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Reference:  Drysdale SB et al. Nirsevimab for Prevention of Hospitalizations due to RSV in Infants. N Engl J Med. 2023

Date: March 29, 2024

Guest Skeptic: Dr. Michael Cosimini is a pediatrician in Portland Oregon. He is the designer of Empiric Game, a medical editor and contributor to Pediatrics Reviews and Perspectives (PedsRAP) and the digital media editor at Academic Pediatrics. He is passionate about podcasting and serious games for medical education.

Dr. Michael Cosimini

Case: A 4-month-old twin girl is brought by her parents to the emergency department (ED) for respiratory distress. She has had congestion, a runny nose, and a cough for the past three days. Her parents think her breathing has been getting worse, and she is breathing faster. On your examination, you see that she is tachypneic with a respiratory rate of 66 breaths per minute. You also note subcostal retractions. Her oxygen saturation on room air is 86%. After nasal suctioning, she remains tachypneic, but her oxygen saturation remains under 90%. A viral swab comes back positive for respiratory syncytial virus (RSV). The decision is made to put her on supplemental oxygen via nasal cannula and admit her to the hospital for close observation. Her parents tell you, “She has a twin brother at home. We heard about this new vaccine for RSV. Does it work?”

Background: RSV is a major cause of respiratory illness in young children. It is common in bronchiolitis which leads to symptoms like coughing, wheezing, and difficulty breathing. RSV is a major reason why infants are hospitalized for respiratory issues, especially during the fall and winter months when RSV infections are more prevalent. 

It’s hard to think about RSV without recalling the quote “Don’t just do something, stand there!” Because there have been so many things that we’ve tried for bronchiolitis that really don’t seem to have had much effect including hypertonic saline (SGEM#157), high-flow nasal oxygen (SGEM#228), corticosteroids, bronchodilators, etc  (SGEM#167).  One thing that has also been tried but not covered on the SGEM is a “vaccine” for RSV. 

Attempts at developing a vaccine against RSV go back decades. The first significant effort to develop an RSV vaccine occurred in the 1960s. A formalin-inactivated RSV vaccine (FI-RSV) was developed and tested in infants and young children. However, instead of protecting against RSV, the vaccine led to worsened infection in many children resulting in some being hospitalized and two deaths. This tragic outcome slowed the development of an RSV vaccine for years. Over the next three decades, researchers sought to understand the immune response to RSV infections and explore potential vaccine targets other than the inactivated virus.

During the 2000s, advances in molecular biology, immunology, and vaccine technology rekindled scientists’ efforts in RSV vaccine development. Researchers began exploring various approaches, including protein subunit vaccines, vectored vaccines, live-attenuated vaccines, and mRNA vaccines. Over the last decade, several RSV vaccine candidates have entered clinical trials. These trials have included vaccines for infants, older children, and at-risk adults, such as the elderly and pregnant women (intending to provide passive immunity to newborns). While some RSV vaccine candidates have shown promise, the challenge has been to find a vaccine that is safe, effective, and can provide long-lasting immunity.

In 2022 in the European Union and UK and 2023 in the US and Canada approved Nirsevimab to prevent RSV. This is a monoclonal antibody that is supposed to neutralize RSV. Nirsevimab specifically targets a protein that is critical for the virus’s ability to enter and infect human cells, thereby stopping the disease process in its tracks. This action does not rely on the recipient’s immune system to activate or produce antibodies, providing immediate protection. This new vaccine technology represents a shift towards monoclonal antibody (mAb) therapy for RSV prevention. 

Some have been offering nirsevimab to healthy term kids primarily discussing it with families using data from MELODY [1]. This RCT enrolled 1,490 kids and showed good safety compared to placebo, reduced medically attended lower respiratory tract infections, but was not powered to show reduced hospitalization. 

Clinical Question: What effect does nirsevimab have on hospitalizations for RSV-associated lower respiratory tract infections in healthy infants? 

Reference:  Drysdale SB et al. Nirsevimab for Prevention of Hospitalizations due to RSV in Infants. N Engl J Med. 2023

  • Population: Infants <12 months with a gestational age of at least 29 weeks entering first RSV season
      • Exclusions: History of immunocompromise, active RSV or lower respiratory tract infection at the time of enrollment, mother received RSV vaccine, eligible for palivizumab. There was a long list of exclusion criteria. 
  • Intervention: Single IM injection of nirsevimab (50 mg or 100 mg depending on weight)
  • Comparison: Standard care with no placebo 
  • Outcome: 
    • Primary: Hospitalization for RSV-associated lower respiratory tract infection, defined as hospital admission and RSV-positive test result.
    • Secondary: Very severe RSV-associated lower respiratory tract infection, defined as hospitalization for RSV-associated lower respiratory tract infection with oxygen saturation of less than 90% and need for supplemental oxygen.
  • Trial: Phase 3b, open-label, pragmatic, randomized trial
  • Authors’ Conclusions: “Nirsevimab protected infants against hospitalization from RSV-associated lower respiratory tract infection and against very severe RSV-associated lower respiratory tract infection in conditions that approximated real-world settings.”

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Unsure. 
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. No
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Unsure
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No. 
  8. All groups were treated equally except for the intervention. Unsure 
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes/Unsure 
  12. Financial conflicts of interest. Multiple conflicts of interest

Results: They recruited 8,058 infants from across 235 sites. 4,037 received nirsevimab and 4,021 had standard of care. Slightly over 20% in each group were neonates (≤28 days). About 14% were less than 37 weeks gestational age.

Key Results: Nirsevimab reduced hospitalizations for RSV-associated lower respiratory tract infections.

  • Primary Outcome: 0.3% of the infants in the nirsevimab group were hospitalized in comparison to 1.5% of infants in the standard care group. This corresponded to an efficacy of 83.2% (95% CI 67.8-92.0). 
  • Secondary Outcomes: Very severe RSV-associated lower respiratory tract infection (oxygen saturation <90%, need for supplemental oxygen) was 0.1% in nirsevimab group and 0.5% in standard care. This corresponded to an efficacy of 75.7% (95% CI 32.8-92.9). 
  • Adverse Events: Overall, there were similar rates of adverse events in both the nirsevimab group and the standard care group. There were slightly more medically attended events (defined as events that prompted the infant’s caregivers to seek unplanned in-person medical advice in any setting) in the nirsevimab group compared to standard care group (29.5% vs 27.4%).

Industry Involvement: It’s important to recognize the level of involvement from Sanofi, who sponsored the trial. They had input in the trial design and performed data analysis in collaboration with the authors. They also funded a medical writer to write the first draft of the manuscript which was then edited by the authors. This does not necessarily mean the results are untrustworthy, but it does raise our skeptical antennae as many industry-sponsored studies tend to report results that are favorable to the sponsor. [2]

The efficacy numbers presented look very impressive, but the absolute numbers are actually very small. When we look at the primary outcome, there was a difference of 1.2% between the groups (0.3% vs 1.5% hospitalization) which is an NNT of 83. The secondary outcome had a difference of 0.4% (0.1% vs 0.5%) which is a NNT of 250.

Open-Label: This trial was unmasked, meaning that parents knew whether or not their child received nirsevimab. It is possible that this influenced parents’ behavior to seek care. This may be mitigated by hospital admission as opposed to presenting to care for RSV like in MELODY.

Their primary outcome was hospitalization for RSV-associated lower respiratory tract infection. Once we add the qualifier, “RSV-associated,” that allows a degree of subjectivity and potential bias. It seems like they used RSV testing to determine whether or not a hospitalization was RSV-associated, but that is also imperfect. What if the child was hospitalized as a side effect of the intervention? While they report the adverse events, it is unclear if any of them resulted in hospitalization.

We may not know the overall rates of hospitalization in the two groups, but they do report that hospitalization for lower respiratory tract infection from any cause during RSV season occurred in 1.1% of infants in the nirsevimab group and 2.4% in the standard care group. This corresponded to an efficacy of 58% (95% CI 39.7-71.2).

Testing for RSV: A confirmation of RSV was made by a positive test result. Testing was performed based on hospital policy or routine practice. The authors note that the use of polymerase-chain reaction assay has been the standard of care for hospitalized children with lower respiratory tract infections in the UK, France, and Germany since the COVID-19 pandemic. The families also had cards to give to the treating clinician to encourage testing for RSV. Is PCR testing for RSV really a gold standard? There is research suggesting that test positivity can linger for as long as 30 days. [3] 

As a reminder, the most recent Choosing Wisely campaign from the American Academy of Pediatrics (AAP) included the statement: Do not obtain comprehensive viral panel testing for patients who have suspected respiratory viral illnesses.[4]

Decision for Admission: The decision to hospitalize a child was up to the discretion of the treating physician. The authors report that this was rarely an investigator in the study, but they do not know how many caretakers may have told the treating physician that their child was enrolled in the study. While the paper makes the claim that “we believe risk of bias was low with respect to the primary end-point analysis,” we are not fully convinced as this may have influenced the decision for admission.

Ultimately, the decision whether or not to admit a young child is subjective. Sometimes it may come down to the treating physician’s tolerance regarding the degree of work of breathing, risk of apnea, the reliability of close follow-up, etc. Also, it is unclear how the geographic location of practice impacts the likelihood of admitting children with RSV. 

RSV Seasonality and Effect Size: RSV is seasonal and variable. This study was done in a season with more than typical RSV so the size of the effect might be smaller in future. 

In Figure 2, it also seems like there were overall fewer infants in the >3 to 6 months and >6 month categories who were hospitalized which made the 95% CI much wider, crossing 0.

The most recent Morbidity and Mortality Weekly Report from the Centers for Disease Control and Prevention actually estimates that nirsevimab is 90% effective at preventing hospitalizations.[5] But this study is not without its limitations such as only having a small portion of the hospitalized infants who received nirsevimab and case control design. 

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusion. But be wary of industry’s role in this trial.

SGEM Bottom Line:  Nirsevimab may reduce RSV-associated hospitalizations in infants. 

Case Resolution: You tell the family that there is a new medication called nirsevimab that has been approved for infants who are born shortly before and during RSV season. There is some research that may prevent hospitalization with minimal side effects.

Clinical Application: Michael has been giving Nirsevimab initially based on the FDA approval and reviewing it in the context of MELODY data. A bigger sample here showing safety is nice to see and a similar rate of prevention of hospitalization to the rate of reduction of presentation to care in the placebo-controlled trial. It is currently recommended by the CDC and AAP.

What Do I Tell the Patient?  There is a medication called nirsevimab that has now been approved. There is some research to suggest that it may protect your child from being hospitalized with RSV. 

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References:

  1. Hammitt LL, Dagan R, Yuan Y, et al. Nirsevimab for prevention of rsv in healthy late-preterm and term infants. N Engl J Med. 2022;386(9):837-846.
  2. Flacco ME, Manzoli L, Boccia S, et al. Head-to-head randomized trials are mostly industry sponsored and almost always favor the industry sponsor. J Clin Epidemiol. 2015;68(7):811-820.
  3. Abels S, Nadal D, Stroehle A, Bossart W. Reliable detection of respiratory syncytial virus infection in children for adequate hospital infection control management. J Clin Microbiol. 2001;39(9):3135-3139.
  4. Mullan PC, Levasseur KA, Bajaj L, et al. Recommendations for choosing wisely in pediatric emergency medicine: five opportunities to improve value. Ann Emerg Med. Published online February 11, 2024:S0196-0644(24)00017-9.
  5. Moline HL, Tannis A, Toepfer AP, et al. Early estimate of nirsevimab effectiveness for prevention of respiratory syncytial virus-associated hospitalization among infants entering their first respiratory syncytial virus season – new vaccine surveillance network, october 2023-february 2024. MMWR Morb Mortal Wkly Rep. 2024;73(9):209-214.