Nirsevimab: A Review

Abstract

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in people of all ages and is the leading cause of hospitalization among infants in the United States. The year 2023 was exciting for RSV prevention. The Food and Drug Administration (FDA) approved 3 new tools for preventing severe lower respiratory tract RSV infections in infants, young children, and elderly persons. In May 2023, the FDA approved 2 vaccines, RSVpreF3 (Arexvy™, GSK) and RSVpreF (Abrysvo™, Pfizer), for adults ages 60 years or older to be given as a single-dose intramuscular injection. July 2023 brought the approval of the first long-acting monoclonal antibody nirsevimab (Beyfortus™, Sanofi and AstraZeneca) for the prevention of RSV disease in infants and young children. Then in August, the FDA approved a vaccine (Abrysvo™, Pfizer) to be given to pregnant women to protect their newborns through passive immunity. This article focuses on nirsevemab that has been recommended by the Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) to be administered for all infants <8 months of age and for children 8 to 19 months of age who are at increased risk for severe RSV disease.

Introduction

Respiratory syncytial virus (RSV) is a leading cause of acute respiratory tract infections in people of all ages and the leading cause for hospitalization among infants in the United States.¹ Most (68%) infants are infected in their first year of life and nearly all (97%) by age 2 years.^2,3 Two percent to 3% of young infants will be hospitalized for RSV with the highest RSV hospitalization rates occurring in the first month of life. Seventy-nine percent of children <2 years of age hospitalized with RSV had no underlying medical conditions.⁴

The Centers for Disease Control and Prevention (CDC) estimates that ∼50,000–80,000 children under the age of 5 years are hospitalized every year in the United States due to severe lower respiratory tract disease caused by RSV^5,6 and 100–300 RSV-associated deaths occur annually among U.S. infants and children in this same age group. RSV infections also resulted in 60,000–160,000 hospitalizations and 6,000–10,000 deaths annually among adults of age 65 years or older.^7–9 Despite the harm caused by RSV, it historically has not received as much attention as the flu or coronavirus disease 2019 (COVID-19).

Finally in 2023, before the start of the RSV season, several new tools for preventing severe lower respiratory tract infections (LRTIs) in infants, young children, and elderly persons became available. In May 2023, the Food and Drug Administration (FDA) approved 2 vaccines, RSVpreF3 (Arexvy™, GSK) and RSVpreF (Abrysvo™, Pfizer), for adults 60 years and older to be given as a single-dose intramuscular injection.¹⁰ July 2023 the FDA approved the first long-acting monoclonal antibody, nirsevimab (Beyfortus™, Sanofi and AstraZeneca), for the prevention of RSV disease in infants and young children.¹¹ In August 2023, the FDA approved a vaccine (Abrysvo™, Pfizer) to be given to pregnant women to protect their newborns through passive immunity.¹²

Nirsevimab

Nirsevimab is a long-acting monoclonal antibody to the RSV fusion protein that was approved by the FDA for the prevention of RSV-associated LRTIs among infants and children age <24 months.

In August 2023, the Advisory Committee on Immunization Practices (ACIP) recommended nirsevimab for infants <8 months of age who are born during or entering their first RSV season and for infants and children 8 to 19 months of age who are at increased risk for severe RSV disease and are entering their second RSV season. In the past, the only product available to prevent severe RSV infection in high-risk infants was palivizumab (Synagis™, Sanofi and AstraZeneca) that was first licensed by the FDA in June 1998 and later recommended for use by the ACIP and American Academy of Pediatrics (AAP) only for children with certain underlying medical conditions, placing them at high risk for severe RSV infection.

Less than 5% of all infants in the United States meet the AAP criteria for palivizumab whose use is further limited by the high cost as well as the requirement for monthly dosing during the RSV season (usually 5 doses).^13,14

Palivizumab and nirsevimab are both recombinant human IgG1 kappa monoclonal antibodies made by DNA technology that provide passive immunity against RSV infections by binding to the F1 and F2 subunits of the RSV fusion (F) protein at a highly conserved epitope and locking the RSV fusion (F) protein. The F protein helps RSV fuse with human cells to infect them and has 2 different conformations, the preF (prefusion) and postF (postfusion) forms. Although palivizumab binds to both the PreF and PostF sites, nirsevimab works by recognizing and binding to a highly conserved epitope on the preF form and works to lock the F protein in the prefusion conformation that blocks viral entry into the host cell.

The same target was used in the RSV vaccines Arexvy and Abrysvo. The preF form is thought to produce the strongest protective effects against RSV. Although there has not been any head-to-head efficacy trials for comparing nirsevimab to palivizumab, nirsevimab has shown greater potency at inhibiting RSV than palivizumab in cell culture and animal models.¹⁵ Nirsevimab also has an Fc region engineered to have an extended half-life.¹⁵ This allows for a single dose of nirsevimab to be given during or entering the RSV season to provide protection for the infants against RSV-associated LRTIs rather than requiring monthly doses of palivizumab.

A single dose of nirsevimab administered before the RSV season protected healthy preterm infants (born between 29–34 weeks gestational age) against RSV-associated LRTI for at least 5 months with a 70.1% efficacy and had a favorable safety profile.¹⁶

Safety and Efficacy

Safety and efficacy studies were conducted for infants born during or entering their first RSV season in multicountry trials that randomized infants in a 2:1 ratio to receive nirsevimab or placebo. Phase 2B trials that enrolled 1,453 preterm infants born at 29 to 34 weeks gestation, and a phase 3 trial that enrolled 3,012 late preterm and term infants born at ≥35 weeks gestation were reviewed by the ACIP Maternal and Pediatric RSV Work Group before making their recommendations on nirsevimab. Among infants aged <8 months who were born during or entering their first RSV season, efficacy was evaluated through 150 days after injection.

Results from the phase 3 and phase 2B trials were pooled and showed that efficacy in preventing medically attended RSV-associated LRTI was 79%, efficacy in preventing RSV-associated LRTI with hospitalization was 80.6%, and efficacy in preventing RSV-associated LRTI with ICU admission was 90%. No deaths attributable to RSV were reported in either trial. The incidence of serious adverse events was not increased in the nirsevimab arm compared with the placebo arm.¹⁷ Pharmacokinetic data from the MELEDY study⁴ supported a similar degree of efficacy in infants born extremely preterm, those with chronic lung disease, and those with congenital heart disease.¹⁸

Recommendations for Use

ACIP and AAP recommend 1 dose of nirsevimab for all infants <8 months of age born during or entering their first RSV season. Infants born shortly before or during the RSV season should receive their first dose of nirsevimab within their first week of life. Ideally this dose should be given before discharge from the hospital whenever possible, otherwise it should be given during the first outpatient visit. Only 1 dose of nirsevimab is recommended for an RSV season. Nirsevimab may be administered to age-eligible infants and children who have not yet had a dose at any time during the season. Recommended dosing for infants weighing <5 kg is 50 mg and that for infants weighing >5 kg is 100 mg.¹⁹

Infants and children 8 to 19 months of age who are at increased risk for severe RSV disease and who are entering their second RSV season should receive 1 dose of nirsevimab shortly before entering or during their second RSV season. This includes children who would otherwise be eligible for palivizumab such as those with chronic lung disease of prematurity who require medical support (chronic corticosteroid therapy, diuretic therapy, or supplemental oxygen) during the 6-month period before the start of the second RSV season; children who are severely immunocompromised; children with cystic fibrosis who have manifestations of severe lung disease (previous hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest imaging that persist when stable) or who have weight-for-length <10th percentile.

In addition, studies have shown American Indian (AI) or Alaska Native (AN) children have been found to experience high rates of severe RSV disease. Some AI/AN children live in communities in remote areas making transportation of children with severe RSV more challenging. Because of this, the ACIP has also included this group for nirsevimab entering their second RSV season. Palivizumab is still not recommended for AI or AN children.²⁰

Recommended dosing for children 8–19 months of age is 1 dose of 200 mg nirsevimab (2–100 mg doses administered at the same time in 2 different sites). If available, a single dose of nirsevimab is preferred to monthly doses of palivizumab for these high-risk children. If nirsevimab is not available, palivizumab-eligible children should receive palivizumab as per AAP recommendations.²¹

Nirsevimab is not recommended for any child who is 20 months of age or older. Nirsevimab could be administered in most of the continental United States from October through the end of March based on pre-COVID-19 pandemic patterns. RSV seasonality in tropical climates (including southern Florida, Guam, Hawaii, Puerto Rico, U.S.-affiliated Pacific islands, and U.S. Virgin Islands) may differ from that of most of the United States. In Alaska, RSV seasonality is less predictable, and the duration of RSV activity is often longer than the national average duration.^22,23

Simultaneous administration of nirsevimab with age-appropriate vaccines is recommended.¹⁹ Nirsevimab is not expected to interfere with the immune response to other routine childhood immunizations.²⁴ Nirsevimab is contraindicated in persons with a history of severe allergic reaction (e.g., anaphylaxis) after a previous dose or to a product component.²⁵

Implementation Challenges

The CDC recommendations for nirsevimab were met with several implementation challenges for the 2023–2024 RSV season.

The high cost of nirsevimab ($495 USD per dose for 50 and 100 mg doses and $990 USD per dose for a 200 mg dose) was a concern for families and providers alike. As with all vaccines recommended by the ACIP, nirsevimab is included in the Vaccines for Children (VFC) program for eligible children (∼50% of U.S. children) at no cost.

Although private sector insurance companies have 1 year from the time of ACIP recommendation for a vaccine to comply with coverage, according to a recent press release by Sanofi, they continue to work closely with providers in the private market and the VFC program to help facilitate ongoing access to available doses for eligible babies. According to the Sanofi press release, “currently insurance coverage is in place for nearly 100% of infants in the U.S.”.²⁶

The biggest challenge has been that the demand for nirsevimab outpaced expectations by the manufacturer, leading to shortages of both the 50 and 100 mg doses. On October 23, 2023, the CDC issued a Health Alert Network advisory 499 to provide guidance for prioritization of nirsevimab given the limited supply.²⁷ In January 2024, 230,000 additional doses of nirsevimab (both 50 and 100 mg formulations) were released by the manufacturer. The additional quantity will allow for up to 40% of the eligible population to receive nirsevimab during the 2023–2024 RSV season.

On January 5, 2024, the CDC issued a COCA Now (CDC Community Outreach and Communication Activity) article recommending that health care providers return to the original recommendations on the use of nirsevimab in young children and recommending that infants and children recommended to receive nirsevimab be immunized as quickly as possible.²⁸ Sanofi and AstraZeneca are exploring ways to make nirsevimab 50 or 100 mg doses for the prevention of RSV readily available for the 2024 to 2025 RSV season. Most of the doses are expected to be available before October, ahead of the traditional RSV season.

Summary

Nirsevimab is a new long acting monoclonal antibody for the prevention of RSV disease in infants and young children at high risk for severe disease. The ACIP and AAP recommend 1 dose of nirsevimab for all infants younger than 8 months of age born shortly before or during their first RSV season and for children 8 to 19 months of age who are at increased risk for severe RSV disease shortly before or during their second RSV season (October to end of March in most of continental U.S. RSV season may differ in tropical climates and Alaska).

Clinical trials showed that 1 dose of nirsevimab administered as an intramuscular injection protected infants for at least 5 months and reduced the risk of severe RSV disease by ∼80%. The incidence of serious adverse events was not increased among the nirsevimab recipients compared with placebo. Nirsevimab is part of the U.S. VFC program. Although there were some implementation challenges including cost and inadequate supply for the 2023–2024 RSV season, it is hopeful that these problems will be resolved for the 2024–2025 RSV season allowing for the original ACIP recommendations on the use of nirsevimab in young children to be fully implemented.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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