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

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

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

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

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

Two parallel approaches are pursued to address the medical need associated to RSV in infancy Maternal Immunization Infant Immunization 28 30 32 34 36 38 40 0 1 2 4 6 8 10 12 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

GSK’s RSV Maternal vaccine program

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

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

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

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

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

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

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

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 http://www.clinicaltrials.gov/ct2/show/study/NCT01905215 15

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. Langley @ the 2014 9th RSV Symposium, Stellenbosch 16

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 (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 Ann-Muriel Steff Vaccine Innovation Conference Toronto 26 May 2015 17

GSK’s RSV Paediatric program

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

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

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

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

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

Thank you 24

NCT01905215: Study design N, number of subjects in the total vaccinated cohort; SCR, screening; , blood sampling; , vaccination