Efficacy of ROTAVAC®

Monovalent 116E Vaccine (BBIL)

Nita Bhandari

Centre for Health Research and Development

Society for Applied Studies, New Delhi, India

A Phase III Randomized Double Blind Placebo Controlled Trial to Evaluate the Protective Efficacy

of Three Doses of Oral Rotavirus Vaccine (ORV) 116E Against Severe Rotavirus Gastroenteritis in Infants

Primary Objective

Efficacy: Evaluate the efficacy of three doses of

ROTAVAC®, 105.0 ffu given concomitantly with childhood

vaccines against severe rotavirus gastroenteritis (≥11 on

the 20-point Vesikari scoring scale) caused by rotavirus,

in comparison with a placebo, occurring after 14 days

after the third dose till the age of 2 years

Severe RV GE Till 12 mo/12-24 mo/ITT up to 24 mo Requiring hospitalization or supervised rehydration therapy

All RV GE Up to 24 mo ageRequiring hospitalization or supervised rehydration therapy

Severe GE Up to 24 mo ageRequiring hospitalization or supervised rehydration therapy

All GE Up to 24 mo ageRequiring hospitalization or supervised rehydration therapy

Very severe GE (≥16 points) Up to 24 mo age

Gastroenteritis: passage of 3 looser-than-normal or watery stools in a 24 hour period with or without vomiting.Severe: ≥11 points on the Vesikari scoring scaleRotavirus: RV in stools

Secondary Objectives: Efficacy

Safety

Immediate adverse events

Adverse events in 2-week period following

administration of each of the three doses

Serious adverse events

Intussusception events

Immunogenicity and Viral shedding

Implementation Strategy

Selection and preparation of sites

(SAS, KEM, CMC, THSTI)

Identification of Subjects

Recruitment of 6800 infants at 6-7 weeks

Administration of ROTAVAC®/placebo (2:1 randomization)

with childhood vaccines: 3 doses at 4 week intervals

Detailed Safety subset (1/3 subjects)

Immunogenicity and viral shedding subset(150 subjects at each site)

Weekly follow up (home visit and phone based)Ascertainment of Primary, Secondary and Safety Outcomes

Management of all illnesses by study team

Follow up till aged 2 years

Study coordinated by Clinical Operations Management Unit

Oversight by Project Management Committee and Vaccine Development Committee

ROTAVAC®

Liquid formulation stored frozen at -20ºC ± 5ºC

Antacid buffer, liquid, given before the vaccine

Stored at room temperature

Childhood vaccines (DPT, Hib and Hep B and

OPV) with three doses of ROTAVAC®/Placebo

Zinc and ORS for all episodes of diarrhea

BCG to those who had not received it previously

Measles, Vitamin A, Boosters (DPT, Hib and Hep B

and OPV)

OPV on National Polio Immunization days

Cointerventions

Families Access to Study Physicians

Mobile phones given to families: Study

contact numbers pre-fed

Weekly contacts made through home

visits or phones; at least one face to

face contact per month

Illnesses managed by study team

Physicians available round the clock.

Home visits made by physician at any

time, if requested

All costs covered by study team

Suspected

Abdominal distension: 2 cm increase in girth over 4 hours

Abdominal lump

Continuous vomiting: ≥3 episodes in an hour

Blood in stools

Management

Pediatrician confirmed presence of signs and symptoms; ultrasonography as

early as possible (not >8 hours)

Pediatric surgeon referral, if intussusception on USG

Stool specimen collected if blood in stools AND any of the above symptoms

present

Intussusception Case Adjudication Committee reviewed cases according

to Diagnostic Certainty Level I of IS (Definite) Criteria developed by Brighton

Collaboration Intussusception Working Group

Intussusception

Flowchart of Subject Disposition

*Discontinued prematurely in the ROTAVAC®/placebo group: Family moved out of study area 58/46, Family

refused further participation 25/12, Death 30/18

N=7848

Subjects screened

N=6799

Subjects enrolled

N=4532

ROTAVAC®

N=2267

Placebo

Reason not enrolled

Non consent: 538

Had an exclusion criteria: 511

Completed follow-up

to age 2 years

4419

Included in the PP

analyses

4354

Included in the PP

analyses

2187

Discontinued prematurely*

113Up to 1 year: 55

Between 1-2 years: 58

Completed follow up

to age 2 years

2191 Discontinued prematurely*

76Up to 1 year: 25

Between 1-2 years: 51

Doses of Administration of ROTAVAC®/Placebo

Received in Enrolled Subjects

No. of subjects

who received

ROTAVAC®

N=4532

Placebo

N=2267

Total

N=6799

Dose 1 4532 (100.0%) 2267 (100.0%) 6799 (100.0%)

Dose 2 4409 (97.3%) 2221 (98.0%) 6630 (97.5%)

Dose 3 4356 (96.1%) 2190 (96.6%) 6546 (96.3%)

Efficacy of ROTAVAC® in Prevention of Gastroenteritis up to 2 Years of Age

Endpoints

nVaccine Efficacy

% (95%CI)p valueROTAVAC®

N= 4354

Placebo

N= 2187

Severe RV GE

Till 2 yrs of age 93 (2%) 102 (5%) 55.1% (39.9, 66.4) <0.0001

Till 1 yr of age 57 (1%) 65 (3%) 56.3% (36.7, 69.9) <0.0001

Severe RV GE requiring hospitalization# or supervised rehydration therapy$

Till 2 yrs of age 92 (2%) 102 (5%) 55.6% (40.5, 66.8) <0.0001

Till 1 yr of age 57 (1%) 65 (3%) 56.3% (36.7, 69.9) <0.0001

Very Severe RV GE

Till 2 yrs of age 12 (<1%) 14 (<1%) 57.2% (0.3, 81.9) 0.0491

Till 1 yr of age 9 (<1%) 9 (<1%) 49.8% (-42.6, 82.4) 0.2176

RV GE of any severity

Till 2 yrs of age 406 (9%) 310 (14%) 36.4% (26.0, 45.3) <0.0001

Till 1 yr of age 226 (5%) 172 (8%) 35.0% (20.2, 46.9) <0.0001

Episodes of severe rotavirus gastroenteritis had a Vesikari score of 11 or greater and presence of rotavirus (Rotaclone positive and

VP6 or VP4 and VP7 positive by RT PCR) strains

Episodes of very severe gastroenteritis had a Vesikari score of 16 or greater#Inpatient admission for at least 6 h in a treatment facility or hospital $Administration of oral rehydration salts or intravenous fluids

EndpointsPP

VE (95% CI)P-value

ITT

VE (95% CI)P-value

Till 1 year of age 24.5 (6.3, 38.9) 0.0104 21.5 (4.4, 35.4) 0.0161

Till 2 years of age 21.7 (6.9, 33.9) 0.0053 19.6 (5.4, 31.6) 0.0083

Efficacy of ROTAVAC® against Severe Gastroenteritis

Irrespective of Etiology: Public Health Implications

With ROTAVAC®, around a fifth of all severe gastroenteritis of any etiology

can be prevented in children under 2 years

Efficacy Analysis for Severe Rotavirus Gastroenteritis by Genotype

up to 2 years of age

ROTAVAC®

N= 4354

Placebo

N= 2187

Vaccine Efficacy

% (95%CI)

All* 93 (2.1%) 102 (4.7%) 55.1% (39.9, 66.4)

G1P[8] 40 (0.9%) 34 (1.6%) 42.0% (5.6, 64.2)

G2P[4] 26 (0.6%) 35 (1.6%) 63.4% (37.4, 78.8)

G12P[6] 8 (0.2%) 13 (0.6%) 69.7% (21.1, 89.1)

G12P[8] 5 (0.1%) 8 (0.4%) 69.2% (-6.8, 92.1)

G9P[4] 9 (0.2%) 1 (<0.1%) -343.5% (-19562, 38.5)

Others** 8 (0.2%) 12 (0.5%) 67.1% (12.6, 88.4)

*Total number of subjects included in PP population is 195; 4 subjects had more than 1 episode of severe RV GE and

therefore the total number of episodes 199 is greater than the total number of subjects

**Includes all genotypes causing seven cases or less (G9P[8], G1P[4], G1P[6], G2P[6], G1P[0], G0P[0], G9P[0],

G12P[11])

Immediate Adverse Events - All Three Doses

ROTAVAC® Placebo

P-valueNo. of subjects=4531

No. of doses=13297

No. of subjects=2265

No. of doses=6678

n (%) n (%)

Vomiting 15 (0.3%) 6 (0.3%) 0.82

Infantile spitting up 4 (0.1%) 1 (0)

Rash - 1

All events were mild; none resulted in hospitalization or death

All Events Occurring Within 30 Minute Period Following Vaccination

Solicited Adverse Events by Verbatim

ROTAVAC® PlaceboP-value

No. of subjects=1530 No. of subjects=768

% %

Fever by history 80.7% 81.4% 0.69

Fever by measured

temperature56.1% 57.0% 0.69

Vomiting 11.4% 10.8% 0.73

Diarrhea 23.6% 21.9% 0.37

Cough 41.0% 41.9% 0.69

Runny nose 37.4% 37.2% 0.96

Irritability 17.5% 17.1% 0.82

Rash 8.1% 9.4% 0.30

Other 28.1% 28.0% 1.00

Child based analysis across all three doses

Reported within 14 days after administration of ROTAVAC®/Placebo in detailed safety follow

up subset

Serious Adverse Events

ROTAVAC® Placebo Odds Ratio

(95% CI)

p-value

No. of

subjects=4531

No. of

subjects=2265

One or more SAE during follow up period

No. of subjects 947 (20.9%) 515 (22.7%)0.898

(0.794, 1.016)0.0850

No. of events 1633 (36.0%) 892 (39.4%)

Related SAE

No. of subjects 1 2 0.250

(0.004, 4.801)0.2592

No. of events 1 2

One subject in ROTAVAC® group had an SAE (urticaria) that was labelled as “related” by the PI because

of its temporal association i.e. occurred within a week of administration

ROTAVAC®/Placebo

No. of subjects=4531/2265P-value

No of children who had an SAE 20.9%/22.7% 0.0850

Infections and infestations 17.5%/19.1% 0.1157

Lower respiratory tract infection 5.8%/5.5% 0.5429

Gastroenteritis 4.9%/5.0% 0.9528

Gastroenteritis Rotavirus 1.8%/3.2% 0.0003

Bronchopneumonia 1.7%/1.7% 1.0000

Pneumonia 1.3%/0.9% 0.1916

Urinary tract infection 0.9%/1.0% 0.8942

Respiratory, thoracic and mediastinal

disorders 2.9%/3.1% 0.7624

Wheezing 2.4%/2.4% 1.0000

General disorders and administration site

conditions 1.7%/1.5% 0.6120

Pyrexia 1.4%/1.3% 0.6603

Nervous system disorders 1.2%/1.6% 0.1164

Febrile convulsions 0.6%/1.0% 0.0945

Gastrointestinal disorders 1.0%/1.1% 0.8023

Restricted to those events occurring in at least 1% of subjects in either group

Serious Adverse Events by MedDRA System Organ Classification and Preferred Terms

30 (0.7%) among the 4531 subjects in

ROTAVAC® group and 18 (0.8%) among the

2267 subjects in placebo group

None considered related to vaccination

Deaths

Intussusception (Brighton Diagnostic Criteria Level 1)

ROTAVAC® Placebo P-Value

(N=4532) (N=2267)

No. of Subjects (%) No. of Subjects (%)

Confirmed IS

meeting

Brighton

Criteria

8/4532 (0.2%) 3/2267 (0.1%) 0.7613

No cases of intussusception occurred between dose 1 and 2 &

dose 2 and 3

Interval between Administration of ROTAVAC®/Placebo

and Occurrence of Intussusception by Brighton Criteria

ROTAVAC® Placebo

(N=4532) (N=2267)

112 days 36 days

128 days 136 days

141 days 605 days

142 days -

241 days -

291 days -

386 days -

587 days -

Immunogenicity: 40.3% seroconverted (≥4 fold increase) in ROTAVAC® group and 18.4% in placebo; OR 2.9 (95% CI 1.7, 5.1; p <0.0001)

Viral Shedding: G9P[11] was shed in 12.2% of ROTAVAC® recipients after dose 1, 2% after dose 2 and 1.3% after dose 3

Conclusions

ROTAVAC® is efficacious in prevention of

severe RVGE (primary endpoint)

RVGE of any severity

severe GE of any etiology

Reduces hospitalizations and supervised rehydration

therapy:

Due to severe RVGE

Due to severe GE

Offers broad protection against most commonly

circulating rotavirus genotypes in India

Lancet 2014; 383:2136-43.

Vaccine 2014; 32 (Suppl 1): A110-116

Well tolerated when administered with other routine

childhood vaccines

Well tolerated with respect to solicited adverse events

(fever, vomiting, diarrhea, cough, runny nose, irritability,

and rash)

At this stage of evaluation, no evidence of increased

risk of intussusception

Moderately immunogenic as measured by serum anti-

RV IgA

Shedding of vaccine strain low

Safety

BBIL led, prospective pharmacovigilance; DCGI

oversight

Limited rollout of ROTAVAC® through the public health

system using self controlled case series method

(recommended by International Regulatory bodies

WHO, CDC, NIH for emerging countries) - investigator

based (CMC, KEM, SAS,INCLEN); interministerial

oversight

Next Steps

Thank you

Kaplan-Meier Survival Curve for Severe Rotavirus Gastroenteritis

Per Protocol Population: Time 0 Represents 15 days after Receipt of the Third Dose of ROTAVAC®

or Placebo

Forest Plot of Incidence Rate Ratio on Log Scale by Case Definition:

Efficacy PP Population

Severe RVGE upto 2 years

Severe RVGE until 1 year

Severe RVGE in 1-2 years

RVGE of any severity upto 2 years

RVGE any severity requiring hospitalization

Severe RVGE requiring hospitalization

Very severe RVGE upto 2 years

RVGE requiring hospitalization >= 6 hrs upto 2 years

or supervised rehydration therapy upto 2 years

or supervised rehydration therapy upto 2 years

1.1 1 10 100Incidence Rate Ratio

Immune Response (GMT) to OPV Serotypes 1, 2, and 3

in Immunogenicity Subset

VisitOPV

Serotype

ROTAVAC®

N=262

Placebo

N=123

Observed

GMT Ratio

(ROTAVAC®/

Placebo)

Two-sided

95% CI on

GMT RatioGMT 95% CI GMT 95% CI

Pre-

vaccination

1 72.7 (58.1, 90.9) 64.9 (48.0, 87.9) 1.12 (0.76, 1.65)

2 49.0 (40.3, 59.7) 44.4 (33.4, 59.0) 1.10 (0.78, 1.56)

3 18.3 (15.1, 22.1) 16.1 (12.4, 20.8) 1.14 (0.82, 1.58)

Post-

vaccination

1 367.5 (310.1, 435.6) 397.6 (309.5, 510.7) 0.92 (0.68, 1.25)

2 421.2 (367.3, 483.0) 440.7 (362.2, 536.2) 0.96 (0.75, 1.21)

3 145.3 (120.3, 175.5) 161.0 (121.0, 214.2) 0.90 (0.64, 1.26)

Vis

it

OPV

Seroty

pe

Titer ≥8 Observed Rate

Difference

(ROTAVAC®/

Placebo)

Two-sided 95%

CI on Rate

DifferenceROTAVAC® (N=262) Placebo (N=123)

n % 95% CI n % 95% CI

Pre

-vac

cin

atio

n 1 214 81.7 (76.5, 86.2) 123 85.4 (77.9, 91.1) -3.7 (-11.0, 4.8)

2 212 80.9 (75.6, 85.5) 123 81.3 (73.3, 87.8 -0.4 (-8.2, 8.5)

3 116 44.3 (38.2, 50.5) 123 46.3 (37.3, 55.6) -2.1 (-12.6, 8.4)

Po

st-v

acci

nat

ion 1 250 95.4 (92.1, 97.6) 123 94.3 (88.6, 97.7) 1.1 (-3.3, 7.0)

2 257 98.1 (95.6, 99.4) 123 98.4 (94.2, 99.8) -0.3 (-3.0, 4.0)

3 234 89.3 (84.9, 92.8) 123 88.6 (81.6, 93.6) 0.7 (-5.5, 8.2)

Seroprotection Rates Against OPV Serotypes 1, 2, and 3 in the

Immunogenicity Subset