.”
Why did GSK stop its trial of a maternal vaccine?
GSK announced in February 2022 that it had voluntarily halted the clinical trials of its maternal vaccine due to an observed safety signal by an independent monitoring committee. That signal was “an imbalance in the proportions of preterm births and neonatal deaths between the vaccine and the placebo groups,” in a phase 3 trial being conducted in 24 countries, as explained in an abstract of research discussed at the international conference held in Portugal this February on RSV preventions and treatments (see page 60).
“We are still investigating the cause of the safety signal and, currently, do not have a mechanistic explanation for it,” a GSK spokesperson told us.
The imbalance “was more associated with low- and middle-income countries,” the abstract said, showing a 57% higher risk of preterm birth for vaccine recipients in such countries compared with the placebo group, and only a 4% higher risk, which wasn’t statistically significant, among vaccine recipients in high-income countries.
“The preterm birth imbalance peaked from August to December 2021 and was not observed consistently from January 2022 onward,” it said. The GSK spokesperson told us the full findings will be published in a peer-reviewed journal, but there’s no timeline for that.
The abstract showed that among 3,496 maternal vaccine recipients, nearly 7% had a preterm delivery, defined as less than 37 weeks’ gestation. Among the 1,739 participants in the placebo group, 5% had a preterm delivery. A full-term pregnancy is 39 weeks.
Those preterm birth rates are below the global background rate of about 10%. These figures vary by country, with 5% to 18% of births occurring preterm, according to the World Health Organization.
In a presentation at the February conference, Ilse Dieussaert, GSK’s vice president of vaccine development, said that the safety signal was observed in one clinical trial but not in others GSK was conducting for the RSV vaccine in pregnant women.
She noted that the imbalance in neonatal deaths was only present for preterm births, not births that occurred at 37 weeks or later. Additionally, Dieussaert said, based the clinical information on each of the neonatal deaths, “we concluded that the events leading to the death of the infants are those that are most commonly observed in premature babies and the complications of being born prematurely.” So, the neonatal death imbalance “is considered to be a consequence of the preterm imbalance” and “is not considered to be an independent safety signal.”
The GSK spokesperson also said the investigation doesn’t affect the phase 3 trial for the older adult RSV vaccine.
In a statement sent to FactCheck.org, Phil Dormitzer, head of vaccine R&D at GSK, said: “We continue to work with study investigators to ensure the best care possible for the women and children involved. These initial findings may be useful for understanding the risks and benefits of RSV maternal immunization more broadly. We continue to collect data and further analysis is ongoing. We are committed to share updates as they become available.”
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