Browsing by Author "Natukunda, Agnes"

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    Assessing community vulnerability to reduced vaccine impact in Uganda and Kenya: A spatial data analysis
    (NIHR Open Research, 2025-03-17) Nalwanga, Robinah; Natukunda, Agnes; Zirimenya, Ludoviko; Kaleebu, Pontiano; Webb, Emily L.
    Despite global efforts to improve on vaccine impact, many African countries have failed to achieve equitable vaccine benefits. Reduced vaccine impact may arise from interplay between structural, social, and biological factors, that hinder communities from achieving full benefits from vaccination programs. However, the combined influence of these factors to reduced vaccine impact and the spatial distribution of vulnerable communities remains poorly understood. In this work, we developed a Community Vaccine Impact Vulnerability Index (CVIVI) that integrates data on multiple risk factors associated with impaired vaccine impact. The index identifies communities are at risk of reduced vaccine impact, and key factors contributing to their vulnerability.
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    Continuous research monitoring improves the quality of research conduct and compliance among research trainees: internal evaluation of a monitoring programme
    (AAS Open Research, 2020) Akello, Mirriam; Coutinho, Sarah; N-Mboowa, Mary Gorrethy; Bukirwa, Victoria D; Natukunda, Agnes; Lubyayi, Lawrence; Nabakooza, Grace; Cose, Stephen; Elliott, Alison M.
    Background: Research site monitoring (RSM) is an effective way to ensure compliance with Good Clinical Practice (GCP). However, RSM is not offered to trainees (investigators) at African Institutions routinely. The Makerere University/Uganda Virus Research Institute Centre of Excellence in Infection and Immunity Research and Training (MUIIPlus) introduced internal monitoring to promote the quality of trainees’ research projects. Here, we share our monitoring model, experiences and achievements, and challenges encountered. Methods: We analysed investigators’ project reports from monitoring visits undertaken from April 2017 to December 2019. Monitors followed a standard checklist to review investigator site files and record forms, and toured site facilities. We planned four monitoring visits for each trainee: one at site initiation, two interim, and a closeout monitoring visit. A team of two monitors conducted the visits. Results: We monitored 25 out of the 26 research projects in progress between April 2017 and December 2019. Compliance with protocols, standard operating procedures, GCP, and GCLP improved with each monitoring visit and all projects achieved 100% compliance at site closeout. All investigators had good work ethics and practice, and appropriate facilities. Initially, some investigators’ files lacked essential documents, and informed consent processes needed to be improved. We realized that non-compliant investigators had not received prior training in GCP/GCLP, so we offered them this training. Conclusions: Routine monitoring helps identify non-compliance early and improves the quality of research. We recommend continuous internal monitoring for all research studies. Investigators conducting research involving human subjects should receive GCP/GCLP training before commencing their projects. Institutional higher degrees and research ethics committees should enforce this as a requirement for project approvals.
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    Effect of intermittent preventive treatment for malaria with dihydroartemisinin-piperaquine on immune responses to vaccines among rural Ugandan adolescents: randomised controlled trial protocol B for the ‘POPulation differences in VACcine responses’ (POPVAC) programme
    (BMJ open, 2020-02-16) Natukunda, Agnes; Nkurunungi, Gyaviira; Oduru, Gloria; Kabuubi, Prossy N.; Mutebe, Alex
    Drivers of lower vaccine efficacy and impaired vaccine-specific immune responses in low-income versus high-income countries, and in rural compared with urban settings, are not fully elucidated. Repeated exposure to and immunomodulation by parasite infections may be important. We focus on Plasmodium falciparum malaria, aiming to determine whether there are reversible effects of malaria infection on vaccine responses.
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    Helminth driven gut inflammation and microbial translocation associate with altered vaccine responses in rural Uganda
    (npj Vaccines, 2025-03-26) Nassuuna, Jacent; Walusimbi, Bridgious; Natukunda, Agnes; Zirimenya, Ludoviko
    Vaccine responses are sometimes impaired in rural, low-income settings. Helminth-associated gut barrier dysfunction and microbial translocation (MT) may be implicated. We used samples from a trial of praziquantel treatment-effects on vaccine responses in Schistosoma mansoni (Sm)-endemic Ugandan islands, measuring intestinal fatty acid-binding protein 2 (I-FABP2), lipopolysaccharide-binding protein, anti-endotoxin core antibodies (EndoCab), soluble CD14 (sCD14) in plasma, and faecal lipocalin-2, occult blood (FOB), and calprotectin (fCAL), and evaluating their associations with baseline helminth infection, praziquantel treatment, and responses to BCG, yellow fever, typhoid, HPV, and tetanus-diphtheria vaccines. Sm associated positively with fCAL and FOB, hookworm with I-FABP2, and any helminth with EndoCab IgM, fCAL and FOB. Sm associated inversely with sCD14. Praziquantel treatment reduced all marker concentrations, significantly fCAL and FOB, implying that Sm-associated gut inflammation and MT is reversible. Associations of assessed markers with vaccine-specific responses were predominantly inverse. Interventions to improve gut barrier function may enhance vaccine responsiveness.
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    Impact of BCG revaccination on the response to unrelated vaccines in a Ugandan adolescent birth cohort: randomised controlled trial protocol C for the ‘POPulation differences in VACcine responses’ (POPVAC) programme
    (BMJ open, 2020-02-16) Zirimenya, Ludoviko1 11 1; Nkurunungi ,Gyaviira; Natukunda, Agnes; Onen, Caroline
    There is evidence that BCG immunisation may protect against unrelated infectious illnesses. This has led to the postulation that administering BCG before unrelated vaccines may enhance responses to these vaccines. This might also model effects of BCG on unrelated infections.
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    NIHR Global Health Research Group on Vaccines for vulnerable people in Africa (VAnguard): Concept and Launch event report
    (NIHR Open Research, 2023-06-27) Zirimenya, Ludoviko; Zalwango, Flavia; Karanja , Henry K.; Natukunda, Agnes; Kiwanuka, Achilles; Chibita, Monica
    Vaccination is an important public health intervention, but not everyone benefits equally. Biological, social and structural factors render some communities vulnerable and unable to secure optimal health benefits from vaccination programmes. This drives health inequity and undermines wider vaccine impact by allowing the persistence of non-immune communities as foci for recurrent disease outbreaks. The NIHR Global Health Research Group on Vaccines for vulnerable people in Africa (VAnguard) aims to understand how biological, social, and structural factors interact to impair vaccine impact in vulnerable African communities.
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    Population differences in vaccine responses (POPVAC): scientific rationale and cross-cutting analyses for three linked, randomised controlled trials assessing the role, reversibility and mediators of immunomodulation by chronic infections in the tropics
    (BMJ open, 2020-06-24) Nkurunungi, Gyaviira; Zirimenya, Ludoviko; Natukunda, Agnes; Ninsiima, Caroline; Akello, Mirriam
    Vaccine-specific immune responses vary between populations and are often impaired in low income, rural settings. Drivers of these differences are not fully elucidated, hampering identification of strategies for optimising vaccine effectiveness. We hypothesise that urban–rural (and regional and international) differences in vaccine responses are mediated to an important extent by differential exposure to chronic infections, particularly parasitic infections. Three related trials sharing core elements of study design and procedures (allowing comparison of outcomes across the trials) will test the effects of (1) individually randomised intervention against schistosomiasis (trial A) and malaria (trial B), and (2) Bacillus Calmette-Guérin (BCG) revaccination (trial C), on a common set of vaccine responses. We will enrol adolescents from Ugandan schools in rural high-schistosomiasis (trial A) and rural high-malaria (trial B) settings and from an established urban birth cohort (trial C). All participants will receive BCG on day ‘0’; yellow fever, oral typhoid and human papilloma virus (HPV) vaccines at week 4; and HPV and tetanus/diphtheria booster vaccine at week 28. Primary outcomes are BCG-specific IFN-γ responses (8 weeks after BCG) and for other vaccines, antibody responses to key vaccine antigens at 4 weeks after immunisation. Secondary analyses will determine effects of interventions on correlates of protective immunity, vaccine response waning, priming versus boosting immunisations, and parasite infection status and intensity. Overarching analyses will compare outcomes between the three trial settings. Sample archives will offer opportunities for exploratory evaluation of the role of immunological and ‘trans-kingdom’ mediators in parasite modulation of vaccine-specific responses.
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    Pre-vaccination Schistosoma mansoni and hookworm infections are associated with altered vaccine immune responses: a longitudinal analysis among adolescents living in helminth-endemic islands of Lake Victoria, Uganda
    (Frontiers in Immunology, 2024-08-29) Natukunda, Agnes; Zirimenya,Ludoviko; Nkurunungi, Gyaviira; Nassuuna, Jacent
    Variations in vaccine responses have been observed between populations. A role for helminth infections has been proposed due to their immunomodulatory properties. In a secondary analysis of data from a randomised trial assessing effects of anthelminthic treatment on vaccine responses, we examined associations between helminth infections at baseline prior to vaccine administration, and vaccine responses among adolescents (9-17 years) in Koome Islands, Lake Victoria, Uganda.
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    Safety and immunogenicity of ChAdOx1 85A prime followed by MVA85A boost compared with BCG revaccination among Ugandan adolescents who received BCG at birth: a randomised, open-label trial
    (Elsevier Ltd, 2024-03) Wajja, Anne; Nassanga, Beatrice; Natukunda, Agnes; Serubanja, Joel; Tumusiime, Josephine; Akurut, Helen; Oduru, Gloria; Nassuuna, Jacent; Kabagenyi, Joyce; Morrison, Hazel; Scott, Hannah; Doherty, Rebecca Powell; Marshall, Julia L; Puig, Ingrid Cabrera; Cose, Stephen; Kaleebu, Pontiano; Webb, Emily L; Satti, Iman; McShane, Helen; Elliott, Alison M; Namutebi, Milly; Nakazibwe, Esther; Onen, Caroline; Apuule, Barbara; Akello, Florence; Mukasa, Mike; Nnaluwooza, Marble; Sewankambo, Moses; Kiwanuka, Sam; Kiwudhu, Fred; Imede, Esther; Nkurunungi, Gyaviira; Nakawungu, Prossy Kabuubi; Kabami, Grace; Nuwagaba, Emmanuel; Akello, Mirriam
    Abstract BACKGROUNDBCG confers reduced, variable protection against pulmonary tuberculosis. A more effective vaccine is needed. We evaluated the safety and immunogenicity of candidate regimen ChAdOx1 85A-MVA85A compared with BCG revaccination among Ugandan adolescents.METHODSAfter ChAdOx1 85A dose escalation and age de-escalation, we did a randomised open-label phase 2a trial among healthy adolescents aged 12-17 years, who were BCG vaccinated at birth, without evident tuberculosis exposure, in Entebbe, Uganda. Participants were randomly assigned (1:1) using a block size of 6, to ChAdOx1 85A followed by MVA85A (on day 56) or BCG (Moscow strain). Laboratory staff were masked to group assignment. Primary outcomes were solicited and unsolicited adverse events (AEs) up to day 28 and serious adverse events (SAEs) throughout the trial; and IFN-γ ELISpot response to antigen 85A (day 63 [geometric mean] and days 0-224 [area under the curve; AUC).FINDINGSSix adults (group 1, n=3; group 2, n=3) and six adolescents (group 3, n=3; group 4, n=3) were enrolled in the ChAdOx1 85A-only dose-escalation and age de-escalation studies (July to August, 2019). In the phase 2a trial, 60 adolescents were randomly assigned to ChAdOx1 85A-MVA85A (group 5, n=30) or BCG (group 6, n=30; December, 2019, to October, 2020). All 60 participants from groups 5 and 6 were included in the safety analysis, with 28 of 30 from group 5 (ChAdOx1 85A-MVA85A) and 29 of 30 from group 6 (BCG revaccination) analysed for immunogenicity outcomes. In the randomised trial, 60 AEs were reported among 23 (77%) of 30 participants following ChAdOx1 85A-MVA85A, 31 were systemic, with one severe event that occurred after the MVA85A boost that was rapidly self-limiting. All 30 participants in the BCG revaccination group reported at least one mild to moderate solicited AE; most were local reactions. There were no SAEs in either group. Ag85A-specific IFN-γ ELISpot responses peaked on day 63 in the ChAdOx1 85A-MVA85A group and were higher in the ChAdOx1 85A-MVA85A group compared with the BCG revaccination group (geometric mean ratio 30·59 [95% CI 17·46-53·59], p<0·0001, day 63; AUC mean difference 57 091 [95% CI 40 524-73 658], p<0·0001, days 0-224).INTERPRETATIONThe ChAdOx1 85A-MVA85A regimen was safe and induced stronger Ag85A-specific responses than BCG revaccination. Our findings support further development of booster tuberculosis vaccines.FUNDINGUK Research and Innovations and Medical Research Council.TRANSLATIONSFor the Swahili and Luganda translations of the abstract see Supplementary Materials section.
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    Schistosome and malaria exposure and urban–rural differences in vaccine responses in Uganda: a causal mediation analysis using data from three linked randomised controlled trials
    (The Lancet Global Health, 2024-11-21) Natukunda, Agnes; Nkurunungi, Gyaviira; Ninsiima, Caroline; Nyanzi, Ruth; Kiwudhu, Fred; Nassanga, Beatrice
    Vaccine immunogenicity and effectiveness vary geographically. Chronic immunomodulating parasitic infections including schistosomes and malaria have been hypothesised to be mediators of geographical variations. We compared vaccine-specific immune responses between three Ugandan settings (schistosome-endemic rural, malaria-endemic rural, and urban) and did causal mediation analysis to assess the role of Schistosoma mansoni and malaria exposure in observed differences. We used data from the control groups of three linked randomised trials investigating the effects of intensive parasite treatment among schoolchildren. All participants received the BCG vaccine (week 0); yellow fever (YF-17D), oral typhoid (Ty21a), human papillomavirus (HPV; week 4); and HPV booster and tetanus–diphtheria (week 28). Primary outcomes were vaccine responses at week 8 and, for tetanus–diphtheria, week 52. We estimated the total effect (TE) of setting on vaccine responses and natural indirect effect (NIE) mediated through current or previous infection with S mansoni or malaria, and baseline vaccine-specific responses.
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    The effect of helminth infection on vaccine responses in humans and animal models: A systematic review and meta-analysis
    (Parasite Immunology, 2022-06-17) Natukunda, Agnes; Zirimenya, Ludoviko; Nassuuna, Jacent; Nkurunungi, Gyaviira; Elliott, Alison M.; Webb, Emily L.
    Vaccination has potential to eliminate infectious diseases. However, parasitic infections such as helminths may hinder vaccines from providing optimal protection. We reviewed existing literature on the effects of helminth infections and their treatment on vaccine responses in humans and animals. We searched literature until 31 January 2022 in Medline, EMBASE, Global health, Scopus, and Web of science; search terms included WHO licensed vaccines and human helminth types. Standardized mean differences (SMD) in vaccine responses between helminth infected and uninfected or anthelminthic treated and untreated individuals were obtained from each study with suitable data for meta-analysis, and combined using a random effects model. Analysis was stratified by whether helminth exposure was direct or prenatal and by vaccine type. This study is registered with PROSPERO (CRD42019123074). Of the 4402 articles identified, 37 were included in the review of human studies and 24 for animal experiments. For human studies, regardless of vaccine type, overall SMD for helminth uninfected/treated, compared to infected/untreated, was 0.56 (95% CI 0.04–1.07 and I2 = 93.5%) for direct helminth exposure and 0.01 (95% CI −0.04 to 0.07 and I2 = 85.9%) for prenatal helminth exposure. Effects of anthelminthic treatment were inconsistent, with no overall benefit shown. Results differed by vaccine type, with responses to live vaccines most affected by helminth exposure. For animal studies, the most affected vaccine was BCG. This result indicates that helminth-associated impairment of vaccine responses is more severe for direct, than for prenatal, helminth exposure. Further research is needed to ascertain whether deworming of individuals before vaccination may help improve responses.
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    The effect of intensive praziquantel administration on vaccine-specific responses among schoolchildren in Ugandan schistosomiasis-endemic islands (POPVAC A): an open-label, randomised controlled trial
    (The Lancet Global Health, 2024-11-23) Nkurunungi, Gyaviira; Nassuuna, Jacent; Natukunda, Agnes; Walusimbi, Bridgious
    Vaccine responses differ between populations and are often impaired in rural and low-income settings. The reasons for this are not fully understood, but observational data suggest that the immunomodulating effects of parasitic helminths might contribute. We hypothesised that Schistosoma mansoni infection suppresses responses to unrelated vaccines, and that suppression could be reversed—at least in part—by intensive praziquantel administration.
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    The Effect of Malaria on Responses to Unrelated Vaccines in Animals and Humans: A Systematic Review and Meta-Analysis
    (Parasite immunology, 2024-10-24) Zirimenya, Ludoviko; Natukunda, Agnes; Nassuuna, Jacent; Nkurunungi, Gyaviira; Kabagenyi, Joyce; Webb, Emily L.
    Vaccine efficacy varies globally, often showing reduced immune responses in low- and middle-income countries, possibly due to the immunomodulatory effects of parasitic infections like malaria. This systematic review evaluates the impact of malaria on immune responses to unrelated vaccines in humans and animals. We systematically searched five databases—MEDLINE, Web of Science, Global Health, Scopus and Embase—up to 5th December 2023. Eligible studies compared immune responses to WHO-approved vaccines between malaria-infected and uninfected groups, or between antimalarial-treated and untreated groups. Meta-analysis was performed using random-effects models with standardised mean differences (SMDs) as summary statistics. The study is registered with PROSPERO (CRD42022298053). Twenty-four articles (17 human, 7 animal) met the inclusion criteria, with 13 human articles contributing data for the meta-analysis. Significant heterogeneity was observed. Vaccine responses were higher in malaria uninfected individuals (SMD 0.34, 95% CI 0.07 to 0.60, I2 = 87.15%) with weaker differences between antimalarial-treated and untreated groups (SMD 0.07, 95% CI −0.01 to 0.16, I2 = 85.01%). The overall SMD for malaria uninfected/treated vs. infected/untreated was 0.15, 95% CI 0.05–0.26, I2 = 90.91. Narrative analysis suggested malaria's adverse impact on vaccine responses in animals. Malaria infection may impair vaccines responses; with preventive treatment of malaria partially reversing these effects, highlighting the need for targeted public health interventions.