An Observational Study to Evaluate Causes of Rotavirus Vaccine Failure in Zambian Children in the Context of Routine Immunization Services
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 420
- 试验地点
- 1
- 主要终点
- Proportion of Immunized Infants Exposed to High Breast Milk Anti-rotavirus Immunoglobulin-A Who Fail to Seroconvert
研究概览
简要总结
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.
详细描述
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 Centre for Infectious Disease Research Zambia (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. A specific log will be maintained to show information on dates and numbers of those invited to the study, reasons for refusal documented.
A senior research nurse, study nurse, and clinical research assistant will be responsible for informed consent and enrolment procedures under the supervision of the investigator. A paediatrician will be available for hands-on consultation when needed.
Cohort Follow-up. Enrolled mothers will be asked to complete demographic and behavioural questionnaires, a participant locator form, and undergo phlebotomy and mechanical expression of breast-milk at the enrolment visit for determination of anti-rotavirus IgG and IgA (in serum and breast-milk). Infants will have a baseline anti-rotavirus IgA and IgG antibodies determined to ascertain baseline exposure to wild-type and transplacental immunoglobulin followed by a second serum IgA determination one month following completion of rotavirus vaccination (at approximately 14-20 weeks).
Infants will then be followed quarterly in-clinic for the remainder of the study and will also make interim clinic visits if the child has diarrhoea. At each visit, the child will be weighed, height measured, and anthropometrics taken, including skin fold for subcutaneous body fat and mid upper arm circumference. During any symptomatic interim visits, assessments will be made of disease severity (by Vesikari scale) and a sample of stool will be collected for determination of rotavirus antigen and genotype if rotavirus positive. The patient will also be sent home with a diarrhoea diary to be completed over the following two weeks. Following identification of an child with severe gastroenteritis, an age-matched control from within the cohort (without recent gastroenteritis) will be brought in for measurement of Vitamin A and serum zinc levels. Children with gastroenteritis will be treated according to national guidelines (per World Health Organization (WHO) Integrated Management of Childhood Illness). If referral is required, the child will be referred to outpatient clinic, or in serious cases the University Teaching Hospital.
Study Procedures. Same as above.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 6 Weeks 至 15 Weeks（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
结局指标
主要结局
Proportion of Immunized Infants Exposed to High Breast Milk Anti-rotavirus Immunoglobulin-A Who Fail to Seroconvert
时间窗: 1 month following full immunization
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.
时间窗: 1 month after full immunisation
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.
Proportion of Immunized Infants Exposed to Maternal HIV Infection Who Fail to Seroconvert
时间窗: 1 month after the two vaccine doses
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.
次要结局
- 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)
研究者
Roma Chilengi
Dr
Centre for Infectious Disease Research in Zambia