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RSV and child pneumonia webinar

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Webinar: Respiratory syncytial virus (RSV) and child pneumonia
Date: Thursday, March 14, 2019
Presentations by Ting Shi, Louis Bont, Marijke Proesmans, and Keith Klugman

Published in: Health & Medicine
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RSV and child pneumonia webinar

  1. 1. Respiratory syncytial virus (RSV) and child pneumonia Pneumonia Innovations Network Webinar Series March 14, 2019
  2. 2. RSV and child pneumonia webinar agenda • Ting Shi, University of Edinburgh: ”Global disease burden estimate of RSV in young children” • Louis Bont, University Medical Center Utrecht: ”RSV clinical presentation and disease severity” • Marijke Proesmans, University Hospital Leuven: ”RSV therapeutics for the future” • Keith Klugman, Bill & Melinda Gates Foundation: ”RSV immunization and future directions” • Questions and discussion session
  3. 3. Global disease burden estimate of RSV in young children Ting Shi, PhD Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics University of Edinburgh Email: ting.shi@ed.ac.uk 3
  4. 4. Introduction 4 • Acute Lower Respiratory Infection (ALRI) remains one of the leading causes of morbidity and mortality in children younger than five years.1 • RSV is the most common viral pathogen identified in children with ALRI.2 • Updated RSV disease burden estimates incorporating latest data are of great importance – gap in knowledge for future 1 Liu 2016; 2 Nair 2010; Figures: CDC Factsheet of RSV in infants and young children
  5. 5. Data source 5 • A systematic review of published articles in 11 databases between 1995 and 2016 (includes 3 Chinese databases), pre-defined inclusion criteria and exclusion criteria • Unpublished studies collected from RSV Global Epidemiology Network (RSV GEN), common case definitions and approaches applied Shi et al. Lancet 2017
  6. 6. Selection criteria Inclusion criteria: • Studies reporting community incidence, hospitalisation, and in-hospital CFR for RSV confirmed ALRI in children aged 0-5 years. • Studies with data for at least 12 consecutive months (except for mortality related data). • Studies reporting RSV-ALRI incidence or mortality for the first year of life. Exclusion criteria: • Studies where RSV was not a primary outcome. • The case definition was not clear or inconsistently applied. • RSV diagnosis was based on serology alone. • The number of hospitalised ALRI cases was <50. 6
  7. 7. PRISMA flow chart 7
  8. 8. Location of incidence and hospital mortality studies 8
  9. 9. Location of hospital proportion studies 9
  10. 10. Results Children younger than 5 years • 33.1 (21.6-50.3) million episodes of RSV-ALRI (1/3 in 1st year of life) • 3.2 (2.7-3.8) million hospitalisations of RSV-ALRI (20% had hypoxemia) • 59600 (47000-74500) in-hospital deaths due to RSV-ALRI • 118200 (94600-149400) overall RSV-ALRI mortality Children younger than six months • 1.4 (1.2-1.7) million hospitalisations of RSV-ALRI • 27300 (20700-36200) in-hospital deaths due to RSV-ALRI 10
  11. 11. Discussion Even though peak hospitalization in children <6 months; substantial burden on hospital in- patient services in 6-11 months [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE][CELLRANGE] [CELLRANGE] [CELLRANGE] [CELLRANGE] 0 10 20 30 40 50 60 70 80 90 100 0-27 days 28-<3m 3-5m 6-8m 9-11m 12-23m Hospitalisationrate(per1000peryear) Age group High income Upper middle income Lower middle income Low income
  12. 12. Discussion 12 Estimated no. of episodes of RSV-severe ALRI in LMIC children in 2015 6.0 (2.1-17.6) million 53% of cases do not reach hospital 3.2 million BURDENONHOSITALINPATIENT SERVICES BURDENNOTACCESSINGHOSPITAL INPATIENTSERVICES CFR in hospitalised cases 2.1 (1.9−2.3)% 51% of deaths were in hospital 59600 (47800-74300) Estimated (severe) RSV-ALRI deaths in children in developing countries 118000 (94500-147200) CFR in communities 1.8% 49% of deaths occur outside hospital 58400 (46700-72900) 47% of cases reach hospital 2.8 (2.1−3.9) million
  13. 13. Clinical Presentation – Disease Severity Louis Bont
  14. 14. Kurt Rhinorrhea Cough Wheeze
  15. 15. Annual Epidemics 0 1000 2000 3000 4000 5000 29-32 37-40 45-48 1-4 9-12 17-20 25-28 33-36 41-44 49-53 5-8 13-16 21-24 29-32 37-40 45-48 1-4 9-12 17-20 25-28 33-36 41-44 49-53 5-8 13-16 21-24 RSVcasesreported Weeks UK: Centre for Disease Control (1996-98) Belgium: Institut Pasteur, Bruxelles Netherlands: Registratie Virologische Lab Norway: National Institute of Public Health
  16. 16. Course of Disease Bronchiolitis Trias 1. Rhinorrhea 2. Cough 3. Wheeze Other Feeding difficulties Shortness of Breath Respiratory Insufficiency Antibiotic use (without need)
  17. 17. RSV Burden of Disease ventilation 0.1% Hospitalization 1% RSV LRTI 10% RSV infection 100% Hall, NEJM 2009
  18. 18. HIV patients South Africa High Prevalence Prospective surveillance <5Y (n=4489) HIV status available (n=2987) 1157 proven RSV cases (HIV+, n=49) Increased Risk: hospitalization (RR=4) and death (RR=31) Moyes, J Iinfect Dis 2013
  19. 19. Otitis Heikkinen J Infect Dis 2016 0 10 20 30 40 50 60 70 80 90 100 <1y (n=11) 1y (n=48) 2y (n=90) 3-6y (n=124) 7-13y (n=25) clinicalsyndrome(%allRSVinfections) wheeze / pneumonia otitis 0 50 100 150 200 250 300 350 400 <1y (n=11) 1y (n=48) 2y (n=90) 3-6y (n=124) 7-13y (n=25) RSV infection (/1000 person years)
  20. 20. Mortality 0% 10% 20% 30% 40% 50% 60% 0 5 10 15 20 25 30 35 40 45 50 55 60 Proportionofpatients Age at RSV-related death, months Comorbidity (n = 183) Comorbidity complete (n = 162) Healthy term (n = 144) Healthy term complete (n = 60) Healthy preterm (n = 31) Healthy preterm complete (n = 21) Scheltema Lancet Glob Health 2017
  21. 21. RSV in the Elderly Falsey NEJM 2006 nr Episodes RSV (admission) Influenza (admission) Death by RSV (%) Death by influenza(%) Elderly 608 519 46 (0) 24 (0) 0 0 COPD / heart disease 540 524 56 (9) 20 (4) 0 0 admissions* 1388 1471 142 233 10 (8) 10 (7) * >65 with COPD/ heart disease
  22. 22. RSV and Asthma Bacharier, JACI 2013 RSV Bronchiolitis in Early Life (RBEL), n=206, < 13 months Asthma < 7y 48% Active asthma 35%
  23. 23. RSV and COPD: the Evidence Berry, AJRCCM 2016 FEV1% predicted 95 vs 86% 0 20 40 60 80 100 120 140 RSV LRTI V'max FRC in infancy Persistently low Lung Function Trajectory (n=56) Normal Trajectory (n=543) P=0.001 P<0.001
  24. 24. Four distinct wheezing phenotypes RSV wheeze Asthma COPD
  25. 25. Conclusions 1. Acute disease Mild (Otitis), Severe (Admission), Mortality 2. Age 3. Long-term consequences
  26. 26. RSV therapeutics for the future M Proesmans MD, PhD Pediatric Pulmonology, University hospital Leuven, Belgium
  27. 27. RSV treatment options in bronchiolitis There are no available curative therapies for RSV infections. The only recommended treatment is supportive.
  28. 28. Search for new treatment options • RSV = ssRNA virus • Codes for 11 proteins • The F-protein • Surface epitope • Responsible for RSV fusion • The most targeted for developing antiviral medicines and vaccines
  29. 29. RSV targets • F-protein • pre and post fusion conformational structure • The viral nucleocapsid: • N (nucleoprotein) • binds the RNA • P (polymerase complex) • SH (small hydrophobic protein) • an ion channel. • M (matrix protein) • forms the inner envelop.
  30. 30. Development of new therapies 1. Immunoglobulins 2. Nucleoside analogues 3. RNA interference 4. Fusion inhibitors
  31. 31. Immunoglobulins • ALX-0171 • Trivalent nanobody • Inhibits virus internalisation by targeting the F-protein • Acute RSV infection: Nebulization • Trial status (Ablynx) • Adults • Phase I • Children • Phase II in RSV-infected infants and toddlers • RI-001 • Intravenous immunoglobulin (IVIG) preparation • Targets the various RSV surface epitopes G, F and SH • Trial status (ADMA Biologics) • Adults • Phase II trial in immunosuppressed adult RSV-infected patients (clinicaltrials.gov)
  32. 32. Nucleoside analogues • ALS-008176/ JNJ-6404157 • Prodrug of an RSV polymerase inhibitor • Acute RSV infections: oral treatment • Trial status (Alios BioPharma/Janssen Pharmaceutical) • Adults • phase I in healthy adults • phase II challenge study in adults • phase II study in RSV-infected adults • Children • RSV bronchiolitis in infants up to 12 Months
  33. 33. Figure 2 : N-protein mRNA cleaving by siRNA-RISC complex The two strands of ALN-RSV01 separate when ALN-RSV01 integrates into the RISC. The siRNA-RISC complex is formed with the guide strand and the passenger strand gets degraded. The complex then binds to the N-protein mRNA, cleaves the mRNA and consequently releases the cleaved pieces. Afterwards the complex is recycled. RNA interference • Small interfering RNA (siRNA) • ds RNA fragments • Sequence-specific neutralization of posttranscriptional mRNA • Custom made siRNA’s with therapeutic aim
  34. 34. RNA interference • ALN-RSV01 • siRNA directed against the mRNA encoding for the RSV nucleocapsid protein (N-protein) • Treatment for acute infection, nebulization • Trial status (Alnylam) • Adults • Phase I trials in healthy adults • Phase II in healthy adults inoculated with RSV • Phase II studies in RSV infected lung transplant patients
  35. 35. Fusion inhibitors: reduce RSV replication by inhibiting RSV F protein • JNJ-53718678 (Janssens) • Adults • Phase I trials in healthy adults • Phase II trial in RSV-inoculated adults • Children • Phase I study in RSV-hospitalized infants aged 1 to 24 Months • Infant study recruiting • GS-5806 (Gilead) • Adults • Phase I study in healthy adults • Phase II studies (healthy, lung transplant, HSCT) • Children • Phase I trial in RSV-hospitalised infants up to 24 Months (withdrawn) • AK0529 (Ark Biosciences) • Adult • Phase I study in healthy adults. • Phase I study in infants aged 1 to 24 Months hospitalized for RSV infection (terminated) • Phase II in RSV-infected infants aged 1 to 24 Months: recruiting • MDT-637 (MicroDose Therapeutx ) • Adults only
  36. 36. Conclusion • Multiple antiviral strategies are currently being developed and tested • The RSV F-protein is the most used target in drug development pipelines • Research in this field is challenging • RSV is an unstable virus prone to mutations • Target group are acutely ill young infants, a difficult group for phase I and II studies • The timing of RSV virus replication in relation to disease presentation
  37. 37. RSV IMMUNIZATION AND FUTURE DIRECTIONS Keith P. Klugman MD, PhD Director, Pneumonia Program Bill & Melinda Gates Foundation, Seattle WA RSV and pneumonia webinar – March 14, 2019
  38. 38. Last updated: March 8, 2019 © Bill & Melinda Gates Foundation | 38 PNEUMONIA INCLUDING NEONATAL SEPSIS IS THE LEADING KILLER OF CHILDREN  Pneumonia was responsible for 921K child deaths in 2015 (812K -1.2M)  45.1% of child deaths are in the neonatal period  22.4% of neonatal deaths (10.1% of all <5 deaths) are due to infectious causes: pneumonia, tetanus, meningitis, and sepsis 15% Pneumonia 15.5% Liu et al. (2016).The Lancet, 388, 3027-3035.
  39. 39. © Bill & Melinda Gates Foundation | 39 PROGRESS IN REDUCTION OF CHILD AND NEONATAL MORTALITYDeathsper1,000LiveBirths Source: Data.unicef.org. - 25 50 75 100 1990 1995 2000 2005 2010 2015 Under-five Mortality Rate Infant Mortality Rate Neonatal Mortality Rate Global Under-five, Infant and Neonatal Mortality Rates (1990-2015) 91 63 36 43 32 19  Despite significant declines, the global MDG target for under-five mortality rate of 30 per 1,000 live births was not achieved by 2015  Neonatal mortality proved more challenging to address and declined at a lower rate than under-five mortality
  40. 40. © Bill & Melinda Gates Foundation | 40 • RSV is the major viral cause of pneumonia in children • Hospital data from 23 countries1 found the median age for RSV-related deaths is 5 months in LMICs • Few data exist on the outcome of apnea, bronchiolitis, and pneumonia associated with RSV in infants without access to hospital care • As we supported the first phase III maternal vaccine trial to prevent infant RSV, we worked with partners to address this question 1Scheltema NM et al. Lancet Glob Health. 2017: Data from the RSV GOLD Study. RESPIRATORY SYNCYTIAL VIRUS (RSV) ASSOCIATED MORTALITY
  41. 41. © Bill & Melinda Gates Foundation | 41 BURDEN OF RSV • Current global mortality in hospitalized infants <6 months estimated at 27,000 • Burden in community (with lack of access to oxygen/other therapies) is unknown; new surveillance efforts may address this knowledge gap Study Setting Evaluation Deaths assessed RSV-positive Zambia 1 Infants (7d – 6m) in Lusaka brought in dead to hospital RSV PCR of NP swab (<48h) 394 40 (10.2%) Argentina 2 Infants (7d – 6m) in Buenos Aires who died at home without medical assistance RSV qPCR of NP swab (<48h) 45 5 (11.1%) CHAMPS Infants (7d – 6m) who died in facility/community in Bangladesh, Kenya, Mali, Mozambique, and South Africa • RSV TAC of NP and lung • Histopathology from MITS • Expert panel assigned immediate and underlying cause of death 161 13 (8.1%) Expert panel determined that RSV was in the causal chain or played a contributory role in 11/161 (6.8%) of the deaths. These data suggest projected global RSV-associated mortality in infants <6m may range from 77,944 to 117,494 deaths Abbreviations: CHAMPS = Child Health and Mortality Prevention Surveillance; MITS = minimally invasive tissue sampling; NP = nasopharyngeal; PCR = polymerase chain reaction; TAC = TAQMAN Array Card Sources: 1 Williams AL et al. RSV-associated respiratory death among Zambian infants. Poster 110 at RSV18. 2 Caballero MT et al. Mortality associated with acute respiratory infections among children at home. JID. 2018
  42. 42. Additional Novavax Trial Takeaways • Geographic imbalance in efficacy: US was low compared to South Africa and rest of the world, might be related to later gestational age at immunization • Next steps focused on discussions on licensure pathways with key regulators Other product development efforts • Alternate maternal vaccine candidates and infant monoclonal antibodies: pre-clinical and clinical phase studies © Bill & Melinda Gates Foundation | 42 Topline Results: Maternal RSV Vaccine Phase 3 Trial, ResVax (Novavax)1 • Primary endpoint (prevention of medically significant RSV LRTI) not met: 39% efficacy (97.5% CI, -1-64) • Secondary and pre-specified exploratory endpoints achieved: 42% (95% CI, 17-59) against RSV hospitalization, 60% (95% CI, 32- 76) against RSV with severe hypoxia • Vaccine reduced all-cause respiratory hospitalization by 25% and all-cause severe hypoxia by 39% through the first 180 days of life, indicating potential for broader public health impact 1Prepare Trial Topline Results. Novavax. www.novavax.com. Accessed February 28, 2019. RECENT DATA FROM RSV PRODUCT DEVELOPMENT EFFORTS
  43. 43. Last updated: March 8, 2019
  44. 44. Questions and discussion
  45. 45. Thank you for joining us!

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