Respiratory Syncytial Virus Vaccines and Monoclonal Antibodies

Respiratory syncytial virus (RSV) is the leading cause of hospitalization for pneumonia and other lower respiratory tract illnesses (LRTI) in infants and children worldwide. In the United States, it is estimated that approximately 150,000 infants are hospitalized annually with RSV pneumonia or bronchiolitis. A review of national databases in the U.S. estimated RSV mortality rates in children at approximately 3–4/10,000 admissions, or approximately 50–160 deaths per year although historic estimates were several-fold higher for premature infants and for those with chronic lung disease, congenital heart disease, or primary immunodeficiency disorders. ^, RSV is the leading viral cause of hospitalization and reduction in pulmonary function for children with cystic fibrosis. In American Indian and Alaska Native children, the risk of hospitalization for RSV is three to five times greater than that of the general U.S. pediatric population. ^, RSV also accounts for a substantial proportion of outpatient visits in U.S. children younger than 5 years.

The burden of RSV in high-income countries is only a small fraction of the global burden. RSV is estimated to cause approximately 33 million cases of LRTI and up to 59,600 deaths in children each year, with more than 90% occurring in low- and middle-income countries (LMICs). While very young infants are at increased risk of RSV morbidity and mortality, >80% of RSV-associated LRTI and more than half of RSV deaths occur in children ages 6 months and older. ^, RSV infection in infancy may also predispose to recurrent wheezing and impaired lung function in early life. ^,

Although traditionally regarded as a pediatric pathogen, RSV also can cause life-threatening pulmonary disease in human stem cell transplant (HSCT) recipients. The elderly are also at risk for severe RSV disease. Nearly 180,000 RSV-associated hospitalizations of the elderly are estimated to occur annually in the United States, with 10,000–14,000 RSV-associated deaths each year. ^, RSV may also contribute to long-term mortality in frail elderly populations.

RSV was discovered in 1956. Its importance as a respiratory pathogen in infants was documented shortly thereafter, but several obstacles have impeded vaccine development. The peak of severe disease occurs in very young infants, who may not respond adequately to vaccination because of immunologic immaturity, suppression of the immune response by maternally derived antibody, or both. ^, Because serious RSV disease can occur in high-risk persons who have experienced previous RSV infection as well as RSV-naïve infants, more than one type of RSV vaccine will be needed to immunize all of those who would benefit from vaccination. In addition, an RSV vaccine must not potentiate naturally occurring RSV disease, as was observed with the formalin-inactivated RSV (FI-RSV) vaccine (see “Past Experience: Formalin-Inactivated Respiratory Syncytial Virus Vaccine”).

Despite these challenges, there has been a tremendous surge in RSV vaccine and monoclonal antibody (mAb) research in the past decade, with more than 39 candidates in development and 25 in clinical trials as of September 2022 ( https://www.path.org/resources/rsv-vaccine-and-mab-snapshot/ ). This chapter describes recent efforts to develop safe and effective RSV vaccines and “vaccine-like” mAbs for populations at risk, with a primary focus on vaccines and mAbs currently being evaluated in clinical trials.

BACKGROUND

Clinical Disease

Reinfection with RSV occurs throughout life, although disease manifestations differ. In young children, RSV infections are associated with a spectrum of respiratory illness, ranging from mild upper respiratory illness (URI) to life-threatening bronchiolitis and pneumonia. In infants less than 6 weeks old, poor feeding and lethargy may predominate, and apnea may occur in the absence of other respiratory signs or symptoms. Otitis media occurs frequently; RSV is the principal cause of viral otitis media in children.

The nature of the relationship between RSV infection in early childhood, recurrent wheezing, and subsequent development of reactive airway disease remains an open but important question, as it may contribute to quantifying the full value of vaccination for RSV prevention strategies. Infants hospitalized with RSV infection frequently have recurrent wheezing and demonstrable abnormalities in pulmonary function in the immediate postacute period and in early life. ^, However, it is not clear whether RSV causes abnormal airway function through lung injury and immunomodulation, whether RSV is only one of many triggers in susceptible persons, or whether both are true: genetic factors influence the immune response to RSV, and RSV elicits particular immune responses that may injure the developing lung. Intervention studies may help to resolve this issue. A placebo-controlled trial of the RSV monoclonal antibody (mAb) palivizumab in late preterm infants demonstrated that the infants who received palivizumab had a significant reduction in total wheezing days compared with those who received placebo at a year of age ; however, no effect on the diagnosis of asthma or in lung function was observed when this cohort was reassessed as 6 years of age. A placebo-controlled trial of the RSV mAb motavizumab in full-term American Indian infants also failed to show an effect on the incidence of medically attended wheezing through 3 years of age, and a recent meta-analysis of observational and intervention studies found insufficient evidence to conclude that prevention of RSV-LRTI would lead to reductions in all-cause wheezing or asthma. It is possible that prevention of RSV LRTI in infancy may have the most substantial impact on long-term respiratory health for particular wheezing endotypes or that the impact may be greatest in the preschool years but diminish over time. The planned RSV vaccine and mAb efficacy trials described later in this chapter will provide important opportunities for further assessment of potential causal relationships between RSV and asthma. ^,

In healthy young adults, RSV infections are typically associated with mild URI. Elderly adults attending adult day care or in long-term care facilities and who are infected with RSV may have a combination of symptoms that include rhinorrhea (67–92%), cough (90–97%), fever (20–56%), and wheezing (6–35%). Pneumonia occurs in up to 10% of these persons. ^, ^,

Immunocompromised patients, particularly those with hematologic malignancies and those undergoing HSCT or lung transplant, are at high risk for severe RSV disease. In these patients, URI precedes LRI, and the presence of rhinorrhea, sinusitis, or otalgia are clinical features that may help to distinguish between RSV and cytomegalovirus pneumonia. The severity of disease depends on the type and magnitude of immunosuppression, with rates of RSV pneumonia of up to 75% in leukemic patients and of RSV pneumonia in 24–79% of HSCT patients. For HSCT recipients, infection that occurs preengraftment is associated with the highest risk of pneumonia and death, but mortality is still high in those who develop pneumonia postengraftment. In the United States, prior infection with human immunodeficiency virus (HIV) does not appear to increase the morbidity and mortality associated with RSV infections in children, although prolonged viral excretion has been reported. However, in South Africa, RSV has been reported to be associated with greater morbidity and mortality in HIV-infected than HIV-noninfected children, although the contribution of other illnesses cannot be excluded.

The Virus

RSV is a member of the family Paramyxoviridae. The viral genome is composed of a single strand of negative-sense RNA that is tightly associated with viral protein to form the nucleocapsid, and the viral envelope is a plasma membrane-derived lipid bilayer that contains virally encoded transmembrane proteins. A viral polymerase that transcribes genomic RNA into messenger RNA is packaged within the virion.

RSV is a member of the genus Pneumovirus and is composed of 15,222 nucleotides that encode three transmembrane surface proteins (F, G, and SH), two matrix proteins (M and M2), three nucleocapsid proteins (N, P, and L), and two nonstructural proteins (NS1 and NS2). The surface fusion (F) and attachment (G) glycoproteins are the only viral components that induce RSV neutralizing antibody and therefore are important targets for vaccine development. The F protein, in combination with proteins G and SH, is responsible for fusion of the viral envelope with the host cell membranes and for the characteristic syncytium formation in cell culture. Its genome is highly conserved between RSV groups. Along with the F protein, the G protein mediates attachment to the host cell surface and is largely responsible for the antigenic diversity observed between RSV groups (see below). A secreted form of the G protein that lacks the N-terminal signal/anchor region also is produced, and it is reported that up to 80% of the G glycoprotein released from cells 24 hours after infection is in this secreted form. The function of the secreted G protein is not known, although it may serve as a decoy for RSV neutralizing antibody or as an inhibitor of innate immune responses. The NS1 and NS2 proteins suppress a key component of host innate immune defense by blocking induction (NS1) or signaling (NS2) of type I and type III interferons (IFNs). The NS2 protein may also contribute to airway obstruction by promoting shedding of infected epithelial cells.

Cross-neutralization studies have shown that RSV isolates can be classified into two groups, designated A and B. Although RSV A and B strains differ in all 10 viral proteins, the G glycoprotein shows the greatest divergence between groups, with only 53% amino acid homology between prototype RSV A and B viruses. Group A RSV infection may cause more severe disease than group B RSV, although this has not been definitively established. ^, The impact of this antigenic dimorphism is not completely understood, but young children experiencing their second RSV infection frequently are reinfected with virus from the same group.

EPIDEMIOLOGY

The SARS-CoV-2 pandemic has had a profound impact on RSV epidemiology and transmission. In the pre-COVID era, RSV epidemics occurred yearly during late fall, winter, and early spring in temperate climates, in the rainy season in some tropical climates, and year-round in other tropical climates. During 2020, implementation of nonpharmaceutical interventions (NPIs) to limit SARS-CoV-2 transmission, including masking, social distancing, and closing of many schools and child care centers, virtually eliminated RSV in many parts of the world ; conversely, the relaxation in use of NPIs has led to the resurgence of RSV at unusual times around the globe, https://emergency.cdc.gov/han/2021/han00443.asp . Prior to 2020, almost all children were infected with RSV by 2 years of age, and approximately 50% were infected twice. As a relatively high proportion of 12–24-month-old children may currently be RSV-naïve, some experts are predicting an increased burden of RSV disease in 2021–2022. Reinfection with RSV can occur throughout life and is often symptomatic; however, RSV generally does not cause LRI in immunocompetent adults and healthy older children.

Humans are the only known reservoir for RSV. Spread of RSV from contaminated nasal secretions occurs via large droplets rather than small-particle aerosols, so close contact with an infected person or contaminated environmental surface is required for transmission. ^, RSV can persist as a fomite on hard surfaces for several hours, ^, and for this reason is an important cause of nosocomial respiratory illness, particularly on pediatric wards.

MECHANISMS OF IMMUNITY AND CORRELATES OF PROTECTION

Virus-specific immune responses are largely responsible for protection against RSV-associated LRI and recovery from RSV infection. Immunity to RSV is mediated via humoral and cellular effectors, including serum antibody (acquired as a result of infection or maternally derived in young infants), secretory antibody, and major histocompatibility complex class I–restricted cytotoxic T lymphocytes. The RSV F glycoprotein also may elicit innate immune responses via Toll-like receptors and CD14. ^, Natural immunity to RSV is incomplete, and reinfection occurs throughout life, as has been demonstrated by epidemiologic studies ^, and challenge studies in healthy young adults. Healthy older children and adults, however, usually are protected against RSV-associated LRI. In general, humoral immune responses (secretory and serum antibodies) appear to protect against infection of the upper and lower respiratory tract, respectively, while cell-mediated responses directed against internal proteins appear to terminate infection and may contribute to viral clearance from the lungs. RSV-specific cytotoxic T lymphocytes (CTLs) have been detected in infants recovering from RSV infection and may contribute to short-term protection, such as reinfection during the same RSV season. Although the adoptive transfer of primed T cells will halt RSV replication in immunodeficient mice, the adoptive transfer of RSV-specific cytotoxic T lymphocytes also may potentiate disease, suggesting that there may be an immune component to RSV illness. CD4 Th2–associated responses have been associated with eosinophilia, increased mucus production, and delayed viral clearance in some small animal models and may also contribute to the pathogenesis of RSV disease.

The role of local immunity in the protection of the upper respiratory tract against RSV is suggested by experimental data from studies in cotton rats and adult volunteers, and by observational data from infants. In adults, the presence of secretory neutralizing antibody, but not serum antibody, correlated with protection of the upper respiratory tract against RSV infection. In infants, the development of immunoglobulin A (IgA) in nasal secretions correlated temporally with viral clearance following natural infection. Conversely, airway neutrophil activation at the time of RSV challenge has been shown to predispose to symptomatic RSV infection.

RSV replicates exclusively in the respiratory epithelium. For this reason, serum neutralizing antibody does not prevent clinically apparent infection, as it does for pathogens that produce viremia, such as measles and varicella. However, high titers of RSV serum neutralizing antibody protect the lower respiratory tract against RSV infection or disease, as has been demonstrated by animal studies, epidemiologic observations in infants and young children, and clinical trials of RSV hyperimmune globulin and monoclonal antibodies in high-risk infants (see “Passive Immunization Against RSV”).

Primary infection with RSV does not always elicit an immune response that will protect the lower respiratory tract because RSV-associated LRI can occur in young children experiencing their second episode of RSV. ^, Young infants often develop levels of neutralizing antibody and F and G glycoprotein antibodies to RSV that are only 15–25% of those observed in older children. However, some of this reduction in antibody response may be because of suppression from maternally derived antibody rather than immunologic immaturity, since very young infants with low levels of maternally derived antibody can develop high titers of serum neutralizing antibody in response to RSV infection. Young infants may also have suboptimal innate immune responses and dysregulated T-cell responses to RSV, though available data are limited. The suboptimal response of some young infants to primary infection with RSV has important implications for vaccine development because it suggests that more than one dose of vaccine may be needed for active immunization of infants, particularly since these infants may have high levels of neutralizing antibody acquired from maternal immunization or from an extended half-life mAb (see “Vaccine Development”).

The immunologic requirements for protection against severe RSV disease are not clearly defined. Although it is known that a high level of serum neutralizing antibody (titers >1:200, as measured in a 60% complement-enhanced plaque reduction neutralization assay) is sufficient for protection of the lower respiratory tract in the cotton rat model and in infants, ^, it is not known whether it is necessary in the case of vaccines that induce a broad range of systemic and mucosal humoral and cellular immune responses. In adults and older children who have been previously infected with RSV, it is reasonable to expect that an effective RSV vaccine will boost levels of serum neutralizing antibodies. However, it is conceivable that vaccination may protect young RSV-naïve infants against severe RSV even if high titers of neutralizing antibodies are not induced. In these infants, “challenge” with a second dose of a live-attenuated vaccine may help to predict whether some protection has been conferred by the first dose (see “Biologically Derived Live-Attenuated Vaccines”). Ultimately, correlates of protection against severe disease in young infants may differ by type of vaccine used and will need to be evaluated in the context of efficacy trials. Given the demonstrated importance of neutralizing antibody in protection against RSV LRTI, the generation of a WHO International Standard for antiserum to RSV is a welcome innovation, and the expression of neutralizing antibody titers in International Units (IUs) across clinical trials should be strongly encouraged.

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