CIDRZ Research
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The CIDRZ Research Repository serves as an open-access archive for peer-reviewed publications, conference papers, and other scholarly outputs from CIDRZ researchers. Our goal is to promote the dissemination of knowledge and support evidence-based public health initiatives.
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Item Characterization of Rotavirus Strains Responsible for Breakthrough Diarrheal Diseases among Zambian Children Using Whole Genome Sequencing.(2023-Nov-26) Mwape I; Laban NM; Chibesa K; Moono A; Silwamba S; Malisheni MM; Chisenga C; Chauwa A; Simusika P; Phiri M; Simuyandi M; Chilengi R; De Beer C; Ojok D; Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.; Institute of Basic and Biomedical Sciences, Levy Mwanawasa Medical University, Lusaka 10101, Zambia.; Division of Medical Virology, Faculty of Medicine and Health Sciences, Stellenbosch University, P.O. Box 241, Cape Town 8000, South Africa.; Influenza Research Institute, University of Wisconsin-Madison, Madison, WI 53706-13380, USA.; University Teaching Hospitals, Lusaka 10101, Zambia.; Enteric Disease and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia, Lusaka P.O. Box 34681, Zambia.; Division of Medical Virology, School of Pathology, Faculty of Health Sciences, University of the Free State, Bloemfontein P.O. Box 339, South Africa.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)The occurrence of rotavirus (RV) infection among vaccinated children in high-burden settings poses a threat to further disease burden reduction. Genetically altered viruses have the potential to evade both natural infection and vaccine-induced immune responses, leading to diarrheal diseases among vaccinated children. Studies characterizing RV strains responsible for breakthrough infections in resource-limited countries where RV-associated diarrheal diseases are endemic are limited. We aimed to characterize RV strains detected in fully vaccinated children residing in Zambia using next-generation sequencing. We conducted whole genome sequencing on Illumina MiSeq. Whole genome assembly was performed using Geneious Prime 2023.1.2. A total of 76 diarrheal stool specimens were screened for RV, and 4/76 (5.2%) were RV-positive. Whole genome analysis revealed RVA/Human-wt/ZMB/CIDRZ-RV2088/2020/Item Fourth Controlled Human Infection Model (CHIM) meeting, CHIM regulatory issues, May 24, 2023.(2024-Feb) Cavaleri M; Kaslow D; Boateng E; Chen WH; Chiu C; Choy RKM; Correa-Oliveira R; Durbin A; Egesa M; Gibani M; Kapulu M; Katindi M; Olotu A; Pongsuwan P; Simuyandi M; Speder B; Talaat KR; Weller C; Wills B; Baay M; Balasingam S; Olesen OF; Neels P; Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand.; PATH Center for Vaccine Innovation and Access, Seattle, WA, USA. Electronic address: rchoy@path.org.; European Vaccine Initiative, Heidelberg, Germany. Electronic address: ole.olesen@euvaccine.eu.; Imperial College London, UK. Electronic address: c.chiu@imperial.ac.uk.; Centre for Infectious Disease Research, Zambia. Electronic address: Michelo.Simuyandi@cidrz.org.; Center for Vaccine Development, University of Maryland School of Medicine, USA. Electronic address: wilbur.chen@som.umaryland.edu.; IABS-EU, Lyon, France. Electronic address: pieter.neels@vaccine-advice.be.; Imperial College London, UK. Electronic address: m.gibani@imperial.ac.uk.; Johns Hopkins Bloomberg School of Public Health, Baltimore, USA. Electronic address: ktalaat@jhu.edu.; KEMRI-Wellcome Trust Research Programme, Kenya. Electronic address: mkapulu@kemri-wellcome.org.; HVIVO plc, UK. Electronic address: b.speder@hvivo.com.; Wellcome Trust, London, UK. Electronic address: shobana.balasingam@wellcome.org.; Johns Hopkins Bloomberg School of Public Health, Baltimore, USA. Electronic address: adurbin1@jhu.edu.; US Food & Drugs Administration, USA. Electronic address: david.kaslow@fda.hhs.gov.; P95 Epidemiology & Pharmacovigilance, Leuven, Belgium. Electronic address: marc.baay@p-95.com.; Food and Drugs Authority, Ghana. Electronic address: gus4tee@gmail.com.; European Medicines Agency, Netherlands. Electronic address: marco.cavaleri@ema.europa.eu.; Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam. Electronic address: bwills@oucru.org.; Wellcome Trust, London, UK. Electronic address: C.Weller@wellcome.org.; Ifakara Health Institute, Tanzania. Electronic address: aolotu@ihi.or.tz.; Fundação Oswaldo Cruz (Fiocruz), Brazil.; Katindi & Company, Kenya. Electronic address: mkatindi@katindilawyers.co.ke.; MRC/UVRI and LSHTM Uganda Research Unit, Uganda; London School of Hygiene and Tropical Medicine, UK. Electronic address: Moses.Egesa@mrcuganda.org.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)Many aspects of Controlled Human Infection Models (CHIMs, also known as human challenge studies and human infection studies) have been discussed extensively, including Good Manufacturing Practice (GMP) production of the challenge agent, CHIM ethics, environmental safety in CHIM, recruitment, community engagement, advertising and incentives, pre-existing immunity, and clinical, immunological, and microbiological endpoints. The fourth CHIM meeting focused on regulation of CHIM studies, bringing together scientists and regulators from high-, middle-, and low-income countries, to discuss barriers and hurdles in CHIM regulation. Valuable initiatives for regulation of CHIMs have already been undertaken but further capacity building remains essential. The Wellcome Considerations document is a good starting point for further discussions.Item Application of a Novel Proteomic Microarray Reveals High Exposure to Diarrhoeagenic(2024-Feb-20) Mwape K; Mubanga C; Chilyabanyama ON; Chibesa K; Chisenga CC; Silwamba S; Randall A; Liang X; Barnard TG; Simuyandi M; Chilengi R; Division of Medical Microbiology, Department of Pathology, Stellenbosch University & National Health Laboratory Service, Tygerberg Hospital Francie van Zijl Drive, P.O. Box 241, Cape Town 8000, South Africa.; Next Generation Sequencing Unit and Division of Virology, School of Pathology, Faculty of Health Sciences, University of the Free State, P.O. Box 339, Bloemfontein 9300, South Africa.; Department of Basic Medical Sciences, Michael Chilufya Sata School of Medicine, Copperbelt University, Ndola P.O. Box 71191, Zambia.; Water and Health Research Center, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, Johannesburg 2028, South Africa.; Enteric Disease and Vaccines Research Unit, Centre for Infectious Disease Research in Zambia, Lusaka P.O. Box 34681, Zambia.; Antigen Discovery Inc., 1 Technology Dr., STE E309, Irvine, CA 92618, USA.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)DiarrhoeagenicItem Human cytomegalovirus seropositivity and its influence on oral rotavirus vaccine immunogenicity: a specific concern for HIV-exposed-uninfected infants.(2024-Jun-20) Laban N; Bosomprah S; Chilengi R; Simuyandi M; Chisenga C; Ng'ombe H; Musukuma-Chifulo K; Goodier M; Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.; Flow Cytometry and Immunology Facility, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine, Fajara, Banjul, The Gambia.; Department of Biostatistics, School of Public Health, University of Ghana, Accra, Ghana.; Enteric Disease and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)Oral rotavirus vaccines demonstrate diminished immunogenicity in low-income settings where human cytomegalovirus infection is acquired early in childhood and modulates immunity. We hypothesized that human cytomegalovirus infection around the time of vaccination may influence immunogenicity. We measured plasma human cytomegalovirus-specific immunoglobulin M antibodies in rotavirus vaccinated infants from 6 weeks to 12 months old and compared rotavirus immunoglobulin A antibody titers between human cytomegalovirus seropositive and seronegative infants. There was no evidence of an association between human cytomegalovirus serostatus at 9 months and rotavirus-specific antibody titers at 12 months (geometric mean ratio 1.01, 95% CI: 0.70, 1.45; P = 0.976) or fold-increase in RV-IgA titer between 9 and 12 months (risk ratio 0.999, 95%CI: 0.66, 1.52; P = 0.995) overall. However, HIV-exposed-uninfected infants who were seropositive for human cytomegalovirus at 9 months old had a 63% reduction in rotavirus antibody geometric mean titers at 12 months compared to HIV-exposed-uninfected infants who were seronegative for human cytomegalovirus (geometric mean ratio 0.37, 95% CI: 0.17, 0.77; P = 0.008). While the broader implications of human cytomegalovirus infections on oral rotavirus vaccine response might be limited in the general infant population, the potential impact in the HIV-exposed-uninfected infants cannot be overlooked. This study highlights the complexity of immunological responses and the need for targeted interventions to ensure oral rotavirus vaccine efficacy, especially in vulnerable subpopulations.Item Seroconversion and Kinetics of Vibriocidal Antibodies during the First 90 Days of Re-Vaccination with Oral Cholera Vaccine in an Endemic Population.(2024-Apr-08) Chisenga CC; Phiri B; Ng'ombe H; Muchimba M; Musukuma-Chifulo K; Silwamba S; Laban NM; Luchen C; Liswaniso F; Chibesa K; Mubanga C; Mwape K; Simuyandi M; Cunningham AF; Sack D; Bosomprah S; Department of Biostatistics, School of Public Health, University of Ghana, Accra P.O. Box LG13, Ghana.; Enteric Disease and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia, Lusaka P.O. Box 34681, Zambia.; Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.; Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)Despite the successful introduction of oral cholera vaccines, Zambia continues to experience multiple, sporadic, and protracted cholera outbreaks in various parts of the country. While vaccines have been useful in staying the cholera outbreaks, the ideal window for re-vaccinating individuals resident in cholera hotspot areas remains unclear. Using a prospective cohort study design, 225 individuals were enrolled and re-vaccinated with two doses of Shanchol™, regardless of previous vaccination, and followed-up for 90 days. Bloods were collected at baseline before re-vaccination, at day 14 prior to second dosing, and subsequently on days 28, 60, and 90. Vibriocidal assay was performed on samples collected at all five time points. Our results showed that anti-LPS and vibriocidal antibody titers increased at day 14 after re-vaccination and decreased gradually at 28, 60, and 90 days across all the groups. Seroconversion rates were generally comparable in all treatment arms. We therefore conclude that vibriocidal antibody titers generated in response to re-vaccination still wane quickly, irrespective of previous vaccination status. However, despite the observed decline, the levels of vibriocidal antibodies remained elevated over baseline values across all groups, an important aspect for Zambia where there is no empirical evidence as to the ideal time for re-vaccination.Item The Incidence and Risk Factors for Enterotoxigenic(2024-Mar-29) Sukwa N; Bosomprah S; Somwe P; Muyoyeta M; Mwape K; Chibesa K; Luchen CC; Silwamba S; Mulenga B; Munyinda M; Muzazu S; Chirwa M; Chibuye M; Simuyandi M; Chilengi R; Svennerholm AM; Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka P.O. Box 34681, Zambia.; Department of Microbiology and Immunology, University of Gothenburg, 40530 Gothenburg, Sweden.; Department of Biostatistics, School of Public Health, University of Ghana, Accra P.O. Box LG13, Ghana.This study aimed to estimate the incidence and risk factors for EnterotoxigenicItem Comparative analysis of cholera serum vibriocidal antibodies from Convalescent and vaccinated adults in Zambia.(2024-Aug-13) Ng'ombe H; Bosomprah S; Phiri B; Muchimba M; Liswaniso F; Chibuye M; Luchen CC; Chibesa K; Musukuma-Chifulo K; Mwape K; Tigere S; Silwamba S; Sinkala A; Simuyandi M; Mbewe N; Kapaya F; Cunningham AF; Chilengi R; Sack D; Chisenga CC; Centre for Infectious Disease Research in Zambia, Corner of Lukasu and Danny Pule Roads, Mass Media, Lusaka, Zambia; Department of Biostatistics, School of Public Health, University of Ghana, Accra, Ghana. Electronic address: Samuel.Bosomprah@cidrz.org.; Zambia National Public Health Institute, Stand 1186, Corner of Chaholi & Addis Ababa Roads Rhodes Park, Lusaka, Zambia.; Centre for Infectious Disease Research in Zambia, Corner of Lukasu and Danny Pule Roads, Mass Media, Lusaka, Zambia.; Ministry of Health, Levy Mwanawasa University Teaching Hospital, Chainama, Off Great East, P.0 Box 310084, Lusaka, Zambia.; Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom.; John Hopkins University, 615 N Wolfe St, Baltimore, United States of America.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)Cholera is responsible for 1.3 to 4.0 million cholera cases globally and poses a significant threat, with Zambia reporting 17,169 cases as of 4th February 2024. Recognizing the crucial link between natural cholera infections and vaccine protection, this study aimed to assess immune responses post cholera infection and vaccination. This was a comparative study consisting of 50 participants enrolled during a cholera outbreak in Zambia's Eastern Province and an additional 56 participants who received oral cholera vaccinations in Zambia's Central Province. Vibriocidal antibodies were plotted as geometric mean titres in the naturally infected and vaccinated individuals. A significant difference (p < 0.047) emerged when comparing naturally infected to fully vaccinated individuals (2 doses) on day 28 against V. cholerae Ogawa. Those who received two doses of the oral cholera vaccine had higher antibody titres than those who were naturally infected. Notably, the lowest titres occurred between 0-9 days post onset, contrasting with peak responses at 10-19 days. This study addresses a critical knowledge gap in understanding cholera immunity dynamics, emphasizing the potential superiority of vaccination-induced immune responses. We recommend post infection vaccination after 40 days for sustained immunity and prolonged protection, especially in cholera hotspots.Item Systematic review of associations between gut microbiome composition and stunting in under-five children.(2024-May-23) Chibuye M; Mende DR; Spijker R; Simuyandi M; Luchen CC; Bosomprah S; Chilengi R; Schultsz C; Harris VC; Department of Global Health, Amsterdam Institute for Global Health and Development (AIGHD), Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.; The Zambia National Public Health Institute (ZNPHI), Lusaka, Zambia.; Division of Infectious Diseases, Department of Internal Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands. v.c.harris@amsterdamumc.nl.; Amsterdam Institute of Infection and Immunity, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Department of Biostatistics, School of Public Health, University of Ghana, Legon, Accra, Ghana.; Research Division, Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; Amsterdam Institute of Infection and Immunity, Amsterdam University Medical Centers, Amsterdam, The Netherlands. v.c.harris@amsterdamumc.nl.; Department of Medical Microbiology and Infection Control, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Department of Global Health, Amsterdam Institute for Global Health and Development (AIGHD), Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands. v.c.harris@amsterdamumc.nl.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)Childhood stunting is associated with impaired cognitive development and increased risk of infections, morbidity, and mortality. The composition of the enteric microbiota may contribute to the pathogenesis of stunting. We systematically reviewed and synthesized data from studies using high-throughput genomic sequencing methods to characterize the gut microbiome in stunted versus non-stunted children under 5 years in LMICs. We included 14 studies from Asia, Africa, and South America. Most studies did not report any significant differences in the alpha diversity, while a significantly higher beta diversity was observed in stunted children in four out of seven studies that reported beta diversity. At the phylum level, inconsistent associations with stunting were observed for Bacillota, Pseudomonadota, and Bacteroidota phyla. No single genus was associated with stunted children across all 14 studies, and some associations were incongruent by specific genera. Nonetheless, stunting was associated with an abundance of pathobionts that could drive inflammation, such as Escherichia/Shigella and Campylobacter, and a reduction of butyrate producers, including Faecalibacterium, Megasphera, Blautia, and increased Ruminoccoccus. An abundance of taxa thought to originate in the oropharynx was also reported in duodenal and fecal samples of stunted children, while metabolic pathways, including purine and pyrimidine biosynthesis, vitamin B biosynthesis, and carbohydrate and amino acid degradation pathways, predicted linear growth. Current studies show that stunted children can have distinct microbial patterns compared to non-stunted children, which could contribute to the pathogenesis of stunting.Item Association of Maternal Immunity with Rotavirus Vaccine Immunogenicity in Zambian Infants.(2016) Chilengi R; Simuyandi M; Beach L; Mwila K; Becker-Dreps S; Emperador DM; Velasquez DE; Bosomprah S; Jiang B; University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; Centres for Disease Control and Prevention, Atlanta, Georgia, United States of America.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)INTRODUCTION: Live attenuated oral vaccines against rotavirus (RV) have been shown to be less efficacious in children from developing countries. Reasons for this disparity are not fully understood. We assessed the role of maternal factors including breast milk RV-specific IgA, transplacentally acquired infant serum RV-specific IgG and maternal HIV status in seroconversion among Zambian infants routinely immunized with Rotarix™ (RV1). METHODS: 420 mother-child pairs were recruited at infant age 6-12 weeks in Lusaka. Clinical information and samples were collected at baseline and at one month following the second dose of RV1. Determination of breast milk RV-specific IgA and serum RV-specific IgA and IgG was done using standardized ELISA. Seroconversion was defined as a ≥ 4 fold rise in serum IgA titre from baseline to one-month post RV1 dose 2, while seropositivity of IgA was defined as serum titre ≥ 40 and antibody variables were modelled on log-base 2. Logistic regression was used to identify predictors of the odds of seroconversion. RESULTS: Baseline infant seropositivity was 25.5% (91/357). The seroconversion frequency was 60.2% (130/216). Infants who were IgA seropositive at baseline were less likely to seroconvert compared to their seronegative counterparts (P = 0.04). There was no evidence of an association between maternal HIV status and seroconversion (P = 0.25). Higher titres of breast milk rotavirus-specific IgA were associated with a lower frequency of seroconverson (Nonparametric test for trend Z = -2.84; P<0.01): a two-fold increase in breast milk RV-specific IgA titres was associated with a 22% lower odds of seroconversion (OR = 0.80; 95% CI = 0.68-0.94; P = 0.01). There was seasonal variation in baseline breast milk rotavirus-specific IgA titres, with significantly higher GMTs during the cold dry months (P = 0.01). CONCLUSION: Low immunogenicity of RV1 vaccine could be explained in part by exposure to high antibody titres in breast milk and early exposure to wild-type rotavirus infections. Potential interference of anti-RV specific IgA in breast milk and pre-vaccination serum RV specific-IgA and IgG titres with RV1 seroconversion and effectiveness requires further research.Item Anti-microbial peptide gene expression during oral vaccination: analysis of a randomized controlled trial.(2016-Nov) Simuyandi M; Kapulu M; Kelly P; Tropical Gastroenterology and Nutrition Group, University of Zambia School of Medicine, Lusaka, Zambia. m.p.kelly@qmul.ac.uk.; Programme for the Awareness and Elimination of Diarrhoea (PAED), Centre for Infectious Disease Research in Zambia.; Tropical Gastroenterology and Nutrition Group, University of Zambia School of Medicine, Lusaka, Zambia.; Barts and the London School of Medicine, London, UK. m.p.kelly@qmul.ac.uk.; Biological Sciences Department, School of Natural Sciences, University of Zambia, Lusaka, Zambia.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)We have observed previously that micronutrient supplementation ameliorated suppression of α-defensin expression during diarrhoea. However, how interactions between anti-microbial peptide (AMP) expression and diarrhoeal disease are altered by micronutrient supplementation remain unclear. Using oral vaccination as a model of intestinal infection, we measured changes in AMP expression during multiple micronutrient supplementation. In the first part, volunteers underwent duodenal jejunal biopsy before and at 1, 2, 4 or 7 days after administration of one of three live, attenuated oral vaccines against rotavirus, typhoid and enterotoxigenic Escherichia coli. In the second part, participants were randomized to receive a multiple micronutrient supplement or placebo for 6 weeks before undergoing intestinal biopsy, vaccination against typhoid and rebiopsy after 14 days. Expression of human alpha-defensin (HD)5, HD6, hBD1, hBD2 and LL-37 was measured by quantitative reverse transcription-polymerase chain reaction. Taken together, the bacterial vaccines, but not rotavirus vaccine, reduced HD5 expression (P = 0·02, signed-rank test) and reduced LL-37 expression in seven of the eight individuals whose biopsies had expression prevaccination (P = 0·03). hBD2 was not detected. In the controlled trial, HD5 and HD6 expression after vaccination was lower [median ratio 0·5, interquartile range (IQR) = 0·07-2·2 and 0·58, IQR = 0·13-2·3, respectively] than before vaccination. There was no significant effect detected of micronutrient supplementation on expression of HD5, HD6, hBD1 or LL-37. We conclude that live attenuated bacterial vaccines, but not rotavirus vaccine, can reduce intestinal α-defensins, and typhoid vaccine reduced LL-37 expression. We found no evidence that micronutrient supplementation in the short term had any impact on anti-microbial peptide expression.