Causes of Rotavirus Vaccine Failure in Zambian Children

NCT01886833 | Completed Results

• 2 other identifiers: ROVAS 011R01AI099601-01
• Study Type: observational
• Target: 420
• Locations: 1 country
• Sites: 1

Brief Summary

Zambia recently introduced routine infant immunization against rotavirus - the most important cause of severe gastroenteritis and diarrhoea mortality in children. Although vaccines like Rotarix are a cost effective tool against infectious diseases, live oral vaccines can be less immunogenic and efficacious in developing world settings as compared with industrialized countries. Reasons behind this phenomenon are not well understood, but may relate to continued maternal antigen exposure and high level maternal immunity that is passed to the foetus/newborn transplacentally and/or through breast milk. Therefore, three arising hypotheses include: (i) high-level rotavirus-specific maternal immunity (in the form of anti-rotavirus breast-milk immunoglobulin A (IgA) and transplacental serum IgG) is a major contributor to failed seroconversion following infant vaccination. (ii) Malnutrition negatively impacts infant immunity and increases the risk of post-vaccination rotavirus gastroenteritis. (iii) Introduction of rotavirus vaccine will alter the molecular epidemiology of circulating rotavirus strains detected in vaccinated children presenting with severe diarrhea. To address these hypotheses, the proposed study will recruit a prospective cohort of 420 mother-infant pairs. These will be enrolled at the time of vaccination and followed for up to four years. Baseline immunological status will be ascertained and seroconversion rates determined a month after full immunization. Incident rotavirus gastroenteritis will be monitored in the vaccinated infants whenever episodes of diarrhoea occur; through this surveillance, the sero-strains of rotaviruses causing disease will be tracked over the four year period. Contributions of HIV infection both in mothers and infants, vitamin A and zinc deficiency, weight for age Z-scores as well as mid upper arm circumference will also be assessed. Knowledge gained from this study will inform future interventional trials on strategies to improve rotavirus vaccine effectiveness in the developing world.

Conditions

Diarrhoea

Keywords

Rotavirus; Diarrhoea; Immunisation; Seroconversion; Breastmilk; HIV; Zinc; Vitamin A; Failure

Outcome Measures

Primary Outcomes (3)

• Proportion of Immunized Infants Exposed to High Breast Milk Anti-rotavirus Immunoglobulin-A Who Fail to Seroconvert

  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.

  1 month following full immunization

• Proportion of Immunized Infants Exposed to Transplacentally-acquired, Rotavirus-specific, Infant Serum IgG Who Fail to Sero-convert.

  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.

  1 month after full immunisation

• Proportion of Immunized Infants Exposed to Maternal HIV Infection Who Fail to Seroconvert

  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.

  1 month after the two vaccine doses

Secondary Outcomes (1)

• Proportion of Immunized Infants With Low Micronutrient Levels (as Indicated by Serum Zinc and Vitamin A), Who Fail to Seroconvert

  1 month after full immunization

Other Outcomes (1)

• Sero-epidemiology of Breakthrough Rotavirus Infection in Immunized Infants

  42 months

Study Arms (1)

Mother-Infant Pair

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.

Eligibility Criteria

• Age: 6 Weeks - 15 Weeks
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

Mother-infant pairs presenting for MCH at Kamwala health facility in Lusaka and where the infant is 6-15 weeks old, will be recruited into the cohort and followed for a period of 1-4 years depending on time of enrolment.

You may qualify if:

• Mother willing to participate voluntarily and able to provide signed informed consent (with witness in the case of illiterate participant)
• Infant eligible for rotavirus vaccine immunization as per national policy (male or female infant, 6-12 weeks old)
• Mother willing to undergo study procedures, including questionnaires, HIV counselling and testing, CD4 testing, and provide breast milk and blood sample at enrolment.
• Mother willing for child to undergo study procedures including full-course rotavirus vaccination, phlebotomy at enrolment and 1 month post-rotavirus vaccination, and presentation to clinic for collection of stool sample when infant has diarrhoea.
• Plans to remain resident in the area and willing to come for scheduled visits for the duration of the study.

You may not qualify if:

• Contraindication to rotavirus vaccination.
• Previous administration of rotavirus vaccine to child.
• Recent immunosuppressive therapy in child (including high-dose systemic corticosteroids).
• History of ever receiving a blood transfusion or blood products, including immunoglobulins within the last 6 months, for mother and child.
• Mother plans for herself or child to move away from the study catchment area within the next two years.
• Any condition deemed by the study investigator to pose potential harm to the participants or jeopardize the validity of study results.

Sponsors & Collaborators

• Centre for Infectious Disease Research in Zambia: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (1)

Centre for Infectious Disease Research in Zambia

Lusaka, 10101, Zambia

Location

Biospecimen

Retention: SAMPLES WITH DNA

Blood samples for immunogenicity testing will be analyzed in batches. Stool samples for rotavirus extraction will also be stored and analyzed in batches.

MeSH Terms

Conditions

Diarrhea; HIV Seropositivity

Condition Hierarchy (Ancestors)

Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Limitations and Caveats

If vaccine strains are a mis-match of vaccine strain and non-vaccine strain that remains constant and unchanged over time, it would favour multiple reasons for vaccine failure, making identification of solutions difficult.

Results Point of Contact

• Title: Dr. Roma Chilengi
• Organization: CIDRZ

Roma.Chilengi@cidrz.org

+2609173724935

Study Officials

• Roma Chilengi, MD, MSc

  Centre for Infectious Disease Research in Zambia

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr

Study Record Dates

• First Submitted: June 22, 2013
• First Posted: June 26, 2013
• Study Start: April 1, 2012
• Primary Completion: April 30, 2015
• Study Completion: April 30, 2016
• Last Updated: August 23, 2018
• Results First Posted: August 23, 2018

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (1)