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1 Japanese Encephalitis Vaccine Dr Monjori Mitra Associate Professor Institute of Child Health Kolkata

2 Issues to Consider Epidemiological status Currently Available Vaccines New Vaccination Modalities The Clinical Trial Currently Underway

3 Japanese Encephalitis Virus History Minor epidemics of “ summer encephalitis in Japan since at least 1870; large outbreak in 1924 causes 6,125 cases with 3,797 deaths Initially called Japanese type B encephalitis to differentiate from epidemic encephalitis lethargica, type A encephalitis Virus first isolated from the brain of a fatal case in 1935 Isolated from Culex tritaeneorhinchus in 1938 Now known to be the principal mosquito vector in most of the geographic distribution of the disease

4 Epidemiology Primarily a disease of rural Asia – Vector mosquitoes proliferate in close association with birds and pigs – Birds and pigs are the major amplifying hosts – Many other mammals and reptiles infected as well, long term viremia documented in bats, others Culex tritaeniorhynchus the principal vector but many other mosquitoes are competent and can transmit – C. pipiens – C. quinquefasciatus – Species of Aedes, Anopheles Virus overwinters in mosquitoes as well as vertical transmission Traditional seasonal spread (spring/summer) heavily impacted by rice paddy flooding

5 Photo by George Risi Cattle May Serve to Modulate JE Activity

6 Incidence and Prevalence Commonest cause of encephalitis in Asia In hyperendemic areas half of all cases occur in children under 4 years of age, nearly all before age 10 Nearly 100% seroprevalence by adulthood in heavily infected areas Epidemic and endemic forms 20,000 cases and 6,000 deaths annually a gross underestimate Mathematical modeling predicts 175,000 annual cases, 43,750 fatalities, 78,750 with disability

7 Incidence and Prevalence Ratio of apparent to inapparent infection ranges from 1:250 in susceptible Asians to 1:63 in adult US marines, 1:18 in Torres strait outbreak Ratio affected by age, virulence of the strain of virus, cross protective immunity from other flaviviruses (dengue) Risk to travelers 1 case per 50,000 months of exposure

8 Epidemiology Geographic range expanding; new areas infected by – Viremic migratory birds- Guam, Saipan – Windblown mosquitoes- Torres strait of Australia

9 Epidemiology July 2005 an outbreak began in northern India and Nepal; by November 10, 2005 Uttar Pradesh and Bihar had 6097 cases, 1400 deaths (23% mortality) Outbreaks clearly related to difficulties and expense of currently available vaccine Uttar Pradesh Bihar


11 Epidemiology Dr. Goetz Reiner 11  Japanese Encephalitis Virus is transmitted to Humans by the bite of infected Mosquito species.  Different mosquitos genera and species of mosquito serve as intermediate host and transmit JE virus. Anopheles species: - hyrcanus, subpictus Culex species: - tritaeniorhynchus, vishnui Mansonia species:-annulifera, indiana  Pigs & birds are primary reservoirs wherein the virus is maintained & amplified  30- 50,000 overt JE cases and 10,000 deaths reported annually worldwide (likely underreported).  30% of survivors suffer from lasting damage to central nervous system  In India JE has shown increasing trend in occurrence and expansion of disease to non- endemic areas in India  In JEV endemic areas, JE is primarily a pediatric disease

12 12 Military deployed to endemic areas Expatriates in rural areas Travelers Key risk groups Residents of rural areas in endemic locations JEVirus –Transmission, Prevalence, Risk

13 JE campaign States & districts 1 Andhra Pradesh 10 2Kerala2 3Uttar Pradesh34+1 4Goa2 5Assam11 6Bihar6 7Haryana6 8Karnataka7+1 9Tamil Nadu9+1 10Maharashtra8 11West Bengal5 12Manipur5 13Nagaland2 14Arunachal Pradesh1 15Uttarakhand1 Total112 JE Vaccination Program – Overview Map showing 112 JE vaccination campaign districts

14 The JE Mass vaccination Drives ( Campaigns ) Coverage * Based on the emergence of new cases JE/ AES and low coverage as per CES report in 9 districts 2 states, it was decided to conduct re-campaigns S.No.Year No. of States covered No. of Districts covered Target population- 1-15 years Total JE vaccination campaign coverage JE vaccination campaign coverage % 1200641110531554930868888.39 22007927217582231843108784.71 32008922200402621688194184.24 420091030271706041809718266.61 52010819 9336609762635481.7 6 2010*re- campaigns 297659936749538097.85 Total118964971887784063280.67

15 JE vaccination campaigns - Year coverage 2006 - 2011

16 JE Vaccination Campaign 2006

17 JE Vaccination Campaign 2007

18 JE Vaccination Campaign 2008

19 JE Vaccination Campaign 2009

20 JE Vaccination Campaign 2010

21 Japanese Encephalitis Disease Incubation 6-16 days. Spectrum from mild febrile headache to severe encephalitis Headache, fever, nausea, vomiting, drowsiness. Abdominal pain and diarrhea common in children Progression over several days to severe disease – Dull, mask-like facies – Muscular rigidity – Cranial nerve palsies – Tremulous eye and extremity muscle movements – Generalized and localized paresis, incoordination, pathologic reflexes Seizures frequent in children, <10% of adults Associated Press

22 Clinical Manifestations Death in 5-40% Some deaths after acute fulminant course, others from cardiopulmonary complications with prolonged coma Children under 10 more likely to die or have residual neurological defects Poor prognosis associated with – Respiratory dysfunction – Babinsky ’ s sign – Frequent or prolonged seizures – Prolonged fever – Albuminuria – High viral replication in the brain Source: Reuters News Agency


24 Epidemiological Data 24

25 Type of vaccine: 1) Live attenuated vaccine (SA 14-14-2 strain) 2) Inactivated, Vero cell-derived, alum-adjuvanted vaccine (SA 14-14-2 strain) 3) Inactivated Vero cell-derived based vaccines (Beijing-1 strain) Schedule: 1) In China, the first dose of the live attenuated vaccine is given subcutaneously at age 8 months, followed by a booster dose at 2 years of age. In some areas, an additional booster is offered at 6–7 years of age. Protection for several years may be achieved also with a single dose of this vaccine. 2) Primary immunization of the inactivated, alum-adjuvanted vaccine consists of two intramuscular doses, 4 weeks apart 3) The inactivated (Bejjing-1-) vaccines: three doses at days 0, 7 and 28, or two doses given preferably 4 weeks apart (0.25 ml for children <3 years, 0.5 ml for all other ages).

26 Booster: The duration of immunity is not well established for the above vaccines. 1) the live attenuated vaccine, a booster dose is recommended in some countries. 2) the Japanese vaccines, a booster is recommended after year 1, and thereafter every 3 years. 3) the inactivated, alum-adjuvanted vaccine, one booster is recommended 12– 14 months after completion of the primary immunization; the possible need for further boosters to be determined. Adverse reactions: Occasional mild local or systemic reactions Before departure: The immunization series should be completed at least 1 week before potential exposure to JEV.

27 A new live attenuated, JE–yellow fever chimeric vaccine has recently been licensed in Australia and Thailand, and will be commercialized from 2012. This vaccine requires a single dose for primary immunization; the possible need for booster doses remains to be determined. Japanese Encephalitis Vaccine

28 Efficacy of the SA 14-14-2 Vaccine against Japanese Encephalitis. Kumar R et al. N Engl J Med 2009;360:1465-1466. Effectiveness of One Dose of SA 14-14-2 Vaccine against Japanese Encephalitis N Engl J Med 2009; 360:1465-1466April 2, 2009April 2, 2009

29 Immunogenicity and efficacy of Live Attenuated SA 14-14-2 Several studies have demonstrated an excellent immune response after a single dose of SA 14-14-2 vaccine, with neutralizing antibody responses produced in 85%-100% of non-immune children. Several field trials in China have yielded protective efficacy rates above 95%. One early case control study found 80% vaccine efficacy in children receiving one dose and 98% for two doses. A more recent study in an endemic area of Nepal reported 99.3% efficacy of a single dose. One year after immunization, a follow up study in the same region reported efficacy of 98.5%.

30 Global Advisory Committee on Vaccine Safety - The SA 14-14-2 live attenuated JE vaccine GACVS has reviewed safety aspects of this vaccine at two of its meetings (twelfth, held on 9-10 June 2005, and fifteenth, held on 29-30 November 2006). GACVS reviewed data related to the safety, immunogenicity and efficacy of the vaccine, and scrutinized data on co-administration with measles vaccine. GACVS concluded that the short-term safety profile of live JE vaccine appears satisfactory and that there appears to be a high level of vaccine efficacy after the administration of a single dose. In relation to serious adverse events reported after mass vaccination campaigns in India during 2006, no direct causality has been established between the reported illnesses and the SA14-14-2 JE vaccine. Nevertheless, GACVS recommended that in future, potential vaccine-related serious adverse events should be better investigated. Furthermore, more investigations are required to assess the possible risk of low frequency adverse events (especially neurological). Since live JE vaccine is currently used in “catch-up” campaigns on many millions of children in Asian countries, the opportunity should be taken to examine whether the vaccine safety profile remains valid in large study populations.

31 Development of Vero cell-derived inactivated JE vaccine

32 Other JE Vaccine Manufacturers VaccineName of the VaccineMfg.StrainDosesScheduleRoutePresentation Inactivated Mouse Brain purified inactivated JE vaccine CRI KasauliNakayama 3 (>3yrs– 1ml and 1-3yrs – 0.5 ml) 0, 7 & 30SCLiquid Mouse Brain purified inactivated JE vaccine (JENCEVAC) Green Cross – Shantha Biotech Nakayama 3 (Adult – 1.0 mL & Children – 0.5 mL) 0, 7 & 30SCLiquid Mouse Brain purified inactivated JE vaccine (JE-VAX) Sanofi Pasteur Nakayama 3 [Adult – 1.0 mL & Children (1-3 Yr.)– 0.5 mL] 0, 7 & 30SCLyophilized Vero cell – Inactivated vaccine (IXIARO) IntercellSA-14-14-2 2 (only >17 Yr. - 0.5 mL) 0 & 28IMLiquid PFS Live Attenuated Live attenuated JE Vaccine ChinaSA-14-14-2 1 (Adults & children - 0.5 mL) 0SCLyophilized Live attenuated JE Vaccine (Chimerivax) AcambisSA-14-14-2 1 [Adult – 1.0 mL & Children (9-36 Months.)– 0.5 mL] 0SCLyophilized Inactivated Vero- derived Purified inactivated JE Vaccine (JENVAC ® ) BBILKolar 2 (Adults & children - 0.5 mL) 0 & 28IMLiquid

33 Comparison between different JE vaccines (Mouse brain, Live (PHK) and Vero cell based ) Inactivated (Biken) Live attenuated (Chinese) Inactivated Intercell and Bio E) IXIARO/ JEEV Strain Nakayama, Beijing-1 SA14-14-2 Substrate Mouse brainPrimary hamster kidney (PHK) cells Vero Cells (Monkey Kidney cells Formulation Lyophilized Liquid Licensed 1954 – Japan 1993 – US 1988 – ChinaIxiaro-Licensed in USA, Australia, Canada & many other countries JEEV – Licensed in India Geographic use Worldwide: traveller vaccine SE Asia – childhood China, IndiaTraveller vaccine Administration Subcutaneous IM Dosage 0.5 mL-children 1.0 mL-adults 0.5 mL-children 1.0 mL-adults 0.25 mL-children 0.5 mL-adults Booster At one year & every 3 yearsAt 6 yearsStudies on going Efficacy 91% – 2 dose80% – 1 dose 97.5% – 2 dose 96 % – 2 dose in adult 95.7% -2 dose in children Protection Antibody levels > or = 1:10 Safety Rare cases of urticaria, angioedema, dyspnea, acute encaphalo-myelitis Serious adverse event reported lower rate of Adverse Events. PAGE 33 *IXIARO

34 Collaboration with NIV & iOWH Dr. Milind Gore National Institute of Virology, Pune, India, Dr. Richard Chin, Director Dr. Raj Shankar Ghosh, Regional Director, South Asia. (now PATH) For JE Vaccine Development has collaborated with

35 Global Scenario - JE Vaccine First Generation Vaccines (Mouse Brain Derived): BIKEN- Japan has been the largest manufacturer and international distributor, but has ceased production. JENCEVAC- Manufactured by Green cross, South Korea. Other manufacturers are found in Taiwan, Thailand and Vietnam

36 Global Scenario - JE Vaccine Second Generation Vaccines: Vero cell derived, Purified inactivated JE vaccine: IXIARO: Manufactured by Intercell AG, Austria. The vaccine was approved for adults. Phase III clinical trials completed in Indian children (BE collaboration). Manufactured by Bharat Biotech International Limited. The vaccine was approved for conducting Phase-II/III clinical trial and trials completed in adults & children.

37 Innovative aspects of BBIL JE Vaccine Novel inactivation process - to keep the Antigenicity increase immunogenicity Increased stability & shelf-life of the vaccine Thermo- stable strain

38 NIV-History of JE virus seed Obtained from: NIV, Pune, India Isolation: JE infected encephalitis patient Strain: Thermostable Kolar Strain (JEV 821564 XY) Passage history: 17 times in suckling mice Original Seed titer: LD 50 per mL = 10 7

39 Purified, inactivated Japanese encephalitis protein Not Less Than 5.0µg/0.5mL (Single Human Dose) Robust manufacturing technology Production facility- Fully validated commercial scale Production capacity- 25 Million doses annually Product & Production profile

40 Pre-clinical study

41 Pre-clinical toxicity (BBIL) Systemic toxicity GroupType of Sample Injection Dose/Dosage (Intramuscular) No. of Rats per group MaleFemale Group I (Control) PBS buffer 4 doses (day 0, 7, 14 & 28)/0.5mL PBS buffer 10 Group IIJENVAC ® 4 doses (day 0, 7, 14 & 28)/0.5mL NLT 5µg 10 Group IIIJENCEVAC 4 doses (day 0, 7, 14 & 28)/ 1mL 10 GroupType of Sample Injection Dose/Dosage (Intramuscular) No. of Rabbits per group MaleFemale Group I (Control) PBS buffer 4 doses (day 0, 7, 14 & 28)/0.5mL PBS buffer 33 Group IIJENVAC ® 4 doses (day 0, 7, 14 & 28)/0.5mL NLT 5µg 33 Group IIIJENCEVAC 4 doses (day 0, 7, 14 & 28)/ 1mL 33 Pre-Clinical studies done as per Schedule-Y

42 Pre-clinical toxicity (BBIL) Systemic toxicity Dose schedule of the vaccine is a maximum of 2SHDs, but in this study 4SHDs were given to the rats and rabbits and no impact was found on the animal safety. Blood samples for evaluation of serum chemistry and hematology were collected from all the animals on 0 th day & 42 nd day. A terminal body weight was obtained shortly prior to necropsy and a complete gross necropsy was conducted on all animals sacrificed during the study. There was no treatment related effects on mortality, clinical observations, body weight, food consumption, water consumption, coagulation, hematology or clinical chemistry analysis and histopathology in both rats & rabbits. Conclusion: Based on the study, Purified Inactivated Japanese Encephalitis Vaccine injection did not alter any of the above parameters in rats and rabbits in the systemic toxicity study conducted for a period of 42 days.

43 Animal Potency study

44 Animal Potency study (Thailand) Project: Study on potency of inactivated Japanese encephalitis vaccines in adult mice Site of Study: Center for Vaccine Development, Mahidol University at Salaya (WHO approved center for JE vaccines) Animal: Female Swiss Albino Inbred strain SPF mice, age 4 weeks Immunization dose/schedule: Vaccine 1:10 dilution 1st dose at Day 0, by I.P. route 01234567 Day 2nd dose at Day 7, by I.P. route

45 Animal Potency study (Thailand) Vaccines: Inactivated JE vaccine: Batch-88DP9001, Source: Bharat Biotech, India Inactivated JE vaccine: Batch-JJ 5210 3, Source: GPO, Thailand Inactivated JE vaccine: Batch 00410002 Source: Korean Green Cross, S. Korea (Nakayama), Serum collection: Collected on day 14 post dose 1 Serologic test: A validated Plaque Reduction Neutralization Test, 50% end point in continuous LLC- MK2 cells as per SOP using JE wild type Beijing strain as challenging virus, was used to evaluate all sera collected during the study period.

46 Result: To evaluate the magnitude of change in circulating neutralizing antibody titers after immunization, titers were measured in all 10 mice immunized. With 2 doses of the Bharat Biotech JE vaccine with GMT 153.55 and 100% seroconversion rate. For GPO, GMT of PRNT was found to be 187.22. Seroconversion rate of those 10 mice being used in the study revealed 90%. For KGC vaccine evaluation, GMT was fount to be 46.21 and 80% seroconversion rate. Animal Potency study (Thailand) Conclusion: Bharat Biotech JE Vaccine, like GPO JE Vaccine confers higher GMT than the Korean Green Cross JE Vaccine. For seroconversion rate, the Bharat JE Vaccine revealed 100% seroconversion rate after 2 doses, while the other 2 vaccines could not.

47 Phase I Clinical Trial

48 Protocol Title: A Phase I, Randomized, Double Blind, Placebo Controlled and Parallel Assignment Study to Evaluate the Safety, tolerability and immunogenicity of inactivated Japanese encephalitis Vaccine Produced by BBIL in healthy adult volunteers. Protocol Number: BBIL/JEV/I/2010 Study Investigator & Centre: Dr. Murali Mohan, MD-General Medicine, Professor, Dept of Medicine, Vydehi Institute of Medical Sciences, Bangalore.

49 A total of 60 healthy adult male subjects of age 18 to 50 years were participated in this study. Cohort 1: 25 vaccine and 5 placebo = 30 subjects (2 doses, day 0 & 28) * Cohort 2: 25 vaccine and 5 placebo = 30 subjects (3 doses, day 0, 7 & 28) * * Dose: As other commercially available vaccines are either 2 doses or 3 doses, hence BBIL has selected 2 & 3 dose schedule in Phase I Clinical Trial. Study Population Number of subjects enrolled Number of Subjects completed Number of subjects dropped out 60 5208

50 Dose and Mode of administration Subjects received either cell culture Inactivated Japanese encephalitis vaccine containing NLT 5µg protein or placebo by intramuscular route as per randomization. Liquid 0.5ml of vaccine/placebo is injected as two doses on day 0 and day 28+/-2 (Cohort-1) and three doses on Day 0, Day 7±1 and Day 28±2 (Cohort-2) by intramuscular route in to the deltoid region

51 Study Objectives Primary objective: Evaluate the safety and tolerability in healthy volunteers of 18 to 50 years. Secondary objective: Immunogenicity in healthy volunteers of 18 to 50 years.

52 Study Procedure & Plan Safety Evaluation: Adverse events, vital signs, Physical and clinical evaluation and laboratory tests. Lab investigations for safety evaluation done at baseline and 56±2 days following administration of either vaccine or placebo. Immunogenicity Evaluation: Immunological assessment at base line, 28±2 and 56±2 day for 50% plaque- reduction neutralization test (PRNT50) antibody titre increase against the JE virus

53 Results (Safety) Adverse events observed Test vaccine (121 doses)* Placebo (25 doses)** Fever10 (8.26%)0 Headache4 (3.35%)1 (4%) Pain at Injection site 4 (3.35%)0 Bodyache3 (2.48%)0 Weakness0 (0.00%)1 (4%) Swelling1 (0.83%)0 Cold1 (0.83%)0 No AEs98 (80.90%)23 (92%)

54 Results (Safety) There was no clinically significant change in any of the vital parameters as well as haematological and other biochemical lab parameters after two and three doses of vaccine administration Subjects were also followed up till day 90 for safety, none of the enrolled subjects were withdrawn from study for vaccine related adverse reactions There was no significant difference between the vaccine and placebo groups for all the common adverse reactions (headache, weakness, swelling & cold) and there is a difference between the groups for fever, pain at injection site & body ache noted. Adverse Events observed in the study group are similar/less with other published clinical studies (Intercell and Sanofi Pasteur). (Ref: Assessment report for IXIARO - European Medicines Agency, 2009)

55 Results (Immunogenicity) The Antibody estimation was carried out by PRNT 50 method for the Immunogenicity evaluation. JE vaccine strain 821564 (homologous virus) is used as a challenge virus. Comparison of GMT: Group Geometric Mean Titre (n) Day 0Day 28Day 56 Vaccine (2-Doses) 6.75 (25) 148.72 (21) 411.23 (20) Vaccine (3-Doses) 6.14 (25) 189.59 (25) 432.47 (25) Placebo 7.16 (10) 8.08 (10) 8.53 (07) Note: No statistical difference between 2 and 3 dose group (p-value >0.05) on 28 th and 56 th day.

56 Results (Immunogenicity) Comparison of % of Seroprotection Group % of Seroprotection (n) Day 0Day 28Day 56 Vaccine (2-Doses) 23.81 (25) 100 (21) 100 (20) Vaccine (3-Doses) 16 (25) 100 (25) 100 (25) Note: No statistical difference between 2 and 3 dose group (p-value >0.05) on 28 th and 56 th day.

57 Results (Immunogenicity) Comparison of % of Seroconversion Group % of Seroconversion (n) Day 0 to 28 Day 0 to 56 Vaccine (2-Doses) 90.48 (21) 100 (20) Vaccine (3-Doses) 96 (25) 100 (25) Placebo 0 (10) 0 (07) Note: No statistical difference between 2 and 3 dose group (p-value >0.05) on 28 th and 56 th day.

58 Results (Immunogenicity) There is no statistically significant difference between the Geometric Mean Titres of the subjects given two and three doses of BBIL’s JE vaccine on day 28 & 56. The percentage of Seroprotection in subjects given two and three doses of BBIL Japanese encephalitis vaccine is 100% on day 28 or day 56. The percentage of Seroconversion (≥4-Fold titer rise) with subjects given two and three doses of BBIL’s Japanese encephalitis vaccine on day 56 was 100%.

59 Analysis & Cross reactivity study - at NIV Considering the expertise of NIV, Pune in the field of JE vaccine sera testing, representative set of blinded samples were sent to NIV, Pune for test validation and cross reactivity evaluation. Serum samples of the phase I clinical trial were tested for anti-JE neutralizing antibodies against homologous (821564) and internationally accepted heterologous (057434) JEV strains by Plaque Reduction Neutralization Test (PRNT) at the National Institute of Virology, Pune. NIV resultsBBIL results ParameterHeterologous virusHomologous virus Time period0 Day28 Day56 Day0 Day28 Day56 Day0 Day28 Day56 Day GMT6.514.818.58.923.027.98.930.451.5

60 Conclusion It can be concluded that BBIL’s Japanese encephalitis vaccine is safe, well tolerated and immunogenic against homologous (821564) and heterologous (057434) JE virus strains in healthy volunteers of age 18-50 years. Hence as the immune response is adequate (100% seroconversion) with two dose vaccination, we wish to carry a large-scale multi-centre Phase III study in diverse population for evaluation of extended safety and immunogenicity of Inactivated Japanese encephalitis vaccine.

61 Phase II/III Clinical Trial

62 Protocol Title: A Phase II/III, Randomized, Single Blinded, Active Controlled Study to Evaluate the Immunogenicity and Safety of inactivated Japanese encephalitis Vaccine in healthy volunteers. Protocol Number: BBIL/JEV/II/III/2011 Study Centers: We have conducted the study in 9 centers in 4 different states stated below across India. 1. Andhra Pradesh 2. West Bengal 3. Karnataka 4. Rajasthan

63 Randomization, Labeling & Decoding  Asian Clinical Trials Statistical Analysis:  Dr.G.S.R Murthy, Indian Statistical Institute, Hyderabad Sera Sample Analysis  NIV – Pune  BBIL - Hyderabad Service providers

64 Study Investigators and sites Dr. J. Venkateswara Rao, Gandhi Medical College, Secunderabad Dr. G. Sampath, Institute of Preventive Medicine, Hyderabad. Dr. P. Venugopal, King George Hospital, Visakhapatnam. Dr. Mukesh Guptha, Saumya Child Clinic, Jaipur Dr. B. Krishnamurthy, Mysore Medical College, Mysore Dr. Monjori Mitra, Institute of Child Health, Kolkata Dr. Sudhakar, Priya Children’s Hospital, Vijayavada Dr. Sri Krishna, Mahavir Hospital, Hyderabad Dr. Bhuvaneswar Rao, Sri Sreenivasa Children’s Hospital, Vijayavada

65 Inclusion Criteria Healthy volunteers of 50 to 1 years. Available for all study related visits and procedures for the entire duration of the study, without any known exposure to JE prior to the first screening visit based on previous clinical history. Willing to give signed written Informed Consent.

66 Subjects with the age less than 1 and above 50 years. Fever of any origin of duration more than 3 days within one month prior to screening or on the day of screening. History of malaise, head ache, anorexia at the time of screening or during the administration of the vaccine under study. Past history of JE infection. Life threatening or serious cardiac (NYHA grades III-IV heart failure), respiratory gastrointestinal, Hepatic, renal, Endocrine, hematological or immune disorders. Past history of / current allergic diseases. Exclusion Criteria

67 Any confirmed or suspected immunosuppressive or immunodeficient condition Use of any marketed or investigational or herbal medicine or nonregistered drug or vaccine for JE or other vaccine in the past 2 months. Clinically relevant abnormal hematology or biochemistry values in the opinion of the investigator. Any criteria, which in the opinion of the investigator, suggests that the subject would not be compliant with the study protocol. Intention to travel out of the area prior to final or follow-up Visit on day 56±2. Previous history of hypersensitive reaction to vaccine or vaccine component.

68  The sample size has been calculated on the following assumptions: allocation ratio of 3:1 (test: reference), 90 % power, a non-inferiority margin of 15%, one sided alpha - 97.5% CI. Based on the above inputs, a total of 600 evaluable subjects are needed (450 in test group and 150 in the Reference group).  A total of 644 healthy subjects of age ≤50 to >1 year participated in this study across 9 centers in India Study Population CategoryAge in yearsTest groupReference group 1≤50 to >18 15656 2≤18 to > 6 14457 3≤6 to ≥1 17853 Total478166 Number of subjects enrolled Number of Subjects completed Number of subjects dropped out 64460836

69 Study Endpoints Primary Endpoint: Proportion of participants achieving 4-fold or greater neutralizing antibody titer in subjects seropositive at baseline (≥1:10) at day 28±2 after a single dose of vaccination. Proportion of participants that are seronegative at baseline (<1:10) will require a PRNT 50 titer of ≥1:10 to meet the criteria for seroconversion at day 28±2 after a single dose of vaccination.

70 Secondary Endpoint: GMT in each group on day 0 and day 28±2. Occurrence of solicited and unsolicited local and systemic AEs within 28 days and 56 days of post vaccination on day 0, 28±2 and 56±2. Occurrence of vaccine-associated SAEs throughout the course of the study. Proportion of participants achieving 4-fold or greater neutralizing antibody titre at day 56 after two doses of vaccination. Study Endpoints

71 Dose and mode of administration Based on the results obtained from Phase I study we have selected the 2 dose schedule in Phase III study. As per the insert instruction, one dose of reference vaccine selected. Test vaccine: Liquid Purified, inactivated Japanese encephalitis protein NLT 5.0µg/0.5mL was injected as two doses on day 0 and day 28±2 by Intramuscular route. Reference vaccine: Lyophilized Reference Vaccine (Live attenuated, SA 14-14-2 Chinese vaccine) 0.5mL was injected subcutaneously after reconstitution with the diluent supplied as one dose on day 0 and Placebo was administered as second dose on day 28±2.

72 Study Objectives The primary objective is to compare the immunogenicity of the Test vaccine with Reference vaccine in terms of seroconversion and Geometric Mean Titers of JEV neutralizing antibody four weeks after two doses. The Secondary objective is to assess and to evaluate the Safety of the cell cultured inactivated Japanese encephalitis Vaccine in healthy volunteers of 50 to 1 years.

73 Trial Profile

74 Results (Safety) Distribution of Adverse Events in ≤50 to >1 year age group Adverse events observed Test Vaccine GroupReference Vaccine Group After 1 st Dose (478 doses) After 2 nd Dose (450 doses) After 1 st Dose (166 doses) After 2 nd Dose (156 Placebo) General Adverse Events Fever93 (19.5%)6 (1.3%)32 (19.3%)2 (1.3%) Body ache12 (2.5%)0 (0%) 5 (3.0%)0 (0%) Vomiting3 (0.6%) 0 (0%)2 (1.2%)0 (0%) Diarrhoea 3 (0.6%)0 (0%)1 (0.6%) Cold 2 (0.4%)0 (0%)2 (1.2%)0 (0%) Cough 2 (0.4%)0 (0%) Myalgia1 (0.2%) 0 (0%)2 (1.2%)0 (0%) Headache 9 (1.9%)2 (0.4%)3 (1.8%)0 (0%) Local Adverse Events Pain at Injection site47 (9.8%)18 (4%)22 (13.2%)6 (3.8%) Total AEs172 (36%)26 (5.8%)69 (41.6%)9 (5.8%) p-values are given in the next to the graphical presentation slide

75 Results (Safety) 58.4% 94.2%

76 Results (Safety) There was no significant difference between the Test vaccine and Reference vaccine groups for adverse reactions noted after first dose of vaccination (p-value >0.05). Adverse Events were reported significantly lower after second dose, when compared to after first dose of test vaccination (p-value <0.001). The AEs reported after second dose in Test group were not significant with the AEs reported after Placebo administration as second dose in Reference group (p-value >0.05).

77 The Antibody estimation by PRNT 50 method for the Immunogenicity. JE vaccine strain 821564 (homologous virus) is used as a challenge virus. Seroprotection: A PRNT 50 antibody titre of more than 1:10 generally is accepted as evidence of protection. Seroconversion: % of subject’s ≥4-fold titer rise from pre to post vaccination titer called as % of Seroconversion (4-fold). Results (Immunogenicity) Note: For subjects with a minimum dilution factor <10 (PRNT50), the titre is set to 5.

78 Results (Immunogenicity) Comparison of Seropositive & Seronegative percentages between the vaccine groups (Age category ≤50 to≥1 year): *Excluding subjects seropositive at base line Parameter Test Vaccine Referen ce Vaccine P- value % of subjects seronegative at base line (Day 0) 88.7282.05>0.05 % of subjects seropositive at base line (Day 0) 11.2817.95>0.05 % of subjects seropositive after single dose (Day 28)* 98.5072.66<0.001

79 Results (Immunogenicity) Seroprotection & Seroconversion of study Groups in ≤50 to ≥1 years All the subjects included Response Time period Test vaccine Reference vaccine p-value % of Seroprotection Day 011.2817.95>0.05 Day 2898.6777.56<0.001 % of Seroconversion (4-fold) Day 0 to 28 93.1457.69<0.001

80 Results (Immunogenicity) Seroprotection & Seroconversion of Test vaccine in different age groups Response Time period Age Group ≤50->18 years ≤18->6 years ≤6-≥1 years P- value % of Seroprotection Day 011.1113.679.46>0.05 Day 2897.2299.2899.41>0.05 Day 5699.31100 >0.05 % of Seroconversion (4-fold) Day 0 to 2889.5893.5395.8>0.05 Day 0 to 5693.0698.5698.82>0.05

81 Results (Immunogenicity) GMT, Seroprotection & Seroconversion comparison in three different age groups GroupVaccine Group Geometric Mean Titre % of Sero prevalence % of Sero protection % of Sero conversion Day 0Day 28Day 0Day 28Day 0 to 28 ≤50->18 years Test Vaccine6.02105.611.1197.2289.58 Reference Vaccine 7.0936.5025.4978.4354.90 ≤18->6 years Test Vaccine6.61134.7113.6799.2893.52 Reference Vaccine 6.4629.7514.8179.6359.26 ≤6-≥1 years Test Vaccine5.67202.09.4699.4195.85 Reference Vaccine 6.0453.6313.7374.5158.82

82 Results (Immunogenicity) Comparison of GMT titers

83 Results (Immunogenicity) Comparison of % of Seroprevalence & Seroprotection

84 Results (Immunogenicity) Comparison of % of Seroconversion

85 Results (Immunogenicity) of Test Vaccine 1 st dose 2 nd dose Day 0 Day 28Day 56 EnrolledCompleted 98.67% Seroprotection 93.14% Seroconversion 99.78% Seroprotection 96.90% Seroconversion

86 Results (Immunogenicity) DayGroup % of Seroconversion (4-Fold) % of Seroconversion (Seronegative to Seropositive) p-values Day 28 Test vaccine93.1496.46>0.05 Reference vaccine57.6975<0.05 Day 56 Test vaccine97.2599.34>0.05 Reference vaccine4155.13<0.05 Seroconversion comparison When two different seroconversion methods are compared, there is no significant difference in the test vaccine group, but there is a significant difference observed in the reference vaccine group. Since there was only one dose of vaccination in reference vaccine group, % of seroconversion decreased on day 56 by both the methods. Due to the second dose vaccine administration in test vaccine group, % of Seroconversion is increased slightly but not significantly on day 56 by both the methods.

87 Results (Immunogenicity) Batch consistency ResponseDay Batch 88DP10001 (SD) 88DP10002 (SD) 88DP10003 (SD) 88DX10001 (MD) 88DX10002 (MD) 88DX10003 (MD) GMT 2896183.7165.8184.4102.0233.6 56308547.5531387.4441.2958.7 Sero protection 015.813. 2898.597.1100.0 56100.099.3100.0 4-Fold Rise 0 to 2891.791.995.993.387.0100.0 0 to 5697.094.999.293.395.7100.0 SD: Single Dose vial, MD: Multi Dose vial No significant difference between batches with respect to final Seroconversion (4-fold raise). Confidence Intervals of all these batches are within the interval (80-120).

88 Results (Immunogenicity) Responses of two different vaccine vial presentations of Test Vaccine Response Presentation Overall Single DoseMulti Dose Number of Subjects39260452 Geometric Mean Titre Day Day 28142.8160.2145.0 Day 56446.0567.7460.5 % of Seroprotection Day 012.53.311.3 Day 2898.5100.098.7 Day 5699.7100.099.8 % of Seroconversion (4-Fold) Day 0 To 2893.193.393.1 Day 0 To 5696.996.796.9  Test vaccines in two different presentations i.e. single and multi-dose vaccine vials are bioequivalent with respect to the responses in seroprotection and seroconversion proportions.  Confidence Intervals of two different presentations are within the interval (80-120).

89 Results (Immunogenicity) Zone wise comparison of the results: A total of 608 subjects completed the study in 9 centers across India, 6 centers from Andhra Pradesh (Coastal zone: 3 & Hyderabad zone 3), 1 from Rajasthan, 1 from West Bengal and 1 from Karnataka. Centers were categorized according to the zones as below: ZoneArea% of Seroprevalence AP 1Coastal, Andhra Pradesh14.18 AP 2Hyderabad, Andhra Pradesh11.11 BJaipur, Rajasthan15.38 CKolkata, W. Bengal15.38 DMysore, Karnataka8.82

90 Results (Immunogenicity) Interpretations:  From the data it reveals that both one dose and two doses show the significant immunogenicity.  There is no difference in % of subjects seronegative and seropositive at baseline, but there is significant difference in % of subjects seropositive after single dose on day 28 between Test & Reference vaccine groups.  From the data of 2 dose study it shows that single dose of test vaccine is sufficient to elicit the immune response. As 28 th day blood sample, subjects has received a single dose were 98.67% seroprotected and 93.14% seroconverted (4 fold) for ≤50- ≥1 years.

91 Results (Immunogenicity)  Seroconversion & Seroprotection percentages on 28 th and 56 th day between different age groups are statistically not significant (>0.05).  After second dose of test vaccine GMT titre was increased exponentially from day 28 (145) to day 56 (460.5).  Seroconversion & Seroprotection percentages on 28 th day between Test and Reference vaccine groups are statistically significant (p-value <0.001).  There is no significant difference among two presentations i.e. single & multi-dose vaccine vials and among different centers with respect to final Seroconversion (4-fold raise) and Seroprotection. Confidence Intervals are within the interval (80-120). Detailed statistics have done.

92 Discussion

93 Comparison with other vaccines Vaccine Geometric Mean Titre (n)% of Seroconversion (n) Day 0Day 56Day 0 to 56 JENVAC ® (Bharat Biotech)6.06 (452)460.53 (452)98.59 (452) IXIARO (Intercell)5.0 (365)243.6 (361)96.4 (352) JEEV (Intercell- BE)9.7 (304)217.97 (277)92.42 (277) JE-VAX (Sanofi Pasteur)5.0 (370)102.0 (364)93.8 (347) Bharat Biotech has compared the trial results to other commercially available vaccine data such as IXIARO from Intercell, JEEV from BE and JE-VAX from Sanofi Pasteur (EMEA, 2009). As from the comparative table, BBIL has higher GMTs and % of seroconversion than the other commercially available vaccines. It shows that BBIL's vaccine is not inferior to the other commercially available vaccines.

94 Other Clinical studies with SA 14-14-2  In a single dose of SA 14-14-2 vaccine study done by NIV, Pune and seroconversion (>10.0.) was 74.28% after 30 days and 5% after 6 months against internationally accepted JE virus strain (057434). Titers are in the range of 10.43- 133.03. (Ref: National Institute of Virology annual report 2007-08)  Another study in China tested between a two-dose one-month immunization schedule and three-month immunization schedule. After the first dose, seroconversion rates varied from 72% (n=53) to 100% (n=56). (Ref: Dr. Robert Siegel, HBIO 115B: The Vaccine Revolution, June 3, 2000)  In one early case control study of SA 14-14-2 vaccine it reported 80% vaccine efficacy in subjects receiving one dose and 98% for two doses (Ref: product insert).

95 Other Clinical studies with SA 14-14-2  Post Marketing surveillance studies carried out in India by ICMR show that the seroconversion is lower (ranging between 35% - 43%) than that reported in other countries. Independent evaluation of vaccine coverage shows that vaccine coverage in the programme were very low.  UNICEF coverage report shows a big difference between reported and evaluated coverage figures e.g., In Dibrugarh it was 90.5% vs. 35.9% and Gorakhpur 97% vs. 52.3 % for reported and evaluated coverage respectively.  (Ref: Minutes of the Expert Group meeting on JE Vaccine constituted by Sec. (DHR) and DG ICMR was held at ICMR Hqs. on 25th Jan.2010.)  Whereas, results obtained for SA 14-14-2 in our study was 77.56% of seroprotection on the 28 th Day. For the test vaccine (BBIL’s vaccine) 98.67% of seroprotection was observed on the 28 th day.

96 Summary  Collaborated with NIV & Institute for OneWorld Health  Indian Thermo-stable strain  Well characterised-MVB/WVB & MCB/WCB  Well equipped Production Facility & Capacity  Experience in QC testing (Rabies, Polio, H1N1& Rota)  Vaccine Potency study at Thailand  Pre-Clinical & Human Clinical studies  Sera Testing at NIV, Pune  Comparable with other vaccines

97 Conclusion

98  It can be concluded that the BBIL’s inactivated Japanese encephalitis vaccine is safe, well tolerated and immunogenic in healthy volunteers in the age group between ≤50 to ≥1, after one or two doses of vaccination.  Hence, a single dose schedule can be used for the campaign immunization (~95% seroprotection and seroconversion after a single dose).  Two dose schedule can be used for routine immunization (~97% seroprotection and seroconversion after two doses). Overall Conclusion

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100 Vaccine strategy for disaster and outbreak situation The growing need is being felt to stockpile of vaccines against certain diseases with potential to cause outbreaks such as Cholera, JE and H1N1 and other seasonal influenza. These vaccines are required for an affected target population and the quantity needed for stockpile should be assessed together with the National Disaster Management Agency (NDMA) The manufacturers of these vaccines have to be communicated of the decision ahead of time for planning production and when the stock expires or is utilized. Adequate budgetary provision for such stockpiles should be created and adequate cold chain equipment earmarked for storage. The NDMA also needs to be intimated about the locations of these stockpiles and effective communication maintained with the agency for delivery of these vaccines during an emergency situation

101 IAPCOI perspective Routine vaccinations to be recommended in high risk zone ???

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