ACIP Evidence to Recommendations for Use of Nirsevimab in Infants born during the RSV season or entering their first RSV season

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Questions: Should one dose of nirsevimab be recommended for infants aged <8 months born during or entering their first RSV season (50 mg for infants <5 kg and 100 mg for infants ≥5 kg)?

Population: Infants aged <8 months born during or entering their first RSV season

Intervention: Nirsevimab (1 injection of 50 mg if <5 kg or 100 mg if ≥5 kg)

Comparison: No nirsevimab prophylaxis

Outcomes:

  • Medically attended RSV-associated lower respiratory tract infection (LRTI)
  • RSV-associated LRTI with hospitalization
  • RSV-associated LRTI with ICU admission
  • RSV-associated death
  • All-cause medically attended LRTI
  • All-cause LRTI-associated hospitalization
  • Serious adverse events (SAEs)

Background:

RSV is the most common cause of hospitalization in U.S. infants.1 The highest hospitalization rates are in the first months of life and risk declines with increasing age in infancy and during early childhood. During the 2017-2020 seasons prior to the COVID-19 pandemic, RSV transmission followed a consistent seasonal pattern, beginning earliest in Florida and the Southeast and peaking during December across most the U.S. However, the COVID-19 pandemic interrupted seasonal circulation of RSV and many other respiratory viruses. Following over a year of limited RSV circulation, the U.S. experienced an interseasonal RSV wave that peaked in July 2021 and continued throughout the Fall into late December. Although some limited regional interseasonal transmission occurred in Summer 2022, largely in the South- and South-Central U.S., the RSV season peaked in November and returned to off-season levels in January, suggesting that RSV circulation may be transitioning to typical winter seasonality.2

It has been estimated that each year among U.S. children aged less than 5 years, RSV is associated with 100 – 300 deaths, 58,000 – 80,000 hospitalizations, nearly 520,000 emergency department visits and approximately 1,500,000 outpatient visits.3-7

On July 17, 2023, the U.S. Food and Drug Administration (FDA) approved the Biologics License Application for a single dose of nirsevimab (Beyfortus, Sanofi, and AstraZeneca) for prevention of RSV-associated LRTI in infants born during or entering their first RSV season and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season.8 This webpage will focus on the Evidence to Recommendation (EtR) for first season indication only. For EtR on the second season indication, please see: https://www.cdc.gov/vaccines/acip/recs/grade/nirsevimab-season2-rsv-infants-children-etr.html. Following FDA’s regulatory action, the ACIP met on August 3, 2023 and voted to Recommend nirsevimab infants born during or entering their first RSV season and aged <8 months at the time of immunization.

Additional background information supporting the ACIP recommendation on the use of Nirsevimab can be found in the relevant publication of the recommendation referenced on the ACIP website.

Public Health Problem

Public Health Problem
Criteria Work Group Judgements Evidence Additional Information
Is the problem of public health importance? Yes Each year among U.S. children aged less than 5 years, RSV is associated with an estimated 100 – 300 deaths, 58,000 – 80,000 hospitalizations, nearly 520,000 emergency department visits, and approximately 1,500,000 outpatient visits.1-5
RSV is the most common cause of hospitalization in U.S. infants.6 The highest hospitalization rates are in the first months of life and risk declines with increasing age in infancy and during early childhood.7 Prematurity and other chronic diseases increase risk of RSV-associated hospitalization, but most hospitalizations are in healthy, term infants.7-8

Benefits and Harms

 

Benefits and Harms
Criteria Work Group Judgements Evidence Additional Information
How substantial are the undesirable anticipated effects? Moderate to large The estimated efficacy for medically attended RSV-associated LRTI was 79.0% (95% confidence interval [CI]: 68.5%, 86.1%), for RSV-associated LRTI with hospitalization was 80.6% (95% CI: 62.3%, 90.1%), and for RSV-associated LRTI with ICU admission was 90.0% (16.4%, 98.8%). Deaths due to RSV respiratory illness could not be evaluated as no deaths due to RSV were recorded in the trials included in the evidence. The estimated efficacy against all-cause medically attended LRTI was 34.8% (95% CI: 23.0%, 44.7%) and 44.9% (95% CI: 24.9%, 59.6%) against all-cause LRTI hospitalization.1-5
Additionally, the sponsor has shared data from an ongoing phase 3b study known as Harmonie.4,6 This study enrolled 8,058 infants. The age at enrollment was: <3 months for 49%, 3-5 months for 24%, ≥6 months for 28% of participants. 85% were born at term and 50% born in season. The study is being conducted in France, UK, and Germany. The participants were randomized to nirsevimab or no injection, meaning the control group was not given a placebo injection. The primary endpoint was RSV hospitalization, which was hospitalization due to LRTI with a positive RSV test. RSV tests were ordered by clinicians for patients with LRTI per standard of care and not systematically on all patients with LRTI hospitalizations. Participants will be followed for 12 months after randomization. At the end of the RSV season, preliminary efficacy results have been released, with a median post-randomization follow up time of 2.5 months. Preliminary results report an efficacy against RSV hospitalization of 83%, against severe disease (defined as an O2 saturation below 90% and oxygen given) of 76%, and against hospitalization with LRTI of all causes during the RSV season of 58%.4,6 These results have not been peer reviewed or published in the scientific literature.
 The Work Group felt that the anticipated effect for the main desirable outcomes was large, but some members felt the effects were moderate.
How substantial are the undesirable anticipated effects? Minimal to small The risk ratio comparing SAEs in infants receiving nirsevimab versus receiving placebo was 0.73 (95% CI: 0.59, 0.89). The trials did not include a sufficient number of participants to detect rare events, such as anaphylaxis.1-5
For Harmonie safety, grade 1 adverse events were reported to be slightly higher in nirsevimab arm (with 29%) versus the no intervention arm (with 25%). The number of Grade 2 and Grade 3 adverse events were similar between the nirsevimab and control arm.4,6 These results have not been peer reviewed or published in the scientific literature.
 The Work Group felt that the anticipated effect for undesirable outcomes was minimal to small.
Do the desirable effects outweigh the undesirable effects? Favors intervention The Work Group felt that the desirable effects of Nirsevimab outweigh the undesirable effects.
What is the overall certainty of this evidence for the critical outcomes? Moderate For the critical outcomes, the certainty of evidence was high for medically attended RSV-associated LRTI and RSV-associated LRTI with hospitalization. Moreover, there was moderate certainty that nirsevimab is effective in preventing medically attended RSV-associated LRTI with ICU admission and that SAEs were likely not more common in the intervention group (i.e., infants receiving nirsevimab) than the placebo group. Furthermore, no deaths were reported due to RSV, therefore this outcome was unable to be evaluated.
In relation to important outcomes, the certainty of evidence was high for all-cause medically attended LRTI as well as all-cause LRTI-associated hospitalization.
The overall, certainty of the evidence was rated as moderate.

Values

Values
Criteria Work Group Judgements Evidence Additional Information
Does the target population feel that the desirable effects are large relative to undesirable effects? Yes/probably yes In a survey, conducted by the University of Iowa, of 523 people who were actively pregnant or pregnant within the last 12 months, about one-third (33%) of respondents thought their baby ‘definitely’ or ‘probably’ would get an RSV infection within one year after being born. Approximately 70% of respondents said they ‘definitely’ or ‘probably’ would get an RSV antibody injection for their baby if safe and effective, approved by FDA, and recommended by CDC.1 The Work Group felt that the target population probably feels that the desirable effects are large relative to undesirable effects.
Is there important uncertainty about or variability in how much people value the main outcomes? No consensus Considering vaccine intentions among survey respondents who were actively pregnant or pregnant within the last 12 months, 63% of respondents said they were more worried or equally worried about their baby experiencing side effects from an RSV antibody injection vs. symptoms if sick with RSV.1
Moreover, 38% of respondents believe that their baby would have no symptoms or mild symptoms if they were to get sick with RSV; and 24% expressed uncertainty about the disease severity or treatability if their baby got sick with RSV. Despite being unsure or perceiving RSV risk to be low, respondents were worried their baby would need to be hospitalized if they got sick with RSV.1
 The Work Group varied in whether they felt there was important uncertainty about, or variability in, how much people value the main outcomes.

Acceptability

Acceptability
Criteria Work Group Judgements Evidence Additional Information
Is the intervention acceptable to key stakeholders? Yes/probably yes In a survey by the Alliance for Patient Access and National Coalition for Infant Health using YouGov to poll U.S. pediatric providers, among 175 providers that responded:
  • 99% agree that parents need more information about RSV
  • 86% report including RSV education as part of routine care
  • 97% said immunizations could help prevent RSV
  • 92% agreed that RSV immunization policy should ensure all children get access.1

The American Academy of Pediatrics has stated that the development of safe and effective RSV immunization is a priority.2 In 2021, the National Foundation for Infectious Disease held a roundtable, which agreed on the importance of rapid adoption and deployment of evidence-based RSV prevention. This roundtable included the National Association of County and City Health Officials.3

Feasibility

Feasibility
Criteria Work Group Judgements Evidence Additional Information
Is the intervention feasible to implement? Probably yes Nirsevimab storage, handling and administration is similar to other routine immunizations for children.1 Nirsevimab is administered as an intramuscular injection using pre-filled, single-use syringes available in two different doses for infants born during or entering their first RSV season:
  • 50mg (0.5 mL) for infants weighing <5 kg or
  • 100 mg (1.0 mL) for infants ≥5 kg

Only one dose of nirsevimab is recommended per RSV season and can be administered simultaneously with other childhood vaccines. Nirsevimab is stored at refrigerator temperatures (2°C-8°C) and may be kept at room temperature (20°C-25°C), when protected from light, for up to 8 hours.2

Jurisdictions may have different scope of practice statutes for who can administer injectable therapeutics vs. vaccines, impacting feasibility. A review of state laws indicates that most states allow medical assistants (who frequently administer vaccines) to also deliver injection drugs; however, organizations may have varied practices.1
CDC determined that nirsevimab is eligible for inclusion in the childhood immunization schedule and Vaccines for Children program and ACIP voted for inclusion of nirsevimab in the Vaccines for Children program.
The Vaccines for Children program is a federally funded program that provides immunizations at no cost to children who might not otherwise be immunized because of inability to pay.3 Nirsevimab is the first monoclonal antibody to be included in the VFC program.
Nirsevimab could be administered to an infant in a hospital or outpatient setting. Only approximately 10% of birthing hospitals participate in the VFC program and nirsevimab is more expensive compared with Hepatitis B vaccine, which is more feasible for hospitals to cover at ~$13–16/dose in the bundled payment model for newborn care.4 It is unknown at this time if nirsevimab will be included in bundled payments for newborn care.
It will be critical to ensure documentation of in-hospital nirsevimab administration in records sent to primary care provider, and there are potential challenges entering nirsevimab in the immunization information system (IIS).
In outpatient settings, communication from the birthing hospitalization on whether an infant received nirsevimab during the birthing hospitalizing will be critical. The demand for nirsevimab is not known.  Pricing as well as a historical lag in insurance payment for new products could impact initial investment by pediatricians.
Coding challenges exists as nirsevimab is classified as a drug vs a vaccine. Drug administration codes do not include a counseling component, and drugs are not eligible for stand-alone counseling. Additionally, the usual time from FDA approval to administration systems being ready to use these new codes for administration is approximately 6-12+ weeks.1
Suspected adverse reactions following administration of nirsevimab alone (i.e., when not coadministered with a vaccine) should be reported through MedWatch. However, suspected adverse reactions following coadministration of nirsevimab with any vaccine should be reported to the Vaccine Adverse Event Reporting System (VAERS).
 The Work Group felt that Nirsevimab is probably feasible to implement.

Resource Use

Resource Use
Criteria Work Group Judgements Evidence Additional Information
Is the intervention a reasonable and efficient allocation of resources? Yes/probably yes The estimated cost of nirsevimab is $495, and the price for the Vaccines for Children (VFC) program is estimated to be $395. Assuming nirsevimab is administered as 50% under VFC and 50% under private insurance, the average price was $445. These prices are not final.
The number needed to immunize with nirsevimab to prevent one health outcome was estimated at 17 for an outpatient visit, 18 for an ED visit, 128 for inpatient, 581 for ICU admission, 24 per inpatient day, and 194 for ICU day.
The cost per health event averted was estimated at $2,662 per outpatient visit, $7473 per ED visit, $19,909 per inpatient admission, $90,494 per ICU admission, $3,687 per inpatient day, and $30,165 per ICU day.
The result of the cost effectiveness model was $102,811 per quality adjusted life year saved.1
 The workgroup felt nirsevimab is or is probably a reasonable and efficient use of resources.

Equity

Equity
Criteria Work Group Judgements Evidence Additional Information
What would be the impact of the intervention on health equity? Probably increased Inclusion in the Vaccines for Children program is critical for maximizing equity to nirsevimab.
Data of seasonal population-based rates of RSV-associated hospitalization among U.S. infants less than 6 months by race and ethnicity during the 2018-2019 through the 2021-2022 season from RSV-NET, indicates that there were differences in hospitalization rates among infants aged less than 6 months old by race and ethnicity, but these differences varied by season. It is important to note that these rates have not been adjusted for RSV testing practices, and thus may under-represent RSV hospitalization rates. However, this should not affect distributions of rates by race and ethnicity.1
Rates of RSV-associated ICU admissions among U.S. infants less than 6 months old by race and ethnicity during those same seasons in RSV-NET, shows that population-based ICU admission rates for non-Hispanic Black infants in RSV-NET were 1.2 to 1.6 times higher than for non-Hispanic White infants across the four seasons.1
In addition, research suggests that some American Indian and Alaska Native (AI/AN) children experience high rates of severe RSV disease. A recent study found the incidence of RSV-associated hospitalization among some AI/AN children aged 12–23 months was 4 to 10 times that of similar-aged children across seven sites in the United States.2 These studies have been limited to specific populations and might not be broadly representative of risk in all AI/AN children. Some AI/AN communities live in remote regions, making transportation of children with severe RSV more challenging.3
 The Work Group felt that with the inclusion in the VFC program, health equity would probably be increased with nirsevimab.

Work Group Interpretation Summary

The Work Group recommended nirsevimab for all infants aged <8 months born during or entering their first RSV season. However, many expressed concerns about feasibility and price of nirsevimab.

Balance of consequences

The Work Group felt that the desirable consequences clearly outweigh undesirable consequences in most settings.

Is there sufficient information to move forward with a recommendation? Yes

Policy options for ACIP consideration

  • ACIP does not recommend the intervention.
  • ACIP recommends the intervention for individuals based on shared clinical decision making.
  • ACIP recommends the intervention.

Draft recommendation (text)

Infants aged <8 months born during or entering their first RSV season are recommended to receive one dose of nirsevimab (50 mg for infants <5 kg and 100 mg for infants ≥5 kg)

On August 3, 2023, ACIP voted (10-0) in favor of recommendation.

Final deliberation and decision by ACIP

ACIP recommends the intervention.

References

Background:

  1. Suh M, Movva N, Jiang X, Bylsma LC, Reichert H, Fryzek JP, et al. Respiratory Syncytial Virus Is the Leading Cause of United States Infant Hospitalizations, 2009-2019: A Study of the National (Nationwide) Inpatient Sample. J Infect Dis. 2022 Aug 15;226(Suppl 2):S154-S63.
  2. Hamid S, Winn A, Parikh R, Jones JM, McMorrow M, Prill MM, et al. Seasonality of Respiratory Syncytial Virus — United States, 2017–2023. MMWR Morb Mortal Wkly Rep. 2023;72:355–361. doi: 10.15585/mmwr.mm7214a1.
  3. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality Associated with Influenza and Respiratory Syncytial Virus in the United States. JAMA. 2003;289(2):179–186. doi:10.1001/jama.289.2.179
  4. Hansen CL, Chaves SS, Demont C, Viboud C. Mortality Associated with Influenza and Respiratory Syncytial Virus in the US, 1999-2018. JAMA Netw Open. 2022;5(2):e220527. doi:10.1001/jamanetworkopen.2022.0527
  5. Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA. The Burden of Respiratory Syncytial Virus Infection in Young Children. New England Journal of Medicine. 2009;360(6):588–98. doi: 10.1056/NEJMoa080487
  6. Rha B, Curns AT, Lively JY, Campbell AP, Englund JA, Boom JA, et al. Respiratory Syncytial Virus–Associated Hospitalizations Among Young Children: 2015–2016. Pediatrics. 2020;146(1):e20193611. doi: 10.1542/peds.2019-3611
  7. McLaughlin JM, Khan FL, Schmitt H-J, Agosti Y, Jodar L, Simões E, et al. Respiratory Syncytial Virus-Associated Hospitalization Rates among US Infants: A Systematic Review and Meta-Analysis. Open Forum Infectious Diseases. 2020;7(Supplement_1): S843. doi: 10.1093/ofid/ofaa439.1897
  8. FDA. FDA Approves New Drug to Prevent RSV in Babies and Toddlers. Press Release. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-prevent-rsv-babies-and-toddlers

Public Health Problem:

  1. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality Associated with Influenza and Respiratory Syncytial Virus in the United States. 2003;289(2):179–186. doi:10.1001/jama.289.2.179
  2. Hansen CL, Chaves SS, Demont C, Viboud C. Mortality Associated with Influenza and Respiratory Syncytial Virus in the US, 1999-2018. JAMA Netw Open. 2022;5(2):e220527. doi:10.1001/jamanetworkopen.2022.0527
  3. Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA. The Burden of Respiratory Syncytial Virus Infection in Young Children. New England Journal of Medicine. 2009;360(6):588-98. doi: 10.1056/NEJMoa080487
  4. Rha B, Curns AT, Lively JY, Campbell AP, Englund JA, Boom JA, et al. Respiratory Syncytial Virus–Associated Hospitalizations Among Young Children: 2015–2016. Pediatrics. 2020;146(1):e20193611. doi: 10.1542/peds.2019–3611
  5. McLaughlin JM, Khan FL, Schmitt H-J, Agosti Y, Jodar L, Simões E, et al. Respiratory Syncytial Virus-Associated Hospitalization Rates among US Infants: A Systematic Review and Meta-Analysis. Open Forum Infectious Diseases. 2020;7(Supplement_1): S843. doi: 10.1093/ofid/ofaa439.1897
  6. Suh M, Movva N, Jiang X, Bylsma LC, Reichert H, Fryzek JP, et al. Respiratory Syncytial Virus Is the Leading Cause of United States Infant Hospitalizations, 2009-2019: A Study of the National (Nationwide) Inpatient Sample. J Infect Dis. 2022;226(Suppl 2):S154–S63.
  7.  Hall CB, Weinberg GA, Blumkin AK, Edwards KM, Staat MA, Schultz AF, et al. Respiratory Syncytial Virus–Associated Hospitalizations Among Children Less Than 24 Months of Age. Pediatrics. 2013;132 (2): e341–e348. doi: 10.1542/peds.2013-0303
  8.  Langley GF and Anderson LJ. Epidemiology and Prevention of Respiratory Syncytial Virus Infections Among Infants and Young Children. The Pediatric Infectious Disease Journal. 2011;30(6): 510–517. doi: 10.1097/INF.0b013e3182184ae7

Benefits and harms:

  1. Hammitt LL, Dagan R, Yuan Y, Baca Cots M, Bosheva M, Madhi SA, et al. Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants. New England Journal of Medicine. 2022;386(9): 837–846. doi: 10.1056/NEJMoa2110275
  2. Muller WJ, Madhi SA, Seoane Nunez B, et al. Nirsevimab for Prevention of RSV in Term and Late-Preterm Infants. New England Journal of Medicine. 2023;388(16):1533–1534. doi: 10.1056/NEJMc2214773
  3. Griffin MP, Yuan Y, Takas T, Domachowske JB, Madhi SA, Manzoni P, et al. Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants. New England Journal of Medicine. 2020;383(5): 415–425. doi: 10.1056/NEJMoa1913556
  4. Sanofi/AstraZeneca, 2023 personal communication, August 2022 – February 2023.
  5. FDA Briefing Document, Nirsevimab https://www.fda.gov/media/169226/download
  6. National Library of Medicine, ClinicalTrials.gov. Study of a Single Intramuscular Dose of Nirsevimab in the Prevention of Hospitalizations Due to Respiratory Syncytial Virus (RSV) Infection in Healthy Term and Preterm Infants During the First Year of Life (VAS00006) https://www.clinicaltrials.gov/study/NCT05437510

Values:

  1. CDC and University of Iowa/RAND survey, unpublished

Acceptability:

  1. Alliance for Patient Access and National Coalition for Infant Health. The Indirect Impact of RSV – RSV Parent & Provider Survey Results. https://admin.allianceforpatientaccess.org/wp-content/uploads/2023/01/AfPA-and-NCfIH_The-Indirect-Impact-of-RSV_Survey-Report_Jan-2023.pdf
  2. Committee on Infectious Diseases and Bronchiolitis Guidelines Committee, et al. Updated Guidance for Palivizumab Prophylaxis Among Infants and Young Children at Increased Risk of Hospitalization for Respiratory Syncytial Virus Infection. Pediatrics. 2014;134(2): e620–e638National Foundation for Infectious Diseases. Call to Action: Reducing the Burden of RSV Across the Lifespan. January 2022. https://www.nfid.org/wp-content/uploads/2022/04/NFID-RSV-Call-to-Action.pdf

Feasibility:

  1. Peacock G. Nirsevimab: Implementation Considerations. Presentation to ACIP 2023. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-08-3/03-RSV-Peacock-508.pdf
  2. Sanofi Pasteur Inc. BEYFORTUS- nirsevimab injection package insert. https://www.accessdata.fda.gov/spl/data/2f08fa60-f674-432d-801b-1f9514bd9b39/2f08fa60-f674-432d-801b-1f9514bd9b39.xml
  3. CDC. Vaccines for Children. https://www.cdc.gov/vaccines/programs/vfc/index.html
  4. CDC. CDC Vaccine Price List. https://www.cdc.gov/vaccines/programs/vfc/awardees/vaccine-management/price-list/index.html

Resource Use:

  1. Jones J. Evidence to Recommendations Framework: Nirsevimab Updates. Presentation to ACIP 2023. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-08-3/02-RSV-jones-508.pdf

Equity:

  1. RSV-NET: unpublished data from 2018-2022
  2. Atwell JE, Hartman RM, Parker D, Taylor K, Brown LB, Sandoval M, et al. RSV among American Indian and Alaska Native children: 2019 to 2020. Pediatrics 2023;e2022060435. doi:10.1542/peds.2022-060435
  3. Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, editors. American Academy of Pediatrics, Committee on Infectious Diseases. Respiratory Syncytial Virus [Section 3]. In: Red Book: 2021–2024 report of the Committee on Infectious Diseases. Itasca, IL: American Academy of Pediatrics; 2021:628–36.
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