Maternal Respiratory Syncytial Virus (RSV) Vaccination: Current Status and Comparison to Monoclonal Antibodies (mAbs) for RSV Prevention in Infants and Children

Respiratory Syncytial Virus (RSV) is a prevalent cause of upper respiratory tract infections (URTI), and can progress to lower respiratory tract infections (LRTI), particularly in vulnerable groups, such as infants, immunocompromised individuals, and the elderly [1]. RSV commonly circulates seasonally in temperate regions, typically from late autumn to early spring. RSV is transmitted through respiratory droplets, as well as proximity to infected individuals or objects that have been contaminated with the virus [2]. Beyond causing immediate illness, RSV infections in infancy have been linked to persistent wheezing and the long-term development of asthma [3].

Infants often experience hospitalization from RSV infection within the first six months, and this is a leading cause of neonatal deaths worldwide [4]. Risk factors for severe RSV infection in infants include preterm delivery and cardiopulmonary disorders [5]. RSV infects almost the entire global population before the age of two, with peak hospitalization rates occurring between the second and third months of life. However, the potential for severe disease persists until approximately five years of age. Approximately 64 million people experience RSV globally, resulting in millions of hospitalizations and thousands of deaths [6]. Most children contract RSV by the age of two years, with reinfections occurring throughout life, usually resulting in mild or asymptomatic cases [7]. RSV-related LRTI, however, can lead to complications, such as respiratory distress, pneumonia, and bronchiolitis, sometimes with fatal outcomes [8].

RSV is a non-segmented RNA virus with two subtypes (RSV A and RSV B) and a genome comprising 10 genes encoding 11 proteins [9]. The G and F proteins on the virus's surface play crucial roles in its entry, replication, and immune modulation [10]. Aantiviral drugs and vaccines primarily targets the F protein, which is a major focus of neutralizing antibodies generated during infection. The G protein, expressed as either membrane-bound or soluble, significantly evades the immune response [11]. Immunization is a key approach for protecting infants and children against RSV, either whether it is passive immunization via monoclonal antibodies (mAbs) and maternal antibodies, or active immunization via RSV vaccination. This narrative review aims to critically compare various immunization methods for children against RSV, discussing the strengths, limitations, and future directions of each. It further discusses the factors influencing a parent's choice of one method over another.

Vaccinating infants and children against RSV has emerged as a critical public health concern, prompting multiple vaccination trials with various iterations. The field of RSV vaccine development is primarily influenced by five key technologies, focusing on four types of active immunizing agents: live attenuated vaccines, particle-based vaccines, subunit-based vaccines, and vector-based vaccines [12]. There have been setbacks in the development of RSV vaccines, most notably the experimental formalin-inactivated vaccination that failed over 50 years ago in young children [13]. Several vaccines were considered too attenuated and inappropriate for future development, including LIDcpΔM2-2 and the chimpanzee-derived replication-deficient adenoviral vector (ChAd155-RSV) [13,14]. Various clinical trials conducted in the 1970s, 1980s, and 1990s investigated various approaches to developing an RSV vaccine in children and showed mixed results. A trial conducted in 1979–1980 evaluated a live RSV vaccine administered parenterally to children under 24 months of age and found it ineffective in preventing RSV infection during epidemics [15].

In 1997, another trial focused on the purified F protein RSV vaccine (PFP-2) among children under 12 months of age with bronchopulmonary dysplasia. It demonstrated safety, immunogenicity, and potential protection against serious RSV disease upon reinfection [16]. Another study in 1993 administered an RSV subunit vaccine primarily composed of F glycoprotein to children aged 18–36 months who had previously been hospitalized for RSV infection. It showed promising results in preventing subsequent RSV infections without significant side effects [17]. Notably, in a vaccine trial in the 1960s, infants and young children were immunized using either a formalin-inactivated whole virion RSV preparation (FI-RSV) or a comparable paramyxovirus preparation (FIPIV). Among those who received FI-PIV and later encountered natural RSV infection in the subsequent season, 5% required hospitalization. In contrast, among those immunized with FI-RSV and subsequently infected with RSV, 80% required hospitalization, resulting in the unfortunate loss of two children's lives [2,18]. Concerns have been raised about non-live vaccine formulations potentially leading to vaccine-enhanced RSV disease, similar to issues that occurred with a formalin-inactivated vaccine administered to infants without prior exposure to the virus in the 1960s [18].

The only vaccine strategies that have been shown not to trigger enhanced disease are live attenuated and live chimeric virus formulations [19]. However, the challenge lies in finding the right equilibrium between attenuation for safety, ensuring immunogenicity, and maintaining genetic stability [20, 21]. After five decades of research and development, no approved RSV vaccine for infants and children is currently available [19]. Table 1 presents a concise overview of studies focused on the development of RSV vaccines for infants and children.

The CDC emphasized that in most cases, both interventions (RSV vaccines to pregnant mothers and mAbs to children) are not necessary, and a choice between maternal vaccination or infant immunization with RSV mAb can be made based on various factors [42]. Factors including expense and insurance coverage, past experiences with RSV, access to healthcare, medical advice from healthcare professionals; and knowledge of RSV risk factors can significantly impact the decision to receive RSV immunization, whether during pregnancy as an RSV vaccine for the mother, or later for the child as mAbs.

One of the main concerns for parents receiving vaccines during pregnancy is the safety of their unborn child. Healthcare providers can play a crucial role in addressing these concerns by providing evidence-based information regarding the safety profiles of vaccines approved for use during pregnancy. Parents are particularly attentive to recommendations from healthcare providers when making decisions regarding vaccination and antibody therapy for their children. Access and affordability also influence parents' decisions regarding vaccination and antibody therapy. Parents may also face barriers to vaccination, such as limited access to healthcare facilities offering maternal vaccination, or difficulty affording the cost of vaccines or antibody therapy for their child. Healthcare providers strive to overcome these obstacles by informing families about available resources, including insurance coverage and assistance programs. RSV immunization is provided through the CDC's Vaccines for Children (VFC) program, covering eligible children at no cost [43]. For underinsured children whose health insurance may not fully cover vaccines or certain recommended vaccines, the VFC Program ensures access to vaccines at Federally Qualified Health Centers (FQHCs) or Rural Health Clinics (RHCs). These facilities in medically underserved areas have arrangements to provide immunization to eligible children.

The VFC Program enhances access to vaccinations and eliminates cost barriers by offering free vaccines to eligible children through a nationwide network of more than 37,000 public and private healthcare providers. The VFC Program covers all Advisory Committee on Immunization Practices (ACIP)-recommended and CDC-approved vaccines for children aged 18 and younger, protecting against 19 diseases, including RSV, Mpox, MMR, and Meningococcal B. This has prevented an estimated 472 million illnesses and 29.8 million hospitalizations [44]. The program has saved nearly $2.2 trillion through illness prevention [45].

A study assessed RSV awareness among pregnant women and healthcare professionals, as well as attitudes toward clinical trials and routine administration of the antenatal RSV vaccine across four hospitals in South England [46]. The findings revealed very low awareness among pregnant women and midwives compared to obstetricians. Certain demographic factors influenced attitudes toward vaccination. Younger pregnant women, those at 21–30 weeks of gestation, and those with prior RSV experience were more likely to participate in the trials [46]. White British women and those at 21–30 weeks of gestation were more open to routine vaccination as well. While willingness to participate in RSV vaccination trials varied among different demographics, the overall acceptance was higher for methods that were routinely recommended. Obstetricians showed more support for both clinical trials and routine vaccinations than midwives. The study emphasized the need for education to facilitate antenatal vaccination implementation and effective public health interventions [46].

One cross-sectional study (with the objective of validating a survey tool) focused on understanding the factors influencing RSV vaccine acceptance among women of childbearing age [47]. The study introduced the “ABCDEF” scale, consisting of Advice, Burden, Conspiracy, Dangers, Efficiency, and Fear, to unravel the complexities of RSV vaccination decision-making. Notably, despite a 70% acceptance rate for a safe, effective, and free RSV vaccine, a noteworthy proportion of the population was hesitant. The study identified “Advice” and “Fear” as pivotal determinants, underscoring the importance of effective communication from credible sources to address concerns and highlight the benefits of vaccination [47].

Another study conducted focused on analysing attitudes toward maternal RSV vaccines among pregnant and lactating individuals in Kenya [48]. The study found an association between first pregnancy and higher vaccine hesitancy among both pregnant and lactating individuals. This raises the possibility that people who are pregnant for the first time may have doubts about maternal vaccinations, and that this may affect their readiness to accept them. This study also found that social norms significantly influenced vaccine hesitancy among lactating individuals. This highlights the importance of cultural and societal influences on vaccine acceptance, emphasizing the need for tailored strategies to address community-specific concerns and perceptions [48].

Despite years of investigation, a dedicated RSV vaccine for children remains unavailable. However, recent FDA approval of maternal RSV vaccines has shifted the paradigm, as these vaccines provide longer-duration protection to infants compared to mAbs. Current guidelines recommend that if a mother receives the RSV vaccine during pregnancy, the infant from that pregnancy may not require mAbs. However, beyond infancy, these guidelines do not provide clarity on dosage adjustment if the mAb is administered. Additionally, there is no indication of whether antibody titers should be measured in infants whose mothers received the RSV vaccine during pregnancy before deciding to administer mAb.

The decision-making process for parents choosing between the maternal RSV vaccine or mAbs for their children is influenced by various factors, including cost-effectiveness, safety concerns, and healthcare recommendations. Further clinical research is necessary to comprehensively compare the safety, efficacy, cost-effectiveness, and disease burden between infants whose mothers received the RSV vaccine and those whose mothers received mAbs. This study will contribute to a more informed and evidence-based approach to RSV immunization strategies for infants and children.