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Vaccination Against Respiratory Syncytial Virus
C H A P T E R
38 Vaccination Against Respiratory Syncytial Virus Tracy J. Ruckwardt, Michelle C. Crank, Kaitlyn M. Morabito and Barney S. Graham Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
I. INTRODUCTION Respiratory syncytial virus (RSV) is an enveloped, negative-sense, nonsegmented RNA virus with a 15-kb genome. RSV has 10 genes that encode 11 recognized proteins. The RNAbinding nucleoprotein (N), phosphoprotein (P), polymerase (L), and transcription processivity factor (M2-1) make up the ribonucleocapsid. The lipid bilayer envelope is supported by the matrix protein (M) and displays the glycoprotein (G), the fusion protein (F), and small hydrophobic ion channel (SH) protein on the surface. The virus also encodes M2-2, which mediates the transition between transcription and replication, and two nonstructural proteins, NS1 and NS2 [1]. RSV was a member of Paramyxoviridae family prior to reclassification in 2016 into the Orthopneumovirus genus of the Pneumoviridae family [2]. Compared to influenza virus, another common cause of respiratory tract infections, the
Mucosal Vaccines DOI: https://doi.org/10.1016/B978-0-12-811924-2.00038-9
diversity of RSV is limited. There are two antigenic subtypes of RSV, A and B, which comprise a single serotype [3]. Most of the diversity is accounted for by G protein, which has less than 50% amino acid sequence identity between subtypes. The F glycoprotein is more conserved, with 89% amino acid identity between subtypes [4]. While F diversity is limited, even small amino acid differences can affect the ability of monoclonal antibodies to neutralize individual viral isolates [5]. Several RSV proteins have been found to interfere with innate and adaptive immune responses [6]. NS1 and NS2 inhibit the induction of type I and III interferon (IFN) by binding to proteins in the IFN pathway (IRF3, MAVS, RIG-I), mediating degradation of other proteins (IKKε, TRAF3, and STAT2) in the IFN pathway, and inhibiting apoptosis of RSV-infected cells [7 11]. The G protein exists in two forms. Membrane-anchored G protein mediates attachment between the virus and cell and is
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key for in vivo infection. The secreted form of the G protein can act as an immune decoy to absorb antibody and reduce neutralizing activity. Additionally, secreted G protein modulates the immune response by altering ERK1 and ERK2 signaling in dendritic cells and by inhibiting activation of NF-κB and the response to TLR2, TLR4, and TLR9 agonists; it has also been shown to induce a Th2 CD41 lymphocyte response that leads to eosinophilia in BALB/c mice [12 16]. The G protein contains a CX3C chemokine-like motif and can bind the fractalkine receptor to affect recruitment of lymphocytes into the respiratory tract [17]. These mechanisms of immune evasion are among many strategies that RSV uses to counteract host defenses and remain a successful human pathogen [6]. Humans are the only natural hosts for RSV, and infection is restricted to the superficial epithelial cells in the airway. Virus both enters and buds from the apical surface of polarized cells and can spread by inducing cell-to-cell fusion, factors that limit the ability of the immune system to fight infection. Viral particles can be filamentous or spherical in shape and can grow to high titers in the nose and upper airway of infected individuals [18]. RSV is a highly contagious pathogen for which there is no licensed vaccine, resulting in yearly epidemics of cocirculating subtype A and B strains that not only impart a substantial financial burden but also contribute to significant morbidity and mortality in susceptible populations.
II. GLOBAL IMPACT AND CLINICAL DISEASE RSV spreads via large droplets or contact with contaminated objects and has an incubation period of 3 5 days. It replicates in the nasopharynx, and if lower respiratory symptoms develop, they appear 1 3 days after the onset of upper airway symptoms. In affected
mucosal tissue, polymorphonuclear cells invade first, with lymphocytes, plasma cells, and macrophages forming peribronchiolar infiltrates. Significant edema and mucus production accompany necrosis of mucosal cells and inflammatory cell infiltrate to narrow or obstruct bronchioles and alveoli [19]. This can lead to collapse or hyperinflation of distal airways as well as the clinical symptom of wheezing [20]. Severe acute lower respiratory tract infections (ALRI) due to RSV infection have been associated with chronic wheezing or asthma later in childhood in multiple epidemiological studies, although the mechanism of this effect is still being debated [21 24]. Clinical disease from RSV ranges from mild upper respiratory symptoms in healthy children and young adults to sometimes deadly lower airway disease in infants, the elderly, and individuals with comorbid heart or lung disease. In most individuals, symptoms include rhinorrhea, cough, decreased appetite, pharyngitis, fatigue, and sometimes otitis media or fever; these symptoms are consistent with other common upper respiratory viral infections. This syndrome lasts an average of 10 days in previously healthy children and adults, and about one quarter of individuals develop lower respiratory tract disease after 3 days [25]. However, in certain populations, including those at the extremes of age and those with comorbid medical conditions, RSV disease can be much more severe. RSV is a ubiquitous viral infection affecting all age groups around the globe. In temperate climates, RSV outbreaks occur seasonally during colder months (October May in the United States) [26], and annual incidence varies. However, about 90% of children have experienced at least one RSV infection by the age of 24 months [27]. Worldwide, RSV is the leading cause of ALRI in children [28]. The number of episodes of RSV ALRI in children under 5 years of age was estimated to be 33.1 million in 2015, and those were predicted to result in 3.2
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million hospitalizations and 60,000 199,000 inhospital deaths [29,30]. Infants under 3 months of age have the highest rate of hospitalization in the United States, and very preterm infants are three times more likely to be hospitalized than infants born at term [31,32]. An estimated 10% 20% of children under 5 years of age in the United States, the majority of whom have no known risk factor for RSV disease, receive medical care for RSV-related illness, which includes 500,000 emergency room visits and 1.5 million primary care visits in addition to the hospitalizations mentioned [7,33]. In children under 6 months of age or those with chronic heart, lung, or immune defects, involvement of the small airways, or bronchiolitis, can cause airway obstruction, wheezing, and pneumonia. The youngest infants with lower airway disease may present with only lethargy, apnea, or hypoxia. Both the size of premature infants’ airways and the comorbid presence of bronchopulmonary dysplasia may explain their predisposition to severe disease, and it is for this population that the only licensed therapeutic for RSV, palivizumab (a recombinant monoclonal antibody specific for mature F protein of RSV; see below) is indicated. These high rates of hospitalizations and deaths make infants, particularly those born preterm, an important population for prevention of RSV infection. At the other extreme of age, RSV causes significant morbidity and mortality in the elderly, particularly those living in long-term care facilities in the United States [34]. In older adults or those with comorbidities, RSV can cause pneumonia or hypoxia that requires mechanical ventilation. Attack rates in congregate care populations are 5% 10%, complicated by significant rates of pneumonia (10% 20%) and death (2% 5%) [35]. More recent studies estimate mortality from RSV infection among US adults over the age of 65 years to be 10,000 per year [36]. RSV was found to be the cause of 7% of total cases and 12.5% of hospitalized cases of
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moderate to severe influenza-like illness in adults over 65 not living in group care, suggesting that RSV infection necessitates hospitalization at a rate comparable to influenza [25,37]. Thus older adults are another key population that would benefit from an RSV vaccine. The natural epidemiology of RSV infection has led to the identification of several target populations for vaccination, each with its own unique risk factors and safety considerations. Direct vaccination of infants prior to their primary infection and of elderly adults with underlying comorbidities would protect the highest-risk groups, but these populations present several challenges for achieving safe and effective immunity. Alternatively, vaccinating young children, who readily transmit disease between and within households, or of pregnant women, who may provide passive protection to their infants, could effectively reduce transmission and disease in groups at the greatest risk. Gaining a better understanding of the epidemiology of infection and correlates of protection in ongoing vaccine efficacy trials in differentaged cohorts will be a critical asset [38,39].
III. CORRELATES OF PROTECTION A significant obstacle to RSV vaccine efforts is the lack of a well-defined correlate of protection [39]. Binding and neutralizing antibodies in maternal, cord, and infant sera have been correlated with protection from infection and/or severe disease in several studies of natural infection, but there has been no consensus on a protective threshold. Additionally, passive transfer of polyclonal, high-titer RSV immunoglobulin has proven an effective strategy to protect highrisk infants from severe disease [40]. Antibodies at the site of infection may play a deterministic role, and either nasal IgA or IgG has been correlated with protection from infection in several studies [41 43]. IgA is the predominant immunoglobulin in the upper respiratory tract,
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exceeding the concentration of IgG by 2.5:1 [44]. IgA is transported from the basolateral to the apical surface of respiratory epithelial cells by the polymeric immunoglobulin receptor, which is cleaved to a secretory component that stabilizes dimeric or polymeric IgA in the mucosal lumen (Chapter 4: Protective Activities of Mucosal Antibodies). Conversely, IgG transudates between alveolar capillaries and alveolar epithelium to dominate and most efficiently protect the lower respiratory tract [45]. Thus IgG access to the upper respiratory tract is limited, and it will be difficult to achieve sufficient levels of neutralizing antibody in the upper airway to completely protect against infection following systemic vaccination. RSV neutralizing antibodies target the F and G surface glycoproteins. The diversity and immunomodulatory properties of the G protein, in addition to the larger number of neutralization-sensitive antigenic sites on the F protein, make F the more commonly selected antigen for candidate antibody-eliciting vaccines. There is proof of concept for this approach as passive prophylaxis with the monoclonal antibody palivizumab, which targets the F protein, has demonstrated efficacy for protecting high-risk infants from severe disease and has been used clinically for this purpose for 20 years. Motavizumab, which is a higher-potency derivative of palivizumab, has shown greater than 80% efficacy in full-term Native American infants [46]. The functional pretriggered form of the RSV F protein is metastable, resulting in the display of both prefusion (pre-F) and postfusion (postF) forms on viral particles [47]. High-resolution structures of pre-F and post-F have aided in the definition of antigenic sites on each conformation, and approximately 50% of the protein surface is shared between pre-F and post-F [48 51]. Sites unique to pre-F, designated antigenic sites Ø and V, are targeted by more potent neutralizing antibodies than sites II and IV that are on the shared surfaces of pre-F and
post-F [52,53]. While site III antibody contact residues are present on both pre-F and post-F surfaces, access to this site is obscured in the post-F conformation. Antibodies that bind to site III have been shown to cross-react with human metapneumovirus [54,55]. Interestingly, the infant immune repertoire is apt to respond to antigenic site III, as potent antibodies targeting this site can be generated with little to no somatic hypermutation [56]. Site I antibodies tend to bind post-F preferentially over pre-F and have weak or no neutralizing activity [53]. The majority of neutralizing antibody in normal adult sera targets the pre-F conformation [52]. Similarly, pre-F targeting antibodies from infected infants demonstrate better neutralization than antibodies targeting G or post-F [57]. Given the potency of pre-F targeting antibodies, it is not surprising that mutations designed to stabilize the F protein in the pre-F conformation have resulted in an immunogen (DS-Cav1) that elicits significantly improved serum neutralizing activity and protection compared to wild-type F or post-F proteins across multiple delivery platforms [48]. Pre-F specific antibodies have been identified that are 10 100 times more potent than palivizumab [53]. The superior potency of neutralizing antibodies to pre-Fspecific antigenic sites may explain the failure to demonstrate efficacy in two recent phase 2b and phase 3 clinical trials that used recombinant protein in the post-F conformation [58,59]. Altogether, these data suggest that stabilization of the F protein in its prefusion conformation may improve the effectiveness of subunit vaccines. Our understanding of correlates is limited in part by a lack of permissive animal models that recapitulate human infection and disease. RSV was shown to cause illness in the first experimental human challenge studies shortly after it was identified as a human pathogen [60,61]. Human challenge studies offer the advantage of knowing the time of infection and in many ways have corroborated studies of natural infection.
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IV. MATERNAL IMMUNIZATION TO PROTECT VULNERABLE INFANTS
Symptoms of disease in experimentally infected adults correlated with viral titer as previously described for RSV-infected infants [62,63]. Nasal IgA was also highly correlated with protection from infection, yet even after experimental infection, individuals were unlikely to reach nasal IgA levels that had been anticipated to be protective against reinfection [42]. This highlights the difficulty of conferring protection in the nose where immune access is limited. Limitations in local immunity may be exaggerated during RSV infection; in contrast to natural influenza virus infection, RSV failed to induce virus-specific IgA memory B cells [42]. This is an area that needs additional work with optimized antigens to better define the role of mucosal IgA responses in RSV immunity. As was previously reported following natural infection in adults and children [64,65], RSV-specific antibody is poorly maintained after experimental infection and can wane to preinfection levels as soon as 6 months post infection [42]. CD81 T cells are known to contribute to RSV immunopathology in animal models [66], but disease is prolonged in children with T cell immunodeficiency [67] and CD81 T cell responses coincide with convalescence in infected infants and experimentally infected adults [68,69]. Most often, studies of RSVspecific T cell responses are confined to peripheral blood where critical populations such as lung-tissue-resident memory T cells (TRM) cannot be measured. Serial bronchoscopy has been used in human challenge experiments to measure CD81 TRM, which were found to accumulate in the airway even through convalescence and have a distinct phenotype from CD81 T cells in the blood of the same subjects. While numbers of preexisting CD81 TRM in the airway did not predict infection, they correlated with reduced disease in individuals who were infected, indicating that T cells may be a crucial second line of defense when antibodies are unable to prevent infection [69]. Care should be taken in interpreting correlates of protection
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from either infection or severe disease gleaned from studies in healthy adults, as they may not be extrapolated to individuals at the extremes of age, in whom RSV has the largest impact, owing to the unique susceptibility factors associated with severe disease in these populations. Many candidates have emerged in the RSV vaccine landscape. These include live attenuated viruses, particle- and subunit-based vaccines, and gene-based vectors. Current approaches have been recently reviewed [59,70], and a list of preclinical and clinical trial candidates is curated and updated regularly by PATH (https://vaccineresources.org/details. php?i 5 1562). This is a rapidly changing list. In addition to defining useful immunological correlates and metrics to evaluate the success of these various approaches, consistent definitions of clinical endpoints should be generated to facilitate comparisons between trials [71,72]. A brief review of the history of vaccination and considerations for selecting candidates for the major target populations will be discussed below. The majority of candidates in the pipeline involve parenteral administration, with only a few intranasal candidates aiming for direct induction of immune responses at the mucosal site of infection.
IV. MATERNAL IMMUNIZATION TO PROTECT VULNERABLE INFANTS Little is known about the clinical impact of RSV infection in pregnant women, but their decreased immunity and increased susceptibility to other viral pathogens may portend an increased susceptibility to more severe outcomes following infection. While vaccinating pregnant women may have some potential to benefit them directly, the primary goal is to bolster neutralizing antibody titers and thus FcRnmediated transport of protective antibodies in
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utero [73]. This strategy is relatively new for RSV but has proven effective for influenza, pertussis, and several other pathogens for which maternal vaccination is used to provide infants with partial protection while they are too young to be effectively immunized [74,75]. Only IgG is capable of FcRn-mediated antenatal transcytosis across the placenta, a process that can result in protective antibody levels in infants that exceed those of their mothers prior to a full-term birth. Protective effects of maternally derived IgG may be limited in the upper airway, but passive transudation into the lung could protect from lower airway disease, and additional protection at the mucosal level may be conferred by IgA and IgG antibody in breast milk [73]. Higher levels of passively transferred maternal RSV-specific IgG have been shown to result in a lower risk of severe RSV disease, yet maternal RSV-specific antibody levels are variable and typically provide protection for only the first few months of life [76 78]. A 0.5-log increase in antibody titers in infants is estimated to extend protection by 19 days, suggesting that maternal immunization could be a feasible approach to protecting infants against severe disease [76]. Because adults have preexisting immunity to RSV, a single injection has the potential to boost maternal antibodies to extend protection of infants through 6 months of age or beyond, when active immunization approaches are more feasible (Chapter 44: Maternal Vaccination for Protection Against Maternal and Infant Bacterial and Viral Pathogens). Vaccines for pregnant women must meet high standards for safety and tolerability. Preexisting immunity and the major goal of enhancing systemic antibody for transfer precludes the use of intranasal vaccines in this population, and current strategies are focused on subunit and particle-based approaches. The candidate that is most advanced in clinical testing is a RSV post-F protein presented as a rosette that is now in phase III testing in pregnant women.
V. RSV IMMUNITY AND VACCINATION IN INFANTS AND YOUNG CHILDREN About half of all hospitalizations for severe RSV disease occur in infants under 6 months of age, so this age group has the most to gain from direct vaccination. This period of high susceptibility for infants is due to the waning of protective maternal antibody and infants’ relatively small airway size and lung capacity. However, infancy is also the most difficult age for vaccination because of lack of preexisting immunity, immunologic immaturity, and, specifically for RSV, safety concerns based on the historical formalin-inactivated vaccine-enhanced disease in young infants. Infants are forced to rely heavily on their innate defenses, which prove limited during early life [79,80]. Infants are biased toward tolerogenic and Th2 types of responses and are known to have limited capacity for somatic hypermutation to optimize antibody affinity [81]. For these reasons, it is likely that the majority of vaccines will be initially targeted to infants older than 6 months of age, in whom immunity has sufficiently matured to generate higher affinity responses with less potential for adverse events. Formalin and heat inactivation of RSV, which had been a previously successful strategy for other viral vaccines for infants, had the unfortunate consequence of enhancing disease following natural RSV infection. Trials conducted with these early vaccines served as a warning against using protein-based or inactivated viruses for this target population [82]. The enhanced respiratory disease associated with immunization with formalin-inactivated RSV (FI-RSV) has long been attributed to the induction of Th2-biased immune responses and granulocyte infiltration [83 85]. The elicitation of high titers of binding antibody with low neutralization capacity was associated with complement fixation and the deposition of immune complexes in the lung [86]. The inactivation
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process to render RSV noninfectious (72 hours at 36 C in 0.025% formalin) altered the antigenic properties of the F protein, resulting in the display of post-F epitopes without preserving the unique, neutralization-sensitive epitopes found only on the functional pre-F conformation [87]. In addition, FI-RSV failed to elicit CD81 T cells, another hallmark of vaccination with antigens that are not processed in the cytoplasm [86]. The copious amount of work done to understand the failings of FI-RSV vaccination in infants has served as a guideline for the clinical development of future vaccines. For the RSV-naı¨ve infant population, liveattenuated approaches have been extensively tested in young children and have a proven safety profile. Live-attenuated vaccines (LAV) are administered intranasally and replicate in the upper respiratory tract. Thus they elicit immunity directly at the site of infection but spread to the lower airway is limited by attenuation of replication and by the presence of maternal antibodies. Most akin to natural infection, live-attenuated RSV offers intrinsic adjuvanting signals that can direct antiviral immunity and have shown no disease enhancement over multiple clinical trials [88]. Iterative modifications have been necessary to ensure an acceptable balance between attenuation and immunogenicity and to prevent viral reversions that could potentially restore pathogenicity. The newest generation of LAV are recombinant derivatives of wild-type RSV. One approach is tailored to avoid type 1 IFN inhibition via ΔNS2 deletions, thereby attenuating replication and improving safety. Another approach is designed to increase transcription and antigen production while limiting replication using ΔM2-2 deletions, which achieves greater immunogenicity despite lower titers of vaccine virus [88]. RSV LAVs are likely to display a combination of pre-F and post-F proteins because retention of the active pre-F protein is critical for infection and replication, effectively ensuring the display of antigenic sites found
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exclusively on pre-F. Some LAV approaches have selectively focused on strains that have a less unstable version of F that maintains a relatively high level of pre-F [89,90]. Alternatively, chimeric parainfluenza LAV vectors are being designed to express RSV G or stabilized pre-F proteins and are being tested in preclinical and early phase trials and may offer the advantage of bivalent protection [59,70,91,92]. While ideal for antigen-naı¨ve populations, LAV are unable to significantly boost immunity in antigenexperienced populations where mucosal immunity prevents replication of the attenuated vaccine [93]. In addition to direct vaccination or boosting maternal antibody levels to facilitate thirdtrimester antenatal transfer of protective antibody, disease outcomes in very young infants may be improved by delivering high-potency, half-life-extended antibodies directed at pre-F exclusive sites. One such antibody, MEDI8897, is currently under clinical evaluation in preterm infants. This antibody has the potential to be accessible to all newborns and is given as a single birth dose [94,95]. While these strategies may protect infants during the critical period of severe RSV disease, the impact of passive antibodies on the generation of de novo immune responses in infants is unknown. Although infants under 6 months of age are more likely to experience severe disease, RSV is responsible for significant morbidity and mortality in children between 6 months and 5 years of age [28]. Young children infected with RSV tend to have high viral titers and extended shedding, and epidemiological studies have implicated them as a common initial source of infection for both infants and the elderly [96,97]. Therefore vaccination of children between 6 months and 5 years of age will directly benefit them and could help to mitigate disease at the extremes of age through decreased transmission. This approach of targeting transmitters with better immunological capacity could be even more effective for
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protecting the elderly than direct vaccination of older adults and would require a smaller number of doses if RSV follows the model that has been shown for influenza [97,98]. Liveattenuated and gene-based approaches that induce Th1 type immunity and antiviral CD81 T cell responses in addition to neutralizing antibodies in young children who may still be RSV naı¨ve are favored methods. After priming by these approaches or by natural infection, protein-based vaccines could be used to boost functional antibody responses. Many of these methods are currently being tested in clinical trials that may afford broad protection across multiple susceptible age groups.
VI. RSV IMMUNITY AND VACCINATION IN OLDER ADULTS The symptoms of RSV infection in older adults are not as easily discriminated from other respiratory infections as they are in infected infants. Most often, infection in older adults is mild to moderate in severity and not wellreported or confirmed by testing. It is estimated that 3% 7% of adults are infected annually [25]. Many anatomical, immunological, and lung functional changes are known to occur with age that predispose older adults to respiratory disease [99]. Chronic obstructive pulmonary disease and other comorbidities contribute to increased susceptibility to RSV disease and may be compounded by immunosenescence and a reduction of functional RSV-specific T cells associated with aging [25]. Owing to these obstacles, vaccine approaches for the elderly may need to involve higher dosages, stronger adjuvants, and potentially repeated administration (Chapter 47: Mucosal Vaccines for Aged: Challenges and Struggles in Immunosenescence). As shown in studies of healthy, young adults, serum and nasal antibody to RSV has an inverse correlation with the risk of becoming
infected, and higher serum neutralizing antibody is associated with less severe infection in the elderly. Despite their seemingly numerous immune limitations, older adults do not have significantly lower baseline RSV antibody titers than younger adults and are just as likely, if not more likely, to have a fourfold rise in antibody titer after natural infection [100]. These findings suggest that an RSV vaccine could boost neutralizing antibody titers, but other factor such as diminished CD81 T cell responses and comorbidities may also play a role in the increased susceptibility of the elderly to RSV infection. The number of variables and range of clinical presentation in the elderly make it increasingly difficult to fully define risk factors and precise correlates of protection for this atrisk population, and a better vaccine may be needed to achieve greater understanding. All adults have preexisting RSV immunity and are not candidates for LAV, owing to overattenuation in antigen-experienced individuals [93]. Thus most current vaccine approaches for the elderly are protein-based, and the recent failures of post-F vaccines in this populations highlight the importance of using pre-F or alternative target antigens to elicit optimal protective antibody responses [59]. Other candidates are gene-based, offering the attractive feature of cytoplasmic generation of antigen and simultaneous boosting of preexisting CD81 T cell responses, which may be a key correlate of protection for this population.
VII. CONCLUDING REMARKS Our improved understanding of the epidemiology and global impact of RSV disease combined with a better understanding of pathogenesis and protein structure has reinvigorated vaccine development, resulting in a large number of candidate vaccines in preclinical and clinical testing. Owing to the specific needs and characteristics of each vulnerable
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REFERENCES
population, different approaches may be required to promote the development of protective antibody and T cell responses in blood or in mucosal secretions and tissues. Vaccines are needed to protect at-risk populations from the immediate illness from acute infection and to mitigate the longer-term consequences of severe disease, including altered lung development and airway reactivity in infants and secondary infections in older adults. Active vaccination strategies have progressed into larger phase 2 and phase 3 clinical trials with efficacy endpoints for infants and older adults, and there is a robust pipeline of products in clinical and preclinical development. Passive approaches to bolster neutralizing activity in infants by direct administration of highly potent monoclonal antibody or by boosting maternal antibody transfer have also progressed to advanced clinical trials. Data obtained from these trials will allow us to further define the immune correlates of protection for each at-risk population with the hope of yielding licensed RSV vaccine products within the next several years.
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respiratory syncytial virus vaccine field. Viral Immunol 2018;. Piedra PA. Clinical experience with respiratory syncytial virus vaccines. Pediatr Infect Dis J 2003;22(Suppl. 2): S94 9. Falsey AR. Respiratory syncytial virus infection in adults. Semin Respir Crit Care Med 2007;28(2):171 81. Habibi MS, et al. Impaired antibody-mediated protection and defective IgA B-cell memory in experimental infection of adults with respiratory syncytial virus. Am J Respir Crit Care Med 2015;191(9):1040 9. Vissers M, et al. Mucosal IgG levels correlate better with respiratory syncytial virus load and inflammation than plasma IgG levels. Clin Vaccine Immunol 2015;23(3): 243 5. Twigg 3rd HL. Humoral immune defense (antibodies): recent advances. Proc Am Thorac Soc 2005;2(5):417 21. Allie SR, Randall TD. Pulmonary immunity to viruses. Clin Sci (Lond) 2017;131(14):1737 62. O’Brien KL, et al. Efficacy of motavizumab for the prevention of respiratory syncytial virus disease in healthy Native American infants: a phase 3 randomised double-blind placebo-controlled trial. Lancet Infect Dis 2015;15(12):1398 408. Liljeroos L, et al. Architecture of respiratory syncytial virus revealed by electron cryotomography. Proc Natl Acad Sci USA 2013;110(27):11133 8. McLellan JS, et al. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 2013;342(6158):592 8. McLellan JS, et al. Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody. Science 2013;340(6136):1113 17. McLellan JS, et al. Structure of respiratory syncytial virus fusion glycoprotein in the postfusion conformation reveals preservation of neutralizing epitopes. J Virol 2011;85(15):7788 96. Graham BS. Vaccine development for respiratory syncytial virus. Curr Opin Virol 2017;23:107 12. Ngwuta JO, et al. Prefusion F-specific antibodies determine the magnitude of RSV neutralizing activity in human sera. Sci Transl Med 2015;7(309):309ra162. Gilman MS, et al. Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors. Sci Immunol 2016;1(6). Corti D, et al. Cross-neutralization of four paramyxoviruses by a human monoclonal antibody. Nature 2013;501(7467):439 43. Wen X, et al. Structural basis for antibody crossneutralization of respiratory syncytial virus and human metapneumovirus. Nat Microbiol 2017;2:16272. Goodwin E, et al. Infants Infected with Respiratory Syncytial Virus Generate Potent Neutralizing Antibodies that Lack Somatic Hypermutation. Immunity 2018;48(2): 339 49 e5.
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[89] Rostad CA, et al. Enhancing the thermostability and immunogenicity of a respiratory syncytial virus (RSV) live-attenuated vaccine by incorporating unique RSV line19f protein residues. J Virol 2018;92 (6). [90] Stobart CC, et al. A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation. Nat Commun 2016;7:13916. [91] Liang B, et al. Improved prefusion stability, optimized codon usage, and augmented virion packaging enhance the immunogenicity of respiratory syncytial virus fusion protein in a vectored-vaccine candidate. J Virol 2017;91(15). [92] Liu X, et al. Attenuated human parainfluenza virus type 1 expressing the respiratory syncytial virus (RSV) fusion (F) glycoprotein from an added gene: effects of prefusion stabilization and packaging of RSV F. J Virol 2017;91(22). [93] Gonzalez IM, et al. Evaluation of the live attenuated cpts 248/404 RSV vaccine in combination with a subunit RSV vaccine (PFP-2) in healthy young and older adults. Vaccine 2000;18(17):1763 72. [94] Domachowske JB, et al. Safety, tolerability, and pharmacokinetics of MEDI8897, an extended half-life
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single-dose respiratory syncytial virus prefusion Ftargeting monoclonal antibody administered as a single dose to healthy preterm infants. Pediatr Infect Dis J 2018;. Zhu Q, et al. A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants. Sci Transl Med 2017;9(388). Munywoki PK, et al. The source of respiratory syncytial virus infection in infants: a household cohort study in rural Kenya. J Infect Dis 2014;209(11): 1685 92. Poletti P, et al. Evaluating vaccination strategies for reducing infant respiratory syncytial virus infection in low-income settings. BMC Med 2015;13:49. Yamin D, et al. Vaccination strategies against respiratory syncytial virus. Proc Natl Acad Sci USA 2016;113 (46):13239 44. Sharma G, Goodwin J. Effect of aging on respiratory system physiology and immunology. Clin Interv Aging 2006;1(3):253 60. Malloy AM, Falsey AR, Ruckwardt TJ. Consequences of immature and senescent immune responses for infection with respiratory syncytial virus. Curr Top Microbiol Immunol 2013;372:211 31.
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38 Vaccination Against Respiratory Syncytial Virus Tracy J. Ruckwardt, Michelle C. Crank, Kaitlyn M. Morabito and Barney S. Graham Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
I. INTRODUCTION Respiratory syncytial virus (RSV) is an enveloped, negative-sense, nonsegmented RNA virus with a 15-kb genome. RSV has 10 genes that encode 11 recognized proteins. The RNAbinding nucleoprotein (N), phosphoprotein (P), polymerase (L), and transcription processivity factor (M2-1) make up the ribonucleocapsid. The lipid bilayer envelope is supported by the matrix protein (M) and displays the glycoprotein (G), the fusion protein (F), and small hydrophobic ion channel (SH) protein on the surface. The virus also encodes M2-2, which mediates the transition between transcription and replication, and two nonstructural proteins, NS1 and NS2 [1]. RSV was a member of Paramyxoviridae family prior to reclassification in 2016 into the Orthopneumovirus genus of the Pneumoviridae family [2]. Compared to influenza virus, another common cause of respiratory tract infections, the
Mucosal Vaccines DOI: https://doi.org/10.1016/B978-0-12-811924-2.00038-9
diversity of RSV is limited. There are two antigenic subtypes of RSV, A and B, which comprise a single serotype [3]. Most of the diversity is accounted for by G protein, which has less than 50% amino acid sequence identity between subtypes. The F glycoprotein is more conserved, with 89% amino acid identity between subtypes [4]. While F diversity is limited, even small amino acid differences can affect the ability of monoclonal antibodies to neutralize individual viral isolates [5]. Several RSV proteins have been found to interfere with innate and adaptive immune responses [6]. NS1 and NS2 inhibit the induction of type I and III interferon (IFN) by binding to proteins in the IFN pathway (IRF3, MAVS, RIG-I), mediating degradation of other proteins (IKKε, TRAF3, and STAT2) in the IFN pathway, and inhibiting apoptosis of RSV-infected cells [7 11]. The G protein exists in two forms. Membrane-anchored G protein mediates attachment between the virus and cell and is
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© 2020 Elsevier Inc. All rights reserved.
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key for in vivo infection. The secreted form of the G protein can act as an immune decoy to absorb antibody and reduce neutralizing activity. Additionally, secreted G protein modulates the immune response by altering ERK1 and ERK2 signaling in dendritic cells and by inhibiting activation of NF-κB and the response to TLR2, TLR4, and TLR9 agonists; it has also been shown to induce a Th2 CD41 lymphocyte response that leads to eosinophilia in BALB/c mice [12 16]. The G protein contains a CX3C chemokine-like motif and can bind the fractalkine receptor to affect recruitment of lymphocytes into the respiratory tract [17]. These mechanisms of immune evasion are among many strategies that RSV uses to counteract host defenses and remain a successful human pathogen [6]. Humans are the only natural hosts for RSV, and infection is restricted to the superficial epithelial cells in the airway. Virus both enters and buds from the apical surface of polarized cells and can spread by inducing cell-to-cell fusion, factors that limit the ability of the immune system to fight infection. Viral particles can be filamentous or spherical in shape and can grow to high titers in the nose and upper airway of infected individuals [18]. RSV is a highly contagious pathogen for which there is no licensed vaccine, resulting in yearly epidemics of cocirculating subtype A and B strains that not only impart a substantial financial burden but also contribute to significant morbidity and mortality in susceptible populations.
II. GLOBAL IMPACT AND CLINICAL DISEASE RSV spreads via large droplets or contact with contaminated objects and has an incubation period of 3 5 days. It replicates in the nasopharynx, and if lower respiratory symptoms develop, they appear 1 3 days after the onset of upper airway symptoms. In affected
mucosal tissue, polymorphonuclear cells invade first, with lymphocytes, plasma cells, and macrophages forming peribronchiolar infiltrates. Significant edema and mucus production accompany necrosis of mucosal cells and inflammatory cell infiltrate to narrow or obstruct bronchioles and alveoli [19]. This can lead to collapse or hyperinflation of distal airways as well as the clinical symptom of wheezing [20]. Severe acute lower respiratory tract infections (ALRI) due to RSV infection have been associated with chronic wheezing or asthma later in childhood in multiple epidemiological studies, although the mechanism of this effect is still being debated [21 24]. Clinical disease from RSV ranges from mild upper respiratory symptoms in healthy children and young adults to sometimes deadly lower airway disease in infants, the elderly, and individuals with comorbid heart or lung disease. In most individuals, symptoms include rhinorrhea, cough, decreased appetite, pharyngitis, fatigue, and sometimes otitis media or fever; these symptoms are consistent with other common upper respiratory viral infections. This syndrome lasts an average of 10 days in previously healthy children and adults, and about one quarter of individuals develop lower respiratory tract disease after 3 days [25]. However, in certain populations, including those at the extremes of age and those with comorbid medical conditions, RSV disease can be much more severe. RSV is a ubiquitous viral infection affecting all age groups around the globe. In temperate climates, RSV outbreaks occur seasonally during colder months (October May in the United States) [26], and annual incidence varies. However, about 90% of children have experienced at least one RSV infection by the age of 24 months [27]. Worldwide, RSV is the leading cause of ALRI in children [28]. The number of episodes of RSV ALRI in children under 5 years of age was estimated to be 33.1 million in 2015, and those were predicted to result in 3.2
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million hospitalizations and 60,000 199,000 inhospital deaths [29,30]. Infants under 3 months of age have the highest rate of hospitalization in the United States, and very preterm infants are three times more likely to be hospitalized than infants born at term [31,32]. An estimated 10% 20% of children under 5 years of age in the United States, the majority of whom have no known risk factor for RSV disease, receive medical care for RSV-related illness, which includes 500,000 emergency room visits and 1.5 million primary care visits in addition to the hospitalizations mentioned [7,33]. In children under 6 months of age or those with chronic heart, lung, or immune defects, involvement of the small airways, or bronchiolitis, can cause airway obstruction, wheezing, and pneumonia. The youngest infants with lower airway disease may present with only lethargy, apnea, or hypoxia. Both the size of premature infants’ airways and the comorbid presence of bronchopulmonary dysplasia may explain their predisposition to severe disease, and it is for this population that the only licensed therapeutic for RSV, palivizumab (a recombinant monoclonal antibody specific for mature F protein of RSV; see below) is indicated. These high rates of hospitalizations and deaths make infants, particularly those born preterm, an important population for prevention of RSV infection. At the other extreme of age, RSV causes significant morbidity and mortality in the elderly, particularly those living in long-term care facilities in the United States [34]. In older adults or those with comorbidities, RSV can cause pneumonia or hypoxia that requires mechanical ventilation. Attack rates in congregate care populations are 5% 10%, complicated by significant rates of pneumonia (10% 20%) and death (2% 5%) [35]. More recent studies estimate mortality from RSV infection among US adults over the age of 65 years to be 10,000 per year [36]. RSV was found to be the cause of 7% of total cases and 12.5% of hospitalized cases of
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moderate to severe influenza-like illness in adults over 65 not living in group care, suggesting that RSV infection necessitates hospitalization at a rate comparable to influenza [25,37]. Thus older adults are another key population that would benefit from an RSV vaccine. The natural epidemiology of RSV infection has led to the identification of several target populations for vaccination, each with its own unique risk factors and safety considerations. Direct vaccination of infants prior to their primary infection and of elderly adults with underlying comorbidities would protect the highest-risk groups, but these populations present several challenges for achieving safe and effective immunity. Alternatively, vaccinating young children, who readily transmit disease between and within households, or of pregnant women, who may provide passive protection to their infants, could effectively reduce transmission and disease in groups at the greatest risk. Gaining a better understanding of the epidemiology of infection and correlates of protection in ongoing vaccine efficacy trials in differentaged cohorts will be a critical asset [38,39].
III. CORRELATES OF PROTECTION A significant obstacle to RSV vaccine efforts is the lack of a well-defined correlate of protection [39]. Binding and neutralizing antibodies in maternal, cord, and infant sera have been correlated with protection from infection and/or severe disease in several studies of natural infection, but there has been no consensus on a protective threshold. Additionally, passive transfer of polyclonal, high-titer RSV immunoglobulin has proven an effective strategy to protect highrisk infants from severe disease [40]. Antibodies at the site of infection may play a deterministic role, and either nasal IgA or IgG has been correlated with protection from infection in several studies [41 43]. IgA is the predominant immunoglobulin in the upper respiratory tract,
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exceeding the concentration of IgG by 2.5:1 [44]. IgA is transported from the basolateral to the apical surface of respiratory epithelial cells by the polymeric immunoglobulin receptor, which is cleaved to a secretory component that stabilizes dimeric or polymeric IgA in the mucosal lumen (Chapter 4: Protective Activities of Mucosal Antibodies). Conversely, IgG transudates between alveolar capillaries and alveolar epithelium to dominate and most efficiently protect the lower respiratory tract [45]. Thus IgG access to the upper respiratory tract is limited, and it will be difficult to achieve sufficient levels of neutralizing antibody in the upper airway to completely protect against infection following systemic vaccination. RSV neutralizing antibodies target the F and G surface glycoproteins. The diversity and immunomodulatory properties of the G protein, in addition to the larger number of neutralization-sensitive antigenic sites on the F protein, make F the more commonly selected antigen for candidate antibody-eliciting vaccines. There is proof of concept for this approach as passive prophylaxis with the monoclonal antibody palivizumab, which targets the F protein, has demonstrated efficacy for protecting high-risk infants from severe disease and has been used clinically for this purpose for 20 years. Motavizumab, which is a higher-potency derivative of palivizumab, has shown greater than 80% efficacy in full-term Native American infants [46]. The functional pretriggered form of the RSV F protein is metastable, resulting in the display of both prefusion (pre-F) and postfusion (postF) forms on viral particles [47]. High-resolution structures of pre-F and post-F have aided in the definition of antigenic sites on each conformation, and approximately 50% of the protein surface is shared between pre-F and post-F [48 51]. Sites unique to pre-F, designated antigenic sites Ø and V, are targeted by more potent neutralizing antibodies than sites II and IV that are on the shared surfaces of pre-F and
post-F [52,53]. While site III antibody contact residues are present on both pre-F and post-F surfaces, access to this site is obscured in the post-F conformation. Antibodies that bind to site III have been shown to cross-react with human metapneumovirus [54,55]. Interestingly, the infant immune repertoire is apt to respond to antigenic site III, as potent antibodies targeting this site can be generated with little to no somatic hypermutation [56]. Site I antibodies tend to bind post-F preferentially over pre-F and have weak or no neutralizing activity [53]. The majority of neutralizing antibody in normal adult sera targets the pre-F conformation [52]. Similarly, pre-F targeting antibodies from infected infants demonstrate better neutralization than antibodies targeting G or post-F [57]. Given the potency of pre-F targeting antibodies, it is not surprising that mutations designed to stabilize the F protein in the pre-F conformation have resulted in an immunogen (DS-Cav1) that elicits significantly improved serum neutralizing activity and protection compared to wild-type F or post-F proteins across multiple delivery platforms [48]. Pre-F specific antibodies have been identified that are 10 100 times more potent than palivizumab [53]. The superior potency of neutralizing antibodies to pre-Fspecific antigenic sites may explain the failure to demonstrate efficacy in two recent phase 2b and phase 3 clinical trials that used recombinant protein in the post-F conformation [58,59]. Altogether, these data suggest that stabilization of the F protein in its prefusion conformation may improve the effectiveness of subunit vaccines. Our understanding of correlates is limited in part by a lack of permissive animal models that recapitulate human infection and disease. RSV was shown to cause illness in the first experimental human challenge studies shortly after it was identified as a human pathogen [60,61]. Human challenge studies offer the advantage of knowing the time of infection and in many ways have corroborated studies of natural infection.
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Symptoms of disease in experimentally infected adults correlated with viral titer as previously described for RSV-infected infants [62,63]. Nasal IgA was also highly correlated with protection from infection, yet even after experimental infection, individuals were unlikely to reach nasal IgA levels that had been anticipated to be protective against reinfection [42]. This highlights the difficulty of conferring protection in the nose where immune access is limited. Limitations in local immunity may be exaggerated during RSV infection; in contrast to natural influenza virus infection, RSV failed to induce virus-specific IgA memory B cells [42]. This is an area that needs additional work with optimized antigens to better define the role of mucosal IgA responses in RSV immunity. As was previously reported following natural infection in adults and children [64,65], RSV-specific antibody is poorly maintained after experimental infection and can wane to preinfection levels as soon as 6 months post infection [42]. CD81 T cells are known to contribute to RSV immunopathology in animal models [66], but disease is prolonged in children with T cell immunodeficiency [67] and CD81 T cell responses coincide with convalescence in infected infants and experimentally infected adults [68,69]. Most often, studies of RSVspecific T cell responses are confined to peripheral blood where critical populations such as lung-tissue-resident memory T cells (TRM) cannot be measured. Serial bronchoscopy has been used in human challenge experiments to measure CD81 TRM, which were found to accumulate in the airway even through convalescence and have a distinct phenotype from CD81 T cells in the blood of the same subjects. While numbers of preexisting CD81 TRM in the airway did not predict infection, they correlated with reduced disease in individuals who were infected, indicating that T cells may be a crucial second line of defense when antibodies are unable to prevent infection [69]. Care should be taken in interpreting correlates of protection
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from either infection or severe disease gleaned from studies in healthy adults, as they may not be extrapolated to individuals at the extremes of age, in whom RSV has the largest impact, owing to the unique susceptibility factors associated with severe disease in these populations. Many candidates have emerged in the RSV vaccine landscape. These include live attenuated viruses, particle- and subunit-based vaccines, and gene-based vectors. Current approaches have been recently reviewed [59,70], and a list of preclinical and clinical trial candidates is curated and updated regularly by PATH (https://vaccineresources.org/details. php?i 5 1562). This is a rapidly changing list. In addition to defining useful immunological correlates and metrics to evaluate the success of these various approaches, consistent definitions of clinical endpoints should be generated to facilitate comparisons between trials [71,72]. A brief review of the history of vaccination and considerations for selecting candidates for the major target populations will be discussed below. The majority of candidates in the pipeline involve parenteral administration, with only a few intranasal candidates aiming for direct induction of immune responses at the mucosal site of infection.
IV. MATERNAL IMMUNIZATION TO PROTECT VULNERABLE INFANTS Little is known about the clinical impact of RSV infection in pregnant women, but their decreased immunity and increased susceptibility to other viral pathogens may portend an increased susceptibility to more severe outcomes following infection. While vaccinating pregnant women may have some potential to benefit them directly, the primary goal is to bolster neutralizing antibody titers and thus FcRnmediated transport of protective antibodies in
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utero [73]. This strategy is relatively new for RSV but has proven effective for influenza, pertussis, and several other pathogens for which maternal vaccination is used to provide infants with partial protection while they are too young to be effectively immunized [74,75]. Only IgG is capable of FcRn-mediated antenatal transcytosis across the placenta, a process that can result in protective antibody levels in infants that exceed those of their mothers prior to a full-term birth. Protective effects of maternally derived IgG may be limited in the upper airway, but passive transudation into the lung could protect from lower airway disease, and additional protection at the mucosal level may be conferred by IgA and IgG antibody in breast milk [73]. Higher levels of passively transferred maternal RSV-specific IgG have been shown to result in a lower risk of severe RSV disease, yet maternal RSV-specific antibody levels are variable and typically provide protection for only the first few months of life [76 78]. A 0.5-log increase in antibody titers in infants is estimated to extend protection by 19 days, suggesting that maternal immunization could be a feasible approach to protecting infants against severe disease [76]. Because adults have preexisting immunity to RSV, a single injection has the potential to boost maternal antibodies to extend protection of infants through 6 months of age or beyond, when active immunization approaches are more feasible (Chapter 44: Maternal Vaccination for Protection Against Maternal and Infant Bacterial and Viral Pathogens). Vaccines for pregnant women must meet high standards for safety and tolerability. Preexisting immunity and the major goal of enhancing systemic antibody for transfer precludes the use of intranasal vaccines in this population, and current strategies are focused on subunit and particle-based approaches. The candidate that is most advanced in clinical testing is a RSV post-F protein presented as a rosette that is now in phase III testing in pregnant women.
V. RSV IMMUNITY AND VACCINATION IN INFANTS AND YOUNG CHILDREN About half of all hospitalizations for severe RSV disease occur in infants under 6 months of age, so this age group has the most to gain from direct vaccination. This period of high susceptibility for infants is due to the waning of protective maternal antibody and infants’ relatively small airway size and lung capacity. However, infancy is also the most difficult age for vaccination because of lack of preexisting immunity, immunologic immaturity, and, specifically for RSV, safety concerns based on the historical formalin-inactivated vaccine-enhanced disease in young infants. Infants are forced to rely heavily on their innate defenses, which prove limited during early life [79,80]. Infants are biased toward tolerogenic and Th2 types of responses and are known to have limited capacity for somatic hypermutation to optimize antibody affinity [81]. For these reasons, it is likely that the majority of vaccines will be initially targeted to infants older than 6 months of age, in whom immunity has sufficiently matured to generate higher affinity responses with less potential for adverse events. Formalin and heat inactivation of RSV, which had been a previously successful strategy for other viral vaccines for infants, had the unfortunate consequence of enhancing disease following natural RSV infection. Trials conducted with these early vaccines served as a warning against using protein-based or inactivated viruses for this target population [82]. The enhanced respiratory disease associated with immunization with formalin-inactivated RSV (FI-RSV) has long been attributed to the induction of Th2-biased immune responses and granulocyte infiltration [83 85]. The elicitation of high titers of binding antibody with low neutralization capacity was associated with complement fixation and the deposition of immune complexes in the lung [86]. The inactivation
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process to render RSV noninfectious (72 hours at 36 C in 0.025% formalin) altered the antigenic properties of the F protein, resulting in the display of post-F epitopes without preserving the unique, neutralization-sensitive epitopes found only on the functional pre-F conformation [87]. In addition, FI-RSV failed to elicit CD81 T cells, another hallmark of vaccination with antigens that are not processed in the cytoplasm [86]. The copious amount of work done to understand the failings of FI-RSV vaccination in infants has served as a guideline for the clinical development of future vaccines. For the RSV-naı¨ve infant population, liveattenuated approaches have been extensively tested in young children and have a proven safety profile. Live-attenuated vaccines (LAV) are administered intranasally and replicate in the upper respiratory tract. Thus they elicit immunity directly at the site of infection but spread to the lower airway is limited by attenuation of replication and by the presence of maternal antibodies. Most akin to natural infection, live-attenuated RSV offers intrinsic adjuvanting signals that can direct antiviral immunity and have shown no disease enhancement over multiple clinical trials [88]. Iterative modifications have been necessary to ensure an acceptable balance between attenuation and immunogenicity and to prevent viral reversions that could potentially restore pathogenicity. The newest generation of LAV are recombinant derivatives of wild-type RSV. One approach is tailored to avoid type 1 IFN inhibition via ΔNS2 deletions, thereby attenuating replication and improving safety. Another approach is designed to increase transcription and antigen production while limiting replication using ΔM2-2 deletions, which achieves greater immunogenicity despite lower titers of vaccine virus [88]. RSV LAVs are likely to display a combination of pre-F and post-F proteins because retention of the active pre-F protein is critical for infection and replication, effectively ensuring the display of antigenic sites found
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exclusively on pre-F. Some LAV approaches have selectively focused on strains that have a less unstable version of F that maintains a relatively high level of pre-F [89,90]. Alternatively, chimeric parainfluenza LAV vectors are being designed to express RSV G or stabilized pre-F proteins and are being tested in preclinical and early phase trials and may offer the advantage of bivalent protection [59,70,91,92]. While ideal for antigen-naı¨ve populations, LAV are unable to significantly boost immunity in antigenexperienced populations where mucosal immunity prevents replication of the attenuated vaccine [93]. In addition to direct vaccination or boosting maternal antibody levels to facilitate thirdtrimester antenatal transfer of protective antibody, disease outcomes in very young infants may be improved by delivering high-potency, half-life-extended antibodies directed at pre-F exclusive sites. One such antibody, MEDI8897, is currently under clinical evaluation in preterm infants. This antibody has the potential to be accessible to all newborns and is given as a single birth dose [94,95]. While these strategies may protect infants during the critical period of severe RSV disease, the impact of passive antibodies on the generation of de novo immune responses in infants is unknown. Although infants under 6 months of age are more likely to experience severe disease, RSV is responsible for significant morbidity and mortality in children between 6 months and 5 years of age [28]. Young children infected with RSV tend to have high viral titers and extended shedding, and epidemiological studies have implicated them as a common initial source of infection for both infants and the elderly [96,97]. Therefore vaccination of children between 6 months and 5 years of age will directly benefit them and could help to mitigate disease at the extremes of age through decreased transmission. This approach of targeting transmitters with better immunological capacity could be even more effective for
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protecting the elderly than direct vaccination of older adults and would require a smaller number of doses if RSV follows the model that has been shown for influenza [97,98]. Liveattenuated and gene-based approaches that induce Th1 type immunity and antiviral CD81 T cell responses in addition to neutralizing antibodies in young children who may still be RSV naı¨ve are favored methods. After priming by these approaches or by natural infection, protein-based vaccines could be used to boost functional antibody responses. Many of these methods are currently being tested in clinical trials that may afford broad protection across multiple susceptible age groups.
VI. RSV IMMUNITY AND VACCINATION IN OLDER ADULTS The symptoms of RSV infection in older adults are not as easily discriminated from other respiratory infections as they are in infected infants. Most often, infection in older adults is mild to moderate in severity and not wellreported or confirmed by testing. It is estimated that 3% 7% of adults are infected annually [25]. Many anatomical, immunological, and lung functional changes are known to occur with age that predispose older adults to respiratory disease [99]. Chronic obstructive pulmonary disease and other comorbidities contribute to increased susceptibility to RSV disease and may be compounded by immunosenescence and a reduction of functional RSV-specific T cells associated with aging [25]. Owing to these obstacles, vaccine approaches for the elderly may need to involve higher dosages, stronger adjuvants, and potentially repeated administration (Chapter 47: Mucosal Vaccines for Aged: Challenges and Struggles in Immunosenescence). As shown in studies of healthy, young adults, serum and nasal antibody to RSV has an inverse correlation with the risk of becoming
infected, and higher serum neutralizing antibody is associated with less severe infection in the elderly. Despite their seemingly numerous immune limitations, older adults do not have significantly lower baseline RSV antibody titers than younger adults and are just as likely, if not more likely, to have a fourfold rise in antibody titer after natural infection [100]. These findings suggest that an RSV vaccine could boost neutralizing antibody titers, but other factor such as diminished CD81 T cell responses and comorbidities may also play a role in the increased susceptibility of the elderly to RSV infection. The number of variables and range of clinical presentation in the elderly make it increasingly difficult to fully define risk factors and precise correlates of protection for this atrisk population, and a better vaccine may be needed to achieve greater understanding. All adults have preexisting RSV immunity and are not candidates for LAV, owing to overattenuation in antigen-experienced individuals [93]. Thus most current vaccine approaches for the elderly are protein-based, and the recent failures of post-F vaccines in this populations highlight the importance of using pre-F or alternative target antigens to elicit optimal protective antibody responses [59]. Other candidates are gene-based, offering the attractive feature of cytoplasmic generation of antigen and simultaneous boosting of preexisting CD81 T cell responses, which may be a key correlate of protection for this population.
VII. CONCLUDING REMARKS Our improved understanding of the epidemiology and global impact of RSV disease combined with a better understanding of pathogenesis and protein structure has reinvigorated vaccine development, resulting in a large number of candidate vaccines in preclinical and clinical testing. Owing to the specific needs and characteristics of each vulnerable
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population, different approaches may be required to promote the development of protective antibody and T cell responses in blood or in mucosal secretions and tissues. Vaccines are needed to protect at-risk populations from the immediate illness from acute infection and to mitigate the longer-term consequences of severe disease, including altered lung development and airway reactivity in infants and secondary infections in older adults. Active vaccination strategies have progressed into larger phase 2 and phase 3 clinical trials with efficacy endpoints for infants and older adults, and there is a robust pipeline of products in clinical and preclinical development. Passive approaches to bolster neutralizing activity in infants by direct administration of highly potent monoclonal antibody or by boosting maternal antibody transfer have also progressed to advanced clinical trials. Data obtained from these trials will allow us to further define the immune correlates of protection for each at-risk population with the hope of yielding licensed RSV vaccine products within the next several years.
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