BackgroundThe COVID-19 pandemic led to unprecedented interest and participation in vaccine trials globally, and a concurrent increase in vaccine hesitancy. Whether this impacted recruitment of healthy volunteers to subsequent non-COVID vaccine trials is not well studied. We explored the impact of the COVID-19 pandemic on motivations for participating in two clinical trials of the same novel anti-plague vaccine, conducted in the United Kingdom (UK) and Uganda in 2021 and 2022.MethodsParticipants enrolled in PlaVac (UK) and PlaVac Uganda, Phase I trials of ChAdOx1 Plague vaccine, were invited to complete an optional questionnaire and semi-structured interview examining motivations for participating, including questions on the impact of the COVID-19 pandemic on their decision. Questionnaires were self-administered and interviewer-administered for UK and Uganda studies, respectively. Interviews were conducted in local languages, transcribed in English, and analysed using thematic analysis. Results were compared between studies.ResultsThirty-one of the 45 (68.9%; 25.8% female) UK trial participants and all 36 (100.0%; 27.8% female) of the Uganda trial participants completed questionnaires responses, and 19 Uganda questionnaire respondents completed interviews. Responses to questions on the impact of the COVID-19 pandemic on volunteering decisions were divergent between countries, with little effect for UK participants but a strong positive effect for Ugandan participants. Themes relating to this effect were "contributor, not cause" in the UK, and in Uganda were preparedness (wanting to contribute to vaccine development to prevent suffering and death from future epidemics), increased awareness (understanding the vaccine development process and seeing rapidly deployed COVID-19 vaccine trials gave them confidence), and personal protection (believing themselves to be protected by the novel plague vaccine). Participants in both studies expressed trust and confidence in the study vaccine which shares the same adenoviral-vectored platform technology used to elicit an immune response (ChAdOx1) with the COVID-19 vaccine ChAdOx1 nCoV-19 (Vaxzevria, AstraZeneca).ConclusionsFor Ugandan participants, COVID-19 and mass vaccination increased knowledge about vaccines and trials and encouraged them to participate in research, but had little impact on UK volunteers. There was no evidence of a negative effect of perceptions of the related ChAdOx1 nCoV-19 vaccine on trial participants' confidence in the novel plague vaccine's safety.Trial registrationsCurrent controlled trial: ISRCTN41077863, prospective registration date: 19/03/2021, and current controlled trial: ISRCTN79243381, prospective registration date 05/08/2022.

Abstract Introduction This qualitative study was conducted to assess participants’ understanding of the PrEPVacc trial design and factors that influenced decisions to participate in the trial. PrEPVacc was a phase IIb, three-arm, two-stage HIV prophylactic vaccine trial with a second randomisation to oral pre-exposure prophylaxis. The main objective was to assess the safety and efficacy of two HIV-1 prophylactic vaccine regimens, each compared to placebo, in preventing the acquisition of HIV. Methods Using a longitudinal approach, qualitative data were collected between October 2021 and September 2023. A sample of 105 participants (7% of trial participants) was purposively selected to participate in three in-depth interviews at 2, 6, and 12 months during the trial. Another 111 (92 females and 19 males) participated in 14 focus group discussions across four sites. Data were analyzed thematically. Results Repeated information sharing sessions facilitated by health workers helped participants understand key trial concepts and the design. Pre-exposure prophylaxis (PrEP) was widely recognised as a protective measure alongside experimental vaccines. While vaccines were preferred for convenience and minimal side effects, individual perceived HIV risk was a main motivation for adhering to PrEP. Supportive relationships with health workers and close family members encouraged engagement in the trial, including acceptance to use the products. However, misinformation and stigma in communities created barriers to participation, with some participants facing social harm. Conclusion Overall, participants demonstrated a good understanding of randomisation, double-blinding, and placebo control, facilitated by clear, repeated communication from health workers. Strengthening strategies to enhance informed consent, reduce stigma, and promote trial acceptance is crucial for successful implementation and retention. Clinical trial registration ClinicalTrials.gov NCT04066881. Registered on December 15, 2020.

OBJECTIVES:Achieving elimination of mother-to-child transmission (eMTCT) remains a challenge in sub-Saharan Africa. Identifying persistent risk factors is critical for addressing remaining gaps in the prevention-of-mother-to-child HIV transmission (PMTCT) cascade. METHODS:We conducted a case-control study among mother-child pairs where cases were mothers of HIV-positive children aged <6 years, while controls were mothers of HIV-exposed but HIV-negative children aged <6 years. Data were collected on sociodemographic characteristics, antiretroviral therapy (ART), antenatal care (ANC), infant-feeding practices, and partner involvement. Logistic regression identified factors independently associated with being a case. RESULTS:A total of 183 mothers (91 cases and 92 controls) were included, with a median age of 30.9 (IQR 27.0-36.0) years. Attending <4 ANC visits (aOR 2.58; 95% CI 1.07-6.22) and mixed feeding before 6 months (aOR 5.56; 95% CI 2.22-13.94) were significantly associated with increased odds of MTCT. Child age ≥4 years (aOR 5.65; 95% CI 2.36-13.51) was associated with HIV-positive status. ART duration >5 years (aOR 0.07; 95% CI 0.03-0.18) and partner support (aOR 0.20; 95% CI 0.07-0.59) were strongly protective. CONCLUSION:Residual MTCT remains associated with modifiable factors across the PMTCT cascade. Strengthening early and sustained ANC attendance, partner involvement, exclusive breastfeeding, and ART retention may accelerate progress towards eMTCT.

Cervical cancer is a leading cause of cancer-related mortality among women in sub-Saharan Africa, and accounts for 80% of female cancer cases in Uganda. The Human Papillomavirus (HPV) vaccine prevents cervical cancer but is mainly administered to school-going girls aged 9-15 y, potentially excluding out-of-school girls. This study assessed knowledge, perceptions, uptake, and preferred delivery strategies among out-of-school girls aged 9-20 y in inland and fishing communities in Masaka, Uganda. Between August and October 2024, we surveyed 428 girls (214 per community) using structured questionnaires. Descriptive statistics summarized participant characteristics, and logistic regression identified factors associated with uptake. The median age was 17 y (IQR: 15-19). Nearly one-fifth (19.9%) were married or cohabiting, and 62.4% had ever had sex. Less than half (44.2%) reported prior knowledge of the HPV vaccine, though most recognized its importance (73.4%) and safety (72.2%). Uptake remained low: 29.9% had received at least one dose, and 12.9% had completed two doses. Prior awareness strongly predicted uptake (aOR = 7.82; 95% CI: 4.67-13.44), with higher uptake in fishing communities (aOR = 2.21; 95% CI: 1.30-3.84). Lower uptake was associated with being out of school for 6-10 y (aOR = 0.24; 95% CI: 0.14-0.40) and prior sexual experience (aOR = 0.51; 95% CI: 0.27-0.96). Among unvaccinated girls, 91.2% expressed willingness to receive the vaccine. Preferred strategies included community outreaches (57.7%), health facility approaches (53.3%), and door-to-door delivery (29.2%). Uptake among out-of-school girls was low despite high willingness, underscoring the need for targeted interventions in high-risk settings.

Measuring product use adherence remains a challenge in HIV prevention trials and routine care setting. We determined agreement among and between non-pharmacokinetic (non-PK) and pharmacokinetic (PK) adherence measures, and also assessed the incremental value of each measure among women using the dapivirine vaginal ring (DVR) in the Ring trial in southwestern Uganda. Between 2013 and 2016, the International Partnership for Microbicides conducted the Ring trial in which women were randomised to dapivirine or placebo vaginal ring in a ratio of 2:1. A total of 197 women were randomised. Four adherence measures were used, including PK: (i) testing of the dapivirine residual levels in used rings and (ii) plasma drug concentrations; non-PK: (iii) self-reported and (iv) ring colour change, all measured every 4 weeks for 2 years. We defined product use adherence as having the expected dapivirine residual levels (≤ 23.5 mg of 25 mg) or plasma concentration (≥ 95 pg/mL) or having used the ring as instructed at ≥ 80

BACKGROUND:F/TAF was shown to be noninferior to F/TDF as pre-exposure prophylaxis (PrEP) in men, but approval was not extended to cisgender women. We report the results of PrEPVacc, in which a predominantly female population was randomly allocated to receive daily oral F/TDF or F/TAF for ∼6 months within a HIV-1 prophylactic vaccine trial. SETTING:Four study sites in 3 African countries (Uganda, Tanzania, South Africa). METHODS:The 2 regimens were compared by the averted infections ratio (AIR)-the proportion of infections averted by F/TAF relative to F/TDF. The counterfactual HIV incidence, an essential component of this metric, was derived from a preceding registration cohort. Dried blood spots (DBS) were collected at regular time points for later assessment of tenofovir diphosphate levels in selected subpopulations. RESULTS:1380 participants (697 F/TDF, 683 F/TAF) were included in the primary analysis (total follow-up 709.2 person-years); 87% were cisgender women. Three HIV infections (0.86/100 person-years) occurred in the F/TAF group versus 2 in the F/TDF group (0.56/100 person-years). The counterfactual HIV incidence was estimated to be 2.59/100 person-years (90% CI: 1.86 to 3.52), giving an AIR of 0.85 (90% CI: 0.31 to 1.66). Based on the week 8 DBS sample, only an estimated 14% of participants were classified as taking 2-3 tablets per week and 9% ≥4 tablets per week. CONCLUSIONS:Despite similar HIV incidence rates, the noninferiority of F/TAF was not demonstrated, probably because of low statistical power primarily driven by low adherence. However, there is compelling evidence from multiple studies supporting the efficacy of F/TAF as PrEP regardless of sex.

INTRODUCTION:Despite global reports of declining HIV incidence, current data are limited. This study presents findings on HIV incidence and risk factors in a HIV trial preparedness cohort. METHODS:Between 18 July 2018 and 13 October 2022, individuals 18-45-year-old were recruited from communities along the trans-African highway and the shores of Lake Victoria in Masaka district, Uganda. Eligible individuals were HIV-negative and met at least one of the following criteria: suspected or confirmed sexually transmitted infection (STI), unprotected sex with ≥2 partners, unprotected sex with a new partner in the past 3 months, or unprotected sex in exchange for money/goods in the past month. Baseline data included demographics, sexual behaviour, and HIV risk factors. Follow-up assessments of HIV risk and sexual behaviour were conducted every six months, while HIV counselling and testing (HCT) were provided every 3 months, with linkage to care for those testing positive. Data were summarised descriptively, and associations with HIV incidence were analysed using uni-variable and multi-variable Poisson regression models. RESULTS:Of the 1422 individuals enrolled, 1115 (78.4%) attended ≥1 follow-up visit; 69% were female and 55% were aged ≤24 years. Over 900.3 person-years of observation (PYO), 24 individuals acquired HIV, yielding an incidence rate (IR) of 2.7 PYO [95% Confidence Interval (CI): 1.8-4.0]. Baseline factors independently associated with incident HIV included female sex [adjusted incidence rate ratio (aIRR) = 6.84 PYO, 95% CI 1.60-29.30], residence in a fishing community [aIRR = 3.04 PYO, 95% CI 1.05-8.78] and recreational drug use in the past 3 months [aIRR = 3.08 PYO, 95% CI 1.19-7.99]. In a separate analysis, using time-updated variables assessed during follow-up, HIV acquisition was associated with sex after alcohol consumption [aIRR = 2.65 PYO, 95% CI 1.11-6.31], and STI diagnosis/treatment within the past 3 months [aIRR = 2.52 PYO, 95% CI 1.09-5.80]. CONCLUSION:HIV incidence remains high among women, fishing community residents, and individuals with high risk behaviours, underscoring the need for targeted interventions to reduce the burden in these populations.

Background: Assessment of efficacy in HIV prevention trials remains a challenge in the era of widespread use of active controls. We investigated use of counterfactual groups to assess treatment efficacy. Methods: We used data from placebo arms of two previous HIV prevention efficacy trials (Pro2000 vaginal microbicide trial, 2005–2009: ISRCTN64716212 and dapivirine vaginal ring trial, 2013–2016: NCT01539226) and four observational cohorts (two in each of the periods; (a) during the conduct of a simulated HIV vaccine efficacy trial (SiVET), 2012–2017, and (b) prior to SiVET (2005–2011)) and compared HIV prevention efficacy trial targeted outcomes with SiVETs. SiVET participants were administered a licensed hepatitis B vaccine at 0, 1 and 6 months mimicking an HIV vaccine efficacy trial schedule. Participants were tested for HIV quarterly for one year. The probability of the SiVET assignment conditioned on the measured participants’ baseline characteristics were estimated using propensity scores (PS) and matched between SiVET and placebo arm of trials. Similar calculations were repeated for observational cohorts in the pre- and during SiVET periods. We compared HIV incidence rate ratio (IRR) between SiVET and the trials or observational data before and after PS matching. Results: This analysis involved data from 3387 participants; observational cohorts before SiVET 1495 (44.2%), placebo arms of previous trials 367 (10.8%), observational cohorts during SiVET conduct 953 (28.1%) and SiVETs 572 (16.9%). Before propensity score matching (PSM), there were significant imbalances in participants’ baseline characteristics between SiVET, and all the other studies and HIV incidence was lower in SiVET. After PSM, the participants’ characteristics were comparable. The HIV incidence in SiVET was similar to that in the previous trial, IRR = 1.01 95% CI: 0.16–4.70), p = 0.968, and observational data during SiVET, IRR = 0.74, 95% CI 0.34–1.54), p = 0.195, but much lower compared to the observational data pre-SiVET, IRR = 0.48, 95% CI: 0.20–1.04), p = 0.023. Conclusions: PSM can be used to create counterfactual groups from other data sources. The best counterfactual group for assessing treatment effect is provided by data collected in the placebo arm of previous trials followed by that from observational data collected concurrently to the current trial (SiVET). Even with PSM, observational data collected prior to the current trial may overestimate treatment effect.

Introduction Recruiting and retaining participants in HIV vaccine trials remains a major challenge, particularly in rural settings, despite HIV continuing to be a global public health concern with approximately 1.3 million new infections reported worldwide in 2023. An effective preventive HIV vaccine is considered the most promising strategy for controlling the epidemic. This study underscores the critical role of community engagement in achieving successful trial outcomes and also assessed the feasibility of retaining at least 90% of enrolled volunteers through to study completion. Insights are drawn from a Phase I HIV vaccine trial conducted at a rural clinical research site in South Western Uganda. Methods A Phase I multicentre study assessed the immunogenicity and safety of a prime-boost HIV vaccination regimen that included modified vaccinia virus Ankara (MVA) after non-replicating simian adenovirus (ChAdOx1). We targeted healthy adults from low-incidence HIV communities, aged between 18 and 50 years. Community leaders and Village Health Teams (VHTs) played a key role in participant mobilisation for stakeholder meetings and pre-screening seminars, while research literacy sessions were conducted throughout the study. Additional strategies include mapping physical addresses, gathering numerous contact details, and making follow-up home visits. Results 22 people were enrolled out of 47 who were screened between October 12 and November 18, 2021. Because every participant showed up for their scheduled visits, the retention rate was 100%. Strong community involvement, ongoing education, positive researcher-participant relationships, and a friendly site environment were all credited with the success. Conclusion Engaging the Community Advisory Board, Village Health Teams (VHTs), and strategies such as research literacy sessions, seminars, mapping addresses, collecting multiple contacts, and reminder calls were pivotal in building trust and ensuring strong participant recruitment and retention. These findings affirm that meaningful community engagement is essential for the feasible and successful conduct of early-phase HIV vaccine trials in rural settings.

BACKGROUND:COVID-19 vaccines significantly reduce severe disease outcomes, but uncertainty remains about long-term protection. We investigated vaccine effectiveness (VE) against SARS-CoV-2 infection over extended periods in the World Health Organisation AFRO-MoVE network studies in Africa. METHODS:Participants with COVID-19-like symptoms were recruited between 2023 and 2024 for a test-negative case-control study conducted across 19-healthcare centres in Uganda. Cases were symptomatic patients with any three of cough, sore-throat, coryza, among others, and PCR-confirmed SARS-CoV-2, while controls were SARS-CoV-2 PCR-negative. Vaccination was verified from vaccination cards, hospital-records, vaccination registry and self-reporting. VE was assessed through three measures: (a) Annual - patients vaccinated in the past 12-months regardless of dose vs those vaccinated >12-months before symptom onset plus unvaccinated; (b) Absolute - patients vaccinated in the past 12-months vs unvaccinated; and (c) Relative - patients vaccinated in the past 12-months vs those vaccinated >12-months before symptom onset. VE was calculated as 1- adjusted odds ratio for three patient groups based on days since the last dose; (1) <365, (2) 7-269 and (3) 270-364 while adjusting for age, sex, calendar-time and chronic conditions. The sensitivity analysis excluded patients that were previously infected with SARS-CoV-2. FINDINGS:In total, 1371 patients, 56 % female were recruited. Of these, 173 were classified as cases, with 97 (56 %) fully vaccinated compared to 701 (59 %) controls, p = 0.830. The overall adjusted VE was moderate, 45 % to 59 %, and remained consistent across the annual, absolute and relative measures. Sensitivity analysis showed consistently lower VE (32 % to 38 %) across all measures. INTERPRETATION:The results suggest that COVID-19 vaccination provides moderate protection against symptomatic SARS-CoV-2 infection up to 12-months after the last dose and highlight the importance of up-to-date vaccinations for high-risk individuals. The lack of clear COVID-19 seasonality in this and other African settings creates a challenge to selecting the optimal timing for annual vaccination.

INTRODUCTION:The emergence of new SARS-CoV-2 variants threatens the effectiveness of global vaccination campaigns. This study examines the vaccination status and associated factors among patients presenting with COVID-19-like symptoms at 19 healthcare facilities in Uganda. MATERIALS AND METHODS:A cross-sectional analysis was conducted using data collected at health facilities to evaluate the effectiveness of COVID-19 vaccines in Uganda from March 2023 to March 2024. Participants were individuals aged 12 years and older with COVID-19-like symptoms who underwent a SARS-CoV-2 qPCR test within 10 days of symptom onset. The study involved obtaining informed consent, collecting medical and vaccination histories (confirmed using vaccination cards and Ministry of Health COVID-19 database), performing physical examinations, administering a questionnaire, and taking oral/nasopharyngeal swabs for SARS-CoV-2 qPCR testing. Vaccination coverage was defined as receiving at least one vaccine dose. Logistic regression was used to identify factors associated with vaccination status. RESULTS:Among 1398 participants enrolled (55.4 % female), the median age was 30.0 years (IQR: 24.0-41.0). Vaccination coverage, was 66.6 %. Residing in Wakiso district compared to the Capital, Kampala was associated with a higher likelihood of vaccination (adjusted odds ratio [aOR] = 1.4, 95 % CI: 1.0-1.8, p = 0.021). Frontline and healthcare workers were more likely to be vaccinated (aOR = 5.0, 95 % CI: 3.6-7.3, p < 0.001), as were individuals with a previous COVID-19 diagnosis (aOR = 2.4, 95 % CI: 1.6-3.9, p < 0.001). CONCLUSIONS:Our results underscore the need for targeted public health messaging and support to promote vaccination, especially among non-healthcare workers. Addressing these gaps is crucial for maintaining high vaccination coverage and mitigating the impact of new SARS-CoV-2 variants on the population.

Men who are mobile for work are a key population at high risk of acquiring HIV. Flexible pre-exposure prophylaxis (PrEP) options, including event-driven (ED) oral PrEP and long-acting injectable cabotegravir (CAB-LA), may offer increased access and acceptability for these men. However, limited data exist on the effectiveness and implementation of CAB-LA and ED PrEP among mobile men in Africa. Our study aims to assess the effectiveness and implementation of CAB-LA and oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) (both daily and ED) through comparison of uptake, retention in care, coital coverage, and participant choice. We will conduct a mixed0method, phase 3b, open-label, hybrid type 2 implementation and effectiveness randomised controlled trial (RCT). The trial will be carried out in 400 HIV-negative men aged 18 years or older in South Africa and Uganda. Men will be randomised 1:1 to either Group A: oral TDF/FTC PrEP (ED or daily) or Group B: CAB-LA over 9 months. After 9 months, participants from both groups will be offered a choice of PrEP (oral TDF/FTC or CAB-LA) for a further 9 months, with the ability to change their choice as required. Various strategies to support PrEP adoption, initiation, and persistence will be implemented, monitored, and reported on using a RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) implementation science framework. This study will provide critical data to inform scalable delivery models for both oral and injectable PrEP among mobile men at high risk for HIV acquisition. Findings will also highlight the potential of PrEP choice delivery and its benefits, offering evidence for governments to consider in the rollout of injectable PrEP in public health systems. Trial registration NCT06133686. Registered on 14 November 2023. PACTR202409632006463. Registered on 2 September 2024.

Abstract Background HIV prevention trials usually require that women of childbearing potential use an effective method of contraception. This is because the effect of most investigational products on unborn babies is unknown. We assessed contraceptive use, prevalence and incidence of pregnancy and associated factors among women in a HIV vaccine preparedness study in Masaka, Uganda. Methods HIV sero-negative women (18–45 years) at high risk of HIV infection identified through HIV counselling and testing (HCT) were recruited between July 2018 and October 2022. Study procedures included collection of baseline socio-demographics and contraceptive use data, quarterly HCT, counselling on and provision of contraceptive methods onsite/through referral, and 6-monthly urine pregnancy tests. Multivariable Logistic and Poisson regression analyses were conducted to determine factors associated with contraceptive use, prevalence, and incidence of pregnancy. Results 652 (73%) of 891 women reported contraceptive use at baseline. Contraceptive use was higher in women who were in a relationship/married/cohabiting [adjusted odds ratio (aOR) = 1.60; 95% confidence interval (CI) 1.07–2.40] or divorced/separated/widowed [aOR = 1.86; 95% CI 1.24–2.79] versus those that were single, and among women reporting transactional sex [aOR = 2.10; 95% CI 1.16–3.80] versus those who did not. Baseline pregnancy prevalence was 4% (95% CI 3–6%) and lower in women who reported using long-acting contraceptive methods (aOR = 0.17; 95% CI 0.07–0.39) versus women who did not use these methods. A total of 65 pregnancies over 301.3 person-years of observation (PYO), an incidence rate of 21.6/100 (95% CI 16.9–27.5) PYO, higher among younger women (≤ 24 versus 25 + years, adjusted incidence rate ratio = 1.97; 95% CI 1.15–3.40). Conclusion We observed a high pregnancy incidence in this cohort. Innovative strategies that promote sustained and consistent use of highly effective contraceptive methods especially for young women will be critical to the success of HIV prevention trials in this and similar populations.

The emergence of SARS-CoV-2 variants has heightened concerns about vaccine efficacy, posing challenges in controlling the spread of COVID-19. As part of the COVID-19 Vaccine Effectiveness and Variants (COVVAR) study in Uganda, this study aimed to genotype and characterize SARS-CoV-2 variants in patients with COVID-19-like symptoms who tested positive on a real-time PCR. Amplicon deep sequencing was performed on 163 oropharyngeal/nasopharyngeal swabs collected from symptomatic patients. Genome assembly, lineage classification and phylogenetic analysis was performed using the Edge Bioinformatics pipeline version 2.4.0, Pangolin version 4.3.1 and iqtree version 2.3.6 software respectively. Of the 163 deep sequences analyzed between April 2023 and March 2024, the most common were XBB.1 lineages and sublineages (113, 69.3%), followed by JN.1* (12, 7.4%), XBB.2* (11, 6.7%) and FL* (11, 6.7%), EG* (7, 4.3%), others (BQ.1.1, FY.4.1, FY.4.1.2, GY.2.1, HK.27.1) (5, 3.1%) and CM* (4, 2.5%). XBB.1* dominated from April to July 2023; thereafter, other variants, including JN.1* were increasingly detected. There was no statistically significant association between vaccine status and lineage assignment (Fisher’s exact test, p-value = 0.994). Our findings showed that the Omicron variant, specifically the XBB.1* lineage, was the dominant circulating virus. However, the emergence of the JN.1 variant that exhibits a significant spike protein mutation profile could impact COVID-19 transmission in Uganda.

The novel antimalarial ganaplacide combined with lumefantrine solid dispersion formulation (LUM-SDF) was effective and well tolerated in the treatment of uncomplicated falciparum malaria in adults, adolescents, and children in a multinational, prospective, randomized, active-controlled Phase II study conducted between August 2017 and June 2021 (EudraCT 2020-003284-25, Clinicaltrials.gov NCT03167242). Pharmacokinetic data from that study are reported here. The trial comprised three parts: a run-in part in 12 adult/adolescent patients treated with a single dose of ganaplacide 200 mg plus LUM-SDF 960 mg assessed potential pharmacokinetic (PK) interactions between ganaplacide and lumefantrine; in Part A, adult/adolescent patients received one of the six ganaplacide-LUM-SDF regimens or artemether-lumefantrine; and in Part B, three dose regimens identified in Part A, and artemether-lumefantrine, were assessed in children aged 2 to <12 years, with body weight ≥10 kg. A rich blood sampling schedule was used for all 12 patients in the PK run-in part and a subset of patients (N = 32) in Part A, with sparse sampling for remaining patients in Parts A (N = 275) and B (N = 159). Drug concentrations were determined by a validated protein precipitation and reverse phase liquid chromatography with tandem mass spectrometry detection method. Parameters including AUCinf, AUClast, AUC0-t, Cmax, and tmax were reported where possible, using non-compartmental analysis. In the PK run-in part, there was no notable increase in ganaplacide or lumefantrine exposure when co-administered. In Parts A and B, ganaplacide exposures increased with dose, but lumefantrine exposure was numerically under dose-proportional. Lumefantrine exposure was higher with ganaplacide-LUM-SDF than with artemether-lumefantrine, although high variability was observed. Ganaplacide and lumefantrine exposures (Cmax and AUC0-24 h) were comparable across age and body weight groups. Drug exposures needed for efficacy were achieved using the dose regimen 400 mg ganaplacide plus lumefantrine 960 mg once daily for 3 days under fasted conditions.

Objectives We assessed associations between intravaginal practices (IVPs) and the incidence of sexually transmitted infections (STIs) and bacterial vaginosis (BV) among women using the dapivirine vaginal ring (DVR) or placebo vaginal ring in southwestern Uganda.Methods This was a retrospective secondary analysis of data collected from women at risk of HIV infection recruited into the Ring Study. The latter evaluated the safety and efficacy of the DVR between 2013 and 2016. At baseline, a behavioural questionnaire was administered to obtain information on sexual activity and IVP (exposure) defined as; insertion inside the vagina of any items aimed at cleaning the vagina for any reason before, during or after sex other than practices to manage menses. Each participant self-inserted the DVR/placebo and replaced it every 4 weeks for 2 years. Outcomes were diagnosis of STIs, that is, Chlamydia trachomatis, Neisseria gonorrhoea, Trichomonas vaginalis (TV), HIV and BV. The incidence rate of STI/BV was estimated, overall, by IVP and trial arm in single-event-per-participant and multiple-event-per-participant analyses.Results Of the 197 women enrolled, 66 (33.5%) were <25 years of age. Overall, 93 (47.2%) practised at least one form of IVP. During the follow-up, 172 (87.3%) women were diagnosed with an STI/BV at least once. The majority had TV (73.6%, n=145). Overall rate of STI/BV was 51.9/100 person-years, 95% CI 44.7 to 60.3 (IVP: yes, 51.0 (40.8–63.8) vs no, 52.6 (43.0–64.4)). IVPs were not statistically significantly associated with rate of individual STIs/BV. Similar results were observed when the analyses were conducted separately for each trial arm.Conclusions IVP was not associated with risk of STIs/BV in the Ring Study.Trial registration number NCT01539226.

Background Emergence of drug resistance demands novel antimalarial drugs with new mechanisms of action. We aimed to identify effective and well tolerated doses of ganaplacide plus lumefantrine solid dispersion formulation (SDF) in patients with uncomplicated Plasmodium falciparum malaria. Methods This open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial was conducted at 13 research clinics and general hospitals in ten African and Asian countries. Patients had microscopically-confirmed uncomplicated P falciparum malaria (>1000 and <150 000 parasites per mu L). Part A identified the optimal dose regimens in adults and adolescents (aged >= 12 years) and in part B, the selected doses were assessed in children (>= 2 years and <12 years). In part A, patients were randomly assigned to one of seven groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days; ganaplacide 800 mg plus lumefantrine-SDF 960 mg as a single dose; once a day ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; once a day ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; or twice a day artemether plus lumefantrine for 3 days [control]), with stratification by country (2:2:2:2:2:2:1) using randomisation blocks of 13. In part B, patients were randomly assigned to one of four groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days, or twice a day artemether plus lumefantrine for 3 days) with stratification by country and age (2 to <6 years and 6 to <12 years; 2:2:2:1) using randomisation blocks of seven. The primary efficacy endpoint was PCR-corrected adequate clinical and parasitological response at day 29, analysed in the per protocol set. The null hypothesis was that the response was 80% or lower, rejected when the lower limit of two-sided 95% CI was higher than 80%. This study is registered with EudraCT (2020-003284-25) and ClinicalTrials.gov (NCT03167242). Findings Between Aug 2, 2017, and May 17, 2021, 1220 patients were screened and of those, 12 were included in the run-in cohort, 337 in part A, and 175 in part B. In part A, 337 adult or adolescent patients were randomly assigned, 326 completed the study, and 305 were included in the per protocol set. The lower limit of the 95% CI for PCR-corrected adequate clinical and parasitological response on day 29 was more than 80% for all treatment regimens in part A (46 of 50 patients [92%, 95% CI 81-98] with 1 day, 47 of 48 [98%, 89-100] with 2 days, and 42 of 43 [98%, 88-100] with 3 days of ganaplacide 400 mg plus lumefantrine-SDF 960 mg; 45 of 48 [94%, 83-99] with ganaplacide 800 mg plus lumefantrine-SDF 960 mg for 1 day; 47 of 47 [100%, 93-100] with ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; 44 of 44 [100%, 92-100] with ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; and 25 of 25 [100%, 86-100] with artemether plus lumefantrine). In part B, 351 children were screened, 175 randomly assigned (ganaplacide 400 mg plus lumefantrine-SDF 960 mg once a day for 1, 2, or 3 days), and 171 completed the study. Only the 3-day regimen met the prespecified primary endpoint in paediatric patients (38 of 40 patients [95%, 95% CI 83-99] vs 21 of 22 [96%, 77-100] with artemether plus lumefantrine). The most common adverse events were headache (in seven [14%] of 51 to 15 [28%] of 54 in the ganaplacide plus lumefantrine-SDF groups and five [19%] of 27 in the artemether plus lumefantrine group) in part A, and malaria (in 12 [27%] of 45 to 23 [44%] of 52 in the ganaplacide plus lumefantrine-SDF groups and 12 [50%] of 24 in the artemether plus lumefantrine group) in part B. No patients died during the study. Interpretation Ganaplacide plus lumefantrine-SDF was effective and well tolerated in patients, especially adults and adolescents, with uncomplicated P falciparum malaria. Ganaplacide 400 mg plus lumefantrine-SDF 960 mg once daily for 3 days was identified as the optimal treatment regimen for adults, adolescents, and children. This combination is being evaluated further in a phase 2 trial (NCT04546633). Copyright (c) 2023 Elsevier Ltd. All rights reserved.

Background HIV risk reduction counselling may reduce risk-taking behaviours. Yet, concerns remain about risk compensation among individuals initiating pre-exposure prophylaxis (PrEP). Objective We assessed changes in risky sexual behaviour indicators among HIV vaccine preparedness study participants who received regular risk reduction counselling and referral for PrEP in Masaka, Uganda. Methods Adults (18-39 years) at high risk of HIV infection were enrolled in the study between July 2018 and December 2021. Data were collected on socio-demographic factors (baseline) and self-reported sexual risk behaviours (baseline, six monthly). HIV testing and risk-reduction counselling and referral for PrEP were done quarterly. Participants who had completed at least 1 year of follow-up were included in the analysis. Proportional differences and McNemar chi-square tests were used to assess changes in the prevalence of self-reported risky sexual behaviour indicators between baseline and 1 year. Logistic regression was used to assess the predictors of unchanged/increased HIV risk at 1 year. Results Three hundred participants [132 (44%) females, 152 (51%) aged & LE;24 years] were included in this analysis. Eighty-one (27%) participants initiated PrEP at 1 year. Compared to baseline, there were significant reductions in the prevalence of the following self-reported HIV risk indicators at 1 year (overall, among non-PrEP initiators, and among PrEP initiators): transactional sex, & GE;6 sexual partners, unprotected sex with & GE;3 partners, sex while drunk, and sexually transmitted infection diagnosis/treatment. Percentage differences ranged from 10% for individuals reporting at least six sexual partners to 30% for those reporting unprotected sex with three or fewer sexual partners. There was weak evidence of association between female gender and unchanged/increased HIV risk at 1 year (adjusted OR: 1.35, 95% CI (0.84-2.17)). No other indicators, including PrEP use, were associated with unchanged/increased HIV risk at 1 year. Conclusion Regular risk-reduction counselling may reduce risky sexual behaviour, while PrEP initiation may not lead to risk compensation.

Background Universal immunisation is the cornerstone of preventive medicine for children, The World Health Organisation (WHO) recommends diphtheria-tetanus-pertussis (DTP) vaccine administered at 6, 10 and 14 weeks of age as part of routine immunisation. However, globally, more than 17 unique DTP-containing vaccine schedules are in use. New vaccines for other diseases continue to be introduced into the infant immunisation schedule, resulting in an increasingly crowded schedule. The OptImms trial will assess whether antibody titres against pertussis and other antigens in childhood can be maintained whilst adjusting the current Expanded Programme on Immunisation (EPI) schedule to provide space for the introduction of new vaccines. Methods The OptImms studies are two randomised, five-arm, non-inferiority clinical trials in Nepal and Uganda. Infants aged 6 weeks will be randomised to one of five primary vaccination schedules based on age at first DTwP-vaccination (6 versus 8 weeks of age), number of doses in the DTwP priming series (two versus three), and spacing of priming series vaccinations (4 versus 8 weeks). Additionally, participants will be randomised to receive their DTwP booster at 9 or 12 months of age. A further sub-study will compare the co-administration of typhoid vaccine with other routine vaccines at one year of age. The primary outcome is anti-pertussis toxin IgG antibodies measured at the time of the booster dose. Secondary outcomes include antibodies against other vaccine antigens in the primary schedule and their safety. Discussion These data will provide key data to inform policy decisions on streamlining vaccination schedules in childhood. Trial registrations ISRCTN12240140 (Nepa1, 7 th January 2021) and ISRCTN6036654 (Uganda, 17 th February 2021).

Background Daily oral pre-exposure prophylaxis (PrEP) use is highly effective against HIV infection. However, the uptake of PrEP among individuals at high-risk of HIV acquisition in sub-Saharan Africa varies because of availability and acceptability. We assessed the acceptability of PrEP among participants in a prospective HIV vaccine preparedness study in Masaka, southwestern Uganda. Methods From November 2018 to August 2019, 20 participants (10 female) were purposively selected for in-depth interviews (IDIs) at 3 and 9 months’ post-enrolment in the vaccine preparedness study. Four focus group discussions (FGD) (two among men) were conducted with 29 individuals categorized as: younger (18–24 years) men, younger (18–24 years) women, older (≥30 years) men, and older (≥30 years) women. Apart from IDI specific questions on recent life history including work experience, relationship history and places lived, topics for IDIs and FGDs included knowledge of HIV, perceptions of HIV risk (including own risk), knowledge of and use of PrEP. The Theoretical Framework of Acceptability was used to structure a thematic framework approach for data analysis. Results Participants understood that PrEP was an oral pill taken daily by HIV negative individuals to prevent acquisition of HIV. Overall, interest in and acceptability of PrEP was high, more than half expressed positivity towards PrEP but were not ready to initiate taking it citing the burden of daily oral pill taking, related side effects, stigma and distrust of PrEP. Fourteen participants (from IDI and FGD) initiated PrEP, although some (one FGD and two IDI participants) stopped taking it due to side effects or perceived reduced risk. Conclusion We observed a keen interest in PrEP initiation among our study participants. However, a limited understanding of PrEP and associated concerns impeded uptake and sustained use. Hence, interventions are needed to address end-user challenges to increase uptake and support adherence.