“Should Not Be Used in Any Infants”: Higher Death Risk in Beyfortus RSV Shot Clinical Trials

This article was initially published on THE DEFENDER.

Infants treated for RSV with the monoclonal antibody nirsevimab have significantly higher mortality rates than those treated with a different monoclonal antibody or with a placebo, according to an analysis by the Japanese journal Med Check of three major randomized control trials.

The report reanalyzed clinical trial data showing that nirsevimab — marketed by Sanofi and AstraZeneca as Beyfortus — reduced RSV-associated lower respiratory tract infection and hospitalizations in both high-risk and healthy infants.

However, babies treated with the drug had a higher mortality rate likely linked to adverse effects — including thrombosis (blood clotting) — from the drug itself, the study found.

“Due to the increased mortality, nirsevimab should not be used in any infants,” the study concluded. “Do not use nirsevimab for universal immunization.”

Shortly after its approval by the European Medicines Association in October 2022, and fast-track approval by the U.S. Food and Drug Administration in July 2023, the U.S., France, Spain and Luxembourg launched universal Beyfortus infant immunization campaigns for the 2023-24 RSV season.

Med Check published its appraisal of the clinical trials shortly after France’s National Agency for the Safety of Medicines and Health Products (ANSM) published its first pharmacovigilance data on the drug, compiled during the 2023-24 season.

The ANSM report tracked adverse events related to Beyfortus in France between Sept. 11, 2023, and April 30, 2024. Of 244,495 doses delivered, 198 adverse events were reported to the pharmacovigilance system, of which 153 were considered serious.

The report identified safety signals for stroke, respiratory conditions and hypotonic-hyporesponsive episodes — when an infant suddenly loses muscle strength and becomes “floppy.” Hypotonic-hyporesponsive episodes also are associated with the diphtheria-tetanus-pertussis, or Tdap, vaccine and other vaccines.

There were also three reports of sudden infant death syndrome (SIDS), although researchers said at least one of them was likely not linked to the drug.

The ANSM said each of the signals would be closely monitored in the future, but that a causal link between Beyfortus and those adverse events had not yet been established. The agency concluded the results confirm that the benefits of using the drug to treat bronchiolitis, an RSV infection, outweigh the risks.

The ANSM continues to recommend all newborn babies receive the Beyfortus shot this RSV season.

RSV is a common respiratory virus that usually causes mild cold-like symptoms. However, it can lead to hospitalization for bronchiolitis or pneumonia in about 1%-2% of infants, especially high-risk infants born preterm or who have chronic lung or congenital heart disease.

Approximately 100 infants reportedly die each year in the U.S. from the illness. By age 3 almost all babies have been infected with RSV, which confers partial immunity and makes subsequent episodes less severe.

The Centers for Disease Control and Prevention (CDC) recommends one dose of nirsevimab/Beyfortus for infants younger than 8 months entering their first RSV season if their mother didn’t receive the RSV maternal vaccine during pregnancy, or if the mother’s immunization status is unknown.

The CDC also recommends the shot for infants and children ages 8-19 months at higher risk of severe RSV disease. The agency lists nirsevimab on the 2024 Childhood Immunization Schedule.

After Beyfortus was approved, a Freedom of Information Act request by The Defender revealed that at least two infant deaths reported to the Vaccine Adverse Event Reporting System or VAERS were linked to the drug.

Nirsevimab showed higher death risk in clinical trials

Nirsevimab and palivizumab, the other monoclonal antibody approved to treat RSV, are both designed to stop infection by binding to the F-protein in cells that the RSV virus would otherwise access to enter and infect a cell.

According to the Med Check study, palivizumab is short-acting — it must be administered monthly — but it has been used for 20 years in high-risk infants. Nirsevimab was designed to be longer-acting and is approved for healthy infants.

The study compared nirsevimab’s effectiveness to that of palivizumab and placebo by reanalyzing data from AstraZeneca and Sanofi’s clinical trials, including the MELODY and the MEDLEY trials.

The trials found reduced hospitalization rates in healthy infants. For example, in one trial with 1,453 infants, the hospitalization rate for RSV-related infection was 0.8% in the nirsevimab group and 4.1% in the placebo group.

There were 12 deaths across the trials in the nirsevimab group and four in the placebo groups, they reported.

In the MELODY trial, which included only healthy babies, no deaths occurred in the placebo group, but five deaths were reported in the nirsevimab group.

The Japanese researchers estimated the cumulative mortality rate in that study for nirsevimab to be 751 deaths per 100,000 person-years, which is “considerably higher than the infant mortality rate in the general population in each country that participated in the clinical trial.”

Additionally, because only healthy infants were included in the trial, the mortality rates should be lower than in the general population, making it highly probable that nirsevimab caused the increased mortality rate, the researchers concluded.

In the MEDLEY trial, which compared nirsevimab with palivizumab in high-risk infants, there was no significant difference in the number of RSV infections needing medical attention in the two groups.

However, four infants in the nirsevimab group died within 151 days of receiving the treatment, while no infants in the palivizumab group died.

In all of the clinical trials analyzed, deaths unrelated to RSV were significantly more common in the nirsevimab group. Three infants died from heart issues and one from an unexpected sudden death. Two infants died from ischemic gastroenteritis, which they said could also be linked to mesenteric thromboembolism, or blood clotting.

One infant died in a traffic accident and one from COVID-19. Two died from unknown causes.

The Japanese researchers concluded that despite nirsevimab’s benefits — longer acting and reducing hospitalizations — for healthy infants it comes with a higher death risk, particularly from thrombosis.

French health data reveal host of adverse events including 3 SIDS deaths

In September 2023, France became one of the first countries to launch a national Beyfortus immunization campaign, offering the shot at no cost and recommending it to all infants before their discharge from the maternity ward.

Uptake was significantly higher than expected, according to the ANSM report, approaching 80%, which led to shortages.

Given the novelty of the drug being administered to newborn infants and the lack of any real-world data on safety or efficacy, ANSM implemented a national pharmacovigilance survey to gather information on all safety concerns that arose during the campaign.

Health officials collected data from the National Pharmacovigilance Database, notable cases reported to the ANSM and any lab-identified cases. They identified nearly 200 adverse events.

The report groups and describes the adverse events by type and provides details about each adverse event case, including whether the event was serious enough or occurred frequently enough to justify a signal.

Three babies died from SIDS:

• A newborn found lifeless two-and-a-half hours after his morning bottle and three days after his Beyfortus shot.
• A newborn who received the Beyfortus shot on the second day of life and died 10 days later.
• An infant who required intensive care at birth but recovered and received its mandatory injections — including Beyfortus — over the first few months of life. Two-and-a-half months after the Beyfortus injection, the baby developed an RSV infection and died three days later.

The French researchers concluded there was doubt about the link between the reported SIDS deaths and Beyfortus, but that the link couldn’t be ruled out. They didn’t identify a signal for SIDS but advised that it should be closely monitored.

Other serious adverse events reported included:

• 7 respiratory, heart and lung disorders.
• 4 gastrointestinal disorders.
• 10 skin and subcutaneous tissue disorders.
• 3 nervous system disorders, including 1 stroke and 2 cases of hypotonia.
• 1 serious kidney disorder.
• 9 “general disorders,” including tachycardia, serious flu-like symptoms and fever.
• 11 cases of injuries, poisoning and intervention complications.
• 1 serious kidney infection.
• 4 administration site abnormalities.
• 148 cases of serious drug inefficacy, where infants developed RSV infections shortly following the injection. Many of the infants who developed RSV infections were hospitalized.

The agency flagged 21 cases as “notable,” including two of the SIDS deaths, the stroke that occurred in a three-day-old infant on the day it received its Beyfortus injection, and two cases of acute dyspnea, which is extreme shortness of breath often caused by cardiac or related issues.

Other notable cases included severe RSV infection, a case of repeated malaise with pallor following injection, a case of suspected staphylococcal toxic shock syndrome, and cases of severe injection site pain.

The French researchers concluded that the respiratory conditions, including the episodes of shortness of breath or other oxygen issues and malaise, constitute a signal of moderate strength and severe risk. They interpreted the one case of stroke as a weak signal and severe risk. They also concluded that systemic effects like hypotonic-hyporesponsive episodes, flu-like illness and digestive issues constituted a signal of moderate strength and low risk.

They also said skin reactions and SIDS should be closely monitored and that the national pharmacovigilance survey should continue.

Despite the nearly 200 detailed cases of adverse events discussed in the report, French media reported the findings were “reassuring.”