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

1. Respiratory syncytial virus (RSV)
and child pneumonia
Pneumonia Innovations Network Webinar Series
March 14, 2019

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. 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. 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. 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• Unpublished studies collected from RSV Global Epidemiology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. 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. PRISMA flow chart
7

8. Location of incidence and hospital
mortality studies
8

9. Location of hospital proportion studies
9

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. 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. 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. Clinical Presentation – Disease Severity
Louis Bont

14. Kurt
Rhinorrhea
Cough
Wheeze

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. Course of Disease
Bronchiolitis Trias
1. Rhinorrhea
2. Cough
3. Wheeze
Other
Feeding difficulties
Shortness of Breath
Respiratory Insufficiency
Antibiotic use (without need)

17. RSV Burden of Disease
ventilation
0.1%
Hospitalization 1%
RSV LRTI 10%
RSV infection 100%
Hall, NEJM 2009

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. 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. 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. 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. RSV and Asthma
Bacharier, JACI 2013
RSV Bronchiolitis in Early Life (RBEL), n=206, < 13 months
Asthma < 7y 48%
Active asthma 35%

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. Four distinct wheezing phenotypes
RSV wheeze Asthma COPD

25. Conclusions
1. Acute disease
Mild (Otitis), Severe (Admission), Mortality
2. Age
3. Long-term consequences

26. RSV therapeutics
for the future
M Proesmans MD, PhD
Pediatric Pulmonology, University hospital Leuven, Belgium

27. RSV treatment options in bronchiolitis
There are no available curative therapies for RSV infections.
The only recommended treatment is supportive.

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. 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. Development of new therapies
1. Immunoglobulins
2. Nucleoside analogues
3. RNA interference
4. Fusion inhibitors

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. 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. 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. 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. 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. 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. 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. 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. © 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. © 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. © 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. 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. Last updated: March 8, 2019

44. Questions and discussion

45. Thank you for joining us!