In this issue of Pediatrics, Rostad et al1 summarize the interim analysis of the safety and immunologic results of 4 approaches to achieve levels of anti-RSV (respiratory syncytial virus) neutralizing antibodies (nAbs) to protect very young infants against severe RSV lower respiratory tract disease, beginning with maternal immunization with an antigen-based RSV prefusion F vaccine (RSVPreF) (Group 1A) or sequential combination of both interventions—maternal immunization with an RSVPreF vaccine followed by passive immunization of infants with anti-RSV nAbs (nirsevimab), either at birth (Group 1B) or at 3 months of age (Group 1C), or passive immunization with anti-RSV nAbs alone at birth (Group 2). To put these approaches in perspective, physicians should recall that attempts to reduce the impact of RSV on young infants have been a multigenerational challenge. Use of a simple formalin-inactivated RSV vaccine in the 1960s led to worsened clinical outcomes during subsequent natural infection.2 Continuing strategies for immunization with genetically modified live viruses have made great strides in balancing immunogenicity with attenuation but have proven most effective beyond the early newborn period.3 Use of prophylactically administered anti-RSV nAbs, first as pooled intravenous immunoglobulin from screened plasma donations and later as a humanized monoclonal anybody against the F-glycoprotein (palivizumab), proved to be effective in reducing RSV infection and severity but, due to expense and the need for monthly administration, was only cost-effective in the smaller percentage of newborns at high risk for severe RSV infection, primarily due to extreme prematurity.4However, recently, 2 products have received wide approval in many countries, including the use of maternal immunization in the mid-third trimester as described in this manuscript or the use of a single dose of longer acting nAbs (nirsevimab), administered shortly after birth, as both approaches are effective in protecting infants against severe RSV lower respiratory tract disease for the first several months of life and are cost-effective when used in every infant. This article by Rostad et al1 examines the safety and pharmacokinetics of nAbs of these 2 standard approaches and adds 2 novel sequential regimens in which maternal immunization is followed by administration of passive nAbs either at birth or 3 months of age. These investigators are reporting the interim data for this study including the safety of all approaches and levels of anti-RSV nAbs from birth up to 3 months of life.First, the authors evaluated the safety of these approaches, in particular the novel sequential use of both products. This is relevant considering the initial problems with the earliest RSV vaccine leading to enhanced disease, as well as increased societal concerns by some regarding any form of immunization for either pregnant women or very young infants. It should be noted that none of the interventions include active immunization of infants. Fortunately, no related serious adverse events were seen, and no differences in adverse events were observed in any group, and those reported were typical for any immunization.1 Though the findings are reassuring, we need to realize that this study is not powered to answer concerns about adverse events, although prelicensure data suggest that both approaches are safe when given individually5,6 and no postmarketing research has suggested unusual patterns of adverse events.One of the strengths of this article is a very detailed evaluation of the type and levels of protective antibodies measurable over time with each approach. The key data in the article by Rostad et al can be found in Figure 2: RSV-A and -B nAbs in mothers and infants by time point and treatment group. As anticipated, graphs A and B show that maternal nAb levels are 10-fold greater in mothers who have received immunization. Graphs C and D emphasize that infants whose mothers were immunized show higher levels of antibodies at birth, whereas a brief gap of lower nAb titers was noted in the group receiving of nirsevimab alone. Importantly, infants who receive nirsevimab show the comparable levels of antibodies against both RSV-A and -B by 6 weeks and maintain higher titers at the 3-month measurement relative to maternal immunization alone. From an immunologic standpoint, this suggests that longer protection will occur if a child receives nirsevimab. Additionally, we cannot comment at this time on the children who are scheduled to be born to a mother who was immunized and to then receive sequential nirsevimab at 3 months as that data have not yet been reported. The exact threshold of protective antibodies for infants against RSV is not known, but their measured nAb titers were similar to the Phase II and Phase III trials of the RSVPreF vaccine and postnatal administered Ab studies that proved the efficacy of either approach.5,7The very detailed immunologic analysis may resonate less to busy general clinicians. What does this mean in the real world? This preliminary study cannot compare the efficacy or effectiveness of any of these 4 approaches. However, it does suggest that children who receive the novel combination of nAbs following maternal immunization do not experience any additional adverse events. This is reassuring if infants are exposed to both either accidentally or when maternal immunization occurs within 14 days prior to birth. Recent literature suggests that the current practice of administration of nAbs to infants shortly after birth may provide superior protection in the first year of life and that protection could extend into the second RSV season.8,9 Is it possible that sequential administration of maternal immunization followed by the use of nAbs at 3 months will provide superior protection against RSV and potentially reduced hospitalizations? A recent study noted that the number of infants needed to receive passive nAbs to prevent an RSV hospitalization in the first RSV season is 36, and it jumps to 123 in the second RSV season.9 Currently, the expense of the combination approaches preclude use of both, except for instances in which infants may be born too soon after maternal immunization to ensure transfer of protective nAbs. This study will continue for additional analysis at the 12-month period to assess the safety, tolerability, and durability of antibodies. If one arm appears superior, will scientific evidence lead to general adoption of one as a preferred approach? Will measurement of type and duration of nAbs correlate directly with protection?Of note, this study only includes term infants due to the restrictions of gestational age for maternal immunization. Another recent study reaffirmed the fact that the children at greatest risk for severe RSV and hospitalizations continue to be premature infants who are only eligible for postnatal administration of nAbs.10 Additionally, high-risk populations may require a separate study.Pediatricians are passionate about embracing approaches to reduce perennial causes of child illness, hospitalizations, and death. RSV remains a primary cause of hospitalizations, and early infection may lead to a lifetime of increased morbidity from respiratory disease. These products represent tremendous advances in our ability to protect the most vulnerable infants.5,6
Rajnik et al. (Mon,) studied this question.