Causes of Rotavirus Vaccine Failure in Zambian Children

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2013 by Centre for Infectious Disease Research in Zambia
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Roma Chilengi, Centre for Infectious Disease Research in Zambia
ClinicalTrials.gov Identifier:
NCT01886833
First received: June 22, 2013
Last updated: NA
Last verified: June 2013
History: No changes posted
  Purpose

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 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.


Condition
Diarrhoea

Study Type: Observational [Patient Registry]
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 42 Months
Official Title: An Observational Study to Evaluate Causes of Rotavirus Vaccine Failure in Zambian Children in the Context of Routine Immunization Services

Resource links provided by NLM:


Further study details as provided by Centre for Infectious Disease Research in Zambia:

Primary Outcome Measures:
  • Proportion of immunized infants exposed to high breast milk anti-rotavirus immunoglobulin-A who fail to seroconvert [ Time Frame: 1 month following full immunization ] [ Designated as safety issue: No ]

    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.


  • Proportion of immunized infants exposed to transplacentally-acquired, rotavirus-specific, infant serum IgG who fail to sero-convert. [ Time Frame: 1 month after full immunisation ] [ Designated as safety issue: No ]

    The co-primary exposure in this cohort is transplacentally acquired anti-rotavirus immunoglubulin-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.


  • Proportion of immunized infants exposed to maternal HIV infection who fail to seroconvert [ Time Frame: 1 month following full immunisation ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Proportion of immunized infants with low micronutrient levels (as indicated by serum zinc and vitamin A), who fail to seroconvert [ Time Frame: 1 month after full immunization ] [ Designated as safety issue: No ]
    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.


Other Outcome Measures:
  • Sero-epidemiology of breakthrough rotavirus infection in immunized infants [ Time Frame: 42 months ] [ Designated as safety issue: No ]

    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 Vesicary 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.



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.


Estimated Enrollment: 420
Study Start Date: April 2013
Estimated Study Completion Date: July 2017
Estimated Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Groups/Cohorts
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.


  Show Detailed Description

  Eligibility

Ages Eligible for Study:   6 Weeks to 15 Weeks
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

The study will be conducted at Kamwala health facility in Lusaka where the Maternal Child Health (MCH) and antiretroviral therapy (ART) clinics as well as the CIDRZ Kamwala Research Unit are co-located. Kamwala has a catchment population of over 10,000 with approximately 30 new infants presenting to MCH each month with 6-14 week (DPT-HiB-Hep) immunisation rates above 95%. Mother-infant pairs will be approached during the initial visit to MCH by the study clinic assistant or peer counsellor with information about this study in the local language of choice. Those generally interested will be invited to the research clinic which is close by, for more detailed information during which motivated mothers will be recruited and taken through the written informed consent process by the study nurse. For illiterate participants, an independent, literate individual will witness and validate the informed consent process.

Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01886833

Contacts
Contact: Roma Chilengi, MD, MSc +260973724935 Roma.Chilengi@cidrz.org
Contact: Bradford M Guffey, MD, MSc +260 968666895 Brad.Guffey@cidrz.org

Locations
Zambia
Centre for Infectious Disease Research in Zambia Recruiting
Lusaka, Zambia, 10101
Contact: Roma Chilengi, MD, MSc    +2609173724935    Roma.Chilengi@cidrz.org   
Contact: Marcellina Hamikondo, BSc    +260977120736    Marcellina.Hamikondo@cidrz.org   
Principal Investigator: Roma Chilengi, MD, MSc         
Sponsors and Collaborators
Centre for Infectious Disease Research in Zambia
Investigators
Principal Investigator: Roma Chilengi, MD, MSc Centre for Infectious Disease Research in Zambia
  More Information

No publications provided

Responsible Party: Roma Chilengi, Dr, Centre for Infectious Disease Research in Zambia
ClinicalTrials.gov Identifier: NCT01886833     History of Changes
Other Study ID Numbers: ROVAS 01, 1R01AI099601-01
Study First Received: June 22, 2013
Last Updated: June 22, 2013
Health Authority: Zambia: Ministry of Health

Keywords provided by Centre for Infectious Disease Research in Zambia:
Rotavirus
Diarrhoea
Dmmunisation
Seroconversion
Breastmilk
HIV
Zinc
Vitamin A
Failure

Additional relevant MeSH terms:
Diarrhea
Signs and Symptoms, Digestive
Signs and Symptoms

ClinicalTrials.gov processed this record on October 02, 2014