Respiratory syncytial virus (RSV) infection remains the leading cause of infant hospitalization. Infections occur seasonally all over the world. Signs and symptoms of the disease vary with age. Newborns may present with periodic breathing or apnea. Young infants typically develop coryza, congestion and cough with or without fever. Many of these first infections are limited to the upper respiratory tract but depending on age and the presence of other risk factors (Table 1), up to 40% of children will progress to lower respiratory tract illness. Coryza, congestion, and cough persist while additional symptoms indicating lower respiratory tract involvement begin to appear. Tachypnea is common, but the sine quo non of infant RSV bronchiolitis is the presence of wheezing. RSV pneumonia is not uncommon, but cases almost always include the features of bronchiolitis as a component of the illness. Treatment of RSV infection involves supportive care until the symptoms of the illness abate. Supplemental oxygen may be necessary. Infants that progress to respiratory failure require mechanical ventilation. The severe congestion and tachypnea can also lead to dehydration because of difficulty in coordinating breathing with feeding.1
Risk Factors for Severe Respiratory Syncytial Virus Infection
In industrialized countries, approximately 2% of otherwise healthy infants are hospitalized for RSV-associated lower respiratory tract illness each year. Rates are higher among those children with known risk factors (Table 1). In addition to the 100,000 annual hospitalizations in the United States, medically attended outpatient visits exceed 2 million, with many children requiring several visits during a single infection to gauge illness severity and re-evaluate the potential need for hospitalization to support their respiratory and/or hydration status.2,3
Worldwide, annual RSV disease burden is estimated to include 34 million children younger than age 5 years who develop lower respiratory tract infection. Of those, 1 in 10 are hospitalized for severe disease. The World Health Organization estimates that there are between 66,000 and 253,000 RSV-associated deaths each year. Nearly all deaths occur in resource poor countries where supportive care is limited or unavailable.4–6
Treatment of RSV Infection
The current standard of treatment for RSV infection is supportive and symptomatic care. Young infants are obligate nose breathers, so frequently clearing secretions from the nose is important, especially around feeding times. RSV bronchiolitis is a wheezing illness, so there is clinical temptation to administer therapies known to alleviate asthma symptoms. However, the pathophysiology of asthma and RSV infection-associated wheezing is different and evidence-based medicine has yet to show that any of the commonly used asthma medication classes reduce RSV illness severity or duration.7 Disappointing results were also found during widespread use of the antiviral medication ribavirin during the 1990s. Existing evidence does not support its routine use because it does not reduce RSV illness severity or duration. Higher potency antivirals remain under investigation in a hope to identify effective therapeutic options in the future.8
Where Do We Stand Now on RSV Prevention?
Approved RSV vaccines are not yet available, but recent discoveries have allowed substantial progress in this area. Passive prevention of severe RSV disease using palivizumab immunoprophylaxis is effective for every population studied to date. Evolution of guidance from the American Academy of Pediatrics Committee on Infectious Diseases (AAP COID) on the use of palivizumab has led to reductions in its use since it was first licensed in 1998.9 The most recent guidance statement limits palivizumab administration to those infants born at less than 29 weeks gestational age. For those with chronic lung disease of prematurity (bronchopulmonary dysplasia), or hemodynamically significant congenital heart disease the indication extends up to 32 weeks gestational age.10 The high cost and requirement for monthly dosing preclude its use in resource-constrained settings and have limited its use in recent years in the US.
Healthy infants, who are born at term, but who are younger than age 6 months when experiencing their first RSV season frequently develop illness that is severe enough to require hospitalization. In the US, average age-specific rates of hospitalization are highest during months 1 (25.9 per 1,000) and 2 (14.3 per 1,000), steadily declining to 3.2 per 1,000 by age 1 year.11 The frequency of severe illness that occurs in the first few months of life is a major limitation when considering infant vaccine development since any preventive measure designed to reduce hospitalization rates would need to include a dosing schedule that proved effective from birth. Globally, the annual reported incidence rates of severe RSV lower respiratory tract infection in children younger than age 2 years range between 10 (US, Hong Kong, South Africa, Kenya, Netherlands) and 60 (Guatemala) per 1,000 children, with several geographic areas reporting rates of 25 per 1,000 children or higher (Brazil, Thailand, United Kingdom, Germany, Ecuador, Spain).12–14 In each instance, the vast majority of hospitalizations occur among infants younger than age 6 months.
High Priority Groups for RSV Prevention
The AAP COID has identified the infant groups at highest risk to receive monthly palivizumab for RSV prophylaxis. Some premature infants, including those born between 29 and 32 weeks gestational age, are known to have hospitalization rates of approximately 8%, yet are not currently identified as candidates for palivizumab prophylaxis. Similarly, premature infants born between 33 and 35 weeks gestational age are hospitalized more frequently for RSV infection compared with term newborns. In the US, approximately 1 in 50 term newborns are hospitalized for RSV-associated illness, while many others receive outpatient medical attention.15 Beyond infancy, other risk groups identified as priorities for RSV vaccine administration when it becomes available include those with underlying cardiopulmonary disease, Down syndrome, congenital abnormalities of the airway, neuromuscular conditions, cystic fibrosis, and immune compromising disorders.16 Adult cohorts identified as priority candidates for RSV vaccine, when available, include pregnant women and people older than age 65 years.
Where Is the RSV Vaccine?
The first trial (1966–1967), sponsored by the National Institutes of Health, was designed to test the safety and efficacy of a formalin-inactivated vaccine candidate (FI-RSV lot 100) in children age 2 months to 7 years. FI vaccines had already been used successfully for polio and influenza, so the proof of concept for the manufacturing process appeared robust. Unfortunately, the investigational, FI-RSV vaccine was shown instead to cause enhanced disease in the studied population among those who were RSV seronegative at the start of the study. The seronegative vaccine recipients who were exposed to and infected with RSV during the follow-up period of the study developed more severe RSV-associated lower respiratory tract infection than those in the control group; two infants died (Table 2).17
Summary of the Results from the 1966–1967 NIH-Sponsored Clinical Trial of an Investigational Formalin-Inactivated RSV Vaccine
The reason for the disastrous outcome of the first clinical RSV vaccine trial was unknown. Intense interest to understand how a FI whole virus vaccine could interact with a seronegative infant's immune system to promote enhanced disease when infected with wild-type RSV led to a flurry of preclinical studies using animal models. These studies resulted in dozens of peer-reviewed publications offering sound explanations, but efforts to develop an RSV vaccine stopped completely, not re-emerging until more than 30 years later.
Efforts to Develop Passive Protection for Patients at High Risk
Despite 30 years of inactivity related to RSV vaccine development, progress in prevention using passive, antibody-based strategies began to gain traction in 1989. RSV-Ig, a pooled human immunoglobulin product with high titers of anti-RSV antibodies, was the first to undergo testing in clinical trials. RSV-Ig demonstrated the ability to prevent RSV infection when administered as monthly intravenous infusions to infant cohorts that are high risk. During the clinical trial for infants with congenital heart disease, increased rates of hospitalization were seen in the infusion recipients, a safety signal related to intravenous administration of a modest fluid volume to infants known to have compromised cardiac function. RSV-Ig was licensed by the US Food and Drug Administration (FDA) in 1996 to prevent RSV infection in premature infants, but due to safety concerns, but was never approved for use in infants with congenital heart disease. Following licensure, real-world use of RSV-Ig was limited by its cost and its requirement for monthly intravenous access to deliver the 4-hour infusion. During this time, the monoclonal anti-RSV antibody, palivizumab, was undergoing phase I and phase II clinical trials. By 1996, early phase trial data were encouraging enough to begin a large scale, phase III efficacy trial. The monoclonal antibody was found to be safe and effective at preventing severe RSV infection among premature infants with and without bronchopulmonary dysplasia and licensed for this indication in 1998. Next, palivizumab was evaluated in infants with congenital heart disease. This phase III trial was done over a 4-year period, ultimately demonstrating safety and efficacy of palivizumab in this high-risk group as well. A Biologic License Addendum (BLA) was filed with the FDA and the expanded indication for use among infants with congenital heart disease was approved in 2003. Like RSV-Ig, palivizumab requires monthly dosing to maintain protective concentrations of circulating anti-RSV antibodies. The primary advantages of palivizumab over RSV-Ig are its ease of administration (monthly intramuscular injections rather than intravenous infusions), and its safety profile among all populations studied. A summary of the timeline for its development in the context of other emerging prevention strategies is shown in Figure 1.
Timeline of respiratory syncytial virus prevention.
Palivizumab reduces severe RSV infection among infants who are high risk by approximately 55%, although efficacy in some high-risk groups (like those with bronchopulmonary dysplasia) is known to be significantly higher. Efforts to improve on the preventive efficacy of palivizumab led to the development and testing of a similar product with a higher affinity for binding to the virus. This monoclonal antibody, motavizumab, underwent a large-scale phase III evaluation between 2002 and 2006 among the same high-risk groups evaluated during the earlier palivizumab trials. Ultimately, motivizumab was shown to be noninferior to palivizumab at preventing RSV hospitalization, but was associated with a higher rate of local injection site skin reactions.18 The FDA review in 2010 resulted in rejection of the BLA, and motavizumab was never licensed for use. As such, palivizumab has remained the standard of care in the prevention of severe RSV infection among infants who are high risk for 20 years.
Despite its success, it is unlikely that palivizumab will remain the standard of care for the prevention of RSV infection for much longer. New strategies designed to further simplify passive antibody prophylaxis entered human clinical trials in 2013. Progress is rapid, and the preliminary results are encouraging. The rationale for this strategy, the basic science discovery that makes it so appealing, a summary of the progress to date, and a future prediction are offered later.
Active Vaccination for the Prevention of RSV Infection
The desire to develop an active vaccine for the prevention of RSV disease stems from its theoretical ability to provide protection against infection that lasts much longer than the 30 days or so afforded by the administration of palivizumab. The major challenges to the development, beyond the early observation of vaccine-enhanced disease that was seen during the FI vaccine trial in the 1960s, are worth highlighting.
First, an infant's immune response during primary RSV infection does not afford immunity from reinfection, although each subsequent infection is usually less severe. The dilemma posed to vaccinologists is to develop a vaccine that provides better protection than natural infection.
The second major challenge worth highlighting is that the highest rates for severe RSV infection occurs between birth and age 3 months. The ability to develop a vaccine that induces an immune response more protective than natural infection, and to deliver the necessary number of doses to provide that response before the risk period begins (at birth) is unrealistic. A proposed solution to this dilemma has led to active research programs designed to boost maternal immunity during pregnancy. Infants born at or near term would be endowed, transplacentally, with the antibodies generated by the mother after the dose of vaccine given during pregnancy. If neutralizing antibody is generated and transferred to the infant prior to birth, it could provide transient protection from RSV in the newborn. During such a period of passive protection, active vaccination could be initiated. The bridging protection afforded by the boosted levels of maternal antibody could, theoretically, allow sufficient time to deliver an active RSV vaccine series to the infant during a period of passive protection.
Successful active vaccination, either through boosting of existing maternal immunity, through immunizing an infant, or by doing both sequentially demands use of immunizing antigens presented in the right context to induce a neutralizing antibody response. Active vaccination of the infant also allows for engagement of the cellular immune response, an event that is lacking from passive immune prophylaxis and maternal immunization approaches. Although a true surrogate of immunity to RSV has never been identified, studies with palivizumab have proven the concept that the presence of the right antibody (ie, anti-RSV fusion [F] protein monoclonal) at the right concentrations can be sufficient to prevent infection when exposed. Determination of the concentration of vaccine-induced neutralizing RSV antibodies achieved with candidate vaccines are therefore one of the necessary outcome measurements needed during active immunization trials.
In 2013, protein chemists successfully purified and crystalized the RSV-F protein revealing a discovery that proved critical in moving RSV vaccine science forward. When the virus attaches to and fuses with the target cell, the RSV-F protein undergoes a dramatic conformational change. The pre-fusion (pre-F) and post-fusion (post-F) proteins contain different and distinct antigenic determinants. RSV-neutralizing antibodies are largely generated against the pre-fusion conformation, while the post-fusion F protein lacks the surface epitopes needed to stimulate a robust neutralizing antibody response. It is now widely accepted that investigational RSV vaccines based on the fusion protein are more likely to succeed if the pre-fusion conformation is used as the vaccine antigen. Preclinical studies performed using serum collected from immunized rabbits clearly demonstrated that serum absorbed with pre-F, but not post-F protein depleted nearly all of the RSV neutralizing antibody from the sample.
Maternal immunization is currently being evaluated in a phase III clinical trial. Infants born to mothers who are vaccinated with the experimental RSV-F vaccines or placebo are being observed from birth to track the timing and severity of incident RSV infections. If maternal immunization is shown to be effective at reducing infant RSV infection-related hospitalizations, it has the potential to change the epidemiology of infant RSV infection as we know it.
RSV-F based vaccines are not the only promise to achieve active immunization programs. Several live attenuated vaccines remain under phase I human study. Gene-based vector vaccines using adenovirus and modified vaccinia Ankara vectors are in phase I and phase II trials, and nucleic acid (both RNA and DNA) based vaccines may soon emerge from preclinical development to phase I studies.19 Preclinical and human clinical trials for each of these approaches, and their stage of development are available.20
Emerging Passive Protection Strategies for RSV Prevention
The current standard of care for RSV prevention is monthly injections of palivizumab administered during RSV season. The concept of transient passive protection provided via active maternal immunization is underway. Maternally derived vaccine-induced anti-RSV antibodies would be expected to have a similar serum half-life when compared with other IgGs. Serum measurements of IgG antibodies, whether maternally derived, or injected (as in the form of palivizumab) show that the half-life of IgG subclass 1, the subclass most efficient at crossing the placenta, is typically 21 to 29 days. Because the antibody concentration threshold that confers protection against RSV is unknown, precise estimates for the duration of protection in infants born to mothers who are immunized are not yet possible.
Emerging passive protection strategies now go beyond maternal immunization. A new monoclonal antibody developed against the pre-fusion conformation of RSV-F has been developed with neutralizing capacity that exceeds that of palivizumab by several-fold offering promise for improved protection. A second feature of the new investigational monoclonal antibody offers the potential to dramatically change the landscape for how immune prophylaxis is used to prevent infant RSV infection. Here, a biochemical change that was made to the antibody molecule included three amino acid substitutions in the Fc portion of the protein.21 The Fc portion of IgG is highly conserved, unlike the antigen binding, unique Fab fragments of the antibody. When the Fc portion is modified by changing a methionine to a tyrosine at position 252, a serine to threonine at position 254, and a threonine to glutamic acid at position 256 (the so-called YTE modification using the single letter abbreviations for the new amino acids tyrosine [Y], threonine [T] and glutamic acid [E]), the serum half-life of the antibody is extended from the typical 21 to 29 days to an impressive 87 to 117 days. Phase II trials are underway to determine whether the predicted pharmacokinetics can be confirmed in infants and to begin to assess its efficacy. A high potency neutralizing monoclonal antibody developed against the pre-fusion form of the RSV-F protein with a half-life exceeding other IgGs (including palivizumab) by 3- to 6-fold offers the theoretical potential for single dose use at the start of a typical 5 month RSV season. If that potential can be demonstrated in a large-scale phase III clinical trial and the ultimate cost is in alignment with typical vaccine prices, one might envision giving a single dose to all infants (term or preterm, with or without risk factors) as they enter their first RSV season. A successful infant RSV prevention program could impact disease-associated morbidity and mortality across the globe.
If this strategy proves successful, one might consider that maternal immunization and active RSV vaccination platforms for use during infancy would become lower priority efforts. However, even if extended half-life anti-RSV monoclonal antibodies are successful in decreasing the impressive public health burden of infant RSV disease, active vaccination programs will need to continue for other high-risk groups. Older children with underlying lung disease, neuromuscular disease, Down syndrome, and adults age 65 years and older would all derive benefits from an active RSV vaccine program. Reducing RSV morbidity in these patient populations is a laudable goal. Moreover, it is unlikely that a single-prevention strategy will prove effective for all who could benefit. It is refreshing to see the variety of vaccine types and delivery systems currently under evaluation. Given the recent discovery of the different RSV-F protein conformations, emerging vaccine antigen delivery systems, such as vector-based technology and nucleic acid based vaccines, and the biochemical trick shown to extend the serum half-life of a monoclonal antibody, the field of RSV vaccinology will continue to fascinate all stakeholders for many years to come.
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Risk Factors for Severe Respiratory Syncytial Virus Infection
Young age at the start of respiratory syncytial virus season
Chronic lung disease of prematurity
Hemodynamically significant congenital heart disease
Anatomic abnormalities of the airways
Older than age 65 years
Low serum neutralizing antibody titers
Summary of the Results from the 1966–1967 NIH-Sponsored Clinical Trial of an Investigational Formalin-Inactivated RSV Vaccine
||Total Number of Infants
|FI-RSV lot 100 (n = 31)
||16 (80%); two deaths
|Control (n = 40)