Respiratory syncytial virus (RSV) is a mild and highly contagious respiratory pathogen; it does not affect most healthy infants in a severe manner, but can have more severe manifestations in vulnerable populations of infants. Its high prevalence and ability to precipitate severe lower respiratory tract infections in some infants make it one of the leading causes of hospitalization in early childhood [1]. There has been a concerted public health effort to devise strategies that shield these infants from the adverse effects of RSV [2,3]. Globally, RSV is estimated to cause the deaths of approximately 118,200 children each year [4]. Of these deaths, approximately half occur in infants under 6 months old, with the vast majority occurring in developing countries; in developed countries, the infection is easily treated with nebulizer therapy with beta-agonists, corticosteroids, and in severe cases, monoclonal antibodies [4,5]. In the United States, an estimated 300-600 deaths are associated with RSV hospitalization; however, many of these children have significant underlying cardiopulmonary disease and have fallen through the safety net of early ambulatory therapy. In the absence of adequate ambulatory nebulization therapy, RSV infection is a leading cause of infant hospitalization in the United States, with an estimated yearly frequency surpassing 2,000 instances of RSV-induced pneumonia per 100,000 infants. Given the heightened vulnerability of infants, the opportunity to reduce the risk of RSV infection using preventive strategies is attractive, particularly in countries with limited access to ambulatory respiratory care [6-8]. Maternal immunization presents a unique opportunity to harness the maternal immune system to protect against RSV transmission [9]. Through the strategic activation of the maternal immune response, there is a theoretical opportunity to confer passive protection to newborns, bolstering their defenses during this critical phase of development [10-12]. However, maternal vaccination in the third trimester has never been attempted, given the risks of vaccine reactions, including a proinflammatory response that could trigger preterm labor and result in prematurely born infants with medical problems far exceeding those of easily treated RSV infections in full-term healthy infants. A recently approved RSV vaccine used during pregnancy, administering an RSV prefusion F protein-based vaccine (RSVpreF) in the late second or third trimester, has been deployed to offer protection against severe RSV-related illnesses in infants during their initial months of life; however, there are no assurances of long-term safety or studies of mutational pressure applied on the virus to worsen the public health problem in the years to come [13].

The RSV pre-fusion F protein is a critical component of the RSV virion. This protein facilitates viral entry into host cells, making it a prime target for immunization strategies. Understanding its structure and function is pivotal for the development of effective interventions against RSV [14-16].

Although selective, the placental barrier allows the transference of maternal antibodies to the developing fetus. This process, which occurs primarily in the third trimester, equips the newborn with a reservoir of protective immunoglobulin G antibodies against RSV, providing a critical second line of defense against invasive diseases that break through the mucosal immune defense system. Strategically timed immunization during pregnancy capitalizes on this natural mechanism, ensuring optimal systemic antibody levels in both mother and infant at the time of birth. This temporal alignment maximizes the potential for shielding the newborn from the perils of RSV; however, there is no evidence that this strategy influences critical mucosal cellular and immunoglobulin A defenses against respiratory pathogens [17].

The United States Food and Drug Administration (FDA), has recently considered two RSVpreF vaccines for approval. The first, sponsored by Glasko Smith Kline (GSK^©) (Brentford, England, UK) [18], was halted in February of 2022 after GSK^© (Brentford) reported detecting a “safety signal” in the study when approximately three times the number of preterm births were seen in the vaccinated group as opposed to placebo [19]. Accordingly, the application was withdrawn based on this safety concern and approval was not granted. The other RSVpreF vaccine, Abrysvo^TM (Pfizer, New York, NY, USA), was sponsored by Pfizer^© (Pfizer) and ultimately received FDA approval in May of 2023, following phase 2B [20] and phase III [21] FDA randomized controlled trials (RCTs). The data from the GSK^© trial (Brentford) [22] and the two Pfizer^© trials (Pfizer) [20,21] have been subsequently published and make up the three RCTs included in this metaanalysis.

The anticipated outcomes include a critical understanding of both maternal safety and the consequences of premature delivery for the infant, a better understanding of RSV immunization strategies, and tangible contributions to the arsenal of interventions available to potentially safeguard maternal and infant health. Through this exploration, it is possible to envision a future in which RSV-related morbidity and mortality in infants are significantly mitigated. However, this may occur at a cost in terms of maternal-fetal safety and mutational pressure on RSV strains that will invariably become resistant to the vaccinated human host.

This meta-analysis aimed to systematically synthesize and evaluate the existing literature on the effectiveness and safety of RSVpreF vaccine administered during pregnancy. By aggregating and analyzing relevant studies, we sought to provide a comprehensive assessment of the impact of this intervention on maternal and infant health outcomes, with a primary focus on safety events and the secondary aim of preventing severe RSV-associated lower respiratory tract illnesses in infants.

We found that RSVpreF vaccination was associated with a 24% increased risk of preterm delivery. In addition, although vaccination resulted in a decrease in severe illness and hospitalization, there was no significant difference in neonatal mortality, with 23 and 12 deaths reported in the vaccination and placebo group, respectively. The consequences of this serious adverse event, including the need for neonatal intensive care, fetal complications, and maternal complications, were not described in the original manuscript and are concerning for application in practice on a broad scale. These data curb enthusiasm for RSV maternal mass vaccination and stress the importance of informed consent for mothers, including serious warnings about the risks of premature labor. However, it is important to note that the exact pathogenesis of preterm labor, infectious or non-infectious, has not yet been identified.

In terms of efficacy, our meta-analysis aimed to systematically synthesize and evaluate the existing literature on the effectiveness and safety of the RSVpreF vaccine administered during pregnancy. In this study, the RSV preF vaccine showed promising results. Over the 360-day observation period, the vaccine notably reduced, but did not eliminate, instances of RSV-associated lower respiratory tract illnesses in the neonates. However, there were no significant reductions in RSV hospitalizations or deaths among infants.

However, reductions in mild cases of RSV appear to have come with a significant tradeoff, as there was an observed increase in preterm deliveries among the participants who received the vaccine. Likely, this significant difference was not observed in the Kampmann et al. [21] trial that led to the FDA approval of Abrysvo^TM (Pfizer) in pregnancy secondary to insufficient power for that outcome. We believe that many strategies can be employed to mitigate the risk of preterm labor if a mother opts for RSV vaccination. Some of these strategies include restricting the use of the vaccine to mothers close to delivery or limiting its usage to pregnancies where there is a significant concern for neonatal susceptibility to viral infection, such as babies with birth defects or those suspected to be delivered prematurely. It is notable that as preterm infants are known to be more susceptible to RSV infection, one likely area of use for this vaccine is in pregnancies that are expected to deliver prematurely, making the practical application of maternal vaccination problematic.

With regard to other safety events, the placebo group had fewer local injection site reactions than the vaccine group. Additionally, mothers in the vaccinated group experienced a higher incidence of systemic symptoms within the first month of vaccination. Interestingly, both groups showed comparable rates of systemic adverse events in the infant participants. These findings provide valuable insights into the efficacy and safety of the RSVpreF vaccine administered during pregnancy, which can inform further discussions on the potential benefits and considerations associated with this immunization strategy.

RSV causes significant morbidity and mortality in young infants worldwide, particularly in low- and middle-income nations [23,24]. A phase 3 trial demonstrated that administering nirsevimab, a monoclonal antibody, provided a substantial level of protection against medically attended RSVrelated lower respiratory tract infections for up to 150 days after injection, with an efficacy of 74.5% (95% CI, 49.6% to 87.1%) [25]. However, infant death after the use of nirsevimab was not consistent with monoclonal antibody use, and there is no assurance regarding the long-term safety of this novel approach. Although nirsevimab has gained authorization in Europe for use in infants from birth during the RSV season, its affordability in low- and middle-income countries remains uncertain. In many regions, the accessibility of monoclonal antibodies is restricted to high-risk populations. Beyond supportive care, no other therapeutic options are currently available [25]. Recent publications suggest that the wide-scale use of nirsevimab may apply non-sterilizing ecological pressure on RSV, resulting in resistant strains that may break through monoclonal protection or cause de novo infections beyond the window of immunity proven by either maternal RSV vaccination or nirsevimab administration at birth.

Vaccination presents the potential for an immune response against various neutralizing epitopes, consequently lowering the risk of immune evasion, as observed with some monoclonal antibody treatments [26]. The passive transmission of maternal antibodies serves as a safeguard for newborns, particularly those who are most fragile, in the critical period immediately after birth, before the development of robust immune responses through active vaccination. Notably, our study revealed that the youngest infant afflicted with severe RSV-related lower respiratory tract illness was a mere 8 days old, underscoring the need for early treatment with hospital or ambulatory nebulization therapy irrespective of RSV vaccination.

Following the approval of Pfizer’s^© (Pfizer), Abrysvo^TM (Pfizer) for lower respiratory tract disease caused by RSV, Melgar et al. [27] evaluated the efficacy of both the GSK^© (Brentford) vaccine and the Pfizer^© (Pfizer) vaccine. They reported that both vaccine variants showed notable effectiveness in preventing symptomatic RSV-associated LRTD in adults aged 60 years and older with just one dose, however, the crude rates of serious adult RSV infection was <1% in both treatment and placebo groups. On June 21, 2023, the Advisory Committee on Immunization Practices suggested that individuals in this age group consider a single RSV vaccine dose in consultation with their healthcare providers. Vaccination against RSV has the potential to reduce significantly rare RSV illnesses in vulnerable older adults. Ongoing monitoring of its safety and efficacy through post-market surveillance will inform future recommendations.

The prefusion F protein is a key antigen on the RSV surface. It plays a critical role in viral entry into the host cells and is the primary target of neutralizing antibodies. The prefusion form of the F protein is the specific conformation that the protein adopts before undergoing a structural change to initiate viral fusion with the host cell membrane. Researchers have shown that antibodies targeting the prefusion F protein exhibit higher neutralizing activity than those targeting the post-fusion form, making it an attractive target for vaccine development. Several studies have demonstrated promising results for pre-fusion F-protein-derived vaccines. These vaccines have shown efficacy in preclinical models, eliciting robust immune responses and providing protection against RSV infection. Additionally, early stage clinical trials have shown encouraging results in terms of safety and immunogenicity in human subjects [28-30]. Caveats concerning RSV vaccination include mutational resistance because of limited antigenic immunity with either pre- or post-fusion protein epitopes.

The safety and adverse event profiles observed in mothers receiving the RSVpreF vaccine were concerning and consistent with findings from prior phase 1-2 clinical trials performed on non-pregnant adults [31-33]. Typically, participants experienced mild to moderate levels of reactogenicity. The profiles of adverse events and serious adverse events tended to be consistently greater with vaccination, and the 24% excess risk of preterm labor and delivery remains a major concern. If RSV vaccination is more broadly applied to complicated and high-risk pregnancies (e.g., preeclampsia and eclampsia), the rates of preterm labor and its complications could be much greater with RSV vaccination. Both groups displayed similar frequencies of systemic adverse events among infant participants.