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.

BACKGROUND: BCG 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. METHODS: After 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). FINDINGS: Six 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). INTERPRETATION: The ChAdOx1 85A-MVA85A regimen was safe and induced stronger Ag85A-specific responses than BCG revaccination. Our findings support further development of booster tuberculosis vaccines. FUNDING: UK Research and Innovations and Medical Research Council. TRANSLATIONS: For the Swahili and Luganda translations of the abstract see Supplementary Materials section.

Unsupervised title and abstract screening for systematic review: a retrospective case-study using topic modelling methodology.

BACKGROUND: The importance of systematic reviews in collating and summarising available research output on a particular topic cannot be over-emphasized. However, initial screening of retrieved literature is significantly time and labour intensive. Attempts at automating parts of the systematic review process have been made with varying degree of success partly due to being domain-specific, requiring vendor-specific software or manually labelled training data. Our primary objective was to develop statistical methodology for performing automated title and abstract screening for systematic reviews. Secondary objectives included (1) to retrospectively apply the automated screening methodology to previously manually screened systematic reviews and (2) to characterize the performance of the automated screening methodology scoring algorithm in a simulation study. METHODS: We implemented a Latent Dirichlet Allocation-based topic model to derive representative topics from the retrieved documents' title and abstract. The second step involves defining a score threshold for classifying the documents as relevant for full-text review or not. The score is derived based on a set of search keywords (often the database retrieval search terms). Two systematic review studies were retrospectively used to illustrate the methodology. RESULTS: In one case study (helminth dataset), [Formula: see text] sensitivity compared to manual title and abstract screening was achieved. This is against a false positive rate of [Formula: see text]. For the second case study (Wilson disease dataset), a sensitivity of [Formula: see text] and specificity of [Formula: see text] were achieved. CONCLUSIONS: Unsupervised title and abstract screening has the potential to reduce the workload involved in conducting systematic review. While sensitivity of the methodology on the tested data is low, approximately [Formula: see text] specificity was achieved. Users ought to keep in mind that potentially low sensitivity might occur. One approach to mitigate this might be to incorporate additional targeted search keywords such as the indexing databases terms into the search term copora. Moreover, automated screening can be used as an additional screener to the manual screeners.

The effect of helminth infection on vaccine responses in humans and animal models: A systematic review and meta-analysis.

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.

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.

INTRODUCTION: 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. METHODS AND ANALYSIS: We have designed a randomised, double-blind, placebo-controlled, parallel group trial of intermittent preventive malaria treatment versus placebo, to determine effects on vaccine response outcomes among school-going adolescents (9 to 17 years) from malaria-endemic rural areas of Jinja district (Uganda). Vaccines to be studied comprise BCG vaccine on day 'zero'; yellow fever, oral typhoid and human papilloma virus vaccines at week 4; and tetanus/diphtheria booster vaccine at week 28. Participants in the intermittent preventive malaria treatment arm will receive dihydroartemisinin/piperaquine (DP) dosed by weight, 1 month apart, prior to the first immunisation, followed by monthly treatment thereafter. We expect to enrol 640 adolescents. Primary outcomes are BCG-specific interferon-γ ELISpot responses 8 weeks after BCG immunisation and for other vaccines, antibody responses to key vaccine antigens at 4 weeks after immunisation. In secondary analyses, we will determine effects of monthly DP treatment (versus placebo) on correlates of protective immunity, on vaccine response waning, on whether there are differential effects on priming versus boosting immunisations, and on malaria infection prevalence. We will also conduct exploratory immunology assays among subsets of participants to further characterise effects of the intervention on vaccine responses. ETHICS AND DISSEMINATION: Ethics approval has been obtained from relevant Ugandan and UK ethics committees. Results will be shared with Uganda Ministry of Health, relevant district councils, community leaders and study participants. Further dissemination will be done through conference proceedings and publications. TRIAL REGISTRATION NUMBER: Current Controlled Trials identifier: ISRCTN62041885.

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.

INTRODUCTION: 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. METHODS AND ANALYSIS: To test this hypothesis, we have designed a randomised controlled trial of BCG versus no BCG immunisation to determine the effect of BCG on subsequent unrelated vaccines, among 300 adolescents (aged 13-17 years) from a Ugandan birth cohort. Our schedule will comprise three main immunisation days (week 0, week 4 and week 28): BCG (or no BCG) revaccination at week 0; yellow fever (YF-17D), oral typhoid (Ty21a) and human papillomavirus (HPV) prime at week 4; and HPV boost and tetanus/diphtheria (Td) boost at week 28. Primary outcomes are anti-YF-17D neutralising antibody titres, Salmonella typhi lipopolysaccharide-specific IgG concentration, IgG specific for L1-proteins of HPV-16/HPV-18 and tetanus and diphtheria toxoid-specific IgG concentration, all assessed at 4 weeks after immunisation with YF, Ty21a, HPV and Td, respectively. Secondary analyses will determine effects on correlates of protective immunity (where recognised correlates exist), on vaccine response waning and on whether there are differential effects on priming versus boosting immunisations. We will also conduct exploratory immunology assays among subsets of participants to further characterise effects of BCG revaccination on vaccine responses. Further analyses will assess which life course exposures influence vaccine responses in adolescence. ETHICS AND DISSEMINATION: Ethics approval has been obtained from relevant Ugandan and UK ethics committees. Results will be shared with Uganda Ministry of Health, relevant district councils, community leaders and study participants. Further dissemination will be done through conference proceedings and publications. TRIAL REGISTRATION NUMBER: ISRCTN10482904.

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.

INTRODUCTION: 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. METHODS AND ANALYSIS: 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. ETHICS AND DISSEMINATION: Ethics approval has been obtained from relevant Ugandan and UK ethics committees. Results will be shared with Uganda Ministry of Health, relevant district councils, community leaders and study participants. Further dissemination will be done through conference proceedings and publications. TRIAL REGISTRATION NUMBERS: ISRCTN60517191, ISRCTN62041885, ISRCTN10482904.

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.

INTRODUCTION: 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. METHODS AND ANALYSIS: We have designed an individually randomised, parallel group trial of intensive versus standard praziquantel (PZQ) intervention against schistosomiasis, to determine effects on vaccine response outcomes among school-going adolescents (9-17 years) from rural Schistosoma mansoni-endemic Ugandan islands. Vaccines to be studied comprise BCG on day 'zero'; yellow fever, oral typhoid and human papilloma virus (HPV) vaccines at week 4; and HPV and tetanus/diphtheria booster vaccine at week 28. The intensive arm will receive PZQ doses three times, each 2 weeks apart, before BCG immunisation, followed by a dose at week 8 and quarterly thereafter. The standard arm will receive PZQ at week 8 and 52. We expect to enrol 480 participants, with 80% infected with S. mansoni at the outset.Primary outcomes are BCG-specific interferon-γ ELISpot responses 8 weeks after BCG immunisation and for other vaccines, antibody responses to key vaccine antigens at 4 weeks after immunisation. Secondary analyses will determine the effects of intensive anthelminthic treatment on correlates of protective immunity, on waning of vaccine response, on priming versus boosting immunisations and on S. mansoni infection status and intensity. Exploratory immunology assays using archived samples will enable assessment of mechanistic links between helminths and vaccine responses. ETHICS AND DISSEMINATION: Ethics approval has been obtained from relevant ethics committes of Uganda and UK. Results will be shared with Uganda Ministry of Health, relevant district councils, community leaders and study participants. Further dissemination will be done through conference proceedings and publications. TRIAL REGISTRATION NUMBER: ISRCTN60517191.

Urban-rural differences in immune responses to mycobacterial and tetanus vaccine antigens in a tropical setting: A role for helminths?

Several vaccines elicit lower efficacy or impaired immune responses in rural compared to urban settings, and in tropical low-income countries compared to high-income countries. An unresolved hypothesis is that immunomodulation by parasitic infections such as helminths (prevalent in rural tropical settings) contributes to suppression of vaccine responses. Among 1-17-year-old Ugandan residents of rural Schistosoma mansoni (Sm)-endemic islands and proximate urban communities with lower helminth exposure, we assessed plasma antibody and whole blood assay cytokine responses to tetanus toxoid (TT) and purified protein derivative of Mycobacterium tuberculosis (PPD). These were taken to represent recall responses to tetanus and BCG vaccination in infancy. PPD-specific responses are additionally induced by tuberculous and non-tuberculous mycobacterial exposure. Urban-rural comparisons showed that PPD-specific IFN-γ and IL-13 and TT-specific IL-13 and IgG concentrations were lower in the rural setting, but that PPD-specific IgE concentrations were higher. Among rural participants, Sm infection was inversely associated with PPD-specific IFN-γ, while nematode infection was positively associated with PPD-specific IgG. Among urban participants, Sm infection was positively associated with PPD-specific responses but inversely associated with TT-specific responses, while nematode infection was inversely associated with TT-specific IgG and IgG4, but no associations were observed with PPD-specific responses. Despite these associations, for the urban-rural comparisons there were no notable changes in test statistics after adjusting for current helminth infections, suggesting that helminths were not the sole explanation for the urban-rural differences observed. Helminths likely work in concert with other environmental exposures and operational factors to influence vaccine response.

Continuous research monitoring improves the quality of research conduct and compliance among research trainees: internal evaluation of a monitoring programme.

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 (MUII-Plus) 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. Median (IQR) compliance rate was 43% (31%, 44%) at site initiation visit for different monitoring items, 70% (54%, 90%) at the 1st interim monitoring visit, 100% (92%, 100%) at 2nd interim 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.

Where No Universal Health Care Identifier Exists: Comparison and Determination of the Utility of Score-Based Persons Matching Algorithms Using Demographic Data.

BACKGROUND: A universal health care identifier (UHID) facilitates the development of longitudinal medical records in health care settings where follow up and tracking of persons across health care sectors are needed. HIV case-based surveillance (CBS) entails longitudinal follow up of HIV cases from diagnosis, linkage to care and treatment, and is recommended for second generation HIV surveillance. In the absence of a UHID, records matching, linking, and deduplication may be done using score-based persons matching algorithms. We present a stepwise process of score-based persons matching algorithms based on demographic data to improve HIV CBS and other longitudinal data systems. OBJECTIVE: The aim of this study is to compare deterministic and score-based persons matching algorithms in records linkage and matching using demographic data in settings without a UHID. METHODS: We used HIV CBS pilot data from 124 facilities in 2 high HIV-burden counties (Siaya and Kisumu) in western Kenya. For efficient processing, data were grouped into 3 scenarios within (1) HIV testing services (HTS), (2) HTS-care, and (3) within care. In deterministic matching, we directly compared identifiers and pseudo-identifiers from medical records to determine matches. We used R stringdist package for Jaro, Jaro-Winkler score-based matching and Levenshtein, and Damerau-Levenshtein string edit distance calculation methods. For the Jaro-Winkler method, we used a penalty (р)=0.1 and applied 4 weights (ω) to Levenshtein and Damerau-Levenshtein: deletion ω=0.8, insertion ω=0.8, substitutions ω=1, and transposition ω=0.5. RESULTS: We abstracted 12,157 cases of which 4073/12,157 (33.5%) were from HTS, 1091/12,157 (9.0%) from HTS-care, and 6993/12,157 (57.5%) within care. Using the deterministic process 435/12,157 (3.6%) duplicate records were identified, yielding 96.4% (11,722/12,157) unique cases. Overall, of the score-based methods, Jaro-Winkler yielded the most duplicate records (686/12,157, 5.6%) while Jaro yielded the least duplicates (546/12,157, 4.5%), and Levenshtein and Damerau-Levenshtein yielded 4.6% (563/12,157) duplicates. Specifically, duplicate records yielded by method were: (1) Jaro 5.7% (234/4073) within HTS, 0.4% (4/1091) in HTS-care, and 4.4% (308/6993) within care, (2) Jaro-Winkler 7.4% (302/4073) within HTS, 0.5% (6/1091) in HTS-care, and 5.4% (378/6993) within care, (3) Levenshtein 6.4% (262/4073) within HTS, 0.4% (4/1091) in HTS-care, and 4.2% (297/6993) within care, and (4) Damerau-Levenshtein 6.4% (262/4073) within HTS, 0.4% (4/1091) in HTS-care, and 4.2% (297/6993) within care. CONCLUSIONS: Without deduplication, over reporting occurs across the care and treatment cascade. Jaro-Winkler score-based matching performed the best in identifying matches. A pragmatic estimate of duplicates in health care settings can provide a corrective factor for modeled estimates, for targeting and program planning. We propose that even without a UHID, standard national deduplication and persons-matching algorithm that utilizes demographic data would improve accuracy in monitoring HIV care clinical cascades.

Elective reconstruction of the ascending aorta for aneurysmal disease restores normal life expectancy. An analysis of risk factors for early and late mortality.

OBJECTIVE: We investigated the survival of patients who had undergone elective reconstruction of the ascending aorta for degenerative aneurysms. The long-term survival was compared to an age- and sex-matched case-control population. An analysis of risk factors, influencing survival was made. METHODS AND RESULTS: From May 1998 to January 2012, 72 patients underwent elective reconstruction of the ascending aorta for degenerative disease at the department of Cardiothoracic Surgery of the Jessa Hospital, Hasselt, Belgium. Sixty patients were treated with Bentall procedures, whereas 12 received valve-sparing procedures. The average age of the patient group was 65.5 years (range 24-80), with 64% males. Thirty-day mortality was 9.7% (consistent with calculated Euroscore II: 9.2%). The long-term survival was 80.9% at 3, 5 and 10 years. No deaths occurred between 3 and 10 years postoperatively. In an age- and sex case-matched Belgian population, 3-, 5- and 10-year survival were 95.7%, 94.7% and 85.2%, respectively. Long-term survival was not significantly different between both groups. Poor NYHA class at the time of surgery (P = 0.041) and COPD (P = 0.028) had a significant impact on global survival. Valve-sparing operations provide similar long-term survival, avoiding thrombo-embolic complications. CONCLUSIONS: Reconstruction of the ascending aorta for degenerative aneurysmal disease restores normal life expectancy, compared with an age- and sex-matched case-control population. Early mortality is consistent with the Euroscore II risk calculation. Whereas late survival progressively declines in the average population, it remains constant in the treated group after 3 years. COPD and poor functional class significantly impair survival. Valve-sparing procedures confer a similar long-term survival as valve replacement.