Trial Outcomes & Findings for Causes of Rotavirus Vaccine Failure in Zambian Children (NCT NCT01886833)

Results Overview

The primary exposure in this cohort is maternal IgA status, as we believe breast milk IgA is the most critical factor in failed vaccination, and maternal IgA has previously been estimated to be either high level (approximately 55%) or undetectable or low level (approximately 45%). We will collect maternal serum and breast-milk IgA at the time of vaccination and then measure infant anti-rotavirus-specific serum IgA levels 1 month following the second dose of Rotarix™ (GlaxoSmithKline) rotavirus vaccine.

Recruitment status

COMPLETED

Target enrollment

420 participants

Primary outcome timeframe

1 month following full immunization

Results posted on

2018-08-23

Participant Flow

420 mother-infant pairs were recruited between April 2013-March 2014 from Kamwala Health Care Clinic during routine immunisation. Enrolled mother-infant pairs will undergo baseline procedures and were followed prospectively until March 2017 at scheduled visits at baseline, 1, 3, 12, 15 and 42 months. and unscheduled visits if infant was unwell.

Participant milestones

Participant milestones
Measure	Mother-infant Pair IgA Proportion of Immunized Infants Exposed to High Breast Milk anti-rotavirus IgA Who Fail to Seroconvert will be calculated comparing baseline to after 1 month of full immunization.
Overall Study STARTED	420
Overall Study COMPLETED	216
Overall Study NOT COMPLETED	204

Reasons for withdrawal

Reasons for withdrawal
Measure	Mother-infant Pair IgA Proportion of Immunized Infants Exposed to High Breast Milk anti-rotavirus IgA Who Fail to Seroconvert will be calculated comparing baseline to after 1 month of full immunization.
Overall Study IgA not available from both periods	204

Baseline Characteristics

Causes of Rotavirus Vaccine Failure in Zambian Children

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Mother-Infant Pair n=420 Participants The study will involve consenting mother-infant pairs from Kamwala health facility in Lusaka where the Maternal Child Health (MCH). Those generally interested will be invited to the research clinic, where more detailed information about the study is offered. Motivated mothers will be recruited and taken through the written informed consent process by the study nurse. Enrolled mother-infant pairs will undergo baseline procedures as earlier described. They will then be followed prospectively until about December 2016. They will be expected to come to the clinic for scheduled visits at baseline, 1, 3, 12, 15 and 42 months. They will be urged to come to the clinic for unscheduled visit should the infant be unwell at any time, and particularly each time the infant experiences diarrhoea.
Age, Continuous	27 months n=5 Participants
Sex: Female, Male Female	232 Participants n=5 Participants
Sex: Female, Male Male	188 Participants n=5 Participants
Region of Enrollment Zambia	420 participants n=5 Participants

PRIMARY outcome

Timeframe: 1 month following full immunization

Population: Of the 420 participants that were enrolled in the study, we had rotavirus specific paired IgA at baseline and post vaccination for 216 infants.

The primary exposure in this cohort is maternal IgA status, as we believe breast milk IgA is the most critical factor in failed vaccination, and maternal IgA has previously been estimated to be either high level (approximately 55%) or undetectable or low level (approximately 45%). We will collect maternal serum and breast-milk IgA at the time of vaccination and then measure infant anti-rotavirus-specific serum IgA levels 1 month following the second dose of Rotarix™ (GlaxoSmithKline) rotavirus vaccine.

Outcome measures

Outcome measures
Measure	Mother-Infant Pair n=216 Participants The proposed study will recruit a prospective cohort of 420 mother-infant pairs. These will be enrolled at the time of vaccination (6-12 week old infant) and followed for up to four years. Baseline immunological status will be ascertained and seroconversion rates determined a month after full immunization.
Proportion of Immunized Infants Exposed to High Breast Milk Anti-rotavirus Immunoglobulin-A Who Fail to Seroconvert	0.602 Proportion of exposed infants

PRIMARY outcome

Timeframe: 1 month after full immunisation

Population: We did not test the serum IgG collected at 1 month following the second dose of Rotarix™ rotavirus vaccine because all infants were seropositve at baseline

The co-primary exposure in this cohort is transplacentally acquired anti-rotavirus immunoglobulin-G. We will collect infant serum at baseline before any vaccination and then measure the levels of anti-rotavirus-specific serum IgG and will also obtain the same at 1 month following the second dose of Rotarix™ rotavirus vaccine.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 1 month after the two vaccine doses

Population: Of the 420 mothers, 125 were confimed HIV+

To evaluate whether maternal HIV infection (as well as level of CD4 count) affects infant vaccine take, we will collect the maternal HIV status, (and CD4 count if +ve). We will then correlate the maternal HIC status and CD4 count levels to infant zero conversion at 1 month after the two vaccine doses.

Outcome measures

Outcome measures
Measure	Mother-Infant Pair n=125 Participants The proposed study will recruit a prospective cohort of 420 mother-infant pairs. These will be enrolled at the time of vaccination (6-12 week old infant) and followed for up to four years. Baseline immunological status will be ascertained and seroconversion rates determined a month after full immunization.
Proportion of Immunized Infants Exposed to Maternal HIV Infection Who Fail to Seroconvert	0.704 Proportion of exposed infants

SECONDARY outcome

Timeframe: 1 month after full immunization

Population: Of the 216 infants with paired serum IgA at baseline and after 1 month of complete immunization, 164 had deficient micronutrients

To evaluation whether nutritional status affects vaccine take, we will assess the immunized infant's nutritional status as indicated by serum level of zinc and vitamin A. These will be correlated to seroconversion results.

Outcome measures

Outcome measures
Measure	Mother-Infant Pair n=164 Participants The proposed study will recruit a prospective cohort of 420 mother-infant pairs. These will be enrolled at the time of vaccination (6-12 week old infant) and followed for up to four years. Baseline immunological status will be ascertained and seroconversion rates determined a month after full immunization.
Proportion of Immunized Infants With Low Micronutrient Levels (as Indicated by Serum Zinc and Vitamin A), Who Fail to Seroconvert	0.5 Proportion micronutritionally deficient

OTHER_PRE_SPECIFIED outcome

Timeframe: 42 months

Population: There were 81 episodes of diarrhoea from which samples were collected. 15 were positive for rotavirus by EIA

Determination of genotype in every rotavirus causing severe gastroenteritis will be done each time stool samples are collected for diarrhoea. Patients presenting with any diarrhoea will be tested for rotavirus and staged clinically (by Vesikari score). Those with severe disease (e.g., Vesikari \>11/20) will be processed for genotype. Thus, we will identify the number of rotavirus cases following vaccination as well as identify the strain in those with severe disease. This will allow for "wild type versus vaccine"strain mismatch evaluation. We anticipate that the circulating strains in the community will change in response to vaccine pressure at the population level. However, when interpreting reasons for vaccine failure, it is critically important to evaluate strain mismatch because the way to approach this type of breakthrough disease is dramatically different than if there is breakthrough infection to vaccine strain rotavirus.

Outcome measures

Outcome measures
Measure	Mother-Infant Pair n=81 stool samples The proposed study will recruit a prospective cohort of 420 mother-infant pairs. These will be enrolled at the time of vaccination (6-12 week old infant) and followed for up to four years. Baseline immunological status will be ascertained and seroconversion rates determined a month after full immunization.
Sero-epidemiology of Breakthrough Rotavirus Infection in Immunized Infants G1P8	4 stool samples
Sero-epidemiology of Breakthrough Rotavirus Infection in Immunized Infants G2P6	3 stool samples
Sero-epidemiology of Breakthrough Rotavirus Infection in Immunized Infants G1P6	2 stool samples
Sero-epidemiology of Breakthrough Rotavirus Infection in Immunized Infants Untypable	6 stool samples
Sero-epidemiology of Breakthrough Rotavirus Infection in Immunized Infants Negative for rotavirus	66 stool samples

Adverse Events

Mother-Infant Pair

Serious events: 51 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Mother-Infant Pair n=420 participants at risk The proposed study will recruit a prospective cohort of 420 mother-infant pairs. These will be enrolled at the time of vaccination (6-12 week old infant) and followed for up to four years. Baseline immunological status will be ascertained and seroconversion rates determined a month after full immunization.
General disorders fever and convulsions	0.48% 2/420 • Number of events 2 • 4 years The quarterly in-clinic follow up of infants will invariably lead to early identification of medical problems. These will be treated immediately in the clinic as per national guidelines. Cases needing hospitalization will be transferred to the University Teaching Hospital.
General disorders Hospitalization	9.3% 39/420 • Number of events 39 • 4 years The quarterly in-clinic follow up of infants will invariably lead to early identification of medical problems. These will be treated immediately in the clinic as per national guidelines. Cases needing hospitalization will be transferred to the University Teaching Hospital.
Gastrointestinal disorders Diarrhoea	0.24% 1/420 • Number of events 1 • 4 years The quarterly in-clinic follow up of infants will invariably lead to early identification of medical problems. These will be treated immediately in the clinic as per national guidelines. Cases needing hospitalization will be transferred to the University Teaching Hospital.
Gastrointestinal disorders Diarrhoea plus vomiting	0.24% 1/420 • Number of events 1 • 4 years The quarterly in-clinic follow up of infants will invariably lead to early identification of medical problems. These will be treated immediately in the clinic as per national guidelines. Cases needing hospitalization will be transferred to the University Teaching Hospital.
Respiratory, thoracic and mediastinal disorders acute pneumonia	0.24% 1/420 • Number of events 1 • 4 years The quarterly in-clinic follow up of infants will invariably lead to early identification of medical problems. These will be treated immediately in the clinic as per national guidelines. Cases needing hospitalization will be transferred to the University Teaching Hospital.
Social circumstances severe burns	0.24% 1/420 • Number of events 1 • 4 years The quarterly in-clinic follow up of infants will invariably lead to early identification of medical problems. These will be treated immediately in the clinic as per national guidelines. Cases needing hospitalization will be transferred to the University Teaching Hospital.
Infections and infestations Fever and malaria	0.24% 1/420 • Number of events 1 • 4 years The quarterly in-clinic follow up of infants will invariably lead to early identification of medical problems. These will be treated immediately in the clinic as per national guidelines. Cases needing hospitalization will be transferred to the University Teaching Hospital.
Injury, poisoning and procedural complications injuries	0.24% 1/420 • Number of events 1 • 4 years The quarterly in-clinic follow up of infants will invariably lead to early identification of medical problems. These will be treated immediately in the clinic as per national guidelines. Cases needing hospitalization will be transferred to the University Teaching Hospital.
General disorders death from unknown causes	0.95% 4/420 • Number of events 4 • 4 years The quarterly in-clinic follow up of infants will invariably lead to early identification of medical problems. These will be treated immediately in the clinic as per national guidelines. Cases needing hospitalization will be transferred to the University Teaching Hospital.

Other adverse events

Adverse event data not reported

Additional Information

Dr. Roma Chilengi

CIDRZ

Phone: +2609173724935

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place