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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 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; Enteric Disease and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.; Department of Biostatistics, School of Public Health, University of Ghana, Accra, Ghana.; Flow Cytometry and Immunology Facility, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine, Fajara, Banjul, The Gambia.; 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 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; Antigen Discovery Inc., 1 Technology Dr., STE E309, Irvine, CA 92618, USA.; Department of Basic Medical Sciences, Michael Chilufya Sata School of Medicine, Copperbelt University, Ndola P.O. Box 71191, Zambia.; Enteric Disease and Vaccines Research Unit, Centre for Infectious Disease Research in Zambia, Lusaka P.O. Box 34681, Zambia.; 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.; Water and Health Research Center, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, Johannesburg 2028, South Africa.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)DiarrhoeagenicItem 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; Department of Microbiology and Immunology, University of Gothenburg, 40530 Gothenburg, Sweden.; Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka P.O. Box 34681, Zambia.; 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 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; Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.; 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.; 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 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.; 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.; 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; Department of Biostatistics, School of Public Health, University of Ghana, Accra, Ghana. Electronic address: Samuel.Bosomprah@cidrz.org.; 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; Amsterdam Institute of Infection and Immunity, 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.; Department of Medical Microbiology and Infection Control, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Research Division, Centre for Infectious Disease Research in Zambia, 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.; 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.; Department of Biostatistics, School of Public Health, University of Ghana, Legon, Accra, Ghana.; Amsterdam Institute of Infection and Immunity, Amsterdam University Medical Centers, 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 Identification of cholera hotspots in Zambia: A spatiotemporal analysis of cholera data from 2008 to 2017.(2020-Apr) Mwaba J; Debes AK; Shea P; Mukonka V; Chewe O; Chisenga C; Simuyandi M; Kwenda G; Sack D; Chilengi R; Ali M; University of Zambia, School of Health Sciences, Lusaka, Zambia.; Zambia National Public Health Institute, Lusaka, Zambia.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)The global burden of cholera is increasing, with the majority (60%) of the cases occurring in sub-Saharan Africa. In Zambia, widespread cholera outbreaks have occurred since 1977, predominantly in the capital city of Lusaka. During both the 2016 and 2018 outbreaks, the Ministry of Health implemented cholera vaccination in addition to other preventative and control measures, to stop the spread and control the outbreak. Given the limitations in vaccine availability and the logistical support required for vaccination, oral cholera vaccine (OCV) is now recommended for use in the high risk areas ("hotspots") for cholera. Hence, the aim of this study was to identify areas with an increased risk of cholera in Zambia. Retrospective cholera case data from 2008 to 2017 was obtained from the Ministry of Health, Department of Public Health and Disease Surveillance. The Zambian Central Statistical Office provided district-level population data, socioeconomic and water, sanitation and hygiene (WaSH) indicators. To identify districts at high risk, we performed a discrete Poisson-based space-time scan statistic to account for variations in cholera risk across both space and time over a 10-year study period. A zero-inflated negative binomial regression model was employed to identify the district level risk factors for cholera. The risk map was generated by classifying the relative risk of cholera in each district, as obtained from the space-scan test statistic. In total, 34,950 cases of cholera were reported in Zambia between 2008 and 2017. Cholera cases varied spatially by year. During the study period, Lusaka District had the highest burden of cholera, with 29,080 reported cases. The space-time scan statistic identified 16 districts to be at a significantly higher risk of having cholera. The relative risk of having cholera in these districts was significantly higher and ranged from 1.25 to 78.87 times higher when compared to elsewhere in the country. Proximity to waterbodies was the only factor associated with the increased risk for cholera (P<0.05). This study provides a basis for the cholera elimination program in Zambia. Outside Lusaka, the majority of high risk districts identified were near the border with the DRC, Tanzania, Mozambique, and Zimbabwe. This suggests that cholera in Zambia may be linked to movement of people from neighboring areas of cholera endemicity. A collaborative intervention program implemented in concert with neighboring countries could be an effective strategy for elimination of cholera in Zambia, while also reducing rates at a regional level.Item Nutritional status, environmental enteric dysfunction, and prevalence of rotavirus diarrhoea among children in Zambia.(2020) Koyuncu A; Simuyandi M; Bosomprah S; Chilengi R; Department of Biostatistics, School of Public Health, University of Ghana, Accra, Ghana.; Centre for Infectious Diseases Research in Zambia, Lusaka, Zambia.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)BACKGROUND: Rotavirus is the most common cause of fatal diarrhoeal disease among children under the age of five globally and is responsible for millions of hospitalizations each year. Although nutritional status and environmental enteric dysfunction (EED) are recognized as important predictors of susceptibility to diarrhoeal disease, no research to date has examined the mechanisms by which undernutrition and EED may protect against prevalence of rotavirus infection. METHODS: We utilized data collected from a study evaluating the effectiveness of Rotarix™ vaccine against severe gastroenteritis among children under the age of 5 in Zambia. The prevalence of malnutrition, wasting, and stunting at the time of study enrollment was calculated using WHO child growth standards. Commercial ELISA kits were used to assess levels of faecal biomarkers for EED: alpha-1-antitrypsin and myeloperoxidase, and calprotectin. Separate multivariate logistic regression models were used to examine each measure of nutritional status and rotavirus diarrhoea including and excluding adjustment for EED. RESULTS: In models that did not include adjustment for EED, malnourished children had 0.66 times the odds of having rotavirus diarrhoea compared to children with normal nutritional status (95% CI: 0.42, 1.0; p = 0.07). EED severity score was significantly higher among controls asymptomatic for diarrhoeal disease compared to cases with rotavirus diarrhoea (p = 0.02). CONCLUSION: The morphological changes associated with EED may confer protection against rotavirus infection and subsequent diarrhoeal disease among children. Further research is critically needed to better understand the complex mechanisms by which nutritional status and EED may impact susceptibility to rotavirus in early life.Item A pilot study on use of live attenuated rotavirus vaccine (Rotarix™) as an infection challenge model.(2020-Oct-27) Chilengi R; Simuyandi M; Chibuye M; Chirwa M; Sukwa N; Laban N; Chisenga C; Silwamba S; Grassly N; Bosomprah S; MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College, London, United Kingdom.; Research Division, Centre for Infectious Disease Research in Zambia, Lusaka, Zambia; Department of Biostatistics, School of Public Health, University of Ghana, Accra, Ghana.; Research Division, Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; Research Division, Centre for Infectious Disease Research in Zambia, Lusaka, Zambia. Electronic address: Roma.Chilengi@cidrz.org.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)BACKGROUND: Rotavirus remains the commonest cause of dehydrating diarrhoea, particularly in developing countries. Human infection challenge studies in children in these countries offers an opportunity to rapidly evaluate new vaccine candidates that may have improved efficacy. We evaluated use of Rotarix™ as a live-attenuated challenge agent. METHODS: We undertook an open label, exploratory study in infants receiving two standard doses of Rotarix™ at 6 and 10 weeks of age in a cohort of 22 Zambian infants. The first vaccine dose was considered as primary vaccination, and the second at day 28 as a live-attenuated virus challenge. Saliva, stool and serum samples were collected on days 0, 3, 5, 7, 14, and 28 following each dose. The primary outcome was stool shedding of rotavirus, determined by NSP2 qPCR. We calculated mean shedding index as average of natural logarithm of viral copies per gram of stool. FINDINGS: After the first dose, viral shedding was high at day 3, peaked by day 5. After the second dose, viral shedding at day 3 was low and reduced gradually in most infants until day 14. Mean shedding index was significantly lower post dose 2 across all infants and timepoints (5.0 virus copies/g of stool [95%CI: 0.3-9.7] vs 10.4 virus copies/g of stool [95%CI: 6.2-14.6]; p-value < 0.0001; rho = 0.20, SD = 4.97. Seroconversion at day 28 was associated with a mean reduction of -1.03 (95%CI = -8.07, 6.01) in viral shedding after challenge dose but this was not statistically significant (p = 0.774). A borderline positive correlation between fold-change in IgA titre at day 28 from day 0 in saliva and serum was observed; Spearman's correlation coefficient, r = 0.69; p = 0.086. INTERPRETATION: Shedding after the 'challenge' dose was reduced compared with the first dose, consistent with the induction of mucosal immunity by the first dose. This supports the use of Rotarix vaccine as a live-attenuated infection challenge. FUNDING: Medical Research Council (UK) through the HIC-Vac Network.Item In-vitro inhibitory effect of maternal breastmilk components on rotavirus vaccine replication and association with infant seroconversion to live oral rotavirus vaccine.(2020) Kazimbaya KM; Chisenga CC; Simuyandi M; Phiri CM; Laban NM; Bosomprah S; Permar SR; Munsaka S; Chilengi R; Department of Biostatistics, School of Public Health, University of Ghana, Legon, Accra, Ghana.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; Department of Pediatrics, Human Vaccine Institute, Duke University, Durham, North Carolina, United States of America.; Department of Biomedical Sciences, School of Health Sciences, University of Zambia, Lusaka, Zambia.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)BACKGROUND: Despite contributing to a significant reduction in rotavirus associated diarrhoea in highly burdened low- and middle-income countries, live attenuated, oral rotavirus vaccines have lower immunogenicity and efficacy in these settings in comparison to more developed countries. Breastmilk has been implicated among factors contributing to this lowered oral vaccine efficacy. We conducted in-vitro experiments to investigate the inhibitory effects of maternal antibody and other non-antibody components in breastmilk on rotavirus vaccine strain (Rotarix) multiplication in MA104 cell culture system and assessed associations with in-vivo vaccine seroconversion in vaccinated infants. METHODS: Breastmilk samples were collected from mothers before routine rotavirus vaccination of their infant at 6 weeks of age. For each sample, whole breastmilk, purified IgA, purified IgG and IgG and IgA depleted breastmilk samples were prepared as exposure preparations. A 96 well microtitre plate was set up for each sample including a control in which only MA104 cells were grown as well as a virus control with MA104 cells and virus only. The outcome of interest was 50% inhibition dilution of each of the exposure preparations calculated as the titer at which 50% of virus dilution was achieved. Samples from 30 women were tested and correlated to vaccine seroconversion status of the infant. HIV status was also correlated to antiviral breastmilk proteins. RESULTS: The mean 50% inhibitory dilution titer when whole breastmilk was added to virus infected MA104 cells was 14.3 (95% CI: 7.1, 22.7). Incubation with purified IgG resulted in a mean 50% inhibitory dilution of 5 (95%CI -1.6, 11.6). Incubating with purified IgA resulted in a mean 50% inhibitory dilution of 6.5 (95% CI -0.7, 13.7) and IgG and IgA depleted breastmilk did not yield any inhibition with a titer of 1.06 (95%CI 0.9, 1.2). Higher milk IgA levels contributed to a failure of infants to seroconvert. HIV was also not associated with any antiviral breastmilk proteins. DISCUSSION AND CONCLUSION: Whole breastmilk and breastmilk purified IgG and IgA fractions showed inhibitory activity against the rotavirus vaccine Rotarix™ whilst IgA and IgG depleted breastmilk with non-antibody breastmilk fraction failed to show any inhibition activity in-vitro. These findings suggest that IgA and IgG may have functional inhibitory properties and indicates a possible mechanism of how mothers in rotavirus endemic areas with high titres of IgA and IgG may inhibit viral multiplication in the infant gut and would potentially contribute to the failure of their infants to serocovert. There was not association of HIV with either lactoferrin, lactadherin or tenascin-C concentrations.