NRU :: Browsing by Author "Nkurunungi, Gyaviira"

Browsing by Author "Nkurunungi, Gyaviira"

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Effect of intensive treatment for schistosomiasis on immune responses to vaccines among rural Ugandan island adolescents: randomised controlled trial protocol A for the ‘POPulation differences in VACcine responses’ (POPVAC) programme
(BMJ open, 2021-02-16) Nkurunungi, Gyaviira; Zirimenya, Ludoviko; Nassuuna, Jacent; Niwagaba, Emmanuel; Amongi, Susan
Several licensed and investigational vaccines have lower efficacy, and induce impaired immune responses, in low-income versus high-income countries and in rural, versus urban, settings. Understanding these population differences is essential to optimising vaccine effectiveness in the tropics. We suggest that repeated exposure to and immunomodulation by chronic helminth infections partly explains population differences in vaccine response.
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.
The Impact of Intensive Versus Standard Anthelminthic Treatment on Allergy-related Outcomes, Helminth Infection Intensity, and Helminth-related Morbidity in Lake Victoria Fishing Communities, Uganda: Results From the LaVIISWA Cluster-randomized Trial
(Clinical infectious diseases, 2019) Sanya, Richard E.; Nkurunungi, Gyaviira; Hoek Spaans, Remy; Nampijja, Margaret; O’Hara, Geraldine; Kizindo, Robert; Oduru, Gloria; Kabuubi Nakawungu, Prossy; Niwagaba, Emmanuel; Abayo, Elson; Kabagenyi, Joyce; Zziwa, Christopher; Tumusiime, Josephine; Nakazibwe, Esther; Kaweesa, James; Muwonge Kakooza, Fred; Akello, Mirriam; Lubyayi, Lawrence; Verweij, Jaco; Nash, Stephen; Ree, Ronald van; Mpairwe, Harriet; Tukahebwa, Edridah; Webb, Emily L.; Elliott, Alison M.
The prevalence of allergy-related diseases is increasing in low-income countries. Parasitic helminths, common in these settings, may be protective. We hypothesized that intensive, community-wide, anthelminthic mass drug administration (MDA) would increase allergy-related diseases, while reducing helminth-related morbidity. Methods. In an open, cluster-randomized trial (ISRCTN47196031), we randomized 26 high-schistosomiasis-transmission fishing villages in Lake Victoria, Uganda, in a 1:1 ratio to receive community-wide intensive (quarterly single-dose praziquantel plus albendazole daily for 3 days) or standard (annual praziquantel plus 6 monthly single-dose albendazole) MDA. Primary outcomes were recent wheezing, skin prick test positivity (SPT), and allergen-specific immunoglobulin E (asIgE) after 3 years of intervention. Secondary outcomes included helminths, haemoglobin, and hepatosplenomegaly. Results. The outcome survey comprised 3350 individuals. Intensive MDA had no effect on wheezing (risk ratio [RR] 1.11, 95% confidence interval [CI] 0.64–1.93), SPT (RR 1.10, 95% CI 0.85–1.42), or asIgE (RR 0.96, 95% CI 0.82–1.12). Intensive MDA reduced Schistosoma mansoni infection intensity: the prevalence from Kato Katz examinations of single stool samples from each patient was 23% versus 39% (RR 0.70, 95% CI 0.55–0.88), but the urine circulating cathodic antigen test remained positive in 85% participants in both trial arms. Hookworm prevalence was 8% versus 11% (RR 0.55, 95% CI 0.31–1.00). There were no differences in anemia or hepatospenomegaly between trial arms. Conclusions. Despite reductions in S. mansoni intensity and hookworm prevalence, intensive MDA had no effect on atopy, allergy- related diseases, or helminth-related pathology. This could be due to sustained low-intensity infections; thus, a causal link between helminths and allergy outcomes cannot be discounted. Intensive community-based MDA has a limited impact in high-schistosomiasis- transmission fishing communities, in the absence of other interventions.
The impact of maternal infection with Mycobacterium tuberculosis on the infant response to bacille Calmette–Gue´rin immunization
(Philosophical Transactions of the Royal Society B: Biological Sciences, 2015) Mawa, Patrice A.; Nkurunungi, Gyaviira; Egesa, Moses; Webb, Emily L.; Smith, Steven G.; Kizindo, Robert; Akello, Mirriam; Lule, Swaib A.; Muwanga, Moses; Dockrell, Hazel M.; Cose, Stephen; Elliott, Alison M.
Bacille Calmette–Gue´rin (BCG) immunization provides variable protection against tuberculosis. Prenatal antigen exposure may have lifelong effects on responses to related antigens and pathogens. We therefore hypothesized that maternal latent Mycobacterium tuberculosis infection (LTBI) influences infant responses to BCG immunization at birth. We measured antibody (n ¼ 53) and cellular (n ¼ 31) responses to M. tuberculosis purified protein derivative (PPD) in infants of mothers with and without LTBI, in cord blood and at one and six weeks after BCG. The concentrations of PPD-specific antibodies declined between birth (median [interquartile range (IQR)]) 5600 ng ml21 [3300–11 050] in cord blood) and sixweeks (0.00 ng ml21 [0–288]). Frequencies of PPD-specific IFN-g-expressing CD4þT cells increased at one week and declined between one and six weeks ( p ¼ 0.031). Frequencies of IL-2- and TNF-a-expressing PPD-specific CD4þT cells increased between one and six weeks ( p ¼ 0.019, p ¼ 0.009, respectively). At one week, the frequency of PPD-specific CD4þT cells expressing any of the three cytokines, combined, was lower among infants of mothers with LTBI, in crude analyses ( p ¼ 0.002) and after adjusting for confounders (mean difference, 95% CI 20.041% (20.082, 20.001)). In conclusion, maternal LTBI was associated with lower infant anti-mycobacterial T-cell responses immediately following BCGimmunization. These findings are being explored further in a larger study.
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.
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.
Risk Assessment for the Implementation of Controlled Human Schistosoma Mansoni Infection Trials in Uganda
(AAS open research, 2019) Koopman, Jan Pieter; Egesa, Moses; Wajja, Anne; Adriko, Moses; Nassuuna, Jacent; Nkurunungi, Gyaviira; Driciru, Emmanuella; Cose, Stephen; Kaleebu, Pontiano; Kabatereine, Narcis; Tukahebwa, Edridah; Elliott, Alison M.
Schistosomiasis is a parasitic infection highly prevalent in sub-Saharan Africa, and a significant cause of morbidity; it is a priority for vaccine development. A controlled human infection model for Schistosoma mansoni (CHI-S) with potential to accelerate vaccine development has been developed among naïve volunteers in the Netherlands. Because responses both to infections and candidate vaccines are likely to differ between endemic and non-endemic settings, we propose to establish a CHI-S in Uganda where Schistosoma mansoni is endemic. As part of a “road-map” to this goal, we have undertaken a risk assessment. We identified risks related to importing of laboratory vector snails and schistosome strains from the Netherlands to Uganda; exposure to natural infection in endemic settings concurrently with CHI-S studies, and unfamiliarity of the community with the nature, risks and rationale for CHI. Mitigating strategies are proposed. With careful implementation of the latter, we believe that CHI-S can be implemented safely in Uganda. Our reflections are presented here to promote feedback and discussion.
Risk factors for asthma among schoolchildren who participated in a casecontrol study in urban Uganda
(Elife, 8,, 2019) Mpairwe, Harriet; Namutebi, Milly; Nkurunungi, Gyaviira; Tumwesige, Pius; Nambuya, Irene; Mukasa, Mike; Onen, Caroline; Nnaluwooza, Marble; Apule, Barbara; Katongole, Tonny; Oduru, Gloria; Kahwa, Joseph; Webb, Emily L; Lubyayi, Lawrence; Pearce, Neil; Elliott, Alison M
Data on asthma aetiology in Africa are scarce. We investigated the risk factors for asthma among schoolchildren (5–17 years) in urban Uganda. We conducted a case-control study, among 555 cases and 1115 controls. Asthma was diagnosed by study clinicians. The main risk factors for asthma were tertiary education for fathers (adjusted OR (95% CI); 2.32 (1.71–3.16)) and mothers (1.85 (1.38–2.48)); area of residence at birth, with children born in a small town or in the city having an increased asthma risk compared to schoolchildren born in rural areas (2.16 (1.60–2.92)) and (2.79 (1.79–4.35)), respectively; father’s and mother’s history of asthma; children’s own allergic conditions; atopy; and cooking on gas/electricity. In conclusion, asthma was associated with a strong rural-town-city risk gradient, higher parental socio-economic status and urbanicity. This work provides the basis for future studies to identify specific environmental/lifestyle factors responsible for increasing asthma risk among children in urban areas in LMICs.
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.
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.
The effect of BCG revaccination on the response to unrelated vaccines in urban Ugandan adolescents (POPVAC C): an open-label, randomised controlled trial
(The Lancet Global Health, 2024-11-24) Nassuuna, Jacent; Zirimenya, Ludoviko; Nkurunungi, Gyaviira; Ninsiima, Caroline; Amongi, Susan
Immune responses induced by several important vaccines differ between populations, with reduced responses in low-income and rural settings compared with high-income and urban settings. BCG immunisation boosts immune responses to some unrelated vaccines in high-income populations. We aimed to test the hypothesis that BCG revaccination can enhance responses to unrelated vaccines in Ugandan schoolchildren.
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.
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.
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.
Uganda Schistosomiasis Symposium 2023: understanding morbidity drivers and developing controlled human infection models for vaccine research
(Trends in Parasitology, 2023) Egesa, Moses; Kiberu, Davis; Sanya, Richard E.; Alabi, Ayodele; Baluku, Joseph Baruch; Oguttu, David W.; Driciru, Emmanuella; Odongo, Matthew; Elliott, Alison M.; Walusimbi, Bridgious; Nkurunungi, Gyaviira
Schistosomiasis impacts African populations most strongly. Despite Uganda’s leading role in the Schistosomiasis Control Initiative for mass drug administration (MDA), about half the population remains at risk and a quarter infected. Prevalence and intensity remain high, and morbidity severe, in northwest Uganda around Lake Albert and the Albert Nile. An effective vaccine could combat repeated infection following MDA, and controlled human infection (CHI) studies could enable such vaccine development. Therefore, the Uganda Schistosomiasis Multidisciplinary Research Center and CHI-in-Africa Network hosted a symposium in Uganda bringing together local and international partners to discuss research on the drivers of schistosomal morbidity and the development of CHI studies for helminth vaccine development in Africa. In this TrendsTalk, we invited 10 early- to mid-career researchers to summarise the symposium proceedings.

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