Helen Ayles

Background: The efficacy and safety of the M72/AS01E tuberculosis (TB) candidate vaccine were evaluated in the phase 2b randomized, placebo-controlled trial NCT01755598. In the trial, participants with Mycobacterium tuberculosis sensitization by a positive interferon-gamma release assay received either M72/AS01E or placebo (randomized 1:1) and were followed for 3 years. In this descriptive study, we genetically characterized M. tuberculosis isolates from participants who developed pulmonary TB during the trial to assess variability among isolates and evaluate the possibility of preferential progression from infection to active TB by certain strains in M72/AS01E and placebo recipients. Methods: M. tuberculosis isolates were recovered from sputum samples and underwent DNA extraction and sequencing to assess lineage, antibiotic resistance profile, genetic variation, and genomic clusters. Results: One hundred isolates (37 M72/AS01E, 63 placebo) were genetically characterized from 50 participants who developed microbiologically confirmed active pulmonary TB during the trial (20 M72/AS01E, 30 placebo). Diverse M. tuberculosis lineages were identified in both M72/AS01E and placebo recipients. No multidrug-resistant strains were detected. Genetic sequences corresponding to the antigenic components of M72/AS01E showed low variation in pepA and high variation in PPE18. However, no apparent preferential distribution of variants was observed in M72/AS01E or placebo recipients. Cluster analyses identified 10 genomic clusters with isolates from >1 participant, illustrating complex transmission dynamics and potential of coinfection by multiple strains within individuals. Conclusions: This descriptive analysis showed no apparent preferential distribution of local M. tuberculosis strains in M72/AS01E or placebo recipients. These results support the continued development of this candidate vaccine. Clinical Trials Registration: The NCT01755598 study was registered at https://Cinicaltrials.gov on 19 December 2012. The trial protocol and statistical analysis plan can be accessed from the trial registration website https://clinicaltrials.gov/study/NCT01755598.

Digital health innovation can fail to move beyond prototype or pilot stages or achieve intended outcomes due to a lack of involvement and attunement to local context. This article shares the potential of place-based co-production to support the development, acceptability and usability of context-attuned, digital health service innovation for young people. To illustrate the approach, we report on a collaborative, interdisciplinary project involving a Zambian public health research partner based in Lusaka, Zambia, three European universities and a not-for-profit digital innovation partner. Our youth-led, co-production process involved 6 stages: recruitment of youth Co-design Leaders; role play-based care pathway co-design; app co-design; digital prototype development; stakeholder consultation; and digital pathway testing. We used a combination of qualitative social science research, community and arts-based, human-centred design and digital innovation methods. Young people traced the digital testing and sampling process from accessing self-testing and sampling kits to laboratory processing of results through to how results should be communicated. They were encouraged to evaluate how these processes would work in the context of their everyday lives. We systematically embedded this ideation work into a technically functional ‘eHealth Yabwela’ app and clinical or laboratory worker-facing web application which young people user tested. Our place-based focus encouraged elicitation of whole pathway, in situ, logistical feasibility alongside social and technical concerns, enabling us to engage with potential adoption and accessibility barriers during the design process. Youth-led co-production created the conditions for participants to lead discussions, voice requirements and hold the project team accountable. Young people recognised that advocacy, overcoming digital inequalities, and further co-production with healthcare workers already facilitating youth-friendly healthcare provision would be needed to integrate the pathway within local systems.

Female genital schistosomiasis (FGS), a gynaecological disease caused by Schistosoma haematobium eggs deposition in the female genital tract, is prevalent in sub-Saharan Africa (SSA), the region with the highest cervical cancer burden globally. Persistent high risk (HR-) human papilloma virus (HPV) infection is necessary for cervical cancer development. We determined the association between FGS and HR-HPV genotypes in Zambian women. Sexually active women aged 15-50, not menstruating or pregnant, were recruited at home and provided two cervicovaginal self-swabs, urine sample, HIV and Trichomonas vaginalis self-tests, and completed a questionnaire. In clinic, midwives collected cervicovaginal swabs and cervical images with point-of-care colposcopy (EVA System, MobileODT^Ⓡ). Swabs were analysed for 14 HR-HPV types (GeneXpert^Ⓡ) and Schistosoma DNA (ITS-2 qPCR); urine for Schistosoma ova by microscopy and circulating anodic antigen (CAA). Visual FGS was defined as colposcopic identification of specific genital lesions, and molecular FGS as Schistosoma-positive cervicovaginal qPCR. Among 2,532 women (median age 28 [IQR:22-36]) recruited at home; 67% (1,694/2,532) completed clinic follow-up. Prevalence of visual FGS, molecular FGS, and HR-HPV were 35.2% [595/1,691], 6.5% [165/2,532], and 28.7% [690/2,401], respectively. Molecular FGS was weakly associated with all HR-HPV (adjusted Odds Ratio [aOR]=1.3, 95% CI 0.9-1.9). Women with molecular FGS were more likely to test positive for HR-HPV 16/18/45 (aOR=1.7, 95%CI 1.0-2.8). No association was observed between visual FGS and HR-HPV infection (95% CI 0.7-1.1). This is the first study to jointly screen for FGS and HR-HPV in Zambia, reporting an association between oncogenic HR-HPV types and molecular FGS.

Background: Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use. Methods and findings: Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507. Interpretation: In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs. Trial registration: ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947.