The Immunology and Safety of Maternal RSV Vaccination (ABRYSVO), Infant Nirsevimab (BEYFORTUS) Immunization, or Both Products

Overview

Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory tract infections (LRTIs) in infants and young children. It is also a leading cause of mortality in children \<5 years of age worldwide. Until recently, no Food and Drug Administration (FDA)-approved vaccines were available to prevent RSV infection. The only prophylactic product for RSV prevention recommended for infants was the monoclonal antibody palivizumab, but administration was limited to those with extreme prematurity, chronic lung disease, or hemodynamically significant congenital heart disease. However, in 2023, the FDA approved two products designed to prevent RSV lower respiratory tract disease (LRTD) in all infants: an active RSV vaccine based on the prefusion F protein (RSVpreF, ABRYSVO, Pfizer) administered during pregnancy, and a passive, long-acting monoclonal antibody (nirsevimab-alip \[henceforth referred to as nirsevimab\], BEYFORTUS, AstraZeneca) administered to infants at birth or at the start of their first RSV season. Both products were evaluated in Phase 3 pivotal clinical trials and have high efficacy in preventing LRTD caused by RSV in infants. Although there is no established correlate of protection against RSV, antibodies have been associated with protection across multiple studies. The clinical development plan for the products did not include comprehensive evaluations of the magnitude and durability of the immune response, nor were the two products tested in a single trial. This study is a prospective, randomized, open-label Phase 4 study with the primary objective of evaluating the magnitude and durability of RSV-specific neutralizing antibodies in infants through 12 months of life following either maternal RSV vaccination, infant nirsevimab administration, or both products combined.

Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory tract infections (LRTIs) in infants and young children. It is also a leading cause of mortality in children \<5 years of age worldwide. Until recently, no Food and Drug Administration (FDA)-approved vaccines were available to prevent RSV infection in infants. Only the monoclonal antibody palivizumab was available to high-risk infants, but administration was limited to those with extreme prematurity, chronic lung disease, or hemodynamically significant congenital heart disease. However, in 2023, the FDA approved two products designed to prevent RSV lower respiratory tract disease (LRTD) in all infants: an active RSV vaccine based on the prefusion F protein (RSVpreF, ABRYSVO, Pfizer) administered during pregnancy and a passive, long-acting monoclonal antibody (nirsevimab, BEYFORTUS, AstraZeneca) administered to infants at birth or at the start of the first RSV season. Both products were evaluated in Phase 3 pivotal clinical trials and were found to have high efficacy in the prevention of RSV LRTD in infants. However, the magnitude and durability of antibody responses following administration of the products have not been directly compared. This is important because although there are no well-established correlates of protection against RSV, serum antibodies have been associated with protection across multiple studies. Furthermore, the added benefit of administering both products to an infant has not been characterized. While cost-effectiveness analyses have demonstrated that administration of both products to the same mother-infant dyad is not cost-effective or indicated, it is likely that some infants may receive both products inadvertently, and still others may benefit from both. These include infants born to women who may not have mounted an adequate antibody response to vaccination (e.g., due to immunocompromise, prematurity, or insufficient time from vaccination to delivery) or who may have had impaired antibody transfer across the placenta (e.g., due to placental pathology). It also includes high-risk infants (e.g., with prematurity or chronic lung disease) who may benefit from an interval dose of nirsevimab for protection in the setting of waning antibodies and off-season RSV circulation. Thus, understanding the safety and immunology of administration of both products vs. either product alone is of clinical and public health importance. These knowledge gaps underlie the objectives for this study. Primary objective: To evaluate the magnitude and durability of RSV-specific neutralizing antibodies in infants through 12 months of life following either maternal RSV vaccination, infant nirsevimab administration, or both products combined. Secondary objective: 1) To describe the safety among infants exposed to maternal RSV vaccination alone, infant nirsevimab administration alone, or both products combined. 2) To describe the tolerability among infants following administration of nirsevimab. 3)To describe the transplacental transfer of RSV-specific antibodies from mother to infant among individuals who received RSV vaccination during pregnancy and those who did not. 4) To describe the magnitude and durability of RSV-specific antibodies in maternal milk through 12 months of life among individuals who received RSV vaccination during pregnancy and those who did not. 5) To describe the magnitude and durability of RSV-specific antibodies through 12 months post-delivery in mothers among the study groups. 6) To evaluate the magnitude and durability of RSV-specific binding antibodies in infants through 12 months of life among the study groups.