Trial Outcomes & Findings for Immunogenicity and Safety of Liquid Bivalent Oral Poliomyelitis Vaccine (NCT NCT02434770)

Last Updated: 2020-03-10

Results Overview

Solicited systemic reactogenicity events evaluated during the week after each vaccination included fever, vomiting, diarrhea, decreased appetite/ poor feeding, irritability, and decreased activity. Reactions were recorded by participant's parents via memory aid. Each event was graded as: Mild (Grade 1): No or minimal interference with usual activities; no medical intervention/therapy required, Moderate (Grade 2): Greater than minimal interference with usual activities; no or minimal medical intervention/therapy required, Severe (Grade 3): Marked limitation in ability to perform usual activities; medical intervention/therapy required, or Potentially life-threatening (Grade 4): Inability to perform basic functions OR Medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death. The overall number of participants who experienced any systemic reaction is reported. Grades are based on maximum severity per participant.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

750 participants

Primary outcome timeframe

7 days after each vaccination (Weeks 0, 6, 10, and 14)

Results posted on

2020-03-10

Participant Flow

Subjects were recruited from the communities in the vicinity of the study clinics (KEMRI/Walter Reed Project Kombewa Clinical Research Center and Obama Children's Hospital in Kisumu and at the Kenya Medical Research Institute/Walter Reed Project in Kericho, Kenya).

Infants were enrolled prior to receipt of the birth dose of bivalent oral poliomyelitis vaccine (bOPV} and were were allocated to 1 of 3 arms: 1. Beijing Bio-Institute Biological Products Co., Ltd. (BBIBP) liquid bOPV Lot 1; 2. BBIBP liquid bOPV Lot 2; and 3. World Health Organization (WHO) prequalified comparator bOPV (BioFarma).

Participant milestones

Participant milestones
Measure	BBIBP bOPV Lot 1 Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 1, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BBIBP bOPV Lot 2 Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 2, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.
Week 1 to Week 18 STARTED	250	250	250
Week 1 to Week 18 Received at Least One Vaccination	249	250	250
Week 1 to Week 18 COMPLETED	235	228	233
Week 1 to Week 18 NOT COMPLETED	15	22	17
Week 18 to Week STARTED	235	228	233
Week 18 to Week COMPLETED	227	220	227
Week 18 to Week NOT COMPLETED	8	8	6

Reasons for withdrawal

Reasons for withdrawal
Measure	BBIBP bOPV Lot 1 Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 1, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BBIBP bOPV Lot 2 Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 2, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.
Week 1 to Week 18 Lost to Follow-up	0	0	2
Week 1 to Week 18 Withdrawal by Subject	6	12	5
Week 1 to Week 18 Received Non-study Polio Vaccine	8	10	9
Week 1 to Week 18 Relocated Out of Study Area	0	0	1
Week 1 to Week 18 Death	1	0	0
Week 18 to Week Lost to Follow-up	2	2	1
Week 18 to Week Withdrawal by Subject	0	0	2
Week 18 to Week Received Non-study Polio Vaccine	6	6	3

Baseline Characteristics

Immunogenicity and Safety of Liquid Bivalent Oral Poliomyelitis Vaccine

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	BBIBP bOPV Lot 1 n=249 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 1, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BBIBP bOPV Lot 2 n=250 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 2, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=250 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	Total n=749 Participants Total of all reporting groups
Age, Continuous	1.0 days n=5 Participants	1.0 days n=7 Participants	1.0 days n=5 Participants	1.0 days n=4 Participants
Sex: Female, Male Female	123 Participants n=5 Participants	111 Participants n=7 Participants	121 Participants n=5 Participants	355 Participants n=4 Participants
Sex: Female, Male Male	126 Participants n=5 Participants	139 Participants n=7 Participants	129 Participants n=5 Participants	394 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	248 Participants n=5 Participants	250 Participants n=7 Participants	250 Participants n=5 Participants	748 Participants n=4 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment Kenya	249 participants n=5 Participants	250 participants n=7 Participants	250 participants n=5 Participants	749 participants n=4 Participants
Length at Enrollment	49.5 centimeters n=5 Participants	49.5 centimeters n=7 Participants	49.0 centimeters n=5 Participants	49.5 centimeters n=4 Participants
Weight at Enrollment	3.2 kilograms n=5 Participants	3.1 kilograms n=7 Participants	3.1 kilograms n=5 Participants	3.1 kilograms n=4 Participants
Body Mass Index (BMI) at Enrollment	12.9 kg/m^2 n=5 Participants	13.0 kg/m^2 n=7 Participants	12.8 kg/m^2 n=5 Participants	12.9 kg/m^2 n=4 Participants

PRIMARY outcome

Timeframe: 7 days after each vaccination (Weeks 0, 6, 10, and 14)

Population: The safety population included all enrolled participants who had safety data available, assigned according to the actual treatment received at Day 0.

Outcome measures

Outcome measures
Measure	BBIBP bOPV Lot 1 n=249 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 1, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BBIBP bOPV Lot 2 n=250 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 2, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=250 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.
Number of Participants Experiencing Any Systemic Reactogenicity, by Maximum Severity Any systemic reaction	187 Participants	179 Participants	175 Participants	—
Number of Participants Experiencing Any Systemic Reactogenicity, by Maximum Severity Grade 1	149 Participants	139 Participants	153 Participants	—
Number of Participants Experiencing Any Systemic Reactogenicity, by Maximum Severity Grade 2	32 Participants	32 Participants	18 Participants	—
Number of Participants Experiencing Any Systemic Reactogenicity, by Maximum Severity Grade 3	6 Participants	8 Participants	4 Participants	—

PRIMARY outcome

Timeframe: From the time of the first vaccination through 28 days after each vaccination (up to Day 126).

Population: Safety population

Adverse events were graded as mild (Grade 1 = No or minimal interference with usual activities; no medical intervention/therapy required), moderate (Grade 2 = Greater than minimal interference with usual activities; no or minimal medical intervention/therapy required), severe (Grade 3 = Marked limitation in ability to perform usual activities; medical intervention/therapy required), or potentially life-threatening (Grade 4 = Inability to perform basic functions OR Medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death). The overall number of participants who experienced any adverse event is reported. Grades are based on maximum severity per participant.

Outcome measures

Outcome measures
Measure	BBIBP bOPV Lot 1 n=249 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 1, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BBIBP bOPV Lot 2 n=250 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 2, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=250 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.
Number of Participants Experiencing Adverse Events Any adverse event	143 Participants	142 Participants	151 Participants	—
Number of Participants Experiencing Adverse Events Grade 1	111 Participants	114 Participants	117 Participants	—
Number of Participants Experiencing Adverse Events Grade 2	24 Participants	17 Participants	27 Participants	—
Number of Participants Experiencing Adverse Events Grade 3	7 Participants	10 Participants	7 Participants	—
Number of Participants Experiencing Adverse Events Grade 4	0 Participants	1 Participants	0 Participants	—
Number of Participants Experiencing Adverse Events Death	1 Participants	0 Participants	0 Participants	—

PRIMARY outcome

Timeframe: Screening and 4 weeks post vaccination 4 (Week 18)

Population: Per Protocol Immunogenicity (PP-IMM) population includes all enrolled participants who were randomized, received all 4 doses of bOPV per the assigned treatment group, had post-vaccination immunogenicity measurement(s),and no major protocol violations that would have potentially interfered with the immunogenicity assessment of the study vaccine.

The assays for determination of anti-poliovirus neutralizing antibodies at the National Institutes for Food and Drug Control (NIFDC) were validated. Anti-polio antibody titer four weeks after the fourth vaccination was adjusted for the decrease in maternal antibodies based on a half-life of 28 days.

Outcome measures

Outcome measures
Measure	BBIBP bOPV Lot 1 n=226 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 1, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BBIBP bOPV Lot 2 n=217 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 2, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=443 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=225 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.
Anti-polio Neutralizing Antibody Geometric Mean Titers (GMT): Serotype 1 Screening	40.9 titer Interval 33.7 to 49.7	41.5 titer Interval 34.0 to 50.6	41.2 titer Interval 35.9 to 47.3	47.7 titer Interval 38.4 to 59.3
Anti-polio Neutralizing Antibody Geometric Mean Titers (GMT): Serotype 1 4 Weeks after vaccination 4	55192 titer Interval 45821.0 to 66478.0	65790 titer Interval 55728.0 to 77668.0	60151 titer Interval 53095.0 to 68144.0	55634 titer Interval 46484.0 to 66586.0

PRIMARY outcome

Timeframe: Screening and 4 weeks post vaccination 4 (Week 18)

Population: Per Protocol Immunogenicity (PP-IMM) population

Outcome measures

Outcome measures
Measure	BBIBP bOPV Lot 1 n=226 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 1, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BBIBP bOPV Lot 2 n=217 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 2, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=443 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=225 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.
Anti-polio Neutralizing Antibody Geometric Mean Titers: Serotype 3 4 Weeks after vaccination 4	11374 titer Interval 9686.0 to 13355.0	12390 titer Interval 10559.0 to 14539.0	11861 titer Interval 10594.0 to 13280.0	8063 titer Interval 6811.0 to 9545.0
Anti-polio Neutralizing Antibody Geometric Mean Titers: Serotype 3 Screening	12.5 titer Interval 10.7 to 14.6	15.6 titer Interval 12.8 to 19.0	13.9 titer Interval 12.3 to 15.8	14.3 titer Interval 12.0 to 17.1

PRIMARY outcome

Timeframe: 4 weeks post vaccination 4 (Week 18)

Population: Per Protocol Immunogenicity (PP-IMM) population

The assays for determination of anti-poliovirus neutralizing antibodies at the National Institutes for Food and Drug Control (NIFDC) were validated. Seroconversion was defined as a titer ≥ 1:8 if seronegative at screening, otherwise a ≥ 4-fold increase in adjusted titers (i.e., adjusted for the decay in maternal antibodies, based on a half life of 28 days).

Outcome measures

Outcome measures
Measure	BBIBP bOPV Lot 1 n=226 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 1, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BBIBP bOPV Lot 2 n=217 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 2, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=443 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=225 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.
Number of Infants With Serotype-specific Anti-polio Neutralizing Antibody Seroconversion 4 Weeks After Last Dose Serotype 1	223 Participants	215 Participants	438 Participants	219 Participants
Number of Infants With Serotype-specific Anti-polio Neutralizing Antibody Seroconversion 4 Weeks After Last Dose Serotype 3	223 Participants	214 Participants	437 Participants	217 Participants

SECONDARY outcome

Timeframe: 4 weeks post vaccination 4 (Week 18)

Population: Participants who received all 4 bOPV vaccinations and ≥ 3 hepatitis B virus vaccinations at least 21 days prior to blood draw.

Anti-HBsAg titers were measured to assess the impact of concomitant administration of BBIBP liquid bOPV on immune responses to other Expanded Programme on Immunization (EPI) vaccines in comparison to that of the WHO pre-qualified bOPV, 4 weeks after the fourth vaccination. The enzyme-linked immunosorbent assay (ELISA) assays for serum antibodies to HBsAg were performed at the Children's Hospital Medical Center (CCHMC). The HBsAb assay was a qualified assay using a kit from BioRad.

Outcome measures

Outcome measures
Measure	BBIBP bOPV Lot 1 n=209 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 1, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BBIBP bOPV Lot 2 n=203 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 2, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=412 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=209 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.
Anti-hepatitis B Surface Antigen (HBsAg) Geometric Mean Titers	320 titer Interval 246.0 to 416.0	322 titer Interval 255.0 to 407.0	321 titer Interval 269.0 to 383.0	267 titer Interval 207.0 to 345.0

SECONDARY outcome

Timeframe: 28 days after vaccination 4

Population: Participants who received all 4 bOPV vaccinations and ≥ 3 hepatitis B virus vaccinations at least 21 days prior to blood draw.

Seroprotection was defined as a HBsAg titer ≥ 1:10 The ELISA assays for serum antibodies to HBsAg were performed at the Children's Hospital Medical Center (CCHMC). The HBsAb assay was a qualified assay using a kit from BioRad.

Outcome measures

Outcome measures
Measure	BBIBP bOPV Lot 1 n=209 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 1, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BBIBP bOPV Lot 2 n=203 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 2, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=412 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=209 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.
Number of Infants With Anti-hepatitis B Surface Antigen (HBsAg) Seroprotection	192 Participants	194 Participants	386 Participants	196 Participants

SECONDARY outcome

Timeframe: 4 weeks post vaccination 4 (Week 18)

Population: Participants who received all 4 bOPV vaccinations and ≥ 2 Rotavirus vaccinations at least 21 days prior to blood draw

Anti-rotavirus immunoglobulin A titers were measured to assess the impact of concomitant administration of BBIBP liquid bOPV on immune responses to other Expanded Programme on Immunization (EPI) vaccines in comparison to that of the WHO pre-qualified bOPV, 4 weeks after the fourth vaccination. The ELISA assay for antibodies to rotavirus was performed at the Children's Hospital Medical Center (CCHMC) using a validated in-house assay.

Outcome measures

Outcome measures
Measure	BBIBP bOPV Lot 1 n=223 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 1, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BBIBP bOPV Lot 2 n=206 Participants Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 2, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=429 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=220 Participants Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.
Anti-Rotavirus Immunoglobulin A (IgA) Geometric Mean Titers	22.7 titer Interval 17.6 to 29.6	35.8 titer Interval 26.8 to 47.8	28.3 titer Interval 23.3 to 34.2	28.6 titer Interval 21.5 to 37.9

Adverse Events

BBIBP bOPV Lot 1

Serious events: 13 serious events

Other events: 143 other events

Deaths: 1 deaths

BBIBP bOPV Lot 2

Serious events: 16 serious events

Other events: 142 other events

Deaths: 0 deaths

BioFarma bOPV

Serious events: 17 serious events

Other events: 151 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Jorge Flores

PATH

Phone: (202) 822-0033

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	BBIBP bOPV Lot 1 n=249 participants at risk Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 1, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BBIBP bOPV Lot 2 n=250 participants at risk Infants received 2 drops of liquid bivalent oral polio vaccine (bOPV) manufactured by BBIBP, Lot 2, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.	BioFarma bOPV n=250 participants at risk Infants received 2 drops of WHO prequalified liquid bivalent oral polio vaccine manufactured by BioFarma, administered directly into the mouth in the first two weeks of life, and at 6, 10, and 14 weeks of age.
Blood and lymphatic system disorders Anemia	0.00% 0/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.80% 2/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.40% 1/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Infections and infestations Breast abcess	0.00% 0/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.40% 1/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Infections and infestations Cellulitis	0.00% 0/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.40% 1/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Infections and infestations Gastroenteritis	0.00% 0/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.80% 2/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.40% 1/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Infections and infestations Malaria	0.00% 0/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.80% 2/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.80% 2/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Infections and infestations Meningitis	0.40% 1/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Infections and infestations Pneumonia	2.4% 6/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	2.8% 7/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	2.4% 6/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Infections and infestations Pyomyositis	0.00% 0/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.40% 1/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Infections and infestations Sepsis	0.40% 1/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.40% 1/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Infections and infestations Sepsis neonatal	1.6% 4/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.80% 2/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	2.0% 5/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Injury, poisoning and procedural complications Head injury	0.00% 0/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.40% 1/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Injury, poisoning and procedural complications Soft tissue injury	0.00% 0/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.40% 1/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Metabolism and nutrition disorders Malnutrition	0.40% 1/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Nervous system disorders Convulsion neonatal	0.00% 0/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.40% 1/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Pregnancy, puerperium and perinatal conditions Jaundice neonatal	1.2% 3/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	1.2% 3/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Gastrointestinal disorders Diarrhoea	0.40% 1/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.
Injury, poisoning and procedural complications Herbal toxicity	0.40% 1/249 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.	0.00% 0/250 • From the time of the first vaccination through completion of the study at 3 months after the last vaccination (Day 182) for serious adverse events and through 28 days after each vaccination (up to Day 126) for non-serious adverse events.