Development of RSV Vaccines AnnMuriel Steff Ph D

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

Acknowledgments 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 RSVassociated 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 Ann-Muriel Steff Vaccine Innovation Conference Toronto 26 May 2015 3

Disease burden and severity of disease shifts with age from lower to upper respiratory tract infections Outpatients With RSV Infection (%) Pneumonia or bronchiolitis Croup Tracheabronchitis Otitis media Upper respiratory tract infection Lower respiratory tract infections Upper respiratory tract infections 60 40 20 0 < 1 year old 1 -6 year(s) old 6 -19 years old 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 Category Vaccine FI-RSV lot 100 (N= 31) Total FI-PIV (N= 40) Total No. of infants RSV infection 20 (65%) Hospitalized 16 (80%) RSV infection 21 (53%) Hospitalized 1 (5%) Adapted from Kim et al. , Am. J. Epiemiol. , 1969 – Alternative ways of immunization are therefore being considered 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 Infant Immunization Maternal 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 Pre. F+/-alum Rec. adenovirus Stage Ph 2 Ph 1 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 Ann-Muriel Steff Vaccine Innovation Conference Toronto 26 May 2015 Preclinical testing of RSV Pre. F antigen Phase 1 study conduct Immunological testing of samples from Phase 1 study 8

GSK’s RSV Maternal vaccine candidate is based on GSK’s proprietary RSV F recombinant antigen – Recent data have shown that Pre. F form is the main target of neutralizing antibodies present in serum of infected individuals PREFUSION POSTFUSION Mc. Lellan et al. , Science, 2013 Adapted with permission from The American Association for the Advancement of Science. – Pre. F antigen was designed to be in pre-fusion conformation – Converging evidence that GSK « Pre. F » 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 Ann-Muriel Steff Vaccine Innovation Conference Toronto 26 May 2015 Preclinical testing of RSV Pre. F antigen Phase 1 study conduct Immunological testing of samples from Phase 1 study 10

GSK’s RSV Maternal vaccine candidate – Supportive preclinical evidence has been obtained in several animal models Ø Immunogenicity in experimentally RSV-primed mice, cotton rats & guinea pigs* Ø Immunogenicity in cows mostly naturally primed by b. RSV* Mice Ann-Muriel Steff Vaccine Innovation Conference Toronto 26 May 2015 Cows * Unpublished data 11

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

GSK’s RSV Maternal vaccine candidate – Supportive preclinical evidence has been obtained in several animal models Ø Lack of enhanced pathology after passive transfer of antibodies in cotton rats* Vaccination Ann-Muriel Steff Vaccine Innovation Conference Toronto 26 May 2015 Passive transfer of serum * 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 Ann-Muriel Steff Vaccine Innovation Conference Toronto 26 May 2015 Preclinical testing of RSV Pre. F antigen Phase 1 study conduct Immunological testing of samples from Phase 1 study 14

GSK’s RSV Maternal vaccine candidate was evaluated in Phase 1 Study groups: 1. Safety/reactogenicity- incl. 12 m FU 2. Immunogenicity (humoral) – incl. 12 m FU Non-Adj. Pre. F – Canada 10 µg Pre. F – Schedule: 1 dose 30 µg Pre. F – N = 128 60 µg Pre. F – Men aged 18 -44 y (16/group) – 2 step staggered design with safety review by i. SRC Pre. F+Alum Scr Pre -D 0 BS (h/b) 10 µg Pre. F Rando 1: 1: 1 Step 1 : 10 -PLAIN -1 D; 10 -ALUM -1 D, 30 -PLAIN -1 D; 30 -ALUM -1 D; CONTROL 1 -1 D Rando 1: 1: 1 Step 2 : 60 -PLAIN -1 D; 60 -ALUM -1 D; CONTROL 2 -1 D 30 µg Pre. F 60 µg Pre. F V 1 D 0 V 2 D 7 V 3 D 30 V 4 D 60 V 5 D 180 V 6 D 360 BS (h/b) BS (i) BS (h/b) BS (i) VACC Ann-Muriel Steff Vaccine Innovation Conference Toronto 26 May 2015 Placebo (2 gps) Saline http: //www. clinicaltrials. gov/ct 2/show/study/NCT 01905215 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 RSV A Neutra (GMT & 95% CI) PCA (GMC & 95% CI) – Highest immunogenicity observed with 30 -ALUM, 60 -PLAIN & 60 -ALUM Ann-Muriel Steff Vaccine Innovation Conference Toronto 26 May 2015 Presented in part by Dr. J. Langley @ the 2014 9 th 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/ct 2/show/study/NCT 02360475) • 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

GSK’s RSV Paediatric vaccine candidate is based on a Chimpanzee-adenovirus vector Non-enveloped, double-stranded DNA virus A Chimpanzee-derived Adenovector … Replication incompetent through E 1 deletion …coding for an RSV poly. Antigen 2 A self-cleavage F 0 DTM F protein Nucleoprotein M 2. 1 flexible linker N } M 2 -1 Neutralising antibodies T-cell epitopes Induction of neutralizing antibodies Induction of CD 8 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 Induce low levels of Nabs Induces RSV-specific CD 4+ & CD 8+ T cells with an overall Th 1 profile Mice Reduces virus in the lung after challenge No signs of vaccine related disease enhancement (mucus production & eosinophil infiltration similar to live RSV) Induces moderate to high levels of Nabs Reduces virus in the nose after challenge (partial protection after IM, complete Cotton rat 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 b. RSV challenge of RSV-naïve calves immunized with two doses of recombinant adenovirus expressing RSV F, N & M 2. 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 Ph 1 data – Epidemiological study ongoing in 9 countries to help defining a “global” casedefinition Ann-Muriel Steff Vaccine Innovation Conference Toronto 26 May 2015 23

Thank you 24

NCT 01905215: Study design N, number of subjects in the total vaccinated cohort; SCR, screening; , blood sampling; , vaccination