Rotavirus Diarrhea, Tropical Enteropathy, Vaccine Virus Shedding
Conditions
Keywords
Oral Vaccines, Vaccine Responsiveness, Tropical Enteropathy
Brief summary
Oral polio and rotavirus vaccines are significantly less effective in children living in the developing world. Tropical enteropathy, which is associated with intestinal inflammation, decreased absorption and increased permeability, may contribute substantially to oral vaccine failure in developing country settings. Other possible causes of oral vaccine underperformance include malnutrition, interference with maternal or breastmilk antibodies, changes in gut microbiota, and genetic susceptibility. Primary Objective: to determine whether tropical enteropathy impairs the efficacy of oral polio and rotavirus vaccines in children in Bangladesh. Secondary Objectives: 1) to determine the impact of an IPV (inactivated polio vaccine) boost on the efficacy of OPV (oral polio vaccine) and 2) to determine the efficacy of Rotarix oral rotavirus vaccine to prevent rotavirus diarrhea The polio and rotavirus randomized clinical trials are embedded as secondary objectives within the exploratory study of tropical enteropathy. The primary and secondary outcome measures are relevant to the randomized clinical trials.
Interventions
BIOLOGICALIPV (inactivated polio vaccine)
Administered per protocol
BIOLOGICALRotarix
Administered per protocol
Sponsors
Bill and Melinda Gates Foundation
University of Virginia
International Centre for Diarrhoeal Disease Research, Bangladesh
Washington University School of Medicine
Stanford University
Centers for Disease Control and Prevention
University of Vermont
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 7 Days
Healthy volunteers
Yes
Inclusion criteria
1. Mother willing to sign informed consent form. 2. Healthy infant aged 0 to 7 days old. 3. No obvious congenital abnormalities or birth defects. 4. No abnormal (frequency and consistency) stools since birth. 5. Stable household with no plans to leave the area for the next one year.
Exclusion criteria
1. Parents are not willing to have child vaccinated at the field clinic. 2. Parents are not willing to have child's blood drawn. 3. Parents are planning to enroll child into another clinical study during the time period of this trial. 4. Mother not willing to have blood drawn and breast milk extracted. 5. Parents not willing to have field research assistant in home two times per week. 6. History of seizures or other apparent neurologic disorders. 7. Infant received any vaccines before start of study, except Bacillus Calmette-Guerin (BCG). 8. Infant has any sibling currently or previously enrolled in this study, including a twin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Presence of Fecal Shedding of Polio Vaccine Virus Determined by Culture (Polio Trial) | 25 days following week 52 visit | Any Sabin type poliovirus in any fecal samples at days 0, 4, 11, 18 or 25 following week 52 dose |
| Number of Participants With One or More Episodes of Rotavirus-associated Diarrhea (Rotavirus Trial) | Birth to one year | Diarrheal episode defined as presence of 3 or more abnormally loose stools in 24h period with \>=72 hours separating episodes. Rotavirus antigen detected by ELISA in diarrheal stool. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Presence of Fecal Polio Virus Shedding Within the Three Sabin Strains (Polio Trial) | 25 days following week 52 visit | Frequency (%) of infants excreting poliovirus at any of the 5 time points (day 0, 4,11,18, 25) post week 52 oral polio vaccine dose. Presence of poliovirus is determined by polymerase chain reaction (PCR) |
| Serum Neutralizing Antibody Response (Polio Trial) | 18-40 weeks | Seropositive defined as antibodies present at ≥1:8 dilution, antibody titers \<1:8 were seronegative. Non-seroconversions are those who did not seroconvert between week 18 (post oral polio vaccine dose 2) and week 40, adjusted for residual maternal antibody |
| Duration of Fecal Shedding of Polio Vaccine Virus, Each Sabin Type (Polio Trial) | from day 4 to day 25 following the week 52 visit | Shedding index, calculated as duration days multiplied by mean log (shedding amount) for Sabin types 1, 2, and 3. Outcome is conditioned on infants with at least one detection by quantitative PCR (qPCR) at day 4,11,18, or 25. If shedding data point was missing it was assumed that the infant was not shedding at that time. Lower shedding index is better outcome |
| Total Duration of Rotavirus-associated Diarrheal Episodes (Rotavirus Trial) | Birth to one year | A diarrheal episode is defined as the presence of 3 or more abnormally loose stools in a 24 hour period with at least 72 diarrhea-free hours separating distinct episodes. Rotavirus positive specimens were determined by ELISA Those with no rotavirus diarrheal episodes are counted as duration 0 |
| Total Number of Diarrheal Episodes (Rotavirus Trial) | Birth to one year | A diarrheal episode is defined as the presence of 3 or more abnormally loose stools in a 24 hour period with at least 72 diarrhea-free hours separating distinct episodes |
| Community Fecal Shedding of Polio Vaccine Virus Just Prior to Oral Polio Vaccine Dose at 52 Weeks (Polio Trial) | post 52 weeks | Only 8 infants were shedding at baseline so results are not presented for this outcome due to insufficient data |
Countries
Bangladesh
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rotarix + IPV (Inactivated Polio Vaccine) Rotarix vaccine at 10 and 17 weeks of age plus IPV (inactivated polio vaccine) boost in place of the routine oral polio vaccine dose at 39 weeks | 175 |
| Rotarix + No IPV (Inactivated Polio Vaccine) Oral Rotarix vaccine at 10 and 17 weeks of age and regular routine oral polio vaccine series | 175 |
| No Rotarix + IPV (Inactivated Polio Vaccine) No Rotarix vaccine and IPV (inactivated polio vaccine) boost in place of the routine oral polio vaccine dose at 39 weeks | 175 |
| No Rotarix + No IPV (Inactivated Polio Vaccine) No Rotarix vaccine and routine oral polio vaccine series | 175 |
| Total | 700 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 1 | 2 | 1 | 0 |
| Overall Study | Lost to Follow-up | 3 | 3 | 7 | 10 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 17 | 20 | 26 | 14 |
Baseline characteristics
| Characteristic | Rotarix + IPV (Inactivated Polio Vaccine) | Total | No Rotarix + No IPV (Inactivated Polio Vaccine) | No Rotarix + IPV (Inactivated Polio Vaccine) | Rotarix + No IPV (Inactivated Polio Vaccine) |
|---|---|---|---|---|---|
| Age, Continuous | 5 days | 5 days | 5 days | 6 days | 5 days |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 175 Participants | 700 Participants | 175 Participants | 175 Participants | 175 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 175 Participants | 700 Participants | 175 Participants | 175 Participants | 175 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Bangladesh | 175 participants | 700 participants | 175 participants | 175 participants | 175 participants |
| Sex: Female, Male Female | 85 Participants | 332 Participants | 73 Participants | 91 Participants | 83 Participants |
| Sex: Female, Male Male | 90 Participants | 368 Participants | 102 Participants | 84 Participants | 92 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 175 | 2 / 175 | 1 / 175 | 0 / 175 |
| other Total, other adverse events | 0 / 175 | 0 / 175 | 0 / 175 | 0 / 175 |
| serious Total, serious adverse events | 16 / 175 | 16 / 175 | 20 / 175 | 21 / 175 |
Outcome results
Primary
Number of Participants With One or More Episodes of Rotavirus-associated Diarrhea (Rotavirus Trial)
Diarrheal episode defined as presence of 3 or more abnormally loose stools in 24h period with \>=72 hours separating episodes. Rotavirus antigen detected by ELISA in diarrheal stool.
Time frame: Birth to one year
Population: Intention to treat. All randomized participants are analyzed in the arms to which they were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IPV (Inactivated Polio Vaccine) | Number of Participants With One or More Episodes of Rotavirus-associated Diarrhea (Rotavirus Trial) | 67 Participants |
| No IPV (Inactivated Polio Vaccine) | Number of Participants With One or More Episodes of Rotavirus-associated Diarrhea (Rotavirus Trial) | 114 Participants |
p-value: 0.0000495% CI: [7, 19.8]Chi-squared
Primary
Presence of Fecal Shedding of Polio Vaccine Virus Determined by Culture (Polio Trial)
Any Sabin type poliovirus in any fecal samples at days 0, 4, 11, 18 or 25 following week 52 dose
Time frame: 25 days following week 52 visit
Population: Intention to treat. All participants analyzed as randomized
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IPV (Inactivated Polio Vaccine) | Presence of Fecal Shedding of Polio Vaccine Virus Determined by Culture (Polio Trial) | 99 Participants |
| No IPV (Inactivated Polio Vaccine) | Presence of Fecal Shedding of Polio Vaccine Virus Determined by Culture (Polio Trial) | 109 Participants |
p-value: 0.495% CI: [-9.6, 3.9]Chi-squared
Secondary
Community Fecal Shedding of Polio Vaccine Virus Just Prior to Oral Polio Vaccine Dose at 52 Weeks (Polio Trial)
Only 8 infants were shedding at baseline so results are not presented for this outcome due to insufficient data
Time frame: post 52 weeks
Secondary
Duration of Fecal Shedding of Polio Vaccine Virus, Each Sabin Type (Polio Trial)
Shedding index, calculated as duration days multiplied by mean log (shedding amount) for Sabin types 1, 2, and 3. Outcome is conditioned on infants with at least one detection by quantitative PCR (qPCR) at day 4,11,18, or 25. If shedding data point was missing it was assumed that the infant was not shedding at that time. Lower shedding index is better outcome
Time frame: from day 4 to day 25 following the week 52 visit
Population: This differs from the total population because it is a subset of total participants, limited to only those who shed the virus as determined by quantitative PCR assay (qPCR) Number analyzed differs from the number of participants shedding in outcome 5 (Presence of fecal polio virus shedding) because this shedding subset is determined using a different assay and time frame
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IPV (Inactivated Polio Vaccine) | Duration of Fecal Shedding of Polio Vaccine Virus, Each Sabin Type (Polio Trial) | Sabin type 1 | 17.9 units on a scale | Standard Deviation 4.8 |
| IPV (Inactivated Polio Vaccine) | Duration of Fecal Shedding of Polio Vaccine Virus, Each Sabin Type (Polio Trial) | Sabin type 2 | 18.4 units on a scale | Standard Deviation 4.7 |
| IPV (Inactivated Polio Vaccine) | Duration of Fecal Shedding of Polio Vaccine Virus, Each Sabin Type (Polio Trial) | Sabin type 3 | 17.7 units on a scale | Standard Deviation 4.5 |
| No IPV (Inactivated Polio Vaccine) | Duration of Fecal Shedding of Polio Vaccine Virus, Each Sabin Type (Polio Trial) | Sabin type 1 | 18.5 units on a scale | Standard Deviation 4.5 |
| No IPV (Inactivated Polio Vaccine) | Duration of Fecal Shedding of Polio Vaccine Virus, Each Sabin Type (Polio Trial) | Sabin type 2 | 19.6 units on a scale | Standard Deviation 3.8 |
| No IPV (Inactivated Polio Vaccine) | Duration of Fecal Shedding of Polio Vaccine Virus, Each Sabin Type (Polio Trial) | Sabin type 3 | 16.4 units on a scale | Standard Deviation 4.4 |
Comparison: Sabin type 1 sheddingp-value: 0.5t-test, 2 sided
Comparison: Sabin type 2 sheddingp-value: 0.2t-test, 2 sided
Comparison: Sabin type 3 sheddingp-value: 0.1t-test, 2 sided
Secondary
Presence of Fecal Polio Virus Shedding Within the Three Sabin Strains (Polio Trial)
Frequency (%) of infants excreting poliovirus at any of the 5 time points (day 0, 4,11,18, 25) post week 52 oral polio vaccine dose. Presence of poliovirus is determined by polymerase chain reaction (PCR)
Time frame: 25 days following week 52 visit
Population: Total Intention to treat population, all participants are included as randomized Number shedding differs from the number analyzed in outcome 3 (Duration of fecal shedding of polio vaccine virus) because shedding detection here is based on positive/negative PCR assay result
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IPV (Inactivated Polio Vaccine) | Presence of Fecal Polio Virus Shedding Within the Three Sabin Strains (Polio Trial) | Sabin type 1 | 67 Participants |
| IPV (Inactivated Polio Vaccine) | Presence of Fecal Polio Virus Shedding Within the Three Sabin Strains (Polio Trial) | Sabin type 2 | 22 Participants |
| IPV (Inactivated Polio Vaccine) | Presence of Fecal Polio Virus Shedding Within the Three Sabin Strains (Polio Trial) | Sabin type 3 | 40 Participants |
| No IPV (Inactivated Polio Vaccine) | Presence of Fecal Polio Virus Shedding Within the Three Sabin Strains (Polio Trial) | Sabin type 1 | 72 Participants |
| No IPV (Inactivated Polio Vaccine) | Presence of Fecal Polio Virus Shedding Within the Three Sabin Strains (Polio Trial) | Sabin type 2 | 33 Participants |
| No IPV (Inactivated Polio Vaccine) | Presence of Fecal Polio Virus Shedding Within the Three Sabin Strains (Polio Trial) | Sabin type 3 | 35 Participants |
Comparison: Sabin type 195% CI: [-7.3, 4.5]
Comparison: Sabin type 295% CI: [-7.2, 0.9]
95% CI: [-3.2, 6.1]
Secondary
Serum Neutralizing Antibody Response (Polio Trial)
Seropositive defined as antibodies present at ≥1:8 dilution, antibody titers \<1:8 were seronegative. Non-seroconversions are those who did not seroconvert between week 18 (post oral polio vaccine dose 2) and week 40, adjusted for residual maternal antibody
Time frame: 18-40 weeks
Population: Intention to treat
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IPV (Inactivated Polio Vaccine) | Serum Neutralizing Antibody Response (Polio Trial) | Non-seroconversion Sabin type 1 | 9 Participants |
| IPV (Inactivated Polio Vaccine) | Serum Neutralizing Antibody Response (Polio Trial) | Non-seroconversion Sabin type 2 | 9 Participants |
| IPV (Inactivated Polio Vaccine) | Serum Neutralizing Antibody Response (Polio Trial) | Non-seroconversion Sabin type 3 | 13 Participants |
| No IPV (Inactivated Polio Vaccine) | Serum Neutralizing Antibody Response (Polio Trial) | Non-seroconversion Sabin type 1 | 79 Participants |
| No IPV (Inactivated Polio Vaccine) | Serum Neutralizing Antibody Response (Polio Trial) | Non-seroconversion Sabin type 2 | 62 Participants |
| No IPV (Inactivated Polio Vaccine) | Serum Neutralizing Antibody Response (Polio Trial) | Non-seroconversion Sabin type 3 | 110 Participants |
95% CI: [-40.7, -26.5]
95% CI: [-31.1, -17.5]
95% CI: [-52.6, -38]
Secondary
Total Duration of Rotavirus-associated Diarrheal Episodes (Rotavirus Trial)
A diarrheal episode is defined as the presence of 3 or more abnormally loose stools in a 24 hour period with at least 72 diarrhea-free hours separating distinct episodes. Rotavirus positive specimens were determined by ELISA Those with no rotavirus diarrheal episodes are counted as duration 0
Time frame: Birth to one year
Population: Intention to treat, all included as randomized
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IPV (Inactivated Polio Vaccine) | Total Duration of Rotavirus-associated Diarrheal Episodes (Rotavirus Trial) | 0 days |
| No IPV (Inactivated Polio Vaccine) | Total Duration of Rotavirus-associated Diarrheal Episodes (Rotavirus Trial) | 0 days |
p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
Total Number of Diarrheal Episodes (Rotavirus Trial)
A diarrheal episode is defined as the presence of 3 or more abnormally loose stools in a 24 hour period with at least 72 diarrhea-free hours separating distinct episodes
Time frame: Birth to one year
Population: Intention to treat population, included as randomized
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IPV (Inactivated Polio Vaccine) | Total Number of Diarrheal Episodes (Rotavirus Trial) | 3 episodes |
| No IPV (Inactivated Polio Vaccine) | Total Number of Diarrheal Episodes (Rotavirus Trial) | 3 episodes |
p-value: 0.981Wilcoxon (Mann-Whitney)