Navigating a New Road Map for Infant RSV Prevention

Respiratory syncytial virus (RSV) infection is widespread among children in the United States, and most are infected during the first year of life.¹ Up to 80,000 hospitalizations annually are associated with RSV in children younger than 5 years.¹ With limited treatment options, preventive medication given during the RSV season, typically October through April, remains the cornerstone for disease management.² Previous strategies focused on children at increased risk of lower respiratory tract infection (LRTI) and severe RSV disease.

In 1996, RSV intravenous immune globulin (RespiGam) was approved by the US Food and Drug Administration (FDA) as an infusion for children younger than 24 months of age with bronchopulmonary dysplasia or a history of premature birth. In 1998, palivizumab (Synagis; Arexis AB) was approved by the FDA as an intramuscular injection for high-risk pediatric patients. Both medications required weightbased dosing calculations, monthly administration (up to 5 doses), and, often, insurance prior authorization.³ RespiGam was discontinued in 2003 (due to palivizumab’s improved potency and logistics), and palivizumab remains available and is widely prescribed for eligible children. However, term infants and otherwise healthy children account for 79% of RSV-associated hospitalizations in patients younger than 2 years.¹ In 2023, 2 new medications were introduced for this population, with updated recommendations from the Centers for Disease Control and Prevention (CDC) to protect all infants with either maternal vaccination during pregnancy or infant receipt of monoclonal antibody.¹ NIRSEVIMAB In July 2023, the FDA approved nirsevimab-alip (Beyfortus; Sanofi) for the prevention of RSV LRTI in children from birth through 24 months.

Nirsevimab is a monoclonal antibody with a prolonged half-life of 71 days⁴ (compared with 20 days for palivizumab⁵), allowing 1 dose to provide passive immunity for approximately 5 months. Although not a vaccine in the traditional sense, nirsevimab has been added to the CDC childhood immunization schedule and is recommended for all infants younger than 8 months “born during or entering their first RSV season” and infants aged 8 to 19 months with increased risk of severe RSV disease entering their second RSV season.

Administration is recommended from October through March for most of the continental United States.⁶ In the phase 3 MELODY trial (NCT03979313), nirsevimab demonstrated 74.5% efficacy (95% CI, 49.6%-87.1%; P < .001) for preventing medically attended RSV-associated LRTI compared to placebo in healthy infants.⁷ Nirsevimab is generally well tolerated, with reported incidence of 0.9% rash and 0.3% injection site reactions, compared with 0.6% and 0% in placebo recipients, respectively.⁴ Nirsevimab is supplied as single-dose prefilled syringes in 50-mg and 100-mg strengths, with flat doses of 50 mg, 100 mg, or 200 mg depending on the patient’s age and weight.⁴ Palivizumab is not needed if patients have received nirsevimab during the season.

MATERNAL RSV VACCINATION
In August 2023, RSV vaccine (Abrysvo; Pfizer) was approved for use in pregnancy, after its initial approval in May 2023 for adults 60 years and older. Maternal antibodies formed by the pregnant recipient are transferred transplacentally to provide passive infant immunization. As with other vaccines, at least 14 days likely are required for antibody development and transfer. The CDC recommends vaccination for pregnant females at 32 to 36 weeks’ gestation to prevent RSV-associated LRTI in infants. Administration with a single dose is recommended from September through January.¹ A second RSV vaccine product (Arexvy; GSK) is only indicated for use in adults 60 years and older. The phase 3 MATISSE trial (NCT04424316) randomly assigned healthy women with uncomplicated, singleton pregnancies to receive RSV vaccine or placebo at 24 to 36 weeks’ gestation. Vaccine efficacy for preventing medically attended severe RSV-associated LRTI was 81.8% (99.5% CI, 40.6%-96.3%) within 90 days after birth.⁸ Local and systemic reactogenicity was similar with other vaccine products. The CDC is monitoring adverse events of interest including preterm birth and hypertensive disorders of pregnancy, which were numerically higher in vaccine recipients without reaching statistical significance.

Preterm birth less than 37 weeks’ gestation was reported in 5.7% (95% CI, 4.9%-6.5%) of vaccine recipients compared with 4.7% (95% CI, 4.1%-5.5%) in placebo recipients. In the United States, the recommended vaccination time frame was narrowed to 32 to 36 weeks’ gestation to mitigate this potential risk,¹ whereas the European Medicines Agency maintains the studied time frame of 24 to 36 weeks’ gestation.⁹

DECISIONS, DECISIONS
With 2 new options for RSV protection, pregnant females are now faced with choosing between obtaining the maternal RSV vaccine during pregnancy or waiting to secure nirsevimab for their infant. The CDC states that “the administration of both products is not needed for most infants.”1 However, some clinical scenarios may warrant further discussion and there are no recommendations that prioritize one therapeutic over the other. This is likely because no comparative efficacy data are available between the 2 options. If babies are born at least 14 days after maternal vaccination, protection is provided immediately at birth, whereas nirsevimab requires a few days to reach maximal concentration.⁴

Advantages of nirsevimab include the direct administration of antibodies rather than relying on maternal immune response, and potentially longer duration of protection.¹ Based on timing, maternal vaccine is not an option for infants born at less than 34 weeks’ gestation or pregnant females who are at less than 32 weeks’ gestation after January. In addition to timing considerations, interdisciplinary collaboration between obstetricians and pediatricians is essential to aiding patient decision-making, reconciling maternal vaccine status, and preventing duplicate therapy.

CHALLENGES DURING THE 2023-2024 SEASON
On October 23, 2023, amid implementing widespread nirsevimab administration, the CDC published a health advisory on its limited availability due to high demand exceeding the manufactured supply.¹⁰ Interim recommendations were issued to prioritize infants at the highest risk for RSV disease and resume palivizumab administration in eligible children,¹¹ pausing the momentum of universal RSV prevention for all infants.

However, other obstacles were limiting medication access well before this announcement. One such obstacle was the high cost for both medications compared with other routine vaccines (TABLE), creating an accessibility issue for many vested interests. Pharmacies and offices faced significant up-front cost to keep these medications in stock. Pregnant patients report being turned away at the pharmacy and facing high out-of-pocket costs.¹²

Although health plans are allowed 1 year to add coverage for new Advisory Committee on Immunization Practices (ACIP)-recommended vaccines, even with insurance coverage, some offices received reimbursement lower than the medication cost.^13,14 This forced health care providers to choose between the financial health of their practice and their responsibility to provide an important therapy to their communities. To improve medication access, ACIP voted to include nirsevimab and maternal RSV vaccine in the Vaccines for Children (VFC) program, which provides federally funded vaccines for around half of the children in the United States.¹⁵ Including nirsevimab’s cost in the bundled payment for birth hospitalization, it has also been advocated by the American Academy of Pediatrics.¹⁵

Nirsevimab is now included for all pediatric patients consistent with current recommendations, whereas the maternal RSV vaccine is included for pregnant females younger than 19 years.¹⁶ However, this does not resolve accessibility issues for either nirsevimab or the maternal RSV vaccine. Although 86% of pediatrician offices are enrolled in VFC,¹⁷ only 10% of birthing hospitals are enrolled.¹⁵ Careful reassessment of the VFC program requirements and the feasibility of participation by providers across different practice sites is necessary to expand vaccine access to families at various life stages.

Lastly, according to the CDC Vaccine Safety Datalink, RSV vaccination coverage in pregnancy was 13.1% as of January 6, 2024, with notable differences across race and ethnicity. The highest coverage was among non-Hispanic Asian persons (18.4%) and the lowest coverage among non-Hispanic Black persons (7.7%).¹⁸ Before the next respiratory virus season, it would be prudent to investigate causes of differences in coverage to ensure equitable access and administration.

LOOKING AHEAD
This respiratory virus season, several new therapies were introduced to reduce the burden of RSV on the health care system. As these medications become more accessible during future seasons, health care providers must familiarize themselves with differences in indication, dosing, and timing of available products, both to discuss the nuances when guiding patients through the decision-making process and to reduce the risk of medication errors.¹⁹

Priorities for future RSV seasons must include ensuring equitable medication access and addressing vaccine hesitancy. As seen this year, logistical challenges were reported by even the most vaccine-motivated patients, and the best-intentioned pharmacies, clinics, hospitals, and health care professionals were limited in their ability to expand medication access.^12-17 Systematic solutions to these financial, medication supply, and health systems barriers are crucial so that health care providers will be equipped to expand immunization coverage across all birth settings in the United States.

References

1. Fleming-Dutra KE, Jones JM, Roper LE, et al. Use of the Pfizer respiratory syncytial virus vaccine during pregnancy for the prevention of respiratory syncytial virus–associated lower respiratory tract disease in infants: recommendations of the Advisory Committee on Immunization Practices — United States, 2023. MMWR Morb Mortal Wkly Rep. 2023;72(41):1115-1122. doi:10.15585/mmwr.mm7241e1

2. Hamid S, Winn A, Parikh R, et al. Seasonality of respiratory syncytial virus — United States, 2017-2023. MMWR Morb Mortal Wkly Rep. 2023;72(14):355-361. doi:10.15585/mmwr.mm7214a1

3. Respiratory syncytial virus immune globulin intravenous: indications for use. American Academy of Pediatrics Committee on Infectious Diseases, Committee on Fetus and Newborn. Pediatrics. 1997;99(4):645-650.

4. Beyfortus. Prescribing information. AstraZeneca; 2023. Accessed December 29, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761328s000lbl.pdf

5. Synagis. Prescribing information. MedImmune; 2014. Accessed December 29, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/103770s5185lbl.pdf

6. Jones JM, Fleming-Dutra KE, Prill MM, et al. Use of nirsevimab for the prevention of respiratory syncytial virus disease among infants and young children: recommendations of the Advisory Committee on Immunization Practices — United States, 2023. MMWR Morb Mortal Wkly Rep. 2023;72(34):920-925. doi:10.15585/mmwr.mm7234a4

7. Hammitt LL, Dagan R, Yuan Y, et al; MELODY Study Group. Nirsevimab for prevention of RSV in healthy late-preterm and term infants. N Engl J Med. 2022;386(9):837-846. doi:10.1056/NEJMoa2110275

8. Kampmann B, Madhi SA, Munjal I, et al; MATISSE Study Group. Bivalent prefusion F vaccine in pregnancy to prevent RSV illness in infants. N Engl J Med. 2023;388(16):1451-1464. doi:10.1056/NEJMoa2216480

9. Willemsen JE, Borghans JAM, Bont LJ, Drylewicz J. Disagreement FDA and EMA on RSV maternal vaccination: possible consequence for global mortality. Pediatr Infect Dis J. 2024;43(1):e1-e2. doi:10.1097/INF.0000000000004173

10. Sanofi Beyfortus (nirsevimab-alip) statement. Sanofi. Updated October 26, 2023. Accessed December 29, 2023. https://www.news.sanofi.us/Sanofi-Beyfortus-Statement

11. Limited availability of nirsevimab in the united states—interim CDC recommendations to protect infants from respiratory syncytial virus (RSV) during the 2023-2024 respiratory virus season. Centers for Disease Control and Prevention. October 23, 2023. Accessed December 29, 2023. https://emergency.cdc.gov/han/2023/han00499.asp

12. Reyes EA. Pregnant people can get a shot to protect babies from RSV, but some hit hurdles. Los Angeles Times. December 13, 2023. Accessed January 18, 2024. https://www.latimes.com/california/story/2023-12-13/rsv-vaccine-pregnant-people-hard-to-find

13. Background: the Affordable Care Act’s new rules on preventive care. Centers for Medicare & Medicaid Services. July 14, 2010. Updated September 6, 2023. Accessed December 29, 2023.https://www.cms.gov/CCIIO/Resources/Fact-Sheets-and-FAQs/preventive-care-background

14. Peebles A. New RSV protections for infants hit cost, insurance hurdles in U.S. rollout. CNBC. October 13, 2023. Accessed January 18, 2024. https://www.cnbc.com/2023/10/13/new-rsv-shots-for-infants-abrysvo-and-beyfortus-face-hurdles-in-us.html

15. AAP to federal leaders: immediate support needed for pediatric practices to ensure all children can benefit from new RSV product. American Academy of Pediatrics. August 1, 2023. Accessed December 29, 2023. https://www.aap.org/en/news-room/news-releases/aap/2023/aapto-federal-leaders-immediate-support-needed-for-pediatric-practices/

16. VFC-ACIP vaccine resolutions: vaccines to prevent respiratory syncytial virus. Centers for Disease Control and Prevention. Last Reviewed: November 9, 2023Accessed December 29, 2023. https://www.cdc.gov/vaccines/programs/vfc/providers/resolutions.html

17. Aragona E, Joshi NS, Birnie KL, Lysouvakon P, Basuray RG. Early experiences with nirsevimab: perspectives from newborn hospitalists. Hosp Pediatr. Published online December 20, 2023. doi:10.1542/hpeds.2023-007639

18. RSV Vax View. Centers for Disease Control and Prevention. Updated January 16, 2024. Accessed January 18, 2024. https://www.cdc.gov/vaccines/imz-managers/coverage/rsvvaxview/index.html

19. Institute for Safe Medication Practices (ISMP). Don’t confuse products used to prevent infections from respiratory syncytial virus. ISMP Medication Safety Alert! Community/Ambulatory Care. 2023;22(11):3-4.