Advantages and disadvantages of the main strategy categories for RSV vaccine development.
Respiratory syncytial virus (RSV) is the leading cause of serious lower respiratory infection (ALRI)-related hospitalization in children worldwide, and a source of morbidity and mortality in high-risk adults. There are strong associations between RSV, persistent wheezing and childhood asthma. Despite extensive research, no effective treatment is available aside from supportive care. The trial of a formalin-inactivated RSV vaccine in the 1960s resulted in priming the severe illness upon natural infection. Palivizumab, a monoclonal antibody approved for RSV prophylaxis in high-risk infants, has only moderately decreased hospital admissions due to RSV infection. Live-attenuated, vector, and protein-based vaccine candidates are being investigated in many clinical trials. Developing a vaccine remains challenging due to finding the right balance between adequate immunogenicity and attenuation of vaccine. Here we review the clinical significance of RSV in infants, young children, high-risk adults, elderly population, pregnant women; clinical manifestations and consequences of RSV infection; the pharmacologic strategies currently available, the current stages of RSV vaccine clinical trials, different strategies, and major hurdles in the development of an effective RSV vaccine.
- respiratory syncytial virus (RSV)
- respiratory infection
- antiviral therapy
- RSV vaccine
- clinical trials
RSV, a member of the Paramyxoviridae family, is an enveloped, negative-sense, single-stranded RNA virus . Especially within the winter months, it is an important cause of morbidity and mortality among young children, the elderly, and immunocompromised individuals . Infection is transmitted by either direct or indirect contact with respiratory droplets, and prior infection does not result in persistent immunity.
RSV accounts for approximately 2.1 million outpatient visits among children younger than 5 years old . Additionally, there are 177,000 hospitalizations and 14,000 deaths among adults older than 65 years due to RSV infection [4, 5] each year in the United States. Human studies have shown strong associations between RSV, persistent wheezing, and childhood asthma [6, 7, 8].
Symptoms usually begin 4–6 days after transmission and present with nasal congestion, rhinorrhea, fever, or cough. RSV is one of the leading causes of lower respiratory tract infection (LRTI), and can cause tachypnea, wheeze, hypoxemia, or respiratory distress, resulting in an emergency department visit or hospital admission . Males are more severely affected than females, and for reasons that are not fully elucidated, Native Americans and Alaskan Native children are more likely than children of other ethnicities to have severe infection requiring hospitalization.
To date, supportive care is the main treatment option for RSV admission [9, 10]. There is no vaccine approved for RSV prophylaxis in the general population. In 1966, the first vaccine for RSV, a formalin-inactivated (FI-RSV) type, was developed. However, it resulted in vaccine-enhanced disease (VED). Among vaccinated infant, 80% developed severe bronchiolitis or pneumonia and two died, compared to only 5% for the placebo group . There was increased eosinophilic and neutrophilic infiltration and mononuclear cells in the lung parenchyma found in the autopsies of two infants that died, which suggests a Th2-biased immune response, however the mechanism of the VED remains unclear .
RSV is composed of 10 genes encoding 11 proteins: small hydrophobic (SH) protein, nucleocapsid associated proteins N, P, L, M2–1, and M2–2, the matrix (M) protein, nonstructural proteins NS1 and NS2, glycoprotein (G), and fusion (F) protein. The SH, N, M2–2, NS2, G, and F proteins are the most commonly manipulated proteins in vaccine production (Figure 1). The SH protein inhibits cell apoptosis through inhibition of the TNF-α pathway . The N protein initiates encapsidation of the genome, the M2–2 protein mediates the balance between transcription and RNA replication, and the NS2 protein inhibits host interferon (IFN) response [14, 15]. G protein mediates viral attachment to the host cell, while F protein enables fusion of the virus [16, 17]. RSV A and RSV B, the two antigenic subtypes, differ in their amino acid sequence of the G protein and reactivity to antibodies, resulting in differences in disease severity . Targeting the F protein is of particular interest, as it is highly conserved between the two antigenic subgroups.
In this chapter, we will discuss the current and candidate antiviral drugs and prophylactic agents against RSV infection and some of the ongoing clinical trials of RSV vaccines. Evaluation of drugs typically proceeds in a methodical order, from studies in healthy adults, to hospitalized adults, to older seropositive children, to seronegative infants/toddlers. For purposes of this chapter, we will highlight the most recent trials where research is ongoing. We will also elucidate many of the complex hurdles that have impeded progress in the development of an effective vaccine.
2. Available pharmacologic strategies
Ribavirin, a synthetic guanosine analogue antiviral agent, was first synthesized in the 1970s. It is believed that ribavirin is phosphorylated intracellularly and can then disrupt purine metabolism by inhibiting inosine monophosphate dehydrogenase, thereby inhibiting nucleic acid synthesis. Furthermore, it promotes antiviral cytokine production and Type 1 T-cell mediated immune responses. Starting in 1993, the American Academy of Pediatrics (AAP) Committee on Infectious Diseases supported the use of Ribavirin for severe RSV infections. However, in 1996, the recommendation changed to “may be considered” . Currently, the use of aerosolized Ribavirin is limited to immunocompromised patients with RSV due to the inconvenient route of delivery, which requires prolonged aerosol administration; risks for potential toxicity, such as teratogenic effects during pregnancy; cost of therapy; and need for hospital admission. The safety of oral ribavirin in moderately to severely immunocompromised adults with PCR-proven RSV infection was examined in a retrospective cohort study. The main outcome of this study was the rate of adverse events, and authors conclude that ribavirin is well tolerated in immunocompromised adults . However, the rate of progression of disease from URTI to the LRTI was not measured. In another retrospective study, immunosuppressed patients were given either oral, intravenous, aerosol or a combination of these treatments and showed that ribavirin therapy reduces progression from RSV URTI to LRTI . In a similar study, Khanna et al. reported that 32% of patients who were treated with ribavirin progressed to LRTI compared to 68% of the untreated group . Their study showed that oral ribavirin therapy was likely as effective as aerosolized therapy. However, because of the sample size and retrospective nature, neither of these studies could determine the precise role of ribavirin therapy in this patient population. In addition, ribavirin is being used for Hepatitis C infection, in conjunction with an interferon agent . Furthermore, a recent study showed that ribavirin inhibited Zika virus replication and Zika virus-induced cell death in mammalian cells .
ALS-008176, a prodrug of a cytidine nucleoside analogue, decreased viral load and more readily cleared RSV than placebo in a randomized, double-blind clinical trial in healthy adults . However, participants’ preexisting immune memory, which may promote RSV clearance, was not assessed . A randomized, double-blind Phase I study assessing both a single and multiple ascending dosing in hospitalized infants (Clinicaltrials.gov identifier #NCT02202356) was completed in February 2018, but results have not been published yet.
During viral entry, the F protein undergoes conformational changes to fuse with the host cell membrane . Presatovir (GS-5806) is an orally bioavailable agent that inhibits these conformational changes, thereby blocking viral fusion . It was found in a Phase 2a trial with healthy adults (Clinicaltrials.gov identifier #NCT01756482) to reduce viral load and severity of disease. However, it also caused low neutrophil counts and increased levels of alanine aminotransferase . Despite these adverse events and because of its promise as an efficacious antiviral agent, a Phase 2b, randomized, double-blind trial in RSV-infected hospitalized adults was completed in April 2017 (Clinicaltrials.gov identifier #NCT02135614). The primary outcome was the time-weighted average change in RSV load from baseline to Day 5. There appeared to be no significant differences between Presatovir and placebo (−0.77 vs. −0.89, respectively,
3. Currently available and under development immuno-prophylaxis
RSV Immunoglobulin (RSV-IVIG, RespiGam) is a pooled hyperimmune polyclonal immunoglobulin preparation made from donors with high titers of anti-RSV antibodies. RSV-IVIG significantly reduced morbidity and mortality in high-risk infants . It was initially licensed in 1996, but taken off the market in 2004, due to the need for long intravenous infusion sessions and supervision in a hospital setting, high volume doses resulting in fluid overload in already at-risk infants, and potential risk for blood-borne pathogens . Furthermore, immunizations with live-attenuated viruses, such as the measles/mumps/rubella (MMR) vaccine, need to be postponed until 9 months after RSV-IVIG infusion.
ALX-0171 is an inhaled trivalent nanobody that targets the RSV F protein . A Phase I/IIa in RSV-infected infants and toddlers was recently completed in February 2016 (Clinicaltrials.gov identifier #NCT02309320). A Phase II dose ranging study RSV-infected hospitalized infants was recently completed in May 2018. Results from both studies have not been published yet.
3.2 Palivizumab and motavizumab
Palivizumab (Synagis), developed by MedImmune (Gaithersburg, MD, USA) in 1998, is the only currently approved prophylaxis agent against RSV infection . It has been shown to reduce severe RSV infections by 55% and reduce RSV hospitalizations by 50%. Palivizumab is a humanized monoclonal IgG1 antibody that recognizes the RSV F protein and is administered intramuscularly monthly, for a maximum of 5 months, during the RSV season. It has no significant adverse side effects and other required live-attenuated vaccines can still be administered. However, because of the high cost, it is selectively given to high-risk infants: preterm infants born at <29 weeks of gestation; infants with chronic lung disease (CLD) of prematurity defined as gestational age <32 weeks of gestation and requirement of supplemental oxygen for the first 28 days of life; hemodynamically significant congenital heart disease; and might be considered for neuromuscular disorders that impair the airway clearance [32, 33].
Motavizumab (MEDI-524, Numax), an affinity-matured derivative of palivizumab, was shown to be more efficient than palivizumab with higher virus neutralizing effects . However, it failed to receive FDA approval due to lack of greater clinical efficacy compared to palivizumab and cutaneous hypersensitivity reactions in some treated infants .
Suptavumab (REGN2222) completed a Phase III trial in July 2017 (Clinicaltrials.gov identifier #NCT02325791). It is a human monoclonal IgG1 antibody against RSV-F . 1177 preterm infants for whom palivizumab was not recommended were randomly assigned to one of three groups: Group 1 received one dose of intramuscular suptavumab and one dose of placebo, Group 2 received two doses of suptavumab, and Group 3 received two doses of placebo. There were no significant differences between the three groups in terms of the primary outcome of preventing medically attended RSV infection up to Day 150 . All further development of Suptavumab has been stopped.
MEDI8897 is another recombinant human monoclonal antibody with a modified Fc region that extends its half-life. MEDI8897 is being developed as RSV prophylaxis for all infants. The phase I (Clinicaltrials.gov identifier #NCT02114268) of study recruited 136 healthy adults, who received either MEDI8897 or placebo intravenously or intramuscularly, a single dose of 300–3000 mg. The half-life of the antibody was 85–117 days across the groups . The phase Ib/IIa of the study, recruited healthy preterm infants with a gestational age of 32–35 weeks. The antibody group received as single intramuscular dose of 10–50 mg MEDI8897. The half-life of the antibody was 62.5–72.9 days. The authors concluded that the antibody has a favorable safety profile and can be administered as single dose during RSV season . A Phase IIb trial in preterm infants’ ineligible for Synagis was completed in 2018 and there is a plan for the Phase III trial in healthy full-term and late pre-term infants in 2019.
4. RSV vaccines under development
To date, there is no vaccine against RSV. Developing a vaccine against RSV remains a challenge, as the proper balance is required in eliciting an immune response, while avoiding vaccine-enhanced disease. While many of the proteins within RSV are being manipulated in different vaccine strategies, RSV F comprises a highly conserved amino acid sequence called antigenic site II, between RSV-A and RSV-B antigenic subgroups, and has been considered an important antigen for an RSV vaccine.
Designing a vaccine against RSV requires careful considerations. Infants, the elderly, and pregnant women are the three targeted populations for RSV vaccine development . Each of the three types of vaccines, live-attenuated, vector delivery, and protein based, have benefits and drawbacks that have to be considered when developing vaccine technology (Table 1). Live-attenuated vaccines contain extracted components of viral proteins and present antigens most similarly to the naturally occurring infection . They stimulate both humoral and cell-mediated immune responses. Live-attenuated vaccines are employed against many viral diseases, like measles, rubella, polio, rotavirus, varicella, and yellow fever.
(For young infants and children <24 months of age)
(For young infants and children <24 months of age)
(For pregnant women and elderly)
Taken from: Rezaee F, Linfield DT, Harford TJ, Piedimonte G. Ongoing developments in RSV prophylaxis: a clinician’s analysis.
One major drawback of live attenuated vaccines is that they cannot be given to patients with compromised immunity including pregnant woman. Vector-delivery system vaccines utilize a non-pathogenic virus genome with inserted portions of RSV proteins. Similar to live-attenuated vaccines, these vaccines increase mucosal IgA and cellular immune responses, yet without the risk of insufficient attenuation . Protein-based vaccines include whole-inactivated viruses, subunit antigens, and particle-based vaccines. Live-attenuated or vector vaccines hold the greatest promise for infants due to the risk of vaccine-enhanced RSV disease. Pregnant women and the elderly are not susceptible to vaccine-enhanced RSV disease, and therefore protein-based RSV vaccines are likely the most effective candidates .
Live-attenuated, vector, and protein-based vaccines each possess advantages and disadvantages. Because non-replicating vaccines may elicit enhanced disease in RSV-naïve infants during subsequent infection, replicating or vectored vaccines might be a better choice in this group [41, 42]. Additionally, active immunization for infants is challenging due to passive immunity received from the mother . Because of these factors, different vaccines may be required for different target populations. Understanding these complexities is crucial in RSV vaccine advancement. We will now discuss in depth the different vaccine strategies and current clinical trials in each category. A list of the vaccine candidates is summarized in Table 2.
|Vaccine type||Current strategies|
|M2–2 gene deletionLID ∆M2–21030s|
LID cp ∆M2–2
NS2 gene deletionΔNS2/Δ1313/1314 L
SH gene deletion
Modified Vaccinia Ankara vectorMVA-RSV
|Particle based vaccineF-protein nanoparticle|
4.1 Live-attenuated vaccines
The tragic results of the formalin-inactivated RSV vaccine in the 1960s spurred research in the development of live-attenuated vaccine candidates. The live virus has parts of the genome deleted and is passaged at gradually lower temperatures. Live-attenuated vaccines require a delicate balance: maintain sufficient viral genome RNA replication to illicit enough antibody response in RSV-naïve infants, yet with a low risk of deattenuation and no harmful effects . Live-attenuated vaccines are, in theory, safe for RSV-naïve infants because it does not exacerbate future exposure to RSV. Furthermore, it may be administered intranasally, which can mimic a milder form of a natural infection, and lead to viral replication in the upper respiratory tract . This will induce mucosal and humoral immunogenicity, despite the potential presence of maternal antibodies acquired transplacentally.
Several live-attenuated RSV vaccine candidates have deletions of a large segment of the M2–2 gene. The M2–2 gene mediates the transition from transcription to RNA replication .
Aside from deleting the M2–2 gene, the NS2 gene is another potential “knock-out” gene for a live-attenuated vaccine. The RSV NS2 gene is known to promote epithelial cell shedding and inhibit host IFN response . ΔNS2/Δ1313/1314 L, a vaccine candidate with a deleted NS2 gene, is genetically stable and moderately temperature-sensitive . Another candidate, RSV 6120/∆NS2/1030s, also has a deleted NS2 gene, in combination with the “1030s” missense mutation, which provides further restriction of replication. Both of these candidates are currently being assessed in both seropositive and seronegative children and infants (Clinicaltrials.gov identifiers #NCT03422237 and #NCT03387137).
Strategies have also targeted the SH gene. The RSV SH gene has multiple functions, including inhibiting cell apoptosis, inhibiting signals from TNF-α, and modifying membrane permeability . One vaccine that has a complete deletion of the SH gene, rA2cp248/404/1030∆SH, demonstrated restricted antibody response in the subjects, as well as viral genotypic and phenotypic instability primarily due to reversion of the 1030 mutation [42, 48]. MEDI-559 differs from rA2cp248/404/1030∆SH by silent nucleotide substitutions throughout the viral genome [42, 50]. A Phase I/IIa trial studying the safety and efficacy of MEDI-559, showed a higher incidence of medically attended LRTI in RSV seronegative infants 5 to <24 months of age and in infants 1 to <3 months of age regardless of baseline serostatus within 28 days, as compared to placebo . RSV neutralizing antibodies were detected in 59% of MEDI-559 recipients, in comparison to 9% of placebo subjects. Interestingly, this microneutralization response was lower than the rA2
In comparison to MEDI-559, RSVcps2 contains 5 nucleotide changes and 1 amino acid substitution. The level of attenuation of RSVcps2 and MEDI-559 was shown to be similar in a study in seronegative chimpanzees . This study also showed that it was temperature-sensitive and phenotypically and genetically stable. A Phase I trial in RSV-seronegative, healthy 6–24 month old children demonstrated that RSVcps2 is safe and effective . Furthermore, unlike MEDI-559, medically attended LRTI was not observed. There were no significant differences in the number of adverse events between the experimental and control groups. However, in comparison to rA2cp248/404/1030ΔSH, RSVcps2 had decreased levels of replication and immunogenicity. The study investigators believe that this is due to the 37 silent nucleotide differences between the two vaccine candidates . An ideal candidate would therefore combine the genetic stability of RSVcps2 and the greater replication and immunogenicity of rA2cp248/404/1030ΔSH. Other ∆SH vaccine candidates include OE4 (RSV-A2-dNS1-dNS2-ΔSH-dGm-Gsnull-line19F) and DB1 (RSV-A2-dNS-ΔSH-BAF), which have both been found to be immunogenic in cotton rats [52, 53].
4.2 Vector delivery systems
Vaccine technology is currently utilizing adenovirus and non-pathogenic viral genomes that can act as immune potentiators of delivery systems. These vaccines contain inserted portions of RSV F, N, and M2–1 proteins . Vector vaccines increase mucosal IgA and cellular immune responses similar to live-attenuated vaccine candidates, yet without the risk of insufficient attenuation . Furthermore, adjuvants used with these vector vaccines could potentially enhance the immune response to the vaccine .
Adenoviruses of serotype 26 (Ad26) are engineered to comprise a nucleotide sequence encoding RSV F protein, which showed efficacy against RSV in mice and cotton rats . Two Phase I, placebo-controlled studies assessed the administration of Ad26.RSV.FA2, given either once or twice, followed by Ad35.RSV.FA2, and vice versa, to adults aged 18–50 years. Ad26.RSV.FA2 was shown to be safe and well tolerated. There was also increased humoral and cellular immunity for 6 months. Ad26.RSV.preF differs by 5 amino acids and contains the pre-fusion conformation stabilized F protein, and showed increased immunogenicity in comparison to Ad26.RSV.FA2 in pre-clinical studies . It is currently undergoing a Phase II clinical trials in adults aged 18–50 years and RSV-seropositive toddlers aged 12–24 months (Clinicaltrials.gov identifier #NCT03303625) and in healthy adults greater than age 60 (Clinicaltrials.gov identifier #NCT03339713). PanAd3-RSV, a vaccine based on the RSV viral proteins F, N and M2–1 encoded by Simian Adenovirus, completed a Phase I trial in subjects 18–75 years of age (ClinicalTrials.gov identifier #NCT01805921) in 2015, alongside a Modified Vaccinia Virus Ankara (MVA) non-replicating vector vaccine candidate. Both of these vector vaccines contain RSV viral proteins F, N and M2–1.
PanAd3-RSV and MVA-RSV were both safe and effective in cotton rats, mice, and calves  and immunogenic in a primate model . Most adverse effects were mild to moderate, self-limiting at the site of injection and the study concluded that the vaccine was safe and immunogenic . Despite the promising results, no current clinical trial is investigating these vaccine candidates. MVA-BN (modified Vaccinia Ankara—Bavarian Nordic) is another MVA-based vaccine undergoing investigation. In August 2018, Bavarian Nordic announced that in a Phase II trial in older adults the MVA-BN vaccine elicited broad antibody and T cell responses to both RSV subtypes that lasted 6 months. Furthermore, a booster shot 1 year later again initiated a robust cellular immune response .
4.3 Protein-based vaccines
Pregnant women and the elderly are not susceptible to vaccine-enhanced RSV disease like infants, and therefore RSV protein-based vaccines are most likely the most effective candidates. Protein-based vaccine candidates include whole-inactivated viruses, subunit antigens, and particle-based vaccines. Vaccinating a pregnant woman can provide passive immunity to the fetus, as RSV-neutralizing antibodies have been shown to pass from mother to fetus
MEDI-7510 is a subunit RSV vaccine candidate that contains the post-fusion F glycoprotein, with or without a glucopyranosyl lipid A (a synthetic TLR-4 agonist) adjuvant . A Phase IIb trial in adults aged 60 and older showed that the vaccine candidate was immunogenic but did not protect the study population from RSV illness .
Novavax’s RSV F-protein nanoparticle vaccine has been trialed in a few Phase I and II studies in healthy human adults and one study of subjects 24 to <72 months of age, and was found to be well-tolerated and immunogenic in all studies [69, 70]. This vaccine consists of nearly the full-length F glycoprotein. This nanoparticle vaccine prompted transplacental antibody transfer within a guinea pig model . Furthermore, in a Phase II study in healthy women of child-bearing age, the vaccine was well tolerated. The peak of Anti-F IgG antibody was day 14 and persisted for 3 months, optimal for administration during the third trimester . Recently, the immunogenicity, with an aluminum adjuvant, was evaluated in a Phase II trial (Clinicaltrials.gov identifier #NCT02247726) in healthy third-trimester pregnant women. In this study in pregnant women, the primary outcome measures were safety and immunogenicity of the vaccine, as well as its impact on the number of infants with medically-attended RSV LRTI and age of onset of the infection. No results have been posted for this study. However, a Phase III study investigation in the same study population is set to be completed in 2019, thereby suggesting that the Phase II trial met its goals.
RSV is one of the most common causes of lower respiratory disease in infants, young children, and the elderly. Treatment is currently limited to supportive care, such as supplemental oxygen, bronchodilators, or corticosteroids. Palivizumab prophylaxis is currently restricted to high-risk infants. There is currently no vaccine to prevent RSV infection. There are many challenges associated with developing an RSV vaccine candidate. When developing a live attenuated vaccine, an equilibrium must be struck between adequate immunogenicity and attenuation of the virus. Non-replicating vaccines, like in some vector-delivery systems and protein-based vaccines, can enhance RSV infection in RSV-naïve infants. Therefore, it may be necessary to develop separate vaccines for each at-risk population: neonates and young children, pregnant women, and the elderly. One highly promising strategy appears to be maternal immunization with a nonreplicating vaccine, as this may provide protection during the first few months of life in the neonate.
We thank Dr. Frank Esper (Department of Infectious Disease, Cleveland Clinic Children’s) for his insightful comments regarding an earlier version of this chapter. This work was supported by a NIH K08 AI112781 (F.R.) grant.
Conflict of interest
The authors report no conflicts of interest.
Wright M, Piedimonte G. Respiratory syncytial virus prevention and therapy: Past, present, and future. Pediatric Pulmonology. 2011; 46(4):324-347
Geoghegan S et al. Mortality due to respiratory syncytial virus. Burden and risk factors. American Journal of Respiratory and Critical Care Medicine. 2017; 195(1):96-103
Hall CB et al. The burden of respiratory syncytial virus infection in young children. The New England Journal of Medicine. 2009; 360(6):588-598
Falsey AR et al. Respiratory syncytial virus infection in elderly and high-risk adults. The New England Journal of Medicine. 2005; 352(17):1749-1759
McClure DL et al. Seasonal incidence of medically attended respiratory syncytial virus infection in a community cohort of adults >/=50 years old. PLoS One. 2014; 9(7):e102586
Stein RT et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet. 1999; 354(9178):541-545
Stensballe LG et al. The causal direction in the association between respiratory syncytial virus hospitalization and asthma. The Journal of Allergy and Clinical Immunology. 2009; 123(1):131-137. e1
Thomsen SF et al. Exploring the association between severe respiratory syncytial virus infection and asthma: A registry-based twin study. American Journal of Respiratory and Critical Care Medicine. 2009; 179(12):1091-1097
Piedimonte G. RSV infections: State of the art. Cleveland Clinic Journal of Medicine. 2015; 82(11 Suppl 1):S13-S18
Rezaee F et al. Ongoing developments in RSV prophylaxis: A clinician’s analysis. Current Opinion in Virology. 2017; 24:70-78
Acosta PL, Caballero MT, Polack FP. Brief history and characterization of enhanced respiratory syncytial virus disease. Clinical and Vaccine Immunology. 2015; 23(3):189-195
Knudson CJ et al. RSV vaccine-enhanced disease is orchestrated by the combined actions of distinct CD4 T cell subsets. PLoS Pathogens. 2015; 11(3):e1004757
Fuentes S et al. Function of the respiratory syncytial virus small hydrophobic protein. Journal of Virology. 2007; 81(15):8361-8366
Bermingham A, Collins PL. The M2-2 protein of human respiratory syncytial virus is a regulatory factor involved in the balance between RNA replication and transcription. Proceedings of the National Academy of Sciences of the United States of America. 1999; 96(20):11259-11264
Liesman RM et al. RSV-encoded NS2 promotes epithelial cell shedding and distal airway obstruction. The Journal of Clinical Investigation. 2014; 124(5):2219-2233
Techaarpornkul S, Barretto N, Peeples ME. Functional analysis of recombinant respiratory syncytial virus deletion mutants lacking the small hydrophobic and/or attachment glycoprotein gene. Journal of Virology. 2001; 75(15):6825-6834
Krarup A et al. A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism. Nature Communications. 2015; 6:8143
Gilca R et al. Distribution and clinical impact of human respiratory syncytial virus genotypes in hospitalized children over 2 winter seasons. The Journal of Infectious Diseases. 2006; 193(1):54-58
American Academy of Pediatrics Committee on Infectious Diseases. Use of ribavirin in the treatment of respiratory syncytial virus infection. Pediatrics. 1993; 92(3):501-504
Marcelin JR et al. Oral ribavirin therapy for respiratory syncytial virus infections in moderately to severely immunocompromised patients. Transplant Infectious Disease. 2014; 16(2):242-250
Avetisyan G et al. Respiratory syncytial virus infection in recipients of allogeneic stem-cell transplantation: A retrospective study of the incidence, clinical features, and outcome. Transplantation. 2009; 88(10):1222-1226
Khanna N et al. Respiratory syncytial virus infection in patients with hematological diseases: Single-center study and review of the literature. Clinical Infectious Diseases. 2008; 46(3):402-412
Novembrino C et al. Interferon-ribavirin therapy induces serum antibodies determining ‘rods and rings’ pattern in hepatitis C patients. Journal of Viral Hepatitis. 2014; 21(12):944-949
Kamiyama N et al. Ribavirin inhibits Zika virus (ZIKV) replication in vitro and suppresses viremia in ZIKV-infected STAT1-deficient mice. Antiviral Research. 2017; 146:1-11
DeVincenzo JP et al. Activity of oral ALS-008176 in a respiratory syncytial virus challenge study. The New England Journal of Medicine. 2015; 373(21):2048-2058
Arasaratnam R. ALS-008176 for respiratory syncytial virus infection. The New England Journal of Medicine. 2016; 374(14):1391
German P et al. Phase 1 first-in-human, single- and multiple-ascending dose, and food effect studies to assess the safety, tolerability, and pharmacokinetics of presatovir for the treatment of respiratory syncytial virus infection. Journal of Clinical Pharmacology. 2018; 58(8):1025-1034
The PREVENT Study Group. Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics. 1997; 99(1):93-99
Roymans D, Koul A. Treatment of respiratory syncytial virus infection: Past, present and future. In: Resch B, editor. Human Respiratory Syncytial Virus Infection. London, United Kingdom: InTech; 2011
Larios Mora A et al. Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs. MAbs. 2018; 10(5):778-795
The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics. 1998; 102(3 Pt 1):531-537
American Academy of Pediatrics Committee on Infectious, D. and C. American Academy of Pediatrics Bronchiolitis Guidelines. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics. 2014; 134(2):415-420
Meissner HC. More on viral bronchiolitis in children. The New England Journal of Medicine. 2016; 375(12):1200
Weisman LE. Motavizumab, a second-generation humanized mAb for the prevention of respiratory syncytial virus infection in high-risk populations. Current Opinion in Molecular Therapeutics. 2009; 11(2):208-218
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. The Lancet Infectious Diseases. 2015; 15(12):1398-1408
Tripp RA et al. Respiratory syncytial virus: Targeting the G protein provides a new approach for an old problem. Journal of Virology. 2018; 92(3):e01302-e01317
Griffin MP et al. Safety, tolerability, and pharmacokinetics of MEDI8897, the respiratory syncytial virus prefusion F-targeting monoclonal antibody with an extended half-life, in healthy adults. Antimicrobial Agents and Chemotherapy. 2017; 61(3):e01714-e01716
Domachowske JB et al. Safety, tolerability and pharmacokinetics of MEDI8897, an extended half-life single-dose respiratory syncytial virus prefusion F-targeting monoclonal antibody administered as a single dose to healthy preterm infants. The Pediatric Infectious Disease Journal. 2018; 37(9):886-892
Graham BS. Vaccine development for respiratory syncytial virus. Current Opinion in Virology. 2017; 23:107-112
Karron RA, Buchholz UJ, Collins PL. Live-attenuated respiratory syncytial virus vaccines. Current Topics in Microbiology and Immunology. 2013; 372:259-284
Wright PF et al. The absence of enhanced disease with wild type respiratory syncytial virus infection occurring after receipt of live, attenuated, respiratory syncytial virus vaccines. Vaccine. 2007; 25(42):7372-7378
Karron RA et al. Identification of a recombinant live attenuated respiratory syncytial virus vaccine candidate that is highly attenuated in infants. The Journal of Infectious Diseases. 2005; 191(7):1093-1104
Chu HY et al. Respiratory syncytial virus transplacental antibody transfer and kinetics in mother-infant pairs in Bangladesh. The Journal of Infectious Diseases. 2014; 210(10):1582-1589
Le Nouen C et al. Genetic stability of genome-scale deoptimized RNA virus vaccine candidates under selective pressure. Proceedings of the National Academy of Sciences of the United States of America. 2017; 114(3):E386-E395
McFarland E. Phase I Placebo Controlled Study of the Infectivity, Safety and Immunogenicity of a Single Dose of a Recombinant Live-Attenuated Respiratory Syncytial Virus Vaccine, LID ΔM2-2 1030s, Lot RSV#010A, Delivered as Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age. National Institutes of Health (NIH), Washington: DC IMPAACT Network; 2016. pp. 16-20
McFarland E et al. High infectivity of recombinant live-attenuated respiratory syncytial virus vaccine (RSV LID ΔM2-2) in infants and children. Open Forum Infectious Diseases. 2015; 2:1924
McFarland E. Phase I Placebo-Controlled Study of the Infectivity, Safety and Immunogenicity of a Single Dose of a Recombinant Live-Attenuated Respiratory Syncytial Virus Vaccine, D46/NS2/N/ΔM2-2-HindIII, Lot RSV#011B, Delivered as Nose Drops to RSV-Seronegative Infants 6 to 24 Months of Age. National Institute of Allergy and Infectious Diseases, Washington, DC: IMPAACT Network; 2017
Luongo C et al. Respiratory syncytial virus modified by deletions of the NS2 gene and amino acid S1313 of the L polymerase protein is a temperature-sensitive, live-attenuated vaccine candidate that is phenotypically stable at physiological temperature. Journal of Virology. 2013; 87(4):1985-1996
Collins PL, Fearns R, Graham BS. Respiratory syncytial virus: Virology, reverse genetics, and pathogenesis of disease. Current Topics in Microbiology and Immunology. 2013; 372:3-38
Malkin E et al. Safety and immunogenicity of a live attenuated RSV vaccine in healthy RSV-seronegative children 5 to 24 months of age. PLoS One. 2013; 8(10):e77104
Buchholz UJ et al. Live respiratory syncytial virus (RSV) vaccine candidate containing stabilized temperature-sensitivity mutations is highly attenuated in rsv-seronegative infants and children. The Journal of Infectious Diseases. 2018; 217(9):1338-1346
Rostad CA et al. A recombinant respiratory syncytial virus vaccine candidate attenuated by a low-fusion F protein is immunogenic and protective against challenge in cotton rats. Journal of Virology. 2016; 90(16):7508-7518
Stobart CC et al. A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation. Nature Communications. 2016; 7:13916
Pierantoni A et al. Mucosal delivery of a vectored RSV vaccine is safe and elicits protective immunity in rodents and nonhuman primates. Molecular Therapy - Methods & Clinical Development. 2015; 2:15018
Anderson LJ et al. Strategic priorities for respiratory syncytial virus (RSV) vaccine development. Vaccine. 2013; 31(Suppl 2):B209-B215
Jorquera PA, Tripp RA. Synthetic biodegradable microparticle and nanoparticle vaccines against the respiratory syncytial virus. Vaccine. 2016; 4(4):E45
Widjojoatmodjo MN et al. Recombinant low-seroprevalent adenoviral vectors Ad26 and Ad35 expressing the respiratory syncytial virus (RSV) fusion protein induce protective immunity against RSV infection in cotton rats. Vaccine. 2015; 33(41):5406-5414
Polack FP. Update on RSV Vaccine Development. Fundacion. Geneva, Switzerland: INFANT; 2017
Green CA et al. Safety and immunogenicity of novel respiratory syncytial virus (RSV) vaccines based on the RSV viral proteins F, N and M2-1 encoded by simian adenovirus (PanAd3-RSV) and MVA (MVA-RSV); protocol for an open-label, dose-escalation, single-centre, phase 1 clinical trial in healthy adults. BMJ Open. 2015; 5(10):e008748
Green CA et al. Chimpanzee adenovirus- and MVA-vectored respiratory syncytial virus vaccine is safe and immunogenic in adults. Science Translational Medicine. 2015; 7(300):300ra126
Bavarian Nordic Announces Positive Data from Phase 2 Extension Study of its Universal RSV Vaccine. 2018, GlobeNewsWire: Copenhagen, Denmark
Stensballe LG et al. Respiratory syncytial virus neutralizing antibodies in cord blood, respiratory syncytial virus hospitalization, and recurrent wheeze. The Journal of Allergy and Clinical Immunology. 2009; 123(2):398-403
Glezen WP et al. Risk of respiratory syncytial virus infection for infants from low-income families in relationship to age, sex, ethnic group, and maternal antibody level. The Journal of Pediatrics. 1981; 98(5):708-715
Walsh EE et al. Virus-specific antibody, viral load, and disease severity in respiratory syncytial virus infection. The Journal of Infectious Diseases. 2018; 218(2):208-217
Rossey I et al. Clinical potential of prefusion RSV F-specific antibodies. Trends in Microbiology. 2018; 26(3):209-219
Brown PM et al. Prenatal exposure to respiratory syncytial virus alters postnatal immunity and airway smooth muscle contractility during early-life reinfections. PLoS One. 2017; 12(2):e0168786
Broadbent L et al. Respiratory syncytial virus, an ongoing medical dilemma: An expert commentary on respiratory syncytial virus prophylactic and therapeutic pharmaceuticals currently in clinical trials. Influenza and Other Respiratory Viruses. 2015; 9(4):169-178
Falloon J et al. An adjuvanted, postfusion F protein-based vaccine did not prevent respiratory syncytial virus illness in older adults. The Journal of Infectious Diseases. 2017; 216:1362-1370
Glenn GM et al. A randomized, blinded, controlled, dose-ranging study of a respiratory syncytial virus recombinant fusion (F) nanoparticle vaccine in healthy women of childbearing age. The Journal of Infectious Diseases. 2016; 213(3):411-422
Glenn GM et al. Safety and immunogenicity of a Sf9 insect cell-derived respiratory syncytial virus fusion protein nanoparticle vaccine. Vaccine. 2013; 31(3):524-532
Glenn GM et al. Modeling maternal fetal RSV F vaccine induced antibody transfer in guinea pigs. Vaccine. 2015; 33(47):6488-6492
August A et al. A Phase 2 randomized, observer-blind, placebo-controlled, dose-ranging trial of aluminum-adjuvanted respiratory syncytial virus F particle vaccine formulations in healthy women of childbearing age. Vaccine. 2017; 35(30):3749-3759