Exploring parental perspectives: Maternal RSV vaccination versus infant RSV monoclonal antibody

ABSTRACT

Introduction

Respiratory Syncytial Virus (RSV) remains a significant global public health concern. While it poses a considerable threat to those of advanced age, the highest risk group are infants in the first year of life. It is estimated globally that RSV is responsible for 3.6 million hospitalizations and over 100,000 deaths annually in children less than five years of age, half of which occur in those less than six months of age.¹ A staggering 97% of RSV attributable deaths occur in low income and middle income countries.¹ Infants born prematurely and those with underlying medical conditions such as congenital heart disease are particularly vulnerable to severe outcomes. However, the majority of infants admitted to hospital with RSV associated lower respiratory tract infections do not have any known additional risk factors for severe disease.^2,3

Until recently, the only preventative therapy available was palivizumab, a monoclonal antibody requiring five monthly doses to be given over the RSV season, licensed for administration only to high-risk infants. However recent scientific advances have resulted in two forms of passive immunization coming to market designed to prevent severe RSV in the first year of life; nirsevimab a long-acting monoclonal antibody (mAb) and RSVpreF, a maternal RSV vaccine.

1. NirsevimabNirsevimab (Beyfortus, Sanofi) is a long acting mAb that was approved in the EU in 2022 and in the US in 2023. It is indicated for the prevention of RSV lower respiratory tract disease in infants during their first RSV season. One dose is thought to provide protection to an infant for 5 months, and possibly longer. How this will be implemented may differ between jurisdictions depending on local immunisation programs and infrastructure. Proposed strategies include year-round or seasonal administration at birth, or a seasonal programme administering a dose to infants under one year of age just prior to the predicted RSV season start, or a combination of the two.

2. RSVpreF maternal RSV vaccineRSVpreF (Abrysvo, Pfizer) is a protein subunit vaccine approved in the US and EU in 2023. It is licenced for the prevention of lower respiratory tract disease caused by RSV in infants from birth through 6 months of age. It is given as a single dose to pregnant women in the late second or third trimester leading to increased transplacental transfer of maternal antibodies to the infant, providing protection to the infant immediately from birth to approximately six months of age, with greatest protection in the first three months when the infant is at highest risk of severe disease.

As these two preventative strategies are under consideration by healthcare decision makers, there are many factors at play which necessitate careful consideration in determining which immunization strategy will be most effective at reducing RSV related diseases in young infants. The process of selecting a vaccine for a given pathogen when many are available is not novel, however choosing between a maternal vaccine and a universal infant monoclonal antibody (mAb) introduces some new considerations, one of which being parental acceptance. Acceptability and uptake of each product will significantly affect the impact of any national strategy for the protection of infants from RSV. It is timely to reflect on what is known about perspectives of pregnant women and parents regarding their acceptance of either maternal vaccination or infant monoclonal antibody, and consider the impact this could have on uptake rates.

Uptake in existing maternal and infant vaccination programs

A predictor of future behavior may be past behavior. Women who have received vaccines in previous pregnancies are more likely to get vaccines in subsequent pregnancies.⁴ Pertussis vaccination during pregnancy is the most similar to RSV vaccination in that the primary aim of vaccination is infant protection. This differs from antenatal COVID-19 and influenza vaccination which aim primarily to prevent severe disease in pregnant women, with infant protection as a secondary outcome. Over 55 countries worldwide recommend pertussis vaccination during pregnancy.⁵ Uptake of this vaccine has been suboptimal in many areas, although it has been gradually increasing over the past decade. The uptake of infant pertussis vaccination, on the other hand, is generally higher in most countries, with many jurisdictions boasting robust uptake rates of above 85% or 90% for infant vaccinations in the first year of life as outlined in Table 1. However, it should be noted that many countries have experienced a decline in vaccine uptake, both infant and maternal, since the onset of the COVID-19 pandemic.^20,21 Accurate data on maternal vaccination uptake is lacking in most jurisdictions. Many countries rely on surveys or cross-sectional studies to estimate uptake rates. In contrast, infant vaccination usually has more robust reporting systems in which all doses given are recorded to provide more accurate uptake rates (Table 1).

Factors influencing vaccination uptake

While the focus of this review will be on parental acceptance of maternal and infant vaccination as a determinant of uptake, it is important to note that acceptability of a vaccine is not the only factor which influences uptake. The WHO has described 18 different determinants of vaccine hesitancy and have grouped these into three main groups; contextual influences, individual and group influences, and vaccine specific issues.²² Researchers from the vaccine confidence project have highlighted that the differential impact of each of these factors vary according to vaccine and context-specific issues.²³ It is crucial that countries consider which factors are likely to play an important role in influencing uptake in their own area. This includes healthcare access and cost, climate, and geographical factors, cultural and religious influences, and past experience with vaccines. Healthcare access can mean different things to different people. In lower resource settings a barrier to access might be the requirement of pregnant women or parents to travel long distances to get a vaccination. In other settings, failure to offer maternal vaccination during antenatal care visits, instead requiring women to make another appointment in a different facility may create a barrier to uptake. Higher levels of education can be a positive predictor of vaccination in some setting, and a negative predictor in others. Healthcare decision makers must look at their local setting to identify facilitators and barriers to both maternal and infant immunization in their area and determine which infant RSV preventative program is feasible in their setting and reduce barriers where possible.

Factors that are likely to influence acceptability of a maternal RSV vaccine

Studies specifically investigating acceptance of maternal RSV vaccines are limited to date. A 2019 Australian study of 495 pregnant women reported that 95% of those surveyed would be likely or very likely to take an RSV vaccine if it was recommended, the most influential advisor reported to be either an obstetrician or midwife.²⁴ Preliminary results from an Irish study carried out in the same year reported that 57% would accept an RSV vaccine if it were available and recommended for pregnant women, and 37% were unsure.²⁵ GPs were the preferred source of information followed by midwives and obstetricians for these Irish women. A survey of 321 pregnant women in England reported in 2019 that 75% would likely accept an RSV vaccine if it was routinely recommended.²⁶ While there may be a paucity of maternal RSV vaccine acceptance data, we can draw from studies on maternal acceptance of other antenatal vaccines, such as tetanus, diphtheria, pertussis (Tdap), influenza, COVID-19, and Group B Streptococcus (GBS) vaccines. The prominent factors previously identified as impacting on maternal immunization uptake include; health care provider recommendation, perceived risk and benefits for the infant, race, birthplace, and access to healthcare.²⁷

Maternal RSV vaccine safety

The clear evidence that safety concerns are among the most important barriers to maternal vaccination highlights the importance of ensuring that the safety data on new maternal RSV vaccines is well communicated to both expectant mothers and to healthcare providers. Safety data from phase three trials on the recently approved RSVpreF maternal RSV vaccine has reported that this vaccine was generally well tolerated, with the majority of adverse events reported mild to moderate in nature.^28,29 The most common adverse event reported in recipients was injection site pain. The incidence of preterm birth (<34 weeks) was slightly higher in the vaccine group (n = 28, 0.8%) compared to the placebo group (n = 23, 0.6%) but the difference was not statistically significant. A trial on a similar PreF conformation subunit vaccine (RSVPreF3-Mat) from a different manufacturer was halted in February 2022 due a safety signal regarding increased preterm births and preterm deaths in their vaccinated cohort.³⁰ This numerical difference in preterm births led to a further review of the data from the Pfizer trial, which has satisfied authorities responsible for marketing authorization but led to different gestational age recommendations in the US and Europe; with the FDA restricting administration to 32–36 weeks and the EMA approving use through 24–36 weeks as was assessed in the trial.³¹ It will be critical, particularly considering this increased scrutiny that healthcare care providers are supported with clear materials that can help them discuss recommendations with their patients. Phase four safety data will be important in facilitating acceptance of the maternal RSV vaccine.

Infant RSV mAb safety

In infants, nirsevimab has exhibited an acceptable safety profile in trials including over 5,000 mAb recipients to date. Adverse event profiles were similar between nirsevimab and placebo recipients. No serious adverse events reported in the trials were considered by investigators to be related to nirsevimab.^32–35 However, this is the first time an mAb would be used in a universal program, and it is a novel product, as such there may be safety concerns about the potential for rare side effects that could not be identified in clinical trials. As with maternal vaccination, phase four safety data will be crucial in addressing concerns of both healthcare workers and parents.

Factors likely to influence RSV monoclonal antibody acceptability and uptake

While maternal vaccination uptake remains suboptimal in many settings, experience with hepatitis B vaccination and infant BCG has shown that uptake of vaccines administered shortly after birth is generally good.^42,43 The administration of vitamin K to newborns soon after birth could also be considered a proxy indicator of potential parental acceptance of mAb administration at birth. For those born in a hospital setting in the US acceptance of Vitamin K is generally high, reportedly over 95%, however this does decrease in the setting of home births and birthing centers.⁴⁴ Nirsevimab is recommended for use this season in the US, France, and Spain. In all three settings, it is advised that it be given to infants soon after birth, ideally prior to discharge.^40,45,46 In certain settings, such as the US where hepatitis B vaccination is given at birth, parents will be accustomed to newborn vaccination. However, in other settings, the first vaccines are given at 8 or 12 weeks of age, consequently vaccinating an infant in their first few days of life may present a new concept for both parents and their healthcare providers.

Additionally, while one might expect similar uptake to other infant vaccinations it should be kept in mind that nirsevimab is different to other infant vaccines. It is a form of passive immunization designed to provide protection for one RSV season. Never before has a mAb been given universally to an entire birth cohort. It should be considered whether this may introduce some hesitancy if parents are unsure about such a novel product.

An international study funded by the marketer of nirsevimab reported that, similar to the outcomes from studies on pregnant women, parents identified healthcare providers as their main information source with pediatricians, GPs, nurses, and mid wives favored differently in different countries depending on the healthcare system.⁴¹ Passive immunization is a new concept to many parents, less than 7% had any knowledge of the concept and only 3.1% had knowledge of mAbs. They also noted that receiving information on mAbs had either a positive or no impact on most parents, as opposed to a negative impact. The overall conclusion was that parents would be less concerned about the mAb technology if it is recommended by healthcare providers and included in a national program.⁴¹ Again, safety information was the most important information to parents. In an unpublished study presented to ACIP in 2023, a CDC survey of 523 mothers found that 70% would give a mAb to their baby if it was recommended by the CDC, of note in this study population 68% had previously heard of RSV, indicating higher levels of RSV knowledge compared to most other studies published in international literature. Whether this reflects a significant increase in general public awareness around RSV due to recent increased media attention or potentially reflects a select sample who are more informed is unclear at this time as the full details are yet to be published.⁴⁷

RSV immunization in low- and middle-income countries

RSV disproportionately affects infants in low- and middle-income settings where the burden of severe disease is highest and associated healthcare costs are considerable. A 2020 metanalysis estimated that the total cost of RSV management in developing countries was €3.13 billion (95% CI, 2.27–5.13), representing 2.7% of healthcare expenditure in these countries.⁴⁸ While the newly available mAb has the potential to significantly reduce the burden of RSV on health systems, the cost of a universal mAb program raises concerns about the affordability in resource-constrained environments. However, the maternal vaccine is anticipated to be priced lower and there is precedent for the success of maternal immunization programs in such settings, as evidenced by the widespread implementation of maternal Tdap/Td vaccination. This success demonstrates that with concerted efforts to make vaccines affordable and accessible, maternal RSV immunization could be a feasible and effective strategy to combat the high burden of RSV disease and improve outcomes for vulnerable populations in low- and middle-income countries. It is also anticipated that more affordable mAbs, aimed at lower resource settings, may come to market in the coming years which would provide greater choice to these countries in need to develop RSV immunization strategies which can be cost-effective in their setting.

Conclusion

As the leading cause of infant pneumonia worldwide, the introduction of two products that could mitigate RSV disease severity during the most vulnerable stages of infancy is a highly encouraging development. This positive stride stands as a testament to the dedication of those engaged in vaccine research.

Protecting young infants from RSV during their first RSV season has the potential to not only save lives and reduce morbidity but also to alleviate the strain on healthcare systems, particularly during the winter months when co-circulation of other respiratory viruses peak causing increased pressure on healthcare capacity. If these innovations can reduce hospitalizations by 60–80%, the implications for pediatric medicine during the winter months could be truly transformative.

Addressing RSV-related mortality on a global scale mandates an equitable purview, encompassing lower resourced settings. It is important that effective, affordable immunizations are made available in parts of the world where RSV-related mortality is highest.

Uptake is a key factor in determining the success of any immunization program. A safe and efficacious vaccine can only be as effective as it’s uptake rate. Both RSV immunization products appear to have an acceptable safety profile and are efficacious against severe RSV disease and hospitalization. Therefore, acceptability and access will need to be seriously considered when deciding which product to recommend and how to implement it. Understanding the factors that steer pregnant women’s decisions toward or away from a recommended vaccine during pregnancy holds the key to planning an effective immunization program for a maternal RSV vaccine. Similarly, considering the motivations underlying parental choices regarding infant vaccination, including their openness to monoclonal antibody use, is of equal significance. In both groups, the pivotal role of healthcare provider recommendations emerges as a common thread, alongside the perceived immunization safety, disease severity, and vaccine efficacy. Notably, the healthcare provider assumes the dual role of vaccine advocate and informational purveyor to the patient. To do this, it is paramount that healthcare workers be equipped with adequate information and time to address this important task if an immunization program is to be effective.

The decision between administering a maternal RSV vaccine or an infant RSV mAb hinges on a multitude of factors that are influenced by the unique country context and location. This includes assessing the healthcare infrastructure supporting existing maternal and infant vaccination programs, as well as the financial feasibility of adopting a particular product into these initiatives. It is crucial to recognize that what may be effective in one country might not be replicable in another; therefore, the choice will necessitate tailored consideration based on regional resources and healthcare delivery capabilities.

Ultimately, by discerning the factors that influence parental decisions, we can facilitate more informed discussions, enhance healthcare communication, and contribute to the design of effective RSV prevention strategies that resonate with the concerns and aspirations of parents worldwide.

Funding Statement

The author(s) reported that there is no funding associated with the work featured in this article.

References