Scientific Publications

Pre-exposure prophylaxis (PrEP) has proven to be a powerful tool in preventing HIV infection. There is limited information about the factors associated with willingness to use different PrEP modalities among adolescent girls and young women (AGYW) in Africa. We assessed willingness to use long-acting injectable PrEP (LAI-PrEP) among 14-24-year-old AGYW at high risk of HIV in Uganda, and associated factors determined using multivariable complementary log-log regression. Of the 285 participants, 69.8% of participants showed willingness to use LAI-PrEP despite only 3.9% having knowledge about it before enrolment. Report of recent transactional sex was high (92.6%). Participants that were divorced/separated (aOR = 1.74, 95% CI 1.03-2.92) and those with multiple sexual partners (aOR = 2.11, 95% CI 1.46-3.06) compared to those with one partner were more likely to be willing to use LAI-PrEP while those that were screened as heavy episodic drinkers (consuming 6 or more drinks on an occasion as per the AUDIT tool) were less likely to be willing to use LAI-PrEP (aOR = 0.61, 95% CI 0.42-0.87). LAI PrEP has shown efficacy in clinical trials; the product is approved for use by the Government of Uganda (MoH) and should be expedited for use by AGYW engaged in paid sex and those with multiple sexual partnerships. As it becomes available, we recommend PrEP education and counseling to increase awareness of LAI PrEP as an alternative HIV prevention method.

Highly effective antiretroviral-based HIV prevention plays an important role in ending the global HIV/AIDS epidemic. However, the sustainable control of the epidemic is hampered by unequal access to prevention options, including HIV testing, alongside with drug resistance and ongoing barriers to accessing sustainable HIV treatment. Therefore, an HIV vaccine, combined with effective prevention and treatment, remains an absolute necessity to control the epidemic. Yet, the recent discontinuation of four major vaccine efficacy studies is raising concerns about the future of HIV vaccine research and development globally, and particularly in the European region where funding for vaccine research and development has shrinked. This viewpoint emphasises that supporting HIV vaccine research and development at the European level remains crucial: it is not only necessary to control the epidemic, but it promotes innovation, strengthens health security, epidemic preparedness, and health sovereignty while contributing to the economies of European nations.

Background: Lassa fever (LF) is a zoonotic haemorrhagic disease caused by Lassa virus (LASV), which is endemic in West African countries. The multimammate rat is the main animal reservoir and its geographic range is expected to expand due to influences like climate change and land usage, and this will place larger parts of Africa at risk. We conducted preclinical development on a promising experimental vaccine that allowed its advancement into human trials. Methods: The LF vaccine is based on a vesicular stomatitis virus (VSV) vector in which the VSV glycoprotein (G) was replaced with the LASV glycoprotein complex (GPC). Earlier studies showed that this vaccine (VSVΔG-LASV-GPC) was efficacious in macaques, thus we regenerated VSVΔG-LASV-GPC using laboratory and documentation practices required to support vaccine manufacturing and human trials. The efficacy of the clinical vaccine candidate was assessed in cynomolgus macaques and more extensive immunologic analysis was performed than previously to investigate immune responses associated with protection. Findings: A single VSVΔG-LASV-GPC vaccination elicited innate, humoural and cellular immune responses, prevented development of substantial LASV viraemia, and protected animals from disease. Vaccinated macaques developed polyfunctional antibodies and serum was shown to neutralize virus expressing GPCs representative of geographically diverse LASV lineages. Interpretation: The VSVΔG-LASV-GPC clinical candidate elicited immunity that protected 10 of 10 vaccinated macaques from disease supporting its use in a clinical development program, which recently progressed to phase 2 clinical trials. Moreover, immunologic analysis showed that virus-neutralizing serum antibodies likely played a role in preventing LASV disease in vaccinated macaques.

High replicative capacity (RC) HIV-1 strains are associated with elevated viral loads and faster disease progression in the absence of antiretroviral therapy. Understanding the mechanisms by which high RC strains adversely affect the host is essential for developing novel anti-HIV interventions. This study investigates cellular metabolism, cytokine induction, and cell-to-cell spread as potential mechanisms differentiating clinical outcomes between low and high RC strains of HIV-1. We constructed chimeric viruses containing patient-derived gag-proteases from HIV-1 subtypes B and C in the NL4-3 backbone. Viral RC was determined using a green fluorescent protein (GFP)-reporter T-cell line assay and cytokine production in T-cells was assessed using Luminex. Virus cell-to-cell spread efficiency was measured through flow cytometry-based detection of p24, while nutrient uptake assays and mitotracker dye detection served as surrogate markers for T-cell metabolism and mitochondrial function. Chimeric subtype C viruses exhibited significantly lower RC compared to subtype B viruses (P = 0.0008). Cytokine profiling revealed distinct cytokine signatures associated with low RC subtype C viruses. Viral RC negatively correlated with tumor necrosis factor alpha (TNF-α), IL-8, and IL-13 induction, while it positively correlated with platelet-derived growth factor (PDGF-bb), IL-7, monocyte chemoattractant protein-1 (MCP-1), fibroblast growth factor (FGF)-basic levels, viral spread efficiency (P = 0.008, r = 0.5), and cellular glucose uptake (P = 0.02, r = 0.5). Conversely, RC was negatively correlated with glutamine levels (P = 0.001, r = −0.7), indicating a link between RC and nutrient utilization. Furthermore, mitochondrial depolarization was elevated in subtype B infections when compared to subtype C infections (P = 0.0008). These findings indicate that high RC strains exert distinct cellular effects that may influence HIV-1 pathogenesis, highlighting the need to develop novel therapeutic strategies.

Background Lassa fever, caused by Lassa virus, is a severe disease, endemic in Western Africa, for which no vaccines or therapeutics are yet approved. Understanding the immune responses elicited by candidate vaccines is key for approval, including characterisation of antibody epitopes recognised and capacity for neutralisation. Methods Here we used negative-stain electron microscopy polyclonal antibody epitope mapping (EMPEM), in-vitro pseudovirus neutralisation assays, and biophysical antibody competition assays to uncover components of polyclonal antibody responses elicited in nonhuman primates 26 days after receipt of a single immunisation with a fully protective, recombinant, replication-competent vesicular stomatitis virus-based vaccine bearing the Lassa virus glycoprotein GPC. Findings Although the vaccinee sera are overall poorly-neutralising, we do directly visualise, within the polyclonal pool, antibodies targeting epitopes on GPC that are consistent with neutralisation, as well as competition with known neutralising mAbs. Nearly every animal, for example, produced antibodies that compete with mAbs against GP1-A and GPC-A neutralising epitopes. The most abundant classes of antibodies, however, are directed against interior interfaces of GPC, while other antibodies recognise post-fusion GPC epitopes not consistent with neutralisation. Interpretation It may be that some individual antibodies in the pool are neutralising, but that the abundance of non-neutralising epitopes reduces potency as measured at the polyclonal level. The finding, however, neutralisation-consistent sites and competition with known neutralising antibodies are important steps in vaccine design toward eliciting more potent neutralisation

Background: People with tuberculosis who complete treatment remain at risk of recurrent disease. The vaccine H56:IC31 has been shown to be safe and immunogenic in phase 1 and 2 studies, but whether it can reduce the risk of tuberculosis recurrence is unknown. Methods: In a double-blind, randomised, placebo-controlled, phase 2b trial in South Africa (five clinical trial sites) and Tanzania (one clinical trial site), we enrolled participants aged 18-60 years, without HIV, who had completed more than 5 months (22 weeks) of treatment for drug-susceptible pulmonary tuberculosis. During trial screening (≤7 days after starting treatment), two sputum samples were obtained and frozen for later comparison to recurrent isolates by whole-genome sequencing (WGS). Eligible participants were randomly assigned (1:1; block size of four) to receive two intramuscular doses in the deltoid, 56 days apart, of H56:IC31 or placebo. After the first dose of H56:IC31 or placebo, participants were followed up until study day 421 (1 year after the second dose) and checked at each visit for tuberculosis signs and symptoms. If tuberculosis was suspected, two sputum samples were obtained: one sample was tested by automated molecular test (Xpert MTB/RIF Ultra) and sent for liquid culture; and the other sample was stored frozen for later analysis by whole-genome sequencing (WGS). At the last visit (day 421), two sputum samples were obtained from all sputum-productive participants, regardless of symptoms, to detect cases of asymptomatic tuberculosis. The primary endpoint was culture-confirmed recurrent pulmonary tuberculosis (due to relapse with the same strain, reinfection by a different strain, or indeterminate) occuring during the period starting at day 70 (14 days after the second dose) and ending on day 421 (1 year after the second dose). Vaccine efficacy against recurrent tuberculosis was derived from Cox proportional hazards models. Secondary endpoints included vaccine efficacy to prevent tuberculosis relapse or reinfection independently, as differentiated by WGS, and safety and immunogenicity outcomes (H56-specific CD4 T-cell responses and humoral anti-H56 IgG responses). Primary analysis of vaccine efficacy was based on modified intention-to-treat (mITT), in all randomly assigned participants except those with tuberculosis disease recurrence or who withdrew before day 70 (or 14 days after the second dose for those who received both doses). Safety was assessed in all randomly assigned participants who received at least one dose of vaccine or placebo. The trial was registered with ClinicalTrials.gov, NCT03512249, and is complete. Findings: 831 participants (mean age 34·7 years [SD 11·1]; 229 [28%] female and 602 [72%] male; 549 [66%] Black) were enrolled from Jan 31, 2019, to Jan 20, 2022; 415 participants were randomly assigned to receive H56:IC31 and 416 to receive placebo. Follow-up was completed by March 20, 2023 (mean follow-up duration 410·1 days [SD 82·8]). In the primary mITT analysis, recurrent tuberculosis occurred in 23 of 400 participants in the H56:IC31 group (12 relapses, eight reinfections, and three indeterminate); and in 14 of 406 in the placebo group (six relapses, seven reinfections, and one indeterminate). Vaccine efficacy for prevention of recurrence was -73·8% (95% CI -246·9 to 9·8; p=0·10). Vaccine efficacy for prevention of relapse was -116·1% (-522·2 to 16·3; p=0·11) and for prevention of reinfection was -21·1% (-245·3 to 56·5; p=0·71). 2 weeks after the planned second dose, H56:IC31 had significantly increased the frequencies of H56-specific CD4 T cells expressing interferon-γ, tumour necrosis factor, interleukin (IL)-2, or IL-17 in vaccinees (median percentage of CD4 T cells, 0·35% [IQR 0·19 to 0·57]) compared with placebo (0·11% [0·09 to 0·23]; p<0·0001). H56-specific IgG responses were significantly higher in H56:IC31 recipients (median arbitrary units per mL, 6·84 [IQR 1·64 to 32·8]) than in placebo recipients (1·94 [1·05 to 3·86]; p<0·0001). A greater proportion of H56:IC31 recipients had mild-to-moderate injection site reactions than placebo recipients (165 [40%] of 415 vs 78 [19%] of 416). No treatment-related serious adverse events were reported. Two participants who received H56:IC31 and six who received placebo died. Interpretation: Vaccination with H56:IC31 at treatment completion for pulmonary tuberculosis did not reduce the risk of recurrent disease. H56:IC31 was well tolerated and immunogenic but might have increased the risk of relapses by endogenous strains.

Pre-exposure prophylaxis (PrEP) has proven to be a powerful tool in preventing HIV infection. There is limited information about the factors associated with willingness to use different PrEP modalities among adolescent girls and young women (AGYW) in Africa. We assessed willingness to use long-acting injectable PrEP (LAI-PrEP) among 14-24-year-old AGYW at high risk of HIV in Uganda, and associated factors determined using multivariable complementary log-log regression. Of the 285 participants, 69.8% of participants showed willingness to use LAI-PrEP despite only 3.9% having knowledge about it before enrolment. Report of recent transactional sex was high (92.6%). Participants that were divorced/separated (aOR = 1.74, 95% CI 1.03-2.92) and those with multiple sexual partners (aOR = 2.11, 95% CI 1.46-3.06) compared to those with one partner were more likely to be willing to use LAI-PrEP while those that were screened as heavy episodic drinkers (consuming 6 or more drinks on an occasion as per the AUDIT tool) were less likely to be willing to use LAI-PrEP (aOR = 0.61, 95% CI 0.42-0.87). LAI PrEP has shown efficacy in clinical trials; the product is approved for use by the Government of Uganda (MoH) and should be expedited for use by AGYW engaged in paid sex and those with multiple sexual partnerships. As it becomes available, we recommend PrEP education and counseling to increase awareness of LAI PrEP as an alternative HIV prevention method.

Background
Africa’s involvement in clinical trials remains very low. Although the crucial role of training initiatives in building clinical trial capacity in Africa has been documented, current efforts fall short as they lack alignment with local contexts. This study aimed to design, develop, implement, and evaluate an innovative clinical trial operations training program for Africa.

Methods
We developed ClinOps, a novel 10-week clinical trial operations training program for study coordinators in Africa to enhance their expertise in four fundamental areas: designing, conducting, managing, and reporting clinical trials. To streamline the learning process, we used cloud-based applications that minimize the need for software installations while maximizing student engagement. VoiceThread facilitated interactive content that could be accessed offline. Moodle, an open-source learning management system, offered a platform for sharing learning tools, mentorship, and rubric-driven competency assessments, including quizzes, forums, tutorials, and group assignments. We utilized Zoom for live tutorials and mentoring as required. Effectiveness of the program was evaluated through quantitative pre- and post-surveys, qualitative end-course evaluations, and a comprehensive monitoring and evaluation framework. The pre- and post-surveys measured changes in trainees’ confidence in clinical trial domains and leadership and coordination skills. End-course evaluations gathered feedback on the course content, organization, technology, and instructional methods. We used Wilcoxon rank test to analyze pre- and post-survey scores and thematic analysis to analyze the qualitative data.

Results
In the initial cohort, 88 study coordinators from 19 countries participated, including 56 (64%) females, with 57 (65%) actively employed as study coordinators during the training, and 85 (97%) possessing prior experience in clinical trial roles. Among these, 71 (81%) successfully completed the course, with 69 (97%) also completing the post-course assessment. Post-training scores demonstrated substantial improvement compared to pre-training scores in each competency area, including in designing (pre-post training median score = 3.6 vs. 4.6, median difference = 1.0, 95% CI 0.8–1.1, p < 0.001), managing (pre-posttest median score = 3.4 vs. 4.2, median difference = 0.6, 95% CI 0.4–0.8, p < 0.001), conducting (pre-post training median score = 3.9 vs. 4.7, median difference = 0.9, 95% CI 0.6-1.0, p < 0.001), and reporting (pre-posttest median score = 3.0 vs. 4.5, median difference = 1.0, 95% CI 0.9–1.5, p < 0.001) clinical trials. The monitoring and evaluation data confirm the program’s adherence to training best practices, including alignment with local priorities, country ownership, pedagogic innovation, institutional capacity building, sustainability, and ongoing partnerships. The end-course evaluation reflects participants’ positive feedback on the program’s structure, content, relevance to their current roles, and overall delivery methods.

Conclusion
The ClinOps program, designed by experts from academia and product development partners, enhanced participants’ clinical trial competencies. To effectively build clinical trials capacity on the continent, training programs should provide thorough competency development in designing, conducting, managing, and reporting trials.

Introduction
Long‐acting injectable cabotegravir (CAB‐LA) for pre‐exposure prophylaxis significantly reduced HIV acquisition in HPTN 084. We report on the safety and CAB‐LA pharmacokinetics in pregnant women during the blinded period of HPTN 084.

Methods
Participants were randomized 1:1 to either active cabotegravir (CAB) plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) placebo or active TDF/FTC plus CAB placebo. Pregnancy testing was performed at each visit; participants with a positive test had study product withheld and were offered open‐label TDF/FTC. Pregnancies were confirmed on two tests at least 4 weeks apart. All participants with a positive pregnancy test prior to November 5, 2020 are included in this analysis. Pregnancy incidence, maternal adverse event (AE) incidence, pregnancy outcomes (including composite outcome of spontaneous abortion <20 weeks, intrauterine foetal death or stillbirth ≥20 weeks, premature birth <37 weeks, or small for gestational age) were assessed. The apparent terminal phase half‐life (t1/2app) of CAB‐LA in pregnant women in HPTN 084 was compared to non‐pregnant women from the phase 2a HPTN 077 trial. Multivariable models assessed associations with t1/2app.

Results
Fifty‐seven pregnancies (30 CAB‐LA, 27 TDF/FTC) were confirmed over 3845 person‐years [py] (incidence 1.5/100 py, 95% CI 1.1−1.9). CAB‐LA group participants had a median 342 days (IQR 192, 497) of CAB‐LA exposure prior to pregnancy detection. Grade 2 or higher maternal AE incidence did not differ by study arm (CAB 157, 95% CI 91−271 per 100 py vs. TDF/FTC 217, 95% CI 124–380 per 100 py; p = 0.256). Most pregnancies (81%) resulted in live births (25 CAB‐LA, 22 TDF/FTC). Composite poor pregnancy outcomes did not differ significantly by group (CAB 6/30 vs. TDF/FTC 4/27; p = 0.476). No congenital anomalies were observed. The CAB t1/2app geometric mean was 52.8 days (95% CI 40.7−68.4) in pregnant women compared to 60.3 days (95% CI 47.7−76.3; p = 0.66) in non‐pregnant women; neither pregnancy nor body mass index were significantly associated with t1/2app.

Conclusions
CAB‐LA concentrations post‐cessation of injections were generally well tolerated in pregnant women. The t1/2app was comparable between pregnant and non‐pregnant women. Ongoing studies will examine the safety and pharmacology of CAB‐LA in women who choose to continue CAB‐LA through pregnancy and lactation.

Lassa virus (LASV) belongs to the Arenavirus family. LASV is endemic in several West Africa countries and causes viral hemorrhagic fevers. The Nigeria CDC has reported that an outbreak in 2024 in 28 states has resulted in 7767 suspected cases of Lassa fever, 971 confirmed cases and 166 confirmed deaths up to 11 August. Since infection with LASV can result in sensorineural hearing loss (SNHL) in up to 30% of patients, there are questions about whether triggering the immune response by immunization with LASV vaccines could potentially cause SNHL, although this has not been shown in clinical trials to date. To address this issue, the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration (BC) Safety Platform for Emergency vACcines (SPEAC) convened a three-hour webinar on 22 September 2023 to review what is known from both animal studies and human clinical trials and how hearing assessments in future clinical trials can help to assess the risk. This report summarizes the evidence presented and provides considerations for hearing assessment in expanded human trials of LASV vaccine candidates in children and adults.

Vaccines are complex and a very diverse group of products with relatively long product life cycles. The manufacturing programs for these vaccines need to be continually updated to comply with evolving regulatory expectations. Members of the Parenteral Drug Association (PDA) Vaccines Interest Group (VIG) authored and published PDA Technical Report No. 89: Strategies for Vaccine Development and Lifecycle Management (TR 89), which seeks to provide context to vaccine developers and manufacturers regarding key aspects of new or legacy vaccines such as control strategy from process development to vaccine life cycle management, comparability and life cycle management including technical, validation, quality, and regulatory perspectives. To further explain and illustrate the concepts and topics discussed, seven relevant situations were selected as either case studies associated with changes implemented or proposed process development strategies, which are discussed in this article. The situations described are: working cell bank, modification or update of externally supplied product contact components for vaccine manufacturing, raw material change, new product at an existing site, vaccine development acceleration by leveraging existing platforms, selection and implementation of potency method, and modeling for stability forecast prediction. For each situation, the applicable key concepts from TR 89 are discussed as follows: Control Strategy, Prior Knowledge, Relying on Pharmaceutical Quality System (PQS), Classification of Parameters, Validation Approach, Use of a Risk-Based Approach, Comparability, Use of ICH Q12, and Additional Regulatory Considerations.

Background/ObjectivesBackground
Orthoebolaviruses and orthomarburgviruses are filoviruses that can cause viral hemorrhagic fever and significant morbidity and mortality in humans. The evaluation and deployment of vaccines to prevent and control Ebola and Marburg outbreaks must be informed by an understanding of the transmission and natural history of the causative infections, but little is known about the burden of asymptomatic infection or undiagnosed disease. This systematic review of the published literature examined the seroprevalence of antibodies to orthoebolaviruses and orthomarburgviruses in sub-Saharan Africa.

Methods
The review protocol was registered on PROSPERO (ID: CRD42023415358) and previously published. Eighty-seven articles describing 85 studies were included, of which seventy-six measured antibodies to orthoebolaviruses and forty-one measured antibodies to orthomarburgviruses.

Results
The results highlight three central findings that may have implications for vaccine development and deployment. First, substantial antibody seropositivity to Ebola virus (EBOV) and Sudan virus (SUDV) was observed in populations from outbreak-affected areas (≤33% seroprevalence among general populations; ≤41% seroprevalence among healthcare workers and close contacts of disease cases). Second, antibody seropositivity to EBOV, SUDV, and Marburg virus (MARV) was observed among populations from areas without reported outbreaks, with seroprevalence ranging from <1 to 21%. Third, in Central and East Africa, MARV antibody seroprevalence was substantially lower than EBOV or SUDV antibody seroprevalence, even in outbreak-affected areas and in populations at a moderate or high risk of infection (with MARV seroprevalence mostly ranging from 0 to 3%).

Conclusions
Whilst gaps remain in our understanding of the significance of antibody seropositivity in some settings and contexts, these findings may be important in considering target indications for novel filovirus vaccines, in defining study designs and strategies for demonstrating vaccine efficacy or effectiveness, and in planning and evaluating vaccine deployment strategies to prevent and control outbreaks.