1. Development of RSV Vaccines
Ann-Muriel Steff, PhD
Head, Preclinical Platform
North America – GSK Vaccines
Vaccine Innovation Conference
Toronto - May 26, 2015

2. Acknowledgments
First of all, I would like to thank the organizers for inviting me to present at this conference. The work I am going to present today on the development of RSV vaccines at GSK has involved several partners that I would also like to thank.
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 2

3. 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
Let me start with a few facts about RSV infections. RSV infections
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 3

4. Outpatients With RSV Infection (%)
Disease burden and severity of disease shifts with age from lower to upper respiratory tract infections
Disease manifestations during primary RSV infection vary widely among individuals, including URI, fever, otitis media, LRI that can vary widely from mild manifestations to life-threatening bronchiolitis and pneumonia, death in rare cases, post infection abnormalities in respiratory function that can persist through adolescence, and possible sensitization to asthma. Numerous host and viral factors have been suggested to be involved in RSV disease, but their roles remain controversial and likely vary in different individuals (Collins and Graham, 2008).
Virtually all children have been at least once infected with RSV by the age of 24 months.
Peak incidence of severe RSV disease occurs in babies aged less than 6 months
Although risk factors exist (prematurity, heart/lung conditions), the majority of babies (~6 out of 10) hospitalised for RSV are healthy
There is significant unmet need in the developing world where RSV can be fatal
Pneumonia or bronchiolitis
Croup
Tracheabronchitis
Otitis media
Upper respiratory tract infection
Lower respiratory tract infections
Upper respiratory tract infections 40 20 60
< 1 year old
1-6 year(s) old
6-19 years old
Outpatients With RSV Infection (%)
Adapted from Paramore et al., Pharmacoeconomics, 2004
Adapted from Hall, NEJM, 2001
Protect healthy infants as early as possible from severe RSV infections
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 4

5. There is no approved vaccine for RSV despite high disease burden and medical need
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
Vaccine
Category
Total No. of infants
FI-RSV lot 100 (N= 31)
RSV infection
20 (65%)
Hospitalized
16 (80%)
Total FI-PIV (N= 40)
21 (53%)
1 (5%)
2 children died: aged 14 and 16 months at time of death, vaccinated at 2 and 5 months of age
Extensive bronchopneumonia
Microscopically, intense inflammation in the lungs
High viral load in the lungs
Adapted from Kim et al., Am.J.Epiemiol., 1969
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 5

6. Two parallel approaches are pursued to address the medical need associated to RSV in infancy
Maternal
Immunization
Infant
Immunization
Weeks Months
Risk for severe RSV disease
Nabs response
in Mother
Nabs passively transferred to neonate
Immune response from active immunization of infant
RSV-primed women
RSV-naïve infants
Candidate
PreF+/-alum
Rec. adenovirus
Stage
Ph2
Ph1
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 6

7. GSK’s RSV Maternal vaccine program

8. Major activities for the early development of GSK’s RSV Maternal vaccine candidate were conducted in Canada
Design of RSV F recombinant antigen
Preclinical testing of RSV PreF antigen
Phase 1 study conduct
Immunological testing of samples from Phase 1 study
Objectives:
To evaluate the safety and reactogenicity of one IM dose of the RSV investigational vaccines as measured by:
Solicited local and general AEs (Days 0–6)
Haematology/biochemistry/anti-HCP
Unsolicited AEs (Days 0–30)
SAEs (up to Day 60)
To evaluate the humoral immunogenicity of one IM dose of the RSV investigational vaccines, up to 60 days post-vaccination, as measured by:
Anti-RSV PreF antibodies
Palivizumab-competing antibodies (PCA)
Neutralizing anti-RSV-A/B antibodies
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 8

9. 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
PREFUSION
POSTFUSION
McLellan et al., Science, 2013 Adapted with permission from The American Association for the Advancement of Science.
PreF antigen was designed to be in pre-fusion conformation
Converging evidence that GSK « PreF » antigen adopts and is stabilized in pre-fusion conformation
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 9

10. Major activities for the early development of GSK’s RSV Maternal vaccine candidate were conducted in Canada
Design of RSV F recombinant antigen
Preclinical testing of RSV PreF antigen
Phase 1 study conduct
Immunological testing of samples from Phase 1 study
Objectives:
To evaluate the safety and reactogenicity of one IM dose of the RSV investigational vaccines as measured by:
Solicited local and general AEs (Days 0–6)
Haematology/biochemistry/anti-HCP
Unsolicited AEs (Days 0–30)
SAEs (up to Day 60)
To evaluate the humoral immunogenicity of one IM dose of the RSV investigational vaccines, up to 60 days post-vaccination, as measured by:
Anti-RSV PreF antibodies
Palivizumab-competing antibodies (PCA)
Neutralizing anti-RSV-A/B antibodies
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 10

11. 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
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015
* Unpublished data 11

12. GSK’s RSV Maternal vaccine candidate – Supportive preclinical evidence has been obtained in several animal models
Efficacy in guinea pig pups after immunization of RSV-primed, vaccinated pregnant guinea pig dams*
Primed
Unprimed
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015
* Unpublished data 12

13. GSK’s RSV Maternal vaccine candidate – Supportive preclinical evidence has been obtained in several animal models
Lack of enhanced pathology after passive transfer of antibodies in cotton rats*
Vaccination
Passive transfer of serum
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015
* Unpublished data 13

14. Major activities for the early development of GSK’s RSV Maternal vaccine candidate were conducted in Canada
Design of RSV F recombinant antigen
Preclinical testing of RSV PreF antigen
Phase 1 study conduct
Immunological testing of samples from Phase 1 study
Objectives:
To evaluate the safety and reactogenicity of one IM dose of the RSV investigational vaccines as measured by:
Solicited local and general AEs (Days 0–6)
Haematology/biochemistry/anti-HCP
Unsolicited AEs (Days 0–30)
SAEs (up to Day 60)
To evaluate the humoral immunogenicity of one IM dose of the RSV investigational vaccines, up to 60 days post-vaccination, as measured by:
Anti-RSV PreF antibodies
Palivizumab-competing antibodies (PCA)
Neutralizing anti-RSV-A/B antibodies
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 14

15. 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
Safety/reactogenicity- incl. 12m FU
Immunogenicity (humoral) – incl. 12m FU
Study groups:
Non-Adj. PreF
10 µg PreF
30 µg PreF
60 µg PreF
PreF+Alum
10 µg PreF
30 µg PreF
60 µg PreF
VACC V1 D0 V2 D7 V3
D30 V4
D60 V6
D360
BS (h/b)
BS (i)
Scr
Pre - V5
D180
Step 1
: 10
PLAIN
1D; 10
ALUM
1D, 30
1D; 30
1D; CONTROL1 1D
Step 2
: 60
1D; 60
1D; CONTROL2
Rando
1:1:1
1:1:1:1:1
Objectives:
To evaluate the safety and reactogenicity of one IM dose of the RSV investigational vaccines as measured by:
Solicited local and general AEs (Days 0–6)
Haematology/biochemistry/anti-HCP
Unsolicited AEs (Days 0–30)
SAEs (up to Day 60)
To evaluate the humoral immunogenicity of one IM dose of the RSV investigational vaccines, up to 60 days post-vaccination, as measured by:
Anti-RSV PreF antibodies
Palivizumab-competing antibodies (PCA)
Neutralizing anti-RSV-A/B antibodies
Placebo (2 gps)
Saline
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 15

16. 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)
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015
Presented in part by Dr. J. the th RSV Symposium, Stellenbosch 16

17. GSK continues the development of an RSV Maternal vaccine candidate
A phase 2 study in women of child-bearing age, evaluating different vaccine formulations, is ongoing (
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
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 17

18. GSK’s RSV Paediatric program

19. A Chimpanzee-derived Adenovector …
GSK’s RSV Paediatric vaccine candidate is based on a Chimpanzee-adenovirus vector
A Chimpanzee-derived Adenovector …
Non-enveloped, double-stranded DNA virus
Replication incompetent through E1 deletion
…coding for an RSV polyAntigen
2A self-cleavage
flexible linker
F0DTM N
M2-1
F protein
Neutralising antibodies
Nucleoprotein
M2.1
T-cell epitopes }
Induction of neutralizing antibodies
Induction of CD8 T cells
Low risk of reproducing vaccine-related RSV disease enhancement
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 19

20. GSK’s RSV Paediatric vaccine candidate Supportive 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)
Calf
Induces high levels of RSV specific Abs & Nabs
Offers protection after challenge (clinical score)
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 20

21. 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*
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015
* Unpublished data 21

22. A vaccine candidate very close to the current GSK RSV Pediatric vaccine candidate was evaluated in Phase 1
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
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 22

23. 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
Ann-Muriel Steff
Vaccine Innovation Conference
Toronto
26 May 2015 23

24. Thank you 24

25. NCT : Study design
N, number of subjects in the total vaccinated cohort; SCR, screening; , blood sampling; , vaccination