Approaching the End of the Era of Uncontrolled Respiratory Syncytial Virus Disease Free

(See the Major Article by Thomas et al, on pages 811–7.)

Much of the world’s attention is focused on disease caused by a novel coronavirus. But in the shadow of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, progress is being made on control of a second RNA respiratory virus that accounts for a considerably greater burden of childhood illness than SARS-CoV-2. Respiratory syncytial virus (RSV) lower respiratory tract disease in the United States and other industrialized countries results in hospital admission for approximately 2% of all children in the first 12 months of life and more deaths than either influenza or SARS-CoV-2 in this age group [1] (Table 1). Currently, no licensed preventive vaccine or broadly recommended monoclonal antibody or antiviral agent is available for prevention or treatment of RSV infections, although numerous products are in development and several are in late-phase clinical trials.

Multiple studies of children with 1 of 3 critical risk factors for severe RSV disease (congenital heart disease, chronic lung disease of prematurity, gestational age <29 weeks) have demonstrated that hospitalization rates may be 2–10 times higher than for otherwise healthy term infants [1]. Despite this higher RSV hospitalization rate among children with risk factors, the far greater number of children who do not have recognized risk factors but still experience severe lower respiratory tract disease explains the greater burden of RSV disease (outpatients as well as inpatients) that occurs among otherwise healthy term infants. The article by Thomas et al in this issue of The Journal of Infectious Diseases addresses this less well-studied aspect of childhood RSV disease, specifically the burden of disease among infants in the first year of life who do not have recognized risk factors [2]. In view of the rapid progress being made with both vaccines and long half-life monoclonal antibodies, a thorough understanding of contemporary RSV epidemiology is important for assessment of future interventions to fully understand the benefit that is anticipated to be demonstrated in randomized clinical trials [3]. RSV hospitalization rates among young children have fallen over time in the United States and elsewhere, so information regarding medically attended acute respiratory illness among outpatients, severe illness, hospitalization, and mortality is important to evaluate the benefits and the economic issues of an intervention.

For decades, attempts to develop a safe and effective RSV vaccine have met with futility [4]. Progress in vaccine development has been slow for several reasons. First, the tragic results of a clinical trial conducted in the 1960s with a formalin-inactivated experimental RSV vaccine resulted in vaccine-enhanced disease in some vaccine recipients [5]. This experience severely impaired interest in developing and conducting trials with a non-live RSV vaccine.

Second, the immune response to RSV has been slow to reveal its secrets. Pulmonary infection initiates a host inflammatory response that recruits immune cells required for viral clearance but also contributes to the severity of disease. This interaction with viral proteins initiates both a protective and a pathogenic response. While the importance of neutralizing antibody to the fusion protein has been recognized, only recently has an understanding emerged regarding the relative importance of the 3 major conformational structures of the fusion protein [6]. The role of antibody to other viral proteins such as the large (298 amino acid), glycosylated surface G protein (the second most prominent viral membrane molecule) remains poorly understood [7]. While important, the role of mucosal immunoglobulin A (IgA) is not clear. In addition, the relative balance between Th1 and Th2 cells and interleukin 17–producing Th17 cells remains uncertain and may influence not only vaccine efficacy but also safety issues [8].

Third, respiratory infections in general are difficult to prevent with intramuscular vaccination. Unlike a virus that undergoes systemic replication (ie, measles virus), RSV primarily infects the apical surface of ciliated epithelial cells of the respiratory tract and viremia is unlikely to occur. Airways of the lung are less accessible to vaccine-induced circulating neutralizing immunoglobulin G (IgG), emphasizing the importance of mucosal immunity.

Fourth, a serologic correlate of protection is helpful in assessing immunogenicity of a candidate vaccine, but this has been difficult to establish for RSV [9–11]. The threshold for a protective neutralizing antibody concentration likely will differ between a seronegative infant and a seropositive child. Early studies demonstrated that elevated maternal antibody concentrations correlated with protection for infants in the first 6 months of life. Studies in infants showed that RSV antibody concentrations correlated inversely with susceptibility to RSV lower respiratory tract disease. Some studies suggest that a serum neutralizing antibody concentration of approximately ≥1:64 reduces the risk of RSV-related hospitalization by ≤30% [11]. Studies suggest that neutralizing antibody concentrations become undetectable in 25%–50% of young children within a year following natural RSV infection, offering one explanation for repeated RSV infections [12].

Fifth, a vaccine will be expected to offer protection against the 2 major subgroups of RSV, type A and type B, including the numerous genotypes that are based on heterogeneity of the G protein. The high mutation rate that occurs in RNA viruses may result in changes within neutralizing epitopes of surface proteins. Palivizumab (Synagis, Medimmune LLC, Gaithersburg, Maryland)–resistant RSV strains have been generated readily by serial passage of wild-type RSV in cell culture in the presence of this monoclonal antibody.

Although secretory IgA is the predominant humoral defense for most pathogens on nasopharyngeal and pulmonary mucosal surfaces, injectable influenza and pneumococcal vaccines offer protection mainly through the induction of serum IgG antibodies. A local protective effect in the lung likely is derived from transudation of IgG antibody onto mucosal surfaces. Prophylaxis with a licensed intramuscular IgG monoclonal antibody (palivizumab) is thought to confer a degree of protection against RSV infection through the same process of transudation in the airways of the lower respiratory tract [13]. Although this monoclonal antibody has been shown to reduce the risk of lower respiratory tract disease in 2 clinical trials, RSV infection of the upper respiratory tract continues to occur in children who receive monthly prophylaxis. Ideally, a vaccine or long half-life monoclonal antibody will result in protection of the mucosal surfaces of both the upper and lower respiratory tract. If sterilizing immunity is provided by protecting the portal of entry (upper airways), viral transmission within a community may be reduced (community immunity).

Pediatric patients most likely to benefit from active or passive RSV immunization can be considered in 2 groups: children less than a few months of age (who are most likely to experience severe morbidity) and children >3 months of age. Because of differences in their immune status, different approaches may be needed for each group. For infants who will be less than a few months of age during the RSV season, 2 approaches are undergoing phase 3 clinical trials. One approach is to immunize pregnant women who anticipate giving birth shortly before or during the RSV season. A vaccine boost for pregnant women, most of whom will be seropositive, will increase circulating maternal IgG antibody concentrations. Results from a randomized trial with a single dose of a fusion protein nanoparticle vaccine administered to 4636 pregnant women between 28 and 36 weeks of gestation demonstrated efficient transplacental transfer of neutralizing antibodies [14]. This nanoparticle vaccine elicits antibodies to neutralizing epitopes on both the pre- and postfusion confirmation of the F glycoprotein. Although the trial did not reach its primary endpoint, secondary endpoints were met, indicating that maternal immunization is a promising approach. A second approach to infant protection is intramuscular administration of a neutralizing, long half-life monoclonal antibody soon after birth resulting in passive protection against infection for at least part of the RSV season [15]. For seronegative infants >3 months of age, active immunization may be most appropriate.

Since discovery of RSV in 1956, treatment of respiratory disease caused by this virus has remained largely unchanged, consisting of supportive care. In the absence of therapeutic pharmaceutical agents, prevention of disease with either active or passive immunization holds great promise. Hopefully, reaching the decades-long goal of disease prevention will provide an end to the era of uncontrolled RSV disease in young children.

Notes

Potential conflicts of interest. H. C. M. is a member of the National Vaccine Advisory Committee for the Department of Health and Human Services and a member of the Vaccine and Related Biologics Products Advisory Committee for the US Food and Drug Administration.

The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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