development of rsv vaccines ann-muriel steff, phd head, preclinical platform north america – gsk...

Development of RSV Vaccines

Ann-Muriel Steff, PhDHead, Preclinical PlatformNorth America – GSK Vaccines

Vaccine Innovation Conference Toronto - May 26, 2015

Acknowledgments

Ann-Muriel SteffVaccine Innovation ConferenceToronto

26 May 20152

http://www.centerforvaccinology.ca/

http://www.google.be/url?url=http://www.conffidence.eu/participants/cer/&rct=j&frm=1&q=&esrc=s&sa=U&ei=lOK7VJ73LoTYauD0gJgK&ved=0CBcQ9QEwAQ&usg=AFQjCNEcBpPTgBQ6vedZaOmErr-5OV4K-w

http://www.path.org/

Respiratory Syncytial Virus is the leading cause of hospitalization in infants < 1 year

– RSV is a seasonal virus causing upper respiratory tract infections, which in 25-40% of young children progress to the lower respiratory tract

– In industrialized countries:– Approximately 2% of children <1 year of age are hospitalized for RSV-

associated LRTIs each year (e.g., > 100,000 hospitalizations/year in the US)

– Worldwide, it is estimated that:– 3.4 million young children developed RSV-associated severe respiratory

infection necessitating hospital admission

– 66,000–199,000 children younger than 5 years die from RSV-associated respiratory infections

– 99% of these deaths occur in developing countries

– Re-infections occur throughout life but with less severe symptoms

3Ann-Muriel SteffVaccine Innovation ConferenceToronto

26 May 2015

Disease burden and severity of disease shifts with age from lower to upper respiratory tract infections

40

20

0

60

< 1 year old 1-6 year(s) old 6-19 years old

Ou

tpat

ien

ts W

ith

RS

V In

fect

ion

(%

)

Pneumonia or bronchiolitisCroupTracheabronchitisOtitis mediaUpper respiratory tract infection

Lower respiratory tract infections

Upper respiratory tract infections

Protect healthy infants as early as possible from severe RSV infections


26 May 20154

Adapted from Paramore et al., Pharmacoeconomics, 2004Adapted from Hall, NEJM, 2001

– One prophylactic treatment available for high-risk infants only (premature, chronic lung disease, congestive heart failure) Palivizumab

– Humanized monoclonal antibody targeting the RSV F surface glycoprotein

– Given intramuscularly every month for 5 months during RSV season

– Demonstrated efficacy (reduce RSV hospitalizations by 45-55% in at-risk children)

– Treatments for symptomatic RSV infection are limited to supportive care

– No vaccines are available despite 50+ years of research !

– Unfortunate experience with a pediatric formalin-inactivated vaccine in the 1960’s

– Alternative ways of immunization are therefore being considered

There is no approved vaccine for RSV despite high disease burden and medical need


26 May 20155

Vaccine Category Total No. of infants

FI-RSV lot 100 (N= 31) RSV infection 20 (65%)

Hospitalized 16 (80%)

Total FI-PIV (N= 40) RSV infection 21 (53%)

Hospitalized 1 (5%)Adapted from Kim et al., Am.J.Epiemiol., 1969

Two parallel approaches are pursued to address the medical need associated to RSV in infancy

28 30 32 34 36 38 40 0 1 2 4 6 8 10 12 Weeks Months

MaternalImmunization

InfantImmunization

Nabs response in Mother

Immune response from active immunization of infant

Nabs passivelytransferred to neonate

Risk for severe RSV disease

RSV-primed women RSV-naïve infants

Candidate PreF+/-alum Rec. adenovirus

Stage Ph2 Ph1


26 May 20156

GSK’s RSV Maternal vaccine program

Major activities for the early development of GSK’s RSV Maternal vaccine candidate were conducted in Canada


26 May 20158

Design of RSV F recombinant

antigen

Preclinical testing of RSV PreF antigen

Phase 1 study conduct

Immunological testing of

samples from Phase 1 study

GSK’s RSV Maternal vaccine candidate is based on GSK’s proprietary RSV F recombinant antigen

– Recent data have shown that PreF form is the main target of neutralizing antibodies present in serum of infected individuals


26 May 20159

– PreF antigen was designed to be in pre-fusion conformation

– Converging evidence that GSK « PreF » antigen adopts and is stabilized in pre-fusion conformation

PREFUSION POSTFUSION

McLellan et al., Science, 2013Adapted with permission from The American Association for the Advancement of Science.



26 May 201510


antigen





GSK’s RSV Maternal vaccine candidate – Supportive preclinical evidence has been obtained in several animal models

Immunogenicity in experimentally RSV-primed mice, cotton rats & guinea pigs*

Immunogenicity in cows mostly naturally primed by bRSV*

Mice Cows


26 May 201511

* Unpublished data


Efficacy in guinea pig pups after immunization of RSV-primed, vaccinated pregnant guinea pig dams*

Primed Unprimed


26 May 201512

* Unpublished data


Lack of enhanced pathology after passive transfer of antibodies in cotton rats*

Vaccination Passive transfer of serum


26 May 201513

* Unpublished data



26 May 201514


antigen





GSK’s RSV Maternal vaccine candidate was evaluated in Phase 1

– Canada

– Schedule: 1 dose

– N = 128

– Men aged 18-44y (16/group)

– 2 step staggered design with safety review by iSRC

1. Safety/reactogenicity- incl. 12m FU2. Immunogenicity (humoral) – incl. 12m FU

Study groups:

VACC

V1D0

V2D7

V3D30

V4D60

V6D360

BS (h/b) BS (h/b)BS (i)

ScrPre-D0

V5D180

BS (h/b)

Step 1 : 10- PLAIN- 1D; 10 - ALUM- 1D, 30- PLAIN- 1D; 30- ALUM- 1D; CONTROL1 - 1D

Step 2 : 60 - PLAIN - 1D; 60 - ALUM - 1D; CONTROL2 -1DRando1:1:1

Rando1:1:1:1:1

BS (h/b)BS (i)

BS (h/b)BS (i)

BS (h/b)BS (i)

BS (h/b)BS (i)

PreF+Alum

10 µg PreF

30 µg PreF

60 µg PreF

Non-Adj. PreF

10 µg PreF

30 µg PreF

60 µg PreF

Placebo (2 gps)

Saline

http://www.clinicaltrials.gov/ct2/show/study/NCT01905215Ann-Muriel SteffVaccine Innovation ConferenceToronto

26 May 201515

GSK’s RSV Maternal vaccine candidate is well tolerated and immunogenic – Phase 1 study results

– All vaccine formulations were well tolerated

– All vaccine formulations were immunogenic and able to boost pre-existing immunity

– Highest immunogenicity observed with 30-ALUM, 60-PLAIN & 60-ALUM

RSV A Neutra (GMT & 95% CI) PCA (GMC & 95% CI)

Presented in part by Dr. J. Langley @ the 2014 9 th RSV Symposium, Stellenbosch


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GSK continues the development of an RSV Maternal vaccine candidate


26 May 201517

– A phase 2 study in women of child-bearing age, evaluating different vaccine formulations, is ongoing (http://www.clinicaltrials.gov/ct2/show/study/NCT02360475)

• Alum-adjuvanted vs non-adjuvanted formulations

• Antigen dose-range

– Development of final production process and scaling-up

– Reproductive toxicology studies before first trial in pregnant women

GSK’s RSV Paediatric program

GSK’s RSV Paediatric vaccine candidate is based on a Chimpanzee-adenovirus vector


26 May 201519

A Chimpanzee-derived

Adenovector …

2A self-cleavage flexible linker

F0DTM N M2-1

…coding for an RSV polyAntigen

F protein Neutralising antibodiesNucleoproteinM2.1 T-cell epitopes}

Non-enveloped, double-stranded DNA virus

Replication incompetent through E1 deletion

Induction of neutralizing antibodies Induction of CD8 T cells Low risk of reproducing vaccine-related RSV disease enhancement

GSK’s RSV Paediatric vaccine candidateSupportive preclinical evidence in several animal model

Species Observations

Mice

Induce low levels of Nabs

Induces RSV-specific CD4+ & CD8+ T cells with an overall Th1 profile

Reduces virus in the lung after challenge

No signs of vaccine related disease enhancement (mucus production & eosinophil infiltration similar to live RSV)

Cotton rat

Induces moderate to high levels of Nabs

Reduces virus in the nose after challenge (partial protection after IM, complete protection after IN vaccination)

Reduces virus in the lung after challenge (complete protection)

No sign of disease enhancement (similar to live RSV)

CalfInduces high levels of RSV specific Abs & Nabs

Offers protection after challenge (clinical score)


26 May 201520

GSK’s RSV Paediatric vaccine candidate protects young calves from bovine RSV infection

– Protection after bRSV challenge of RSV-naïve calves immunized with two doses of recombinant adenovirus expressing RSV F, N & M2.1 antigens administered intramuscularly*


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* Unpublished data

A vaccine candidate very close to the current GSKRSV Pediatric vaccine candidate was evaluated in Phase 1


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– A phase 1 trial of limited size was conducted with Chimpanzee adenovector encoding same RSV polyantigen:• Well tolerated

• Induced B-cell & RSV neutralizing antibody responses

• Note that Phase 1 population (RSV-primed adults) differ from target population(RSV-naïve infants) making immunogenicity little representative

– New Phase 1 study with larger sample size & new vaccine adenoviral backbone starting in 2015

– Finalization of the preclinical package supporting studies in RSV-seronegative children

GSK RSV vaccine programs – Concluding remarks

– Main focus on the disease burden caused by RSV in infants & young children:

• Maternal: first 6 months of life

• Paediatric: first 2 years of life

Two parallel approaches, both at an early development stage with supportive Ph1 data

– Epidemiological study ongoing in 9 countries to help defining a “global” case-definition


26 May 201523

Thank you

24

NCT01905215: Study design

N, number of subjects in the total vaccinated cohort; SCR, screening; , blood sampling; , vaccination

development of rsv vaccines ann-muriel steff, phd head, preclinical platform north america – gsk...

Documents

year rsv

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rsv infection20

rsv infection21

rsv hospitalizations

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