Respiratory syncytial virus (RSV) - WHO SAGE meeting 12

Respiratory syncytial virus (RSV)
vaccines
Sid 1. 2016-09-26
Global epidemiology and annual disease
burden estimates for RSV
• RSV most important cause of viral lower respiratory tract disease in
infants and children globally
• Most severe disease in infants <6 months – bronchiolitis but also
large disease burden in the elderly
• Estimated annual disease burden in children <5 years:
– 33.8 million new episodes of RSV
– 3.4 million hospital admissions
– 66,000 to 199,000 (253 000 in 2010) deaths
• Strong association between RSV in infancy and recurrent wheeze
Sid 2. 2016-09-26
Antal rapporterade fall av RSV i Sverige per vecka säsong
2010-2011, samt 2012-2013 till 2015-2016
Totalt 2934 lab verifierade fall av RSV rapporterats under säsongen 2015-2016.
75 IVA-vårdade, flest fall barn 0-6 mån (40 %) och pat över 65 år (20 %).
Sid 3. 2016-09-26
Palivizumab (Synagis)
• Monoklonal antikropp (Mab) riktat mot RSV fusionsprotein (F)
Minskar risken för sjukhusinläggning med ca 50% i högriskgrupper
• Godkändes 1999, profylax mot RSV-infektion hos högriskbarn <2år
• DYRT!
• Restriktiva rekommendationer i Sverige:
– Extrem underburenhet födda före 26 gravveckor och <6 mån
– Bronkopulmonell dysplasi hos barn <12 mån
– Allvarlig hjärtsjukdom hos barn <12 mån
Sid 4. 2016-09-26
Target populations for
RSV vaccines
– Infants <6 months
– highest risk of severe disease
– Infants 6 months and older
– prevent disease and decrease transmission to infants and elderly
– Pregnant women
– protect newborns by placental antibody transfer
– Elderly
- risk of severe disease
– Other risk groups:
– premature infants, the immunocompromised, those with congenital
heart/lung disease
Sid 5. 2016-09-26
Feasibility for vaccine development
• Primary RSV infection occurs in most infants within 2 years of age
with almost all children infected by 3 years of age.
• Infections recur throughout life. Natural immunity increases
and disease become less severe - young children and adults mild
upper respiratory infection.
• Older adults risk of severe RSV disease – could be attributed to
underlying diseases and/or immunosenescence
• RSV-specific NT ab protects against disease in animal models,
Prophylactic Mab reduce incidence of severe disease in children
• Reduced incidence of RSV disease during first months of life
correlates with higher concentrations of RSV-spec maternal ab
Sid 6. 2016-09-26
Vaccine-enhanced RSV disease in the 1960s
• Ökad risk för svår sjukdom
(ERD) i vaccingrp efterföljande RSV säsong: 80%
vs 5% kontroller, 2 barn
dog. Bara ERD hos RSVnaiva barn, ej äldre barn
• Data tydde på en vaccinprimad Th2-associerad
immunpatologi.
• ERD setts i flera djurmodeller
• Konsekvens: bara levande
attenuerade RSV vaccin
testade på spädbarn. Inga
fynd av ERD
Sid 7. 2016-09-26
RSV vaccine and immunization pipeline
• 60 RSV vaccine candidates in development, 16 are in clinical
trials.
• 3 main classes of products:
– subunit vaccines mainly in development for maternal immunization
and elderly
– live attenuated or recombinant viral vector vaccines for paediatric
vaccination
– long-acting monoclonal antibodies (mAb) targeted for seasonal or
birth dosing using a one-dose regimen.
Sid 8. 2016-09-26
Sid 9. 2016-09-26
Sid 10. 2016-09-26
Results in seniors - Resolve trial
Novavax nanoparticle RSV-F candidate vaccine
• Phase 3 RCT study including 11 856 adults >60 years USA
• Endpoints:
– efficacy against moderate-to-severe RSV LRTD: -7.9%
– efficacy against all respiratory symptoms related to RSV: 12.6%
• Both endpoints failed!
• Why? Mild season, unexpected low attack rate. Immunogenicity
still to be analyzed.
• In a phase 2 rollover study with RSV vaccination of 1600 elderly
first and second season, vaccine efficacy was 44% and 75% resp.
Sid 11. 2016-09-26
Passive immunization using mAbs
• Palivizumab off patent 2015.
• WHO and University of Utrecht plan to develop a `biosimilar´ of
palivizumab and reduce costs. MA expected end 2017.
• Medimmune develops a long-acting mAb (MED18897)
– targets site on prefusion F, and neutralizes all RSV A and B isolates tested
– single fixed IM dose expected to protect up to 6 months
– given at birth or start of RSV season
– Phase Ia completed.
Sid 12. 2016-09-26
WHO activities
• March 2015 WHO meeting to clarify pathways towards policy
recommendations and financing of RSV vaccines and long-acting mAbs.
• RSV surveillance - a pilot component to the WHO Global Influenza
Surveillance and Response System to understand RSV disease burden,
seasonality and strain selection. Sentinel surveillance sites to provide
incidence estimates including denominators.
• A work plan and timeline for development of RSV international standard
reagents will be presented to the ECBS in 2016. Priority NT assays.
• WHO-SAGE, emphasize the need to link maternal immunization
platform strengthening with other vaccines and that the generation
of cost-effectiveness and impact data was a priority.
• SAGE suggests mobilizing resources to follow up subjects from RCT to
evaluate the long term effects of RSV interventions in the context of
uncertainties on whether RSV infection causes recurrent wheeze.
Sid
.
Tack för
uppmärksamheten!