How Gut Health Affects Immune Responses to the Oral Rotavirus Vaccine in Adults in Zambia

Официальное название

Temporal and Spatial Immune Profiling of Oral Rotavirus Vaccine Responses in Zambian Adults With Environmental Enteropathy

Обзор

The Rotavirus SpatioTrasncriptomics (Rota-Omics) study is a multidisciplinary research project aimed at understanding why oral rotavirus vaccines perform less effectively in some low- and middle-income countries, including Zambia. Rotavirus remains one of the leading causes of severe diarrheal disease in infants and young children worldwide, despite the widespread introduction of vaccines such as Rotarix® and Rotavac®. Although these vaccines have greatly reduced childhood deaths in many countries, vaccine effectiveness is often lower in settings where the burden of disease is highest. Understanding the reasons behind this reduced protection is critical for improving child health globally. A major focus of the study is Environmental Enteropathy (EE), also known as Environmental Enteric Dysfunction (EED), a chronic inflammatory condition of the small intestine that is common in low-resource settings. EE is associated with damage to the intestinal lining, chronic immune activation, poor nutrient absorption, and impaired gut barrier function. These changes are thought to interfere with the body's ability to respond effectively to oral vaccines, which rely on strong intestinal immune responses. The RotaOmics study uses a systems biology approach to investigate how the immune system, gut microbiome, nutrition, and intestinal inflammation interact to influence rotavirus vaccine responses. The term "omics" refers to advanced technologies that allow researchers to study genes, proteins, microbes, and other biological processes at a large scale. By combining these approaches, the study aims to identify biological markers and immune pathways associated with strong or weak vaccine responses. The study involves the collection of samples such as blood, stool, saliva, and breast milk from mothers and infants at different time points before and after vaccination. These samples are analysed using laboratory methods including antibody testing, molecular pathogen detection, microbiome sequencing, and immune profiling. The study also evaluates markers of gut inflammation and intestinal health. One important goal of the project is to identify correlates of protection, which are measurable biological indicators that predict whether a vaccine is likely to protect against disease. Identifying these markers could help guide the development of improved vaccines or supportive interventions to enhance vaccine performance in vulnerable populations. The study also contributes to a broader understanding of mucosal immunity, which refers to immune responses occurring in the gastrointestinal tract. Since many enteric infections begin in the gut, understanding intestinal immune function is important not only for rotavirus vaccines but also for other oral vaccines and diarrheal diseases. In addition to its scientific objectives, RotaOmics includes a strong capacity-building component. The project supports training for local scientists, clinicians, and laboratory personnel in areas such as molecular biology, immunology, genomics, bioinformatics, and data analysis. By strengthening local research expertise and infrastructure, the study aims to support long-term scientific development and improve regional capacity for infectious disease research and outbreak response. Overall, the RotaOmics study seeks to generate new insights into why oral rotavirus vaccines underperform in some settings and to identify strategies that may improve vaccine effectiveness and child health outcomes in Zambia and similar regions worldwide.

Вмешательства

• Биопрепарат Rotarix®,
  This is an infant vaccine, but this study participants in this study will receive a double oral Rotarix dose at baseline as per study design.

Первичные конечные точки

• Proportion of participants completing all scheduled study procedures [Срок оценки: Through study completion, an average of 1 year.]
• Sample Quality Control (QC) Success Rate [Срок оценки: Through study completion, an average of 1 year.]
• Proportion of intestinal biopsy samples meeting predefined quality control thresholds [Срок оценки: Through study completion, an average of 1 year.]
• Pre-analytical Sample Processing Efficiency [Срок оценки: Periprocedural]

Вторичные конечные точки (3)

• Clinical Follow-up Retention Rate [Срок оценки: Through study completion, an average of 1 year.]
• Regulated Gene Expression Profiles [Срок оценки: Baseline, and up to 52 weeks post-enrollment.]
• Correlation of Mucosal Spatial Transcriptomics with Systemic Immunity [Срок оценки: Baseline, and up to 52 weeks post-enrollment.]

Критерии участия

Критерии включения

• Age ≥ 18 years and ≤ 50 years.
• Able and willing to provide written informed consent.
• Reside within Lusaka district and available for scheduled follow-up.
• Willing to undergo two endoscopy procedures with serial sample collection.

Критерии исключения

• Pregnant or breastfeeding.
• Active gut disease requiring treatment (e.g., active peptic ulcer disease, gastrointestinal bleeding).
• Known severe immunodeficiency (HIV with CD4 < 200 cells/mm³, current cancer chemotherapy, systemic corticosteroids equivalent to >20 mg/day prednisolone for >2 weeks).
• Severe comorbidities rendering endoscopy unsafe (e.g., severe cardiopulmonary disease, uncontrolled hypertension, oropharyngeal abnormalities).
• Use of anticoagulants where suspension is unsafe or unwillingness to withhold anticoagulation when clinically indicated.
• Receipt of any live vaccine within 30 days prior to enrolment or planned live vaccine within 30 days after Rotarix administration.
• Any condition judged by the investigator to compromise participant safety or data integrity.
• Participants who had a recent diarrhoea episode, or who have taken NSAID drugs or antibiotics, will be eligible for re-assessment after a month without this disqualifier.

Pregnancy testing and counselling: Women of reproductive potential will require a negative urine pregnancy test within 24 hours prior to endoscopy and vaccination and will be counselled to avoid pregnancy during the first 30 days post-vaccination.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Zambia · 1 центр

• TROPGAN — Lusaka

Публикации

• Kang G. Success from the South: the rotavirus vaccine story and its lessons. Lancet. 2024 Jan 6;403(10421):111-116. doi: 10.1016/S0140-6736(23)02520-5. Epub 2023 Nov 28. No abstract available. PMID 38040012
• Bein A, Fadel CW, Swenor B, Cao W, Powers RK, Camacho DM, Naziripour A, Parsons A, LoGrande N, Sharma S, Kim S, Jalili-Firoozinezhad S, Grant J, Breault DT, Iqbal J, Ali A, Denson LA, Moore SR, Prantil-Baun R, Goyal G, Ingber DE. Nutritional deficiency in an intestine-on-a-chip recapitulates injury hallmarks associated with environmental enteric dysfunction. Nat Biomed Eng. 2022 Nov;6(11):1236-124 PMID 35739419
• Gu Y, Bartolome-Casado R, Xu C, Bertocchi A, Janney A, Heuberger C, Pearson CF, Teichmann SA, Thornton EE, Powrie F. Immune microniches shape intestinal Treg function. Nature. 2024 Apr;628(8009):854-862. doi: 10.1038/s41586-024-07251-0. Epub 2024 Apr 3. PMID 38570678
• Bhattacharjee A, Burr AHP, Overacre-Delgoffe AE, Tometich JT, Yang D, Huckestein BR, Linehan JL, Spencer SP, Hall JA, Harrison OJ, Morais da Fonseca D, Norton EB, Belkaid Y, Hand TW. Environmental enteric dysfunction induces regulatory T cells that inhibit local CD4+ T cell responses and impair oral vaccine efficacy. Immunity. 2021 Aug 10;54(8):1745-1757.e7. doi: 10.1016/j.immuni.2021.07.005. Epub PMID 34348118
• Kummerlowe C, Mwakamui S, Hughes TK, Mulugeta N, Mudenda V, Besa E, Zyambo K, Shay JES, Fleming I, Vukovic M, Doran BA, Aicher TP, Wadsworth MH 2nd, Bramante JT, Uchida AM, Fardoos R, Asowata OE, Herbert N, Yilmaz OH, Kloverpris HN, Garber JJ, Ordovas-Montanes J, Gartner ZJ, Wallach T, Shalek AK, Kelly P. Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodelin PMID 36044598
• Marie C, Ali A, Chandwe K, Petri WA Jr, Kelly P. Pathophysiology of environmental enteric dysfunction and its impact on oral vaccine efficacy. Mucosal Immunol. 2018 Sep;11(5):1290-1298. doi: 10.1038/s41385-018-0036-1. Epub 2018 Jul 9. PMID 29988114
• Li H, Wu H, Ma W, Li S, Cai J, Lin Y, Zhang J, Wang Y, Zhang C. Spatial transcriptomics: a bibliometric analysis with large language model on English literatures. Brief Bioinform. 2025 Aug 31;26(5):bbaf553. doi: 10.1093/bib/bbaf553. PMID 41139313
• Tan J, Taitz J, Sun SM, Langford L, Ni D, Macia L. Your Regulatory T Cells Are What You Eat: How Diet and Gut Microbiota Affect Regulatory T Cell Development. Front Nutr. 2022 Apr 20;9:878382. doi: 10.3389/fnut.2022.878382. eCollection 2022. PMID 35529463

Идентификаторы

NCT: NCT07626606 · 7400-2025

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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