New therapies for acute RSV infections: where are we?
Respiratory syncytial virus (RSV) infection is one of the main causes of infant hospitalization and mortality. The single-stranded RNA virus codes for 11 proteins of which the F protein, a surface epitope responsible for RSV fusion, is the most targeted for developing antiviral medicines and vaccines. The peak of symptoms occurs around day 4 to 6 of illness and the airway obstruction is merely caused by the host immune inflammatory response. Risk factors for severe bronchiolitis are prematurity, comorbidity, and/or being immunocompromised. At present, there are no curative therapies available for RSV infections and treatment is supportive only. Development of new antiviral medicines is however promising. The aim of this review is to give a summary of the most important new antiviral therapies in clinical development for RSV infection and to explain their mode of action. We therefore performed a literature search on this topic.
What is known:
• RSV bronchiolitis is a very important pediatric disease as it is one of the main causes of infant hospitalization and mortality. By the age of 2 years, 95% of all the infants worldwide will have been infected.
• The only recommended therapy is supportive since there are no existing curative therapies yet.
What this study adds:
• This review gives an overview of the current progress in the research field of RSV antivirals with background information on their mode of action.
KeywordsRSV Bronchiolitis Antiviral medication-mode of action
American Academy of Pediatrics
Bronchiolitis obliterans syndrome
Lower respiratory tract infection
National Institute for Health Care and Excellence
RNA-induced silencing complex
Respiratory syncytial virus
Small interfering RNA
Treatment-emergent adverse effects
Ying Xing performed the literature search and selection of articles with supervision of Marijke Proesmans. The first article draft was written by Ying Xing. Marijke Proesmans extensively worked with her towards the final draft.
Compliance with ethical statements
Conflict of interest
Ying Xing has no conflict of interest to declare. Marijke Proesmans is the principal investigator for the drugs JNJ-53718678 and ALX-0171.
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent was obtained from all individual participants included in the study: not applicable for this type of manuscript.
- 3.Alnylam Pharmaceuticals Inc. (2005) Alnylam initiates phase i clinical study of ALN-RSV01, an RNAi therapeutic for the treatment of respiratory syncytial virus (RSV) infection. [cited 2017 November 15]. Available from: http://investors.alnylam.com/news-releases/news-release-details/alnylam-initiates-phase-i-clinical-study-aln-rsv01-rnai
- 4.Ark Biosciences Inc. (2015) Ark biosciences’ anti-RSV AK0529 successfully completes phase I study. [cited 2017 November 17]. Available from: http://www.arkbiosciences.com/index.php?g=&m=article&a=index&id=17&cid=12
- 5.Battles MB, Langedijk JP, Furmanova-Hollenstein P, Chaiwatpongsakorn S, Costello HM, Kwanten L, Vranckx L, Vink P, Jaensch S, Jonckers THM, Koul A, Arnoult E, Peeples ME, Roymans D, McLellan JS (2016) Molecular mechanism of respiratory syncytial virus fusion inhibitors. Nat Chem Biol 12(2):87–93CrossRefGoogle Scholar
- 8.Depla E. (2014) Ablynx: Development of ALX-0171, an inhaled Nanobody ® for the treatment of respiratory syncytial virus infection in infants. [cited 2017 November 1]; Available from: http://www.ablynx.com/uploads/data/files/rsv_hah-2014.pdf
- 9.Depla E. (2015) Ablynx: ALX-0171: safety, efficacy and therapeutic potential of an inhaled anti-RSV Nanobody. [cited 2017 November 1]; Available from: http://www.ablynx.com/uploads/data/files/alx-0171rddconferencemay2015.pdf
- 10.Detalle L, Stohr T, Palomo C, Piedra PA, Gilbert BE, Mas V, Millar A, Power UF, Stortelers C, Allosery K, Melero JA, Depla E (2016) Generation and characterization of ALX-0171, a potent novel therapeutic nanobody for the treatment of respiratory syncytial virus infection. Antimicrob Agents Chemother 60(1):6–13CrossRefGoogle Scholar
- 12.DeVincenzo J, Cehelsky JE, Alvarez R, Elbashir S, Harborth J, Toudjarska I, Nechev L, Murugaiah V, van Vliet A, Vaishnaw AK, Meyers R (2008) Evaluation of the safety, tolerability and pharmacokinetics of ALN-RSV01, a novel RNAi antiviral therapeutic directed against respiratory syncytial virus (RSV). Antivir Res 77(3):225–231CrossRefGoogle Scholar
- 13.DeVincenzo J, Lambkin-Williams R, Wilkinson T, Cehelsky J, Nochur S, Walsh E, Meyers R, Gollob J, Vaishnaw A (2010) A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus. Proc Natl Acad Sci U S A 107(19):8800–8805CrossRefGoogle Scholar
- 18.Gadomski AM, Scribani MB (2014) “Bronchodilators for bronchiolitis”. Cochrane Database Syst Rev Jun 17(6):CD001266Google Scholar
- 19.Glanville A, Musk M, Zamora M, Hodges T, Arcasoy S, Sommerwerck U, Alnylam Pharmaceuticals Inc. et al. (2012) Results of a phase 2b multi-center, randomized, double-blind, placebo-controlled study of an RNAi therapeutic, ALN-RSV01, in respiratory syncytial virus (RSV)-infected lung transplant patients. [cited 2017 November 15]. Available from: http://www.alnylam.com/web/assets/RSV01-109-ERS-Oral-Final-24Aug2012.pdf
- 20.Glezen WP, Taber LH, Frank AL, Kasel JA (1986) Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child 140(6):543–546Google Scholar
- 22.Graham BS, Anderson LJ (2013) Challenges and opportunities for respiratory syncytial virus vaccines. Curr Top Microbiol Immunol 372:391–404Google Scholar
- 24.Hall CB, Weinberg GA, Blumkin AK, Edwards KM, Staat MA, Schultz AF, Poehling KA, Szilagyi PG, Griffin MR, Williams JV, Zhu Y, Grijalva CG, Prill MM, Iwane MK (2013) Respiratory syncytial virus-associated hospitalizations among children less than 24 months of age. Pediatrics 132(2):e341–e348CrossRefGoogle Scholar
- 26.Huntjens DRH, Ouwerkerk-Mahadevan S, Brochot A, Rusch S, Stevens M, Verloes R (2017) Population pharmacokinetic modeling of JNJ-53718678, a novel fusion inhibitor for the treatment of respiratory syncytial virus: results from a phase I, double-blind, randomized, placebo-controlled first-in-human study in healthy adult subjects. Clin Pharmacokinet 56(11):1331–1342CrossRefGoogle Scholar
- 28.Israel S, Rusch S, DeVincenzo J, Boyers A, Fok-Seang J, Huntjens D et al (2016) Effect of oral JNJ-53718678 (JNJ-678) on disease severity in healthy adult volunteers experimentally inoculated with live respiratory syncytial virus (RSV): a placebo-controlled challenge study. Open Forum Infect Dis 3(Suppl 1):650Google Scholar
- 30.Kim YI, Pareek R, Murphy R, Harrison L, Farrell E, Cook R, DeVincenzo J (2017) The antiviral effects of RSV fusion inhibitor, MDT-637, on clinical isolates, vs its achievable concentrations in the human respiratory tract and comparison to ribavirin. Influ Other Respir Viruses 11(6):525–530CrossRefGoogle Scholar
- 31.Mazur NI, Martinón-Torres F, Baraldi E, Fauroux B, Greenough A, Heikkinen T, Manzoni P, Mejias A, Nair H, Papadopoulos NG, Polack FP, Ramilo O, Sharland M, Stein R, Madhi SA, Bont L, Respiratory Syncytial Virus Network (ReSViNET) (2015) Lower respiratory tract infection caused by respiratory syncytial virus: current management and new therapeutics. Lancet Respir Med 3(11):888–900CrossRefGoogle Scholar
- 34.Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, O'Brien KL, Roca A, Wright PF, Bruce N, Chandran A, Theodoratou E, Sutanto A, Sedyaningsih ER, Ngama M, Munywoki PK, Kartasasmita C, Simões EAF, Rudan I, Weber MW, Campbell H (2010) Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 375(9725):1545–1555CrossRefGoogle Scholar
- 35.National Institute for Health and Care Excellence: Bronchiolitis in children: diagnosis and management | Guidance and guidelines | NICE. (2015) [cited 2018 May 24]; Available from: https://www.nice.org.uk/guidance/NG9
- 36.Ostadabbas S, Bulach C, Ku DN, Anderson LJ, Ghovanloo M (2014) A passive quantitative measurement of airway resistance using depth data. Conf Proc IEEE Eng Med Biol Soc 2014:5743–5747Google Scholar
- 37.Perron M, Stray K, Kinkade A, Theodore D, Lee G, Eisenberg E, Sangi M, Gilbert BE, Jordan R, Piedra PA, Toms GL, Mackman R, Cihlar T (2015) GS-5806 inhibits a broad range of respiratory syncytial virus clinical isolates by blocking the virus-cell fusion process. Antimicrob Agents Chemother 60(3):1264–1273CrossRefGoogle Scholar
- 39.Ramirez JA (2008) RSV infection in the adult population. Manag Care 17(11,Suppl 12):13–15 discussion 18-9 Google Scholar
- 40.Régnier SA, Huels J (2013) Association between respiratory syncytial virus hospitalizations in infants and respiratory sequelae: systematic review and meta-analysis. Pediatr Infect Dis J 32(8):820–826Google Scholar
- 41.Roymans D, Alnajjar SS, Battles MB, Sitthicharoenchai P, Furmanova-Hollenstein P, Rigaux P, Berg JV, Kwanten L, Ginderen MV, Verheyen N, Vranckx L, Jaensch S, Arnoult E, Voorzaat R, Gallup JM, Larios-Mora A, Crabbe M, Huntjens D, Raboisson P, Langedijk JP, Ackermann MR, McLellan JS, Vendeville S, Koul A (2017) Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor. Nat Commun 8(1):167CrossRefGoogle Scholar
- 42.Samuel D, Xing W, Niedziela-Majka A, Wong JS, Hung M, Brendza KM, Perron M, Jordan R, Sperandio D, Liu X, Mackman R, Sakowicz R (2015) GS-5806 inhibits pre- to postfusion conformational changes of the respiratory syncytial virus fusion protein. Antimicrob Agents Chemother 59(11):7109–7112CrossRefGoogle Scholar
- 47.Wang G, Deval J, Hong J, Dyatkina N, Prhavc M, Taylor J, Fung A, Jin Z, Stevens SK, Serebryany V, Liu J, Zhang Q, Tam Y, Chanda SM, Smith DB, Symons JA, Blatt LM, Beigelman L (2015) Discovery of 4’-chloromethyl-2’-deoxy-3’,5’-di-O-isobutyryl-2’-fluorocytidine (ALS-8176), a first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus infection. J Med Chem 58(4):1862–1878CrossRefGoogle Scholar