Development Update on RSV Vaccine - Fernando P. Polack, MD Fundacion INFANT

Update on RSV Vaccine
    Development
     Fernando P. Polack, MD
       Fundacion INFANT

Topics for review

 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

                                                                              2

RSV Epidemiology

New Global Burden Estimates

RSV Global Epi Network (RSV
           GEN)
         Second meeting -
         First meeting -
         Jun 2015
         Nov 2013

      71 sites (76 unpublished   4

Location of incidence and hospital
           mortality studies (n=157)

Funded by Bill & Melinda Gates Foundation   5

15)
 RSV Global Burden Estimates (2005)

     30.5
       33.8(95%
            (95%CI,
                 CI,19.5-47.9)
                     193-46.2) million episodes of RSV LRI annually in children < 5
       years (22% of all ALRI episodes)

        3.4 million episodes requiring hospitalization
         2.8

     95,000-149,000
       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

                                                                                6
Lancet, in press

RSV Epidemiology

Hospital-based mortality

Byinghton CL et al. Pediatrics 2015

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

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

DOES THE AGE DISTRIUBTION OF DEATHS
IN THE COMMUNITY RESEMBLE RSV DEATHS OR HOSPITALIZATIONS?

                                          Hospitalizations

                                          Community deaths

                            19

Community deaths (May-August 2016)
                            15
                                                                     RSV
percentage from the total

                                                                     RV
                            10                                       H1N1
                                                                     MPV
                                                                     PIV 3
                            5

                            0

                                                                st
                                         ne
                                  ay

                                                        ly
                                                      Ju

                                                               gu
                                 M

                                       Ju

                                              2016           Au

                                                     20

RSV was detected in 22% of all-cause home fatalities during
                the respiratory season.

                                40
        number of nasal swabs

                                30
                                              17/37
                                20            (46%)
                                                          8/17
                                                         (47%)
                                10

                                0
                                     Total   Positives   RSV

                                             21

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

Medimmune – preF mAb
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.

                                                                       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

           1http://www.uu.nl/en/news/first-consortium-of-local-manufacturers-to-make-affordable-biosimilars-available-for-low-income
                                                                                                                             38

RSV vaccines and monoclonal
         antibodies

         Infant vaccines

Janssen RSV junior Vaccine: Ad26.RSV.preF
          Vector                               Antigen                         Administration

   Replication-incompetent       RSV fusion protein from the RSV A2         Begin immunization
    human type 26                  strain                                      at 2 month of age
    adenovirus
                                  Ad26.RSV.FA2: prototype vaccine            IM, 2 to 3-doses
   Elicits Th1 response           expressing native F protein
                                                                              Co-administered
   Expected to be similar        Ad26.RSV.preF: lead vaccine                 with other childhood
    to natural infection and       candidate expressing optimized              vaccines
    live attenuated vaccines       prefusion stabilized F protein
    which do not predispose
    to ERD in humans              FA2 and preF protein sequences differ
                                   by only 5 amino acids

                                                                                                  41

Janssen RSV Vaccine Phase 1 studies in
             adult and elderly subjects
                     Prototype Ad26.RSV.FA2 in adults

Safety                                    Immunogenicity

   Ad26.RSV.FA2 was shown to be safe        Ad26.RSV.FA2 increased humoral
    and well tolerated (59 subjects)          and cellular immunity that was
                                              durable for 6 months.
   No serious adverse events, no
    adverse events that led to               Ad26.RSV.FA2 enhanced the Th1-
    withdrawal from study vaccine             type responses with no increase in
                                              Th2-type responses (CD4 ICS)

                          Ad26.RSV.preF in elderly

•   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                                                       42

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

RSV Vaccines for the Elderly

 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
                                                 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)