Fernando P. Polack, MD

Fundacion INFANT

Update on RSV Vaccine

Development

RSV Epidemiology • New morbidity and mortality estimates from GEN

• Mortality at the hospital in industrialized and developing countries

• Mortality in the community

• Recurrent wheezing and asthma

RSV vaccines and monoclonal antibodies • Maternal immunization to protect infants

• Monoclonal antibodies for infants

• Pediatric vaccines

• Vaccines for the elderly

Other considerations • Standardization of neutralizing antibody assays

• Considerations about enhanced RSV disease

• PPC and Roadmap documents

Topics for review

2

RSV Epidemiology

New Global Burden Estimates

First meeting - Nov 2013

4 71 sites (76 unpublished studies)

Second meeting - Jun 2015

RSV Global Epi Network (RSV

GEN)

Location of incidence and hospital

mortality studies (n=157)

5 Funded by Bill & Melinda Gates Foundation

33.8 (95% CI, 193-46.2) million episodes of RSV LRI annually in children < 5

years (22% of all ALRI episodes)

3.4 million episodes requiring hospitalization

66,000-199,000 deaths in 2005, 99% in developing countries

Updated estimates for RSV ALRI, severe ALRI (community based and

hospitalized) and deaths in press by the RSV Global Epidemiology Network

(RSV-GEN) . Publication expected this year

RSV Global Burden Estimates (2005)

6 Lancet, in press

30.5 (95% CI, 19.5-47.9)

2.8

15)

95,000-149,000

RSV Epidemiology

Hospital-based mortality

Byinghton CL et al. Pediatrics 2015

Geogeghan S et al, AJRCCM 17 Funded by Bill & Melinda Gates Foundation

Geogeghan S et al, AJRCCM 17

Geogeghan S et al, AJRCCM 17

Geogeghan S et al, AJRCCM 17

Geogeghan S et al, AJRCCM 17

Geogeghan S et al, AJRCCM 17

Mortality at the hospitals

• RSV is the most frequent viral pathogen

associated with post-neonatal infant mortality.

• The virus was detected in 16% of all-cause

hospital deaths; 57% of LRTI deaths where tests

were performed.

• Its CFR was lower than that of non-RSV LRTI

cases. Its importance relied on its dominating

role as an agent of severe LRTI (65%), rather

than on its specific lethality.

Geogeghan S et al, AJRCCM 17

Mortality at the hospitals

• In contrast to industrialized countries, RSV killed term, previously “healthy” infants.

• Deaths had a strong association with bacterial sepsis (GPC) and pneumothoraxes.

• The role of co-morbidities, young age, and other factors was less ostensible.

RSV Epidemiology

Mortality in the community

Community deaths in infants

Funded by Bill & Melinda Gates Foundation

19

DOES THE AGE DISTRIUBTION OF DEATHS

IN THE COMMUNITY RESEMBLE RSV DEATHS OR HOSPITALIZATIONS?

Hospitalizations

Community deaths

20

Community deaths (May-August 2016)

May

June Ju

ly

Aug

ust

0

5

10

15RSV

RV

H1N1

MPV

PIV 3

2016

perc

enta

ge f

rom

the tota

l

21

0

10

20

30

40

17/37(46%)

8/17(47%)

Total Positives RSV

num

ber

of

nasal sw

abs

RSV was detected in 22% of all-cause home fatalities during

the respiratory season.

RSV mortality

• Is a significant problem, particularly due to the overwhelming dominance of RSV as an agent of LRTI in the winter.

• Needs, at least, a second factor: in industrialized countries: co-morbidities. in developing countries -at hospitals: suboptimal medical care (pneumothoraxes) and secondary bacterial infections (and those factors predisposing to them). -in the community: social, cultural, infectious and/or logistical factors affecting access to health care.

Zanone S. Lancet Resp Med 2016

RSV Epidemiology

Recurrent wheezing and asthma

Blanken MO et al. NEJM 2013

Palivizumab and recurrent wheezing

• 444 late preterm infants until age 6 years

(349 vs 95).

• Recurrent wheezing: 15.3% vs. 31.6%

(p=0.003)

• Physician diagnosed asthma: 15.3% vs.

18.2% *Asthma defined as RW+ high IgE and/or family history of allergy

Mochizuki H et al. AJRCCM 2017

Other interesting topics

• Replacement and competition (Hartert TV. J Infect Dis

2017)

• Subgroups of healthy infants with increased

susceptibility for severe LRTI (Caballero MT. J Clin

Invest 2015)

RSV LRTI Prevention

RSV vaccines and monoclonal

antibodies

Maternal immunization to protect infants

Novavax– post-F nanoparicles (alum)

• RCT, placebo-controlled, group sequential: pregnant women 28-36 weeks of pregnancy to prevent symptomatic RSV-associated LRTI with hypoxemia for 90 days in infants

• Follow up: mothers until 6 months post-delivery, infants follow

up for 12 months.

• Minimum of 4,600 women. Entering Y3.

• US, Mexico, Argentina, Chile, New Zeland, Australia, South Africa, Spain, UK, Philippines.

• First interim analysis for efficacy in Q1/Q2 2018.

Glaxo Smith Kline – preF antigen

• Active immunization of pregnant women during the 3rd trimester of pregnancy to prevent RSV-associated LRTI in infants

• Single dose to boost pre-existing immune response

• Immunization in the third trimester

• Recombinant subunit PreF antigen

• First study in pregnant women will be launched this year – Phase III planned for 2019.

RSV vaccines and monoclonal

antibodies

Monoclonal antibodies

Characteristics • MEDI8897: Passive RSV vaccine strategy using RSV F mAb

• Fully human, high potency IgG1 mAb derived from human B-cells

• YTE half-life extension technology

• Targets site on RSV prefusion F

• Neutralizes all RSV A and B clinical isolates tested

• Single fixed IM dose given; expected to protect up to 6 months

• Given at birth or at onset of RSV season

Program Status • Phase 1a adult FTIH complete (N=136)

• Phase 1b/2a in 32-35 week gestational age infants (N=89); complete.

• Phase 2b clinical efficacy in 29-35 week gestational age infants planned

for 2016 (N=1,500)

• FDA fast track designation granted, study endpoints agreed with EMA-

PDCO, FDA.

Medimmune – preF mAb

36

Regeneron

• Extended half life mAb against RSV preF.

• Completed phase III RCT in premature infants –

data analysis in progress (coming months).

• Planning phase III efficacy RCT in full term

infants.

Biosimilar palivizumab (post-F) – WHO

and University of Utrecht

• Palivizumab off patent in 2015

• Plan to develop a ‘biosimilar’ of palivizumab and reduce costs through

– Using latest technologies (i.e. high expression cell line)

– A novel development and financing plan1

• Coordinated by the Utrecht Center of Excellence for Affordable Biotherapeutics for Public Health

• Funded through a consortium of manufacturers – Agreement signed on 9 March 2016

– Estimated price $US 250 per child for full 5 courses

– First market authorization expected end 2017

– Roll out the product in LMICs

38

1http://www.uu.nl/en/news/first-consortium-of-local-manufacturers-to-make-affordable-biosimilars-available-for-low-income

RSV vaccines and monoclonal

antibodies

Infant vaccines

Janssen RSV junior Vaccine: Ad26.RSV.preF

Vector

Replication-incompetent human type 26 adenovirus

Elicits Th1 response

Expected to be similar to natural infection and live attenuated vaccines which do not predispose to ERD in humans

Administration

Begin immunization at 2 month of age

IM, 2 to 3-doses

Co-administered with other childhood vaccines

Antigen

RSV fusion protein from the RSV A2 strain

Ad26.RSV.FA2: prototype vaccine expressing native F protein

Ad26.RSV.preF: lead vaccine candidate expressing optimized prefusion stabilized F protein

FA2 and preF protein sequences differ by only 5 amino acids

41

Janssen RSV Vaccine Phase 1 studies in adult and elderly subjects

42

Safety

Ad26.RSV.FA2 was shown to be safe

and well tolerated (59 subjects)

No serious adverse events, no

adverse events that led to

withdrawal from study vaccine

Prototype Ad26.RSV.FA2 in adults

Ad26.RSV.preF in elderly

Immunogenicity

Ad26.RSV.FA2 increased humoral

and cellular immunity that was

durable for 6 months.

Ad26.RSV.FA2 enhanced the Th1-

type responses with no increase in

Th2-type responses (CD4 ICS)

• Study ongoing in 72 older adults, > 60 years of age

• Preliminary data suggest favorable safety profile

• Ad26.RSV.preF showed better immunogenicity compared to Ad26.RSV.FA2 in pre-clinical models

Glaxo Smith Kline Pediatric Program

• Active immunization of infants for the prevention of RSV-

associated LRTI

• Two-dose regimen from 6 wks onwards (min 1 year

protection)

• Co-administration with routine paediatric vaccines

• Chimpanzee Adenovirus (ChAd155) encoding three

RSV antigens (F, N and M2.1)

• Phase I: complete in adults. Toddlers 12-24 months

ongoing.

Bavarian Nordic - MVA

• Based on the MVA-BN vector approved in EU& Canada, encoding FA, GA+GB, N and M2

• Phase I (63 healthy subjects) – no unexpected adverse reactions, immunogenic (boosted humoral responses durable for 6 months and T cell responses).

• Phase II: enrolled 421 subjects ≥55 years old (identify optimal dose).

• Optimal group(s) carried forward into 2017 RSV season

with a booster dose

Sanofi- NIAID

• The program continues to characterize live attenuated RSV vaccines based on two families of attenuating mutations: one with deletion of the M2-2 gene, and one with deletion of the interferon antagonist NS2. These candidates have been evaluated singly and shown promising results (see NCT01893554, and NCT03102034)

• Head-to-head studies of lead candidates using the 2 approaches expected in the near future

RSV vaccines and monoclonal

antibodies

Elderly vaccines

Novavax (NCT02608502)

RSV postfusion F 135 mcg

Endpoints: 10 mod-severe RSV-LRTD*, 20 RSV-LRTD, any RSV- ARD

MedImmune/Astra Zeneca (NCT02508194)

RSV soluble postfusion F with GLA (TLR4 agonist)

Endpoint: any acute RSV respiratory illness

RSV Vaccines for the Elderly

47 .

Other important considerations

• Harmonizing neutralization assays (WHO/ NIBSC/PATH) – there are currently ~10 PRNT assays (cell lines-virus-methods). Provide standards.

• Pediatric vaccines and risk for ERD (VRBPAC, FDA in May 2017).

• 2017 Roadmap and PPC for RSV Vaccines (WHO) available.

WHO strategic vision for RSV vaccines

Acknowledgements

• Ruth Karron (Johns Hopkins University)

• Harish Nair (University of Edimburgh)

• Greg Glenn (Novavax)

• Ilse Dieussaert (GSK)

• Myra Widjojoatmodjo (Janssen)

• Eduardo Forleo Neto (Regeneron)

• Fernando Maellas (mAbxience)

• Nathalie Samy (Bavarian Nordic)

• Johan Vekemans (WHO)