Approach to prevention of respiratory syncytial virus disease in infants by passive immunization

Case description

Jenny is a 32-year-old woman (G1P0—1 pregnancy, 0 births) who lives in an urban centre. She presents to your office as she has had a positive home pregnancy test result. According to the dates of her last menstrual period, she is 6 weeks pregnant and her expected date of delivery is in November. Jenny would like to know more about her options to protect her infant from respiratory syncytial virus (RSV). Specifically, she is wondering if she should get RSVpreF, the new vaccine administered during pregnancy. She would also like information about the monoclonal antibody (mAb) nirsevimab for infants.

Sources of information

Information on the burden of RSV disease in infants in high-income countries came from a literature review.¹ Evidence on the effectiveness, efficacy, and safety of nirsevimab was derived from observational studies and 3 randomized controlled trials.^2-9 Evidence on the efficacy and safety of RSVpreF for prevention of RSV disease in infants was derived from 2 randomized controlled trials.^10,11 Publicly available evidence presented and discussed by review agencies (such as the US Food and Drug Administration’s Antimicrobial Drugs Advisory Committee and its Vaccines and Related Biological Products Advisory Committee) was also reviewed.^12-18 Further information was obtained from the product monographs of palivizumab, nirsevimab, and RSVpreF.^19-21 Moreover, this article references new guidance published on May 17, 2024, by Canada’s National Advisory Committee on Immunization (NACI) on the prevention of RSV disease in infants.²²

Main message

Burden of disease. Respiratory syncytial virus infects almost all infants globally by 2 years of age.²³ Risk factors for severe RSV disease in infants include prematurity, age younger than 1 year, pre-existing cardiorespiratory disease, being immunocompromised, and residence in Indigenous, remote, or northern communities.²⁴ Although these infants are at higher risk of severe outcomes, overall burden to the health care system is mostly due to medical care for healthy, full-term infants.¹

Respiratory syncytial virus immunizing products. There are 3 immunizing products available for preventing severe RSV disease in infants: 2 mAbs, palivizumab and nirsevimab; and 1 vaccine given during pregnancy, RSVpreF. All 3 products augment the modest level of passive immunity infants receive at baseline through transplacental transfer of antibodies developed by a pregnant woman’s or pregnant person’s previous natural RSV infections.²⁵ Monoclonal antibodies provide infants with passive immunity by direct injection with protective antibodies. This differs from active immunity where antibodies are elicited against vaccine antigens. RSVpreF is a protein subunit vaccine given during pregnancy, where active vaccination of the pregnant woman or pregnant person results in prefusion F protein–specific antibodies being passed to their infants via transplacental transfer for protection after birth.¹¹ For nirsevimab and RSVpreF, the passively transferred antibodies are directed against the prefusion-stabilized F protein on the surface of RSV by binding to the surface F protein of the RSV virus and inhibiting viral activity.^11,26,27

Until 2023 palivizumab was the only option available to prevent severe RSV disease in infants and young children. In Canada palivizumab cannot be purchased privately. It is available only through publicly funded provincial programs to a small number of infants at highest risk of severe outcomes from RSV disease due to prematurity (typically those younger than 30 to 32 weeks’ gestational age); those with specific medical conditions such as bronchopulmonary dysplasia or congenital heart disease; or those residing in remote, northern Inuit communities.²⁸ Recipients typically require 4 once-monthly injections¹⁹ at an average cost of $1227 per dose.²⁹

In April 2023 a new long-acting mAb, nirsevimab, was authorized by Health Canada. It is administered through intramuscular injection and is authorized for infants entering or during their first RSV season and for children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season.²⁰ As an immunizing product for healthy infants, nirsevimab is a relatively expensive intervention with a list price of $952 per dose.²⁹

In January 2024 Health Canada approved the RSVpreF subunit protein vaccine for use in pregnancy. A separate indication for people 60 years of age or older to prevent RSV disease in older adults was also authorized for this vaccine.¹⁹ RSVpreF is administered at 32 to 36 weeks of gestation.²¹ Typically, 2 weeks are needed between administration of RSVpreF and birth to allow for adequate transfer of maternal antibodies.²² The list price of RSVpreF is $230 per dose.²⁹

All RSV immunizing products are for prophylactic use only and not for treatment of disease. In the United States, administration errors have been observed; for example, infants have been given RSVpreF while pregnant women and pregnant people have been given a different RSV vaccine that is authorized only for adults 60 years of age or older (see Safety section below).^30,31 The use of both RSVpreF and an mAb is not necessary except in specific circumstances (see Case resolution below).

Effectiveness and efficacy. For infants in their first RSV season, nirsevimab results in a reduction in hospitalizations, with observational studies from the 2023 to 2024 RSV season reporting effectiveness ranging from 82% to 90%.^5-9 Evidence also suggests that nirsevimab results in a reduction in intensive care unit (ICU) admissions and medically attended RSV disease.^2,3,7 For infants at high risk in their first and second RSV seasons, evidence suggests nirsevimab likely results in a reduction in ICU admissions, hospitalizations, and medically attended RSV disease compared with palivizumab.^4,32 There was limited evidence on the effect of nirsevimab against infant mortality due to RSV disease. Available data indicate that a single dose of nirsevimab provides a consistent level of protection over 150 days and is expected to be effective up to 8 months after administration based on pharmacokinetic data.^2,3,33

Evidence suggests that RSVpreF administered to pregnant women and pregnant people results in a reduction in ICU admission, hospitalization, and medically attended RSV disease in their infants during their first RSV season.¹¹ As with nirsevimab, there was limited evidence available on the effect of RSVpreF against infant mortality due to RSV disease. In a clinical trial RSVpreF efficacy was observed to be highest at 90 days after birth and decreased steadily after this point.¹¹ The protection conferred by RSVpreF is unlikely to last longer than 6 months in infants due to waning levels of passively transferred antibodies.¹¹

Nirsevimab has not been compared directly with RSVpreF in a clinical trial but may be more effective based on separate studies showing 76.4% efficacy at 150 days for nirsevimab and 51.3% efficacy at 180 days for RSVpreF against medically attended RSV.^3,11

The efficacy of RSVpreF in preventing RSV disease in pregnant women and pregnant people themselves was not evaluated in clinical trials and is therefore unknown at this time.

Safety. Evidence suggests that nirsevimab does not increase the risk of serious adverse events (AEs) (eg, death, hospitalization, substantial disability), severe systemic AEs (eg, fever), or local AEs (eg, redness or swelling at the injection site) compared with placebo or palivizumab.^2-4

When RSVpreF is administered in pregnancy, receipt does not result in an increase in severe systemic AEs for pregnant recipients or their infants compared with placebo. However, for pregnant women and pregnant people, RSVpreF may increase the risk of severe local AEs (specifically redness, swelling, and pain) compared with placebo.^10,11

The frequency of serious AEs was similar in pregnant participants and infants across the RSVpreF and placebo recipients.^12-15 However, a numerical imbalance in preterm births was observed between RSVpreF and placebo recipients, but it did not reach statistical significance.^10,11,16,17 A similar vaccine, the RSVPreF3 vaccine, was halted in a phase III trial for pregnant women due to a statistically significant difference in preterm births (RSVPreF3 has subsequently been authorized by Health Canada for the prevention of RSV disease in adults 60 years of age or older).^18,34,35 It is not known at this time if there is a causal relationship between the vaccine and preterm birth, and vaccine safety data continue to be monitored. To mitigate any potential risk of preterm birth due to RSVpreF, Health Canada limited the authorized dosing interval to 32 through 36 weeks of gestation.²¹

Recommendations from NACI. The National Advisory Committee on Immunization has recently published updated guidance on the prevention of RSV disease in infants that includes all authorized RSV immunization products.²²

Case resolution

As RSVpreF is administered to pregnant women or pregnant persons after 32 weeks of gestation and mAbs are administered to infants after birth, Jenny has some time to make her decision. Jenny’s decision to receive RSVpreF will depend on the availability of the various RSV immunizing products in her jurisdiction, what products are publicly funded, whether she has private insurance (eg, through her employer) that might cover either product, and the health status of her infant after birth. These decision points may change with the changing availability of products in public programs and in the private market.

Some provinces and territories may implement a universal nirsevimab program for the 2024 to 2025 RSV season. For example, Quebec announced it will provide nirsevimab free of charge for all infants younger than 6 months of age starting in September 2024; similarly, Ontario’s government will publicly fund nirsevimab for infants and children at high risk up to 24 months of age.^36,37 In this case, infants will receive nirsevimab after birth, and RSVpreF during pregnancy is not needed. However, if it is expected that nirsevimab will not be administered (eg, due to parent preference that the infant does not receive nirsevimab), RSVpreF can be considered at 32 to 36 weeks of gestation. Ontario has stated it will provide pregnant women with the option to receive RSVpreF.³⁷

Jenny may live in a province or territory that has a limited publicly funded nirsevimab or palivizumab program only for infants who are born prematurely or who have certain medical or social conditions that increase the infant’s risk of severe RSV disease. Jenny can consider receiving RSVpreF in pregnancy, which would provide adequate protection in the case that her infant is born at full term and without any identified medical or social risk conditions; nirsevimab would not be needed in this case as minimal extra protection would be gained. It also may not be possible for Jenny to access nirsevimab on the private market for her full-term healthy infant due to availability or prohibitive cost. However, if the infant is born less than 2 weeks after administration of RSVpreF or qualifies for nirsevimab after birth because of prematurity or a risk condition, NACI recommends the infant still receive nirsevimab if it is available, regardless of Jenny’s RSVpreF vaccination status.²²