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New therapies for acute RSV infections: where are we?

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Abstract

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.

Conclusion: There are currently at least eight antivirals being investigated in clinical trials. They all use different approaches to either focus on preventing viral fusion with host cells or inhibiting virus replication. Some target RSV surface epitopes like the F protein to halt fusion, others aim for RNA chain termination, while small interfering RNAs downregulate viral protein production.

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.

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Abbreviations

AAP:

American Academy of Pediatrics

AE:

Adverse effects

BOS:

Bronchiolitis obliterans syndrome

CMP:

Cytidine monophosphate

Ig:

Immunoglobulin

IVIG:

Intravenous immunoglobulin

LRTI:

Lower respiratory tract infection

miRNA:

MicroRNA

NICE:

National Institute for Health Care and Excellence

RISC:

RNA-induced silencing complex

RNAi:

RNA interference

RSV:

Respiratory syncytial virus

siRNA:

Small interfering RNA

SNP:

Single-nucleotide polymorphism

TEAE:

Treatment-emergent adverse effects

References

  1. Agoti CN, Otieno JR, Gitahi CW, Cane PA, Nokes DJ (2014) Rapid spread and diversification of respiratory syncytial virus genotype ON1, Kenya. Emerg Infect Dis 20(6):950–959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Aherne W, Bird T, Court SD, Gardner PS, McQuillin J (1970) Pathological changes in virus infections of the lower respiratory tract in children. J Clin Pathol 23(1):7–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):87–93

    Article  CAS  PubMed  Google Scholar 

  6. Byington CL, Wilkes J, Korgenski K, Sheng X (2015) Respiratory syncytial virus-associated mortality in hospitalized infants and young children. Pediatrics 135(1):e24–e31

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cilla G, Sarasua A, Montes M, Arostegui N, Vicente D, Pérez-Yarza E et al (2006) Risk factors for hospitalization due to respiratory syncytial virus infection among infants in the Basque Country, Spain. Epidemiol Infect 134(3):506–513

    Article  CAS  PubMed  Google 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):6–13

    Article  CAS  PubMed  Google Scholar 

  11. Deval J, Hong J, Wang G, Taylor J, Smith LK, Fung A et al (2015) Molecular basis for the selective inhibition of respiratory syncytial virus RNA polymerase by 2’-fluoro-4’-chloromethyl-cytidine triphosphate. PLoS Pathog 11(6):1004995

    Article  CAS  Google 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):225–231

    Article  CAS  PubMed  Google 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):8800–8805

    Article  PubMed  PubMed Central  Google Scholar 

  14. DeVincenzo JP, Whitley RJ, Mackman RL, Scaglioni-Weinlich C, Harrison L, Farrell E et al (2014) Oral GS-5806 activity in a respiratory syncytial virus challenge study. N Engl J Med 371(8):711–722

    Article  CAS  PubMed  Google Scholar 

  15. DeVincenzo JP, McClure MW, Symons JA, Fathi H, Westland C, Chanda S et al (2015) Activity of oral ALS-008176 in a respiratory syncytial virus challenge study. N Engl J Med 373(21):2048–2058

    Article  CAS  PubMed  Google Scholar 

  16. Douglas JL, Panis ML, Ho E, Lin KY, Krawczyk SH, Grant DM, Cai R, Swaminathan S, Cihlar T (2003) Inhibition of respiratory syncytial virus fusion by the small molecule VP-14637 via specific interactions with F protein. J Virol 77(9):5054–5064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Falsey AR, Koval C, DeVincenzo JP, Walsh EE (2017) Compassionate use experience with high-titer respiratory syncytial virus (RSV) immunoglobulin in RSV-infected immunocompromised persons. Transpl Infect Dis 19(2):12657

    Article  CAS  Google Scholar 

  18. Gadomski AM, Scribani MB (2014) “Bronchodilators for bronchiolitis”. Cochrane Database Syst Rev Jun 17(6):CD001266

  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):543–546

    CAS  PubMed  Google Scholar 

  21. Glezen WP, Greenberg SB, Atmar RL, Piedra PA, Couch RB (2000) Impact of respiratory virus infections on persons with chronic underlying conditions. JAMA 283(4):499–505

    Article  CAS  PubMed  Google Scholar 

  22. Graham BS, Anderson LJ (2013) Challenges and opportunities for respiratory syncytial virus vaccines. Curr Top Microbiol Immunol 372:391–404

    CAS  PubMed  Google Scholar 

  23. Griffiths C, Drews SJ, Marchant DJ (2017) Respiratory syncytial virus: infection, detection, and new options for prevention and treatment. Clin Microbiol Rev 30(1):277–319

    Article  CAS  PubMed  Google 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–e348

    Article  PubMed  Google Scholar 

  25. Hislop AA (2002) Airway and blood vessel interaction during lung development. J Anat 201(4):325–334

    Article  PubMed  PubMed Central  Google 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):1331–1342

    Article  CAS  PubMed  Google Scholar 

  27. Impact-RSV Study Group (1998) Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 102(3):531–537

    Article  Google 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):650

    Article  Google Scholar 

  29. Johnson JE, Gonzales RA, Olson SJ, Wright PF, Graham BS (2007) The histopathology of fatal untreated human respiratory syncytial virus infection. Mod Pathol 20(1):108–119

    Article  CAS  PubMed  Google 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):525–530

    Article  CAS  Google 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):888–900

    Article  PubMed  Google Scholar 

  32. Meissner HC (2016) Viral bronchiolitis in children. N Engl J Med 374(1):1793–1794

    Article  CAS  PubMed  Google Scholar 

  33. Mori M, Morio T, Ito S, Morimoto A, Ota S, Mizuta K, Iwata T, Hara T, Saji T (2014) Risks and prevention of severe RS virus infection among children with immunodeficiency and Down’s syndrome. J Infect Chemother 20(8):455–459

    Article  PubMed  Google 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):1545–1555

    Article  PubMed  PubMed Central  Google 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 2014:5743–5747

    PubMed  Google 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):1264–1273

    Article  CAS  PubMed  Google Scholar 

  38. Ralston SL, Lieberthal AS, Meissner HC, Alverson BK, Baley JE, Gadomski AM, and the American Academy of Pediatrics et al (2014) Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics 134:1474–1502

    Article  Google Scholar 

  39. Ramirez JA (2008) RSV infection in the adult population. Manag Care 17(11,Suppl 12):13–15 discussion 18-9

    PubMed  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):820–826

    PubMed  Google 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):167

    Article  CAS  PubMed  PubMed Central  Google 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):7109–7112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Smyth RL, Fletcher JN, Thomas HM, Hart CA (1997) Immunological responses to respiratory syncytial virus infection in infancy. Arch Dis Child 76(3):210–214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sullender WM (2000) Respiratory syncytial virus genetic and antigenic diversity. Clin Microbiol Rev 13(1):1–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Taleb SA, Al Thani AA, Al Ansari K, Yassine HM (2018) Human respiratory syncytial virus: pathogenesis, immune responses, and current vaccine approaches. Eur J Clin Microbiol Infect Dis 37(10):1817–1827

    Article  CAS  PubMed  Google Scholar 

  46. Walsh EE, Falsey AR (2012) Respiratory syncytial virus infection in adult populations. Infect Disord Drug Targets 12(2):98–102

    Article  CAS  PubMed  Google 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):1862–1878

    Article  CAS  PubMed  Google Scholar 

  48. Zamora MR, Budev M, Rolfe M, Gottlieb J, Humar A, Devincenzo J et al (2011) RNA interference therapy in lung transplant patients infected with respiratory syncytial virus. Am J Respir Crit Care Med 183(4):531–538

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Marijke Proesmans.

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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.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study: not applicable for this type of manuscript.

Additional information

Communicated by Peter de Winter

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Xing, Y., Proesmans, M. New therapies for acute RSV infections: where are we?. Eur J Pediatr 178, 131–138 (2019). https://doi.org/10.1007/s00431-018-03310-7

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  • DOI: https://doi.org/10.1007/s00431-018-03310-7

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