dr. s. broor all india institute of medical sciences new ......all india institute of medical...

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Dr. S. Broor

All India Institute of Medical Sciences

New Delhi

India

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Delhi

Ballabgarh

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Urban tertiary care hospital

All India Institute of Medical Sciences (AIIMS)

Rural Primary and Secondary care

Ballabgarh information from Dr. Sanjay Rai, Centre for Community Medicine, 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

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� 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

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� Study Duration: 2009-2012

� 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

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Weekly home visits: sample if febrile acute respiratory

illness (FARI)

All ages in 3 villages in active surveillance ) (~17000

individuals)

Vaccinate fall: 6 m0-10 year (~3600): randomized by

household, TIV or inactivated poliovirus vaccine (IPV) as

control

Primary outcome: reduction in realtime RT-PCR confirmed

influenza infections in vaccine recipients and households

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2009-2010 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.

http://www.cdc.gov/flu/about/qa/vaccine-selection.htm

Inactivated and live vaccines

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� 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 2nd and 3rd 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

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• 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, realtime RT-PCR used

to detect influenza.

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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.

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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 outor were unavailable

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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%)

Children in the Vaccine Study: Year 1

Partially vaccinated = 1 of 2 planned vaccine doses for ages 6 months – 8 years

~ 90% fully or partially immunized

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village Consent

(+)

Consent

refused

Not

available

Atali 6363 5 522

Chandawali 4694 13 587

Dayalpur 5854 29 717

total 16,911 (90%) 47 (0.3%) 1,826 (9.7%)

% is proportion of eligible individuals.

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Age Total # (%) Male/Female (Ratio)

0000----5 years5 years5 years5 years 2510 (13.8) 1362/1148 (1.12)




45 45 45 45 ----59 years59 years59 years59 years 1985 (10.9) 999/986 (1.01)

60+ years60+ years60+ years60+ years 1250 (6.8) 584/666 (0.88)

TotalTotalTotalTotal 18,220 9612/8608 (1.12)

90% of the eligible population agreed to participate in surveillance

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0.00

-5.00

0.00

5.00

10.00

15.00

20.00

25.00

30.00

35.00

40.00

45.00

Week

48 ( 2009)

52 3 7

11

15

19

23

27

31

35

39

43

47

51 3 7

11

15

19

23

27

31

35

39

43

47

51 3 7

11

15

19

23

27

2009 2010 2011 2012

%+ve H1n1 pdm %+ve Inf B % =ve H3N2

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Nov'09 Nov'09 Nov'09 Nov'09 ----Jan'10Jan'10Jan'10Jan'10

Feb'10Feb'10Feb'10Feb'10----April'10April'10April'10April'10

May'10 May'10 May'10 May'10 ----July'10July'10July'10July'10

Aug '10 Aug '10 Aug '10 Aug '10 ––––Oct’ Oct’ Oct’ Oct’ 10101010 OverallOverallOverallOverall

Average Population under surveillanceAverage Population under surveillanceAverage Population under surveillanceAverage Population under surveillance 7854 15893 16457 16906 14938

Person weeksPerson weeksPerson weeksPerson weeks 95414 191532 211637 213148 711731

Incident FARI CasesIncident FARI CasesIncident FARI CasesIncident FARI Cases 1515 1158 1789 4933 9395

Total Influenza Positive (%) 24 9 10 23 19

2009A/H1N1 Positivity (%)2009A/H1N1 Positivity (%)2009A/H1N1 Positivity (%)2009A/H1N1 Positivity (%) 231 (21) 1(0) 10(1) 507(13) 749 (10)

Seasonal influenzaSeasonal influenzaSeasonal influenzaSeasonal influenza positivity (%)positivity (%)positivity (%)positivity (%) 34(3) 88 (9) 143(9) 396 (10) 661(9)

Incidence of Influenza Incidence of Influenza Incidence of Influenza Incidence of Influenza ((((per 1000 person years)per 1000 person years)per 1000 person years)per 1000 person years)

205 (185-227)

28( 23-34)

43( 37-50)

278 (262-294)

128 (122-134)

Incidence for Incidence for Incidence for Incidence for 2009A(H1N1) 2009A(H1N1) 2009A(H1N1) 2009A(H1N1) Influenza Influenza Influenza Influenza (per (per (per (per 1000 person years) 1000 person years) 1000 person years) 1000 person years)

179 (160-199)

0.0 (0-1) 3 (1-5)156( 144-

168)68(64-72)

Incidence for Seasonal Influenza Incidence for Seasonal Influenza Incidence for Seasonal Influenza Incidence for Seasonal Influenza (B)(B)(B)(B)(per (per (per (per 1000 person years) 1000 person years) 1000 person years) 1000 person years)

26 (19-35)

28 (23-34)

40( 34-47)

116 (106-127)

58 (54-62)

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N=3,697

Total FARIs 2,744

Total person-weeks observation 148,528

A(H1N1)pdm09 269 (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

Children in the Vaccine Study: Year 1 Virology

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Provided by S. Broor

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� Phase 2

� Period of study : 2012-2014

� 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 2nd year

(2013) , followed by weekly surveillance till 2014

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2012-2013 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

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Villages of Villages of Villages of Villages of

BallabgarhBallabgarhBallabgarhBallabgarh

1111stststst

DoseDoseDoseDose 2222ndndndnd DoseDoseDoseDose

Dayalpur 1078 39

Chandawali 1044 49

Atali 1303 64

Total 3425 152

94% of eligible children received age appropriate vaccination (Age group 6 month- 10 years

Two rounds of vaccination were held children received 1 or 2 doses appropriate to age

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Villages of Villages of Villages of Villages of

BallabhgaBallabhgaBallabhgaBallabhga

rhrhrhrh

The age group-wise enrollments

0-<5 yrs 5-<15yrs 15-<65yrs

65yrs and

above Total

DayalpurDayalpurDayalpurDayalpur 538 1088 3936 321 5883

ChandawaChandawaChandawaChandawa

lililili 558 946 2984 174 4661

AtaliAtaliAtaliAtali 682 1358 4240 291 6571

Total Total Total Total

enrollmenenrollmenenrollmenenrollmen

tstststs 1778 3392 11160 786 17116

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Viruses # (% positive)

Total samples 382 /129 (33.7%)

respiratory syncytial virus (RSV) 11 (8.5%)

adenovirus 13 (10%)

parainfluenza 1 7 (5.4%)



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 commonononon

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Month wise distribution of non-influenza respiratory

viruses

March-april May-June July-Aug Sep-Oct

RSV ADV PIV1/2/3 HMPV hRV CoV1/2/3/4

Months

Nu

mb

er o

f P

osi

tives

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Percentage positivity of samples in different age groups

45

3438

35

18

30

41

30

0

20

40

60

80

100

120

140

0-5 >5-10 >10-

20

>20-

30

>30-

40

>40-

50

>50-

60

>60

Total samples

Total no. of pathogen detected

%positivity

Age groupTotal

samples

Total no.

of

pathogen

detected

%

positiive

0-5 132 60 45

>5-10 47 16 34

>10-20 48 18 38

>20-30 40 14 35

>30-40 33 6 18

>40-50 20 6 30

>50-60 32 13 41

>60 30 9 30

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( Total paired samples tested 164

Viruses Seroconversion

N (%)

Seroconversion

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 titre rise by ≥ 4 fold

� ~50% of the paired tested samples belong to control group

� Age group : 3-7 years

HAI assays on vaccine recipients in 2009 and 2010

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2009 ( Total paired samples tested 164 2010 (Total Paired Samples Tested 371)

Viruses No. (%) with Sero-protective

levels /GMTViruses

No. (%) with Sero-

protective levels/GMT

(Pre -

vaccination )

(Post -

vaccination)

(Pre -

vaccination )

(Post –

vaccination)

(B/Brisbane/60/

2008)

23 (14.%)/ 22.9 69 (42%)/82 (B/Brisbane/60/

2008)

219 (59.%)/

81.1

257 69.3%)/

129.3

(A/H3/Brisbane/10

/2007)

98 (59.8%)/

67.7

117(71.3%)/

158.4(A/H3/Perth/16/

2009 like strain

derived from

A/Victoria/210/

2009

260 (70.1%)

/169.7

286 (77%)/

303.4

(A/H1/Brisbane

/59/2007)

27 (16.5%)/

23.2

80 (48.8%)/

103.9(A/H1/California/7

/2009)

207 (55.8%)

/108.7

248 (66.8%)

/162.2

� HAI Antibody titers ≥ 40 considered seroprotective.

Seroprotective Antibody Levels pre-vaccination

and post-vaccination

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� 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),

3rd 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

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� To assess genetic drift of pandemic H1N1, H3, and Influenza

B over at least 5 years (2009-2014)

� 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

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� 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

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� 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 Vaccine against laboratory confirmed

influenza among children 2-10 years of age in a rural

north Indian community

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� 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

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� 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 vs Placebo comparisons have not been done in a limited resource setting. Since a large community based TIV vs Placebo trial is already underway at Ballabgarh AIIMS, the same is a not that important an objective for the present study

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� 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

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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 vs Placebo : 622 in each group totals to 1866 child years

� For TIV VS placebo (466 in each group) = 912 child years )

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� 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 2013

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� Broor S, Sullender WS, Fowler K, Gupta V, Widdowson MA, Krishnan A, Lal RB. Demographic Shift of Influenza A(H1N1)pdm09 during and after Pandemic, Rural India. Emerg. Infect. Dis. 18:1472-1475, 2012.

� Sullender W, Fowler K, Anand K, Gupta V, Moulton L, Lafond K, Widdowson M-A, Lal RB 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,30:5235-5239, 2012.

� Mir MA, Lal RB, Sullender W, Krishnan A, Singh Y, Broor S. Genetic Diversity of HA1 Domain of hemagglutinin gene of the pandemic influenza A (H1N1) 2009 viruses in north India. J Med Virol. 84:386-393, 2012.

� Fowler K, Broor S, Sullender W, Gupta V, Debjani RP, Widdowson MA, Lal RB, Krishnan A. Incidence rate of symptomatic Influenza A(H1N1)pdm09 and seasonal influenza infection in a rural Indian community. Submitted

� Debjani RP, Gupta V, Broor S, Sullender W, Fowler K, Widdowson M-A, Lal RB, 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

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� Wayne Sullender, University of Colorado Denver: PI

� Shobha Broor, Department of Microbiology, All India Institute of Medical Sciences (AIIMS), New Delhi India : India main collaborator

� Anand Krishnan (phase 1); Shashi Kant (phase 2) Comprehensive Rural Health Services Project, Ballabgarh and Centre for Community Medicine, AIIMS, Delhi, India : community health partners

� Karen Fowler, University of Alabama Birmingham USA : Study data management and analysis

� Vivek Gupta, INCLEN Trust, Delhi ((phase 1) : Study co-ordinator for community

� Narender Arora INCLEN Trust, Delhi ((phase 2) : INCLEN Trust partner

� Renu Lal, Influenza co-ordinator US Embassy, India, CDC

� Marc-Alain Widdowson, Influenza Division, CDC

Funded by the Influenza Division of the CDC

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� 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

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virus typesvirus typesvirus typesvirus types Northern Northern Northern Northern Hemisphere 2009Hemisphere 2009Hemisphere 2009Hemisphere 2009----2010 vaccine2010 vaccine2010 vaccine2010 vaccine

Circulating Circulating Circulating Circulating strains, strains, strains, strains, BallabhgarhBallabhgarhBallabhgarhBallabhgarh

Vaccine: circulating virus Vaccine: circulating virus Vaccine: circulating virus Vaccine: circulating virus match match match match

Vaccination 2009 (completed)Vaccination 2009 (completed)Vaccination 2009 (completed)Vaccination 2009 (completed)(H1N1)pdm09 A/Brisbane/10/20

07Pandemic 2009A/H1N1

Mismatch

H3N2 A/Brisbane/59/2007

None

Influenza B B/Brisbane/60/2008

Influenza B Good Match

Vaccination 2010 (completed)Vaccination 2010 (completed)Vaccination 2010 (completed)Vaccination 2010 (completed)(H1N1)pdm09 A/California/7/20

09 Yes Yes

H3N2 A/Perth/16/2009 some Seqquencing of 7 H3 has shown good homology

Influenza B B/Brisbane/60/2008

Yes 30/35 are Victoria lineage, and 5 of Yamagata lineage)

Vaccination 2011 (Completed)Vaccination 2011 (Completed)Vaccination 2011 (Completed)Vaccination 2011 (Completed)(H1N1)pdm09 A/California/7/20

09 TBD TBD

H3N2 A/Perth/16/2009 TBD TBDInfluenza B B/Brisbane/60/20

08TBD TBD

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Entrance to large compound with several families

Two families share common space Separate door and shared entry

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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.

dr. s. broor all india institute of medical sciences new ......all india institute of medical...

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