2/27/2013. Dr. S. Broor All India Institute of Medical Sciences New Delhi India

Transcription

1 Dr. S. Broor All India Institute of Medical Sciences New Delhi India 1

2 Delhi Ballabgarh 2

3 Urban tertiary care hospital Rural Primary and Secondary care All India Institute of Medical Sciences (AIIMS) Rural Intensive Field Practice Area 2 Primary Health Centres, 12 sub-centers 28 villages, pop. 84, 748 Individual unique numbers in data base Longitudinal data on health indices and demographics Ballabgarh information from Dr. Sanjay Rai, Centre for Community Medicine, AIIMS 3

4 Studies in 2 phases Influenza vaccine direct and indirect efficacy Determine direct efficacy of influenza vaccination in children 6 mths-10 yrs Determine indirect effects of influenza vaccination among household contacts of vaccinated children Define influenza clinical disease and outcomes Define the Incidence rates and Epidemiological characteristics of influenza disease Determine optimum time period for influenza immunization Provide information about influenza and influenza vaccines in children that will be useful for decision makers in India and globally 4

5 Study Duration: Double blind Community Trial of Killed Trivalent Influenza Vaccine (NH) with Inactivated Polio vaccine as Control vaccine given in fall or early winter of each year Surveillance case definition for Influenza : Febrile Acute Respiratory Illness (FARI) Design: prospective, household randomized, controlled, participant/observer/investigator blinded 5

6 All ages in 3 villages in active surveillance ) (~17000 individuals) Weekly home visits: sample if febrile acute respiratory illness (FARI) Vaccinate fall: 6 m0-10 year (~3600): randomized by household, TIV or inactivated poliovirus vaccine (IPV) as control Primary outcome: reduction in realtimert-pcr confirmed influenza infections in vaccine recipients and households 6

7 Northern Hemisphere (did not include pandemic virus) an A/Brisbane/59/2007 (H1N1)-like virus *an A/Brisbane/10/2007 (H3N2)-like virus a B/Brisbane/60/2008-like virus 2010, 2011 Northern Hemisphere an A/California/7/2009 (H1N1)-like virus; an A/Perth/16/2009 (H3N2)-like virus; a B/Brisbane/60/2008-like virus. Inactivated and live vaccines 7

8 Children >6 months of age and <through 10 years of age to received either influenza or control vaccine In the first year of the study children 6 mo to 8 y of age received 2 doses, those 9 and 10 y old one dose. In 2 nd and 3 rd years a single dose of vaccine was planned but this changed in response to 2009 pandemic,. In year 2 also 2 doses were given Children in control group received a licensed inactivated polio vaccine (IPV) on the same schedule 8

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10 Case definition of FARI: Adult or child with self reported fever (now or past 7 d) AND any symptom of respiratory infection (e.g. cough, sore throat, rhinorrhea, or coryza). Active surveillance: field workers make weekly home visits and inquire as to the occurrence of FARI. FARI clinical assessments include include measurement of temperature, and respiratory rates, evaluation for cyanosis and respiratory distress, and oxygen saturation by pulse oximetry. Nasal and throat swabs obtained at FARI events, realtimert-pcr used to detect influenza. 10

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12 Study database links: 1) an electronic Rural Health Information System database with house numbers and demographic data 2) paper forms used for field data collection that were optimized for optical character recognition 3) an in-house created laboratory data base that stored sample testing and laboratory results Scanned proformas uploaded to a secure server, downloaded at UAB, processed with TELEform software, and converted to a SAS database. Dr. Karen Fowler responsible for data management. Each week 17,000 individuals received home visits, generating ~ 884,000 person weeks of observation per year. Febrile respiratory infections generate ~38,000 proformas per year. 12

13 Year (Eligible N) Fully Vaccinated (%) Partially Vaccinated (%) No vaccine (%) at least 1 dose (%) 2009 (3697) 3016 (82%) 358 (10%) 323 (9%) 3374 (91%) 2010 (3832) 3263 (85%) 239 (6%) 330 (9%) 3502 (91%) 2011 (3690) 3376 (91%) 100 (3%) 214 (6%) 3476 (94%) % are from eligible population, however some children moved out or were unavailable 13

14 Children in the Vaccine Study: Year 1 Fully Vaccinated N=3,016 Partially Vaccinated N=358 Unvaccinated N=323 Total N=3,697 Age (years) µ ± SD 5.3 ± 3.0 yrs 3.8 ± 2.6 yrs 5.1 ± 3.0 yrs 5.1 ± 3.0 yrs Age 9-10 yrs 597 (90.9%) 0 (0) 60 (9.1%) 657 (17.8%) Age 0-8 yrs 2,419 (79.6%) 358 (11.8%) 263 (8.6%) 3,040 (82.2%) Sex Girls 1,333 (81.3%) 162 (9.9%) 145 (8.8%) 1,640 (44.4%) Boys 1,683 (81.8%) 196 (9.5%) 178 (8.6%) 2,057 (55.6%) Partially vaccinated = 1 of 2 planned vaccine doses for ages 6 months 8 years ~ 90% fully or partially immunized 14

15 village Consent (+) Consent refused Not available Atali Chandawali Dayalpur total 16,911 (90%) 47 (0.3%) 1,826(9.7%) % is proportion of eligible individuals. 15

16 Age Total #(%) Male/Female (Ratio) 0-5 years 2510 (13.8) 1362/1148 (1.12) 6-18 years 4714 (25.9) 2574/2140 (1.2) years 4068 (22.3) 2070/1998 (1.04) years 3693 (20.3) 2023/1670 (1.21) years 1985 (10.9) 999/986 (1.01) 60+ years 1250 (6.8) 584/666 (0.88) Total 18, /8608 (1.12) 90% of the eligible population agreed to participate in surveillance 16

17 %+ve H1n1 pdm %+ve Inf B % =ve H3N /27/ Week 48 ( 2009)

18 Nov'09 - Jan'10 Feb'10- April'10 May'10 - July'10 Aug '10 Oct 10 Overall Average Population under surveillance Person weeks Incident FARI Cases Total Influenza Positive (%) A/H1N1 Positivity (%) 231 (21) 1(0) 10(1) 507(13) 749 (10) Seasonal influenza positivity (%) 34(3) 88 (9) 143(9) 396 (10) 661(9) Incidence of Influenza (per 1000 person years) 205 ( ) 28( 23-34) 43( 37-50) 278 ( ) 128 ( ) Incidence for 2009A(H1N1) Influenza (per 1000 person years) 179 ( ) 0.0 (0-1) 3 (1-5) 156( ) 68(64-72) Incidence for Seasonal Influenza (B) (per 1000 person years) 26 (19-35) 28 (23-34) 40( 34-47) 116 ( ) 58 (54-62) 18

19 Children in the Vaccine Study: Year 1 Virology N=3,697 Total FARIs 2,744 Total person-weeks observation 148,528 A(H1N1)pdm (9.8%) Influenza B 259 (9.4%) Influenza A/H3N2 6 (0.2%) FARI Incidence 961 per 1000 p-yrs* A(H1N1)pdm09 Incidence 94 per 1000 p-yrs * Influenza B Incidence 91 per 1000 p-yrs * *not adjusted for non sampled 19

20 Provided by S. Broor 20

21 Phase 2 Period of study : Same study plan as phase 1 but the timing of vaccination changed to spring /early summer 2012 immunization in spring/summer carried out, continue vaccination in spring through the 2 nd year (2013), followed by weekly surveillance till

22 Northern Hemisphere an A/California/7/2009 (H1N1)pdm09-like virus; an A/Victoria/361/2011 (H3N2)-like virus; a B/Wisconsin/1/2010-like virus (from the B/Yamagata lineage of viruses) Two rounds of vaccination were held Northern Hemisphere formulation of TIV was used as Southern hemisphere vaccine was not available as yet and the constituents of both formulation were the same 22

23 Villages of Ballabgarh 1 st Dose 2 nd Dose Dayalpur Chandawali Atali Total Two rounds of vaccination were held children received 1 or 2 doses appropriate to age 94% of eligible children received age appropriate vaccination (Age group 6 month- 10 years 23

24 Villages of Ballabhga rh The age group-wise enrollments 0-<5 yrs 5-<15yrs 15-<65yrs 65yrs and above Total Dayalpur Chandawa li Atali Total enrollmen ts

25 Viruses #(% positive) Total samples 382 /129(33.7%) respiratory syncytial virus (RSV) 11 (8.5%) adenovirus 13 (10%) parainfluenza 1 7 (5.4%) parainfluenza 2 3 (2.3%) parainfluenza 3 10 (7.6%) metapneumovirus 5 (3.9%) rhinovirus 57 (44.2%) coronavirus 229E 2 (1.5%) coronavirus OC43 21 (16.3%) coronavirus NL63 3 (2.3%) coronavirus HKU1 10 (7.6%) mixed 6 (2%) influenza (-) samples from vaccine study from all ages March to Oct months in 2010 Used 11 individual realtime PCR assays Demonstrates 33.7% (+) for other viruses, CoV and rhinovirus most common on 25

26 Month wise distribution of non-influenza respiratory viruses Number of Positives March-april May-June July-Aug Sep-Oct Months RSV ADV PIV1/2/3 HMPV hrv CoV1/2/3/4 26

27 Percentage positivity of samples in different age groups Total samples Total no. of pathogen detected Age group Total samples Total no. of pathogen detected % positiive %positivity > > > > > > > >5-10 >10-20 >20- >30- >40- >50-60 >60 27

28 HAI assays on vaccine recipients in 2009 and 2010 ( Total paired samples tested 164 Viruses Seroconversion Seroconversion N (%) N (%) (B/Brisbane/60/2008) 70 (42.7%) (B/Brisbane/60/2008) 94 (25.3%) (A/H3/Brisbane/10/200 7) 67 (40.9%) (A/H3/Perth/16/2009 like strain derived from A/Victoria/210/2009) 146 (39.4%) A/H1 /Brisbane /59/2007) 71 (43.3%) (A/H1/California/7/2009 ) 141 (38%) To all 3 viruses 56 (34.1%) All 3 viruses 57 (15.4) Seroconversion= HAI titrerise by 4 fold ~50% of the paired tested samples belong to control group Age group : 3-7 years 28

29 SeroprotectiveAntibody Levels pre-vaccination and post-vaccination 2009 ( Total paired samples tested (Total Paired Samples Tested 371) Viruses (B/Brisbane/60/ 2008) No. (%) with Sero-protective Viruses levels /GMT (Prevaccination ) vaccination) (Post- 23 (14.%)/ (42%)/82 (B/Brisbane/60/ 2008) No. (%) with Seroprotective levels/gmt (Prevaccination ) vaccination) (Post 219 (59.%)/ %)/ (A/H3/Brisbane/10 /2007) (A/H1/Brisbane /59/2007) 98 (59.8%)/ (16.5%)/ (71.3%)/ (48.8%)/ (A/H3/Perth/16/ 2009 like strain derived from A/Victoria/210/ 2009 (A/H1/California/7 /2009) HAI Antibody titers 40 considered seroprotective. 260 (70.1%) / (55.8%) / (77%)/ (66.8%) /

30 Phase 1 study will define direct (total) and indirect protective effects of fall TIV immunization in children Extension of study in phase2 will assess pre-monsoon immunization Enrollment and immunization rates for Influenza vaccine high, reflecting on high community acceptance Likely no benefits of vaccination in first year (due to vaccine mismatch), 3 rd yr vaccination done Emergence of pandemic H1N1 emphasized the importance of multi-year studies of influenza vaccine Weekly FARI Surveillance in ~16,000 villagers providing incidence data for Pandemic H1N1 in first year Ancillary investigations bring added value to the study and include measures of immunity and nutrition and testing for other respiratory viruses Efficacy analyses are under way 30

31 To assess genetic drift of pandemic H1N1, H3, and Influenza B over at least 5 years ( ) India is producing trivalent LAIV, likely licensure by end of 2012: An efficacy trial proposed in different village Rural villages study platform offers opportunities for further studies of influenza such as maternal immunization against influenza, other vaccines, the role of malnutrition in ARIs, the contribution of mixed viral infections, bacterial-viral interactions, exposure to indoor air pollution, etc 31

32 Assess the efficacy of a Live attenuated Influenza Vaccine that has been indigenously developed in India Compare the efficacy of Live Attenuated Influenza Vaccine (LAIV) with efficacy of inactivated trivalent influenza vaccine in the cohort 32

33 To study the relative efficacy of Live Attenuated Influenza Vaccine as compared to placebo against laboratory confirmed influenza among children 2-10 years of age in a rural north Indian community To study the relative efficacy of inactivated trivalent Influenza Vaccine as compared to Live Attenuated Influenza Vaccineagainst laboratory confirmed influenza among children 2-10 years of age in a rural north Indian community 33

34 An open-label three armed community superiority trial Age group: 2-10 Years (depends on licensing) Outcome of interest direct protection only Unit of Randomization -Individuals 34

35 LAIV -Procured preferably from an Indian Manufacturer Must be DCGI approved and not an experimental agent. Selection of the vaccine would be done after a review of licensing status of approved and available formulations in India. TIV - Procured preferably from an Indian Manufacturer Must be DCGI approved and not an experimental agent. Selection of the vaccine would be done after a review of licensing status of approved and available formulations in India. Placebo - Should be present as we feel that LAIV vsplacebo comparisons have not been done in a limited resource setting. Since a large community based TIV vsplacebo trial is already underway at BallabgarhAIIMS, the same is a not that important an objective for the present study 35

36 Blinded preferable but given the practicalities, may have to be open label trial If blinding is to be done then The TIV arm receives an intranasal placebo The LAIV arm receives an i.m. placebo/control Placebo arm receives both intranasal and i.m. placebo/control 36

37 Assumptions for calculating sample size: Annual incidence of Influenza in target age group: 150/1000 person yrs. (conservative) Probability of Type-I Error: 5% Probability of Type-II Error: 20% / Power of 80% Protective Efficacy of LAIV: 80% Protective Efficacy of TIV: 50% Sample Size For LAIV Vs TIV vsplacebo : 622 in each group totals to 1866 child years For TIV VS placebo (466 in each group) = 912 child years ) 37

38 ARI platform on 1700 children currently in place. One new village to be added. Weekly ARI surveillance in place with testing for influenza viruses Awaiting clearance for government for LAIV followed by institutional clearances Proposed vaccination from mid

39 BroorS, SullenderWS, Fowler K, Gupta V, WiddowsonMA, Krishnan A, LalRB. Demographic Shift of Influenza A(H1N1)pdm09 during and after Pandemic, Rural India. Emerg. Infect. Dis. 18: , SullenderW, Fowler K, AnandK, Gupta V, Moulton L, LafondK, WiddowsonM- A, LalRB and Broor S. Design and initiation of a study of the direct and indirect effects of influenza vaccine given to children in rural India. Vaccine,30: , Mir MA, LalRB, SullenderW, Krishnan A, Singh Y, Broor S. Genetic Diversity of HA1 Domain of hemagglutiningene of the pandemic influenza A (H1N1) 2009 viruses in north India. J Med Virol. 84: , Fowler K, Broor S, SullenderW, Gupta V, DebjaniRP, WiddowsonMA, LalRB, Krishnan A. Incidence rate of symptomatic Influenza A(H1N1)pdm09 and seasonal influenza infection in a rural Indian community. Submitted DebjaniRP, Gupta V, Broor S, SullenderW, Fowler K, WiddowsonM-A, LalRB, Krishnan A. Clinical Presentation of Pandemic Influenza 2009 A /H1N1 and Influenza B identified through active community surveillance in North India. Ind. J. Med. Res. In Press 39

40 Wayne Sullender, University of Colorado Denver: PI ShobhaBroor, Department of Microbiology, All India Institute of Medical Sciences (AIIMS), New Delhi India : India main collaborator AnandKrishnan(phase 1); ShashiKant (phase 2) Comprehensive Rural Health Services Project, Ballabgarhand Centre for Community Medicine, AIIMS, Delhi, India : community health partners Karen Fowler, University of Alabama Birmingham USA : Study data management and analysis VivekGupta, INCLEN Trust, Delhi ((phase 1) : Study co-ordinatorfor community NarenderAroraINCLEN Trust, Delhi ((phase 2) : INCLEN Trust partner RenuLal, Influenza co-ordinator US Embassy, India, CDC Marc-Alain Widdowson, Influenza Division, CDC Funded by the Influenza Division of the CDC 40

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43 Why is this an issue? As a unit for allocation To measure socio-economic status What is the problem: complex scenario Shared resources: land, livestock Partly shared: kitchen, household expenses Individually used: clothes / items Level of interaction among members Sharing of courtyard used to define a household. Slide from Dr. Krishnan Anand 43

44 virus types Northern Hemisphere vaccine Circulating strains, Ballabhgarh Vaccine: circulating virus match Vaccination 2009 (completed) (H1N1)pdm09 A/Brisbane/10/20 Pandemic Mismatch A/H1N1 H3N2 A/Brisbane/59/20 None 07 Influenza B B/Brisbane/60/20 08 Influenza B Good Match Vaccination 2010 (completed) (H1N1)pdm09 A/California/7/20 Yes Yes 09 H3N2 A/Perth/16/2009 some Seqquencing of 7 H3 has shown good homology Influenza B B/Brisbane/60/20 08 Yes 30/35 are Victoria lineage, and 5 of Yamagata lineage) Vaccination 2011 (Completed) (H1N1)pdm09 A/California/7/20 TBD TBD 09 H3N2 A/Perth/16/2009 TBD TBD Influenza B B/Brisbane/60/20 08 TBD TBD 44

45 Entrance to large compound with several families Two families share common space Separate door and shared entry 45

46 Initial plan was to perform the study in 2 villages, one influenza and one control vaccine Concern about village to village variability and limited number of randomization units lead to consideration of other randomization units: Individual (limits indirect protection in home if some children immunized and some not) Groups within the villages: mohallas(challenges in defining and social mixing) Household(reduces community level indirect protection) Chose household randomization. 46