Matt Price

Background/Objectives: 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.

South African adolescents are at-risk for HIV infection due to engaging in high-risk sexual behaviours. Understanding the factors influencing sexual decision-making is crucial for developing effective HIV prevention strategies. We conducted a qualitative study with adolescents and caregivers in Rustenburg, South Africa to explore individual and interpersonal factors that influence adolescent sexual decision-making. Focus Group Discussions (FGDs) were conducted in English and Setswana with 17 adolescents (13 females and 4 males) and 19 caregivers (17 females and 2 males) between April and July 2018. Thematic analysis revealed that while adolescents had access to sexual education from various sources, this knowledge did not translate into healthy sexual decision-making. Lack of effective communication and support between caregivers and adolescents in discussing sexual behaviours are a contributing barrier. Although adolescents expressed a strong need to be understood and supported by caregivers regarding sexual behaviours, there was perceived distrust, judgemental attitude from caregivers, poor role models of a father figure, and the traditional taboo nature of having these discussions with caregivers. While female adolescents and female caregivers discussed sexual matters, this type of communication was limited with adolescent males. Male adolescents were uncomfortable communicating with either caregiver, fearing caregiver judgemental attitudes and being misunderstood. Female caregivers perceived male caregiver roles to be absent and non-engaging. Caregivers desired to support their children, yet they seemed to doubt their skills. Communication tools and guidance on how adolescents and caregivers could communicate about sexual matters could create enabling environments for adolescents to make informed, healthy decisions regarding their sexual behaviours. Further, future interventions could consider gain-framed messaging to address adolescents translating knowledge of sexual behaviours to making healthy sexual choices. Improving equitable male caregiver role at home, is of particular importance in supporting adolescent sexual decision-making, and should be prioritized.

HIV-1 subtypes have distinct geographical distributions, with subtypes A, C, and D and inter-subtype recombinants circulating in sub-Saharan Africa. Historically, individuals living with subtype A viruses exhibit slower CD4 decline and progression to AIDS diagnosis. Despite this, there are few authentic infectious molecular clones (IMCs) of subtype A or AC recombinant transmitted founder (TF) viruses with which to investigate viral impacts on pathogenesis. In this study, we constructed 16 authentic subtype A1 and 4 A1C recombinant IMCs from the IAVI Rwandan Protocol C acute infection cohort and characterized these viruses phenotypically. The virus replicative capacity (RC) scores varied over 50-fold, but the natural substitution of non-consensus amino acids in the p17(MA) domain of Gag was generally linked to higher RC levels. Sensitivity to a panel of broadly neutralizing antibodies (bNAbs) showed that all but one TF was sensitive to N6, which targets the CD4 binding site, while bNAbs PG16 and PGT 128 had a similar level of potency but reduced breadth against our panel of viruses. In contrast, bNAb 10E8V4 revealed high breadth but much lower potency. This panel of well-characterized, authentic subtype A and AC recombinant IMCs provides a resource for studies on the role of the virus subtype in HIV-1 transmission, pathogenesis, and vaccine design.

South African adolescents are at-risk for HIV infection. Understanding the factors influencing sexual decision-making is crucial for developing effective HIV prevention strategies. We conducted a qualitative study with adolescents and caregivers in Rustenburg, South Africa to explore individual and interpersonal factors that influence adolescent sexual decision-making. Focus Group Discussions (FGDs) were conducted in English and Setswana with 17 adolescents (13 females and 4 males) and 19 caregivers (17 females and 2 males) between April and July 2018. Thematic analysis revealed that while adolescents had access to sexual education from various sources, where the knowledge does not translate into healthy sexual decision-making. A contributing barrier was the lack of effective communication and support between caregivers and adolescents in discussing topics related to sexual activity. Although adolescents expressed a strong need to be understood and supported by caregivers regarding their sexual activity, there was perceived distrust, judgemental attitude from caregivers, poor role models of a father figure, and the traditional taboo of having these discussions with caregivers. While female adolescents and female caregivers discussed sensitive matters, this type of communication was limited with adolescent males. Male adolescents were uncomfortable communicating with either caregiver, fearing caregiver judgemental attitudes and being misunderstood. Female caregivers perceived male caregiver roles to be absent and non-engaging when it came to adolescent education and support in sexual matters. Caregivers desired to support their children, yet they seemed to doubt their skills. Communication tools and guidance on how adolescents and caregivers could communicate about sensitive matters could create enabling environments for adolescents to make informed, healthy decisions regarding their risky sexual behaviours. To address adolescent intention-behaviour gap, future interventions could consider gain-framed messaging within intervention packages to promote healthy sexual choices.

Adolescents face a higher risk for HIV, STIs, and unintended pregnancy than any other age group in sub–Saharan Africa, and have unique health care needs as they navigate this period of growth and developmental milestones. We conducted the Youth Friendly Services study among adolescents in Rustenburg, South Africa to address some of these concerns. Participants aged 12–19 were followed quarterly for 12 months, asked at baseline about demographics, their sexual behavior, and tested for HIV, STIs, and pregnancy (girls). Report of sexual activity was not a requirement for enrollment. Assent and parental consent were obtained for participants under 18. Some follow up visits fell during COVID-mandated shutdowns, and we worked with participants to reschedule and extend follow up as appropriate. Here we present data on reported behaviors, participant attrition, risk of HIV, other STI, and pregnancy. From May 2018 to August 2019, we enrolled 223 HIV-negative, non-pregnant adolescents (64% girls). The median age was 17 (IQR: 14–18). Among the 119 (53%) participants who reported being sexually active at baseline, the median age at first sex was 16 years (IQR: 15–17). During follow-up, an additional 16 (7%) participants reported having their first sexual encounter. Among the sexually active participants, the incidence of HIV was 1.5 cases / 100 person-years at risk (PYAR, 95% CI: 0.4–6.0), the incidence of chlamydia was 15.7 cases (95% CI: 10.1–24.4), gonorrhea was 4.7 cases (95% CI: 2.1–10.5), and HSV was 6.3 cases (95% CI: 3.1–12.6); we observed no cases of incident syphilis. The incidence of pregnancy among sexually active girls was 15.0 pregnancies / 100 PYAR (95% CI: 8.5–26.5). Despite small numbers, the incidence of most STIs was significantly higher in females compared to males. We also observed two pregnancies and 5 incident STIs among participants who reported never having had sex, these tended to be younger participants. From March to September 2020, the clinic was shut down for COVID-19, and 53 study visits were postponed. Follow up was concluded in November 2020, a total of 19 participants were lost to follow up, however only one participant dropped off-study during COVID-19 shutdowns. Retention at the final visit was 91.5%. We successfully completed a prospective study of adolescents to learn more about the risks they face as they navigate sexual debut in the context of a program of youth-friendly counseling and services. Among self-reported sexually active participants, we observed a high rate of HIV, STI and pregnancy, however we also observed pregnancy and STIs among those who reported no sexual activity.

Introduction: Women in fishing communities have both high HIV prevalence and incidence, hence they are a priority population for HIV prevention and treatment interventions. However, their mobility is likely to compromise the effectiveness of interventions. We assessed the acceptability, feasibility and of using phones and global positioning system (GPS) devices for tracking mobility, to inform future health research innovations. Methods: A mult-site formative qualitative study was conducted in six purposively selected Fishing Communities on the shores of Lake Victoria in Kenya, Tanzania, and Uganda. Participants were selected based on duration of stay in the community and frequency of movement. Sixty-four (64) women participated in the study (16 per fishing community). Twenty-four (24) participants were given a study phone; 24 were asked to use their own phones and 16 were provided with a portable GPS device to understand what is most preferred. Women were interviewed about their experiences and recommendations on carrying GPS devices or phones. Twenty four (24) Focus Group Discussions with 8–12 participants were conducted with community members to generate data on community perceptions regarding GPS devices and phones acceptability among women. Data were analyzed thematically and compared across sites/countries. Results: Women reported being willing to use tracking devices (both phones and GPS) because they are easy to carry. Their own phone was preferred compared to a study phone and GPS device because they were not required to carry an additional device, worry about losing it or be questioned about the extra device by their sexual partner. Women who carried GPS devices suggested more sensitization in communities to avoid domestic conflicts and public concern. Women suggested changing the GPS colour from white to a darker colour and, design to look like a commonly used object such as a telephone Subscriber Identity Module (SIM) card, a rosary/necklace or a ring for easy and safe storage. Conclusion: Women in the study communities were willing to have their movements tracked, embraced the use of phones and GPS devices for mobility tracking. Devices need to be redesigned to be more discrete, but they could be valuable tools to understanding movement patterns and inform design of interventions for these mobile populations.

Schistosomiasis is a disease caused by parasitic flatworms of the Schistosoma spp., and is increasingly recognized to alter the immune system, and the potential to respond to vaccines. The impact of endemic infections on protective immunity is critical to inform vaccination strategies globally. We assessed the influence of Schistosoma mansoni worm burden on multiple host vaccine-related immune parameters in a Ugandan fishing cohort (n = 75) given three doses of a Hepatitis B (HepB) vaccine at baseline and multiple timepoints post-vaccination. We observed distinct differences in immune responses in instances of higher worm burden, compared to low worm burden or non-infected. Concentrations of pre-vaccination serum schistosome-specific circulating anodic antigen (CAA), linked to worm burden, showed a significant bimodal distribution associated with HepB titers, which was lower in individuals with higher CAA values at month 7 post-vaccination (M7). Comparative chemokine/cytokine responses revealed significant upregulation of CCL19, CXCL9 and CCL17 known to be involved in T cell activation and recruitment, in higher CAA individuals, and CCL17 correlated negatively with HepB titers at month 12 post-vaccination. We show that HepB-specific CD4⁺ T cell memory responses correlated positively with HepB titers at M7. We further established that those participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination, but higher regulatory T cells (Tregs) post-vaccination, suggesting changes in the immune microenvironment in high CAA could favor Treg recruitment and activation. Additionally, we found that changes in the levels of innate-related cytokines/chemokines CXCL10, IL-1β, and CCL26, involved in driving T helper responses, were associated with increasing CAA concentration. This study provides further insight on pre-vaccination host responses to Schistosoma worm burden which will support our understanding of vaccine responses altered by pathogenic host immune mechanisms and memory function and explain abrogated vaccine responses in communities with endemic infections.

Introduction: Immunological protection against human immunodeficiency virus-1 (HIV-1) infection is likely to require both humoral and cell-mediated immune responses, the latter involving cytotoxic CD8 T-cells. Characterisation of CD8 T-cell mediated direct anti-viral activity would provide understanding of potential correlates of immune protection and identification of critical epitopes associated with HIV-1 control.Methods: The present report describes a functional viral inhibition assay (VIA) to assess CD8 T-cell-mediated inhibition of replication of a large and diverse panel of 45 HIV-1 infectious molecular clones (IMC) engineered with a Renilla reniformis luciferase reporter gene (LucR), referred to as IMC-LucR. HIV-1 IMC replication in CD4 T-cells and CD8 T-cell mediated inhibition was characterised in both ART naive subjects living with HIV-1 covering a broad human leukocyte antigen (HLA) distribution and compared with uninfected subjects.Results & discussion: CD4 and CD8 T-cell lines were established from subjects vaccinated with a candidate HIV-1 vaccine and provided standard positive controls for both assay quality control and facilitating training and technology transfer. The assay was successfully established across 3 clinical research centres in Kenya, Uganda and the United Kingdom and shown to be reproducible. This IMC-LucR VIA enables characterisation of functional CD8 T-cell responses providing a tool for rational T-cell immunogen design of HIV-1 vaccine candidates and evaluation of vaccine-induced T-cell responses in HIV-1 clinical trials.

Region-specific laboratory reference intervals (RIs) are important for clinical trials and these data are often sparse in priority areas for research, including Africa. We reviewed data on RIs from Africa to identify gaps in the literature with a systematic review of PubMed for RI studies from Africa published ≥2010. Search focus included clinical analytic chemistry, hematology, immunological parameters and RIs. Data from adults, adolescents, children, pregnant women, and the elderly were included. We excluded manuscripts reporting data from persons with conditions that might preclude clinical trial participation in studies enrolling healthy volunteers. Of 179 identified manuscripts, 80 were included in this review, covering 20 countries with the largest number of studies in Ethiopia (n = 23, 29%). Most studies considered healthy, nonpregnant adults (n = 55, 69%). Nine (11%) studies included pregnant women, 13 (16%) included adolescents and 22 (28%) included children. Recruitment, screening, enrollment procedures and definition of age strata varied across studies. The most common type of RIs reported were hematology (66, 83%); 14 studies (18%) included flow cytometry and/or T cell counts. Other common tests or panels included liver function assays (32, 40%), renal function assays (30, 38%), lipid chemistries (17, 21%) and serum electrolytes (17, 21%). The number of parameters characterized ranged from only one (three studies characterized either CD4+ counts, D-dimer, or hemoglobin), to as many as 40. Statistical methods for calculating RIs varied. 56 (70%) studies compared their results to international RI databases. Though most presented their data side-by-side with international data with little accompanying analysis, nearly all reported deviation from comparator RI data, sometimes with half or more of otherwise healthy participants having an “out of range” result. We found there is limited local RI data available in sub-Saharan Africa. Studies to fill this gap are warranted, including efforts to standardize statistical methods to derive RIs, methods to compare with other RIs, and improve representative participant selection.

Background: There is limited information on factors that influence oral pre-exposure prophylaxis (PrEP) uptake and adherence among adolescent girls and young women (AGYW). We conducted a qualitative methods study to explore experiences, facilitators and barriers of PrEP uptake and adherence to PrEP among AGYW at risk of Human Immunodeficiency Virus (HIV) infection in Kampala, Uganda. Methods: This study was nested in a prospective cohort study that offered daily oral PrEP to AGYW. Between April 2019 and October 2020 we conducted in-depth interviews with 26 AGYW aged 14–24 years who had been offered or had been using PrEP for at least 6 months, including PrEP adherers (8), non-adherers (8) and those who had declined PrEP (10). After 12 months, follow-up interviews were conducted with 12 AGYW who had adhered to PrEP and those who had dropped it. Thematic analysis was conducted and data were further examined and categorized into the 5 constructs of the Socio-Ecological Model (SEM). Results: PrEP uptake and adherence were facilitated by factors including: perceptions that one’s own or partner’s sexual behaviour was high risk, a negative attitude towards condoms, social support and wanting to maintain a negative HIV status after receiving a negative HIV test result. Good adherence to PrEP was enabled by effective counselling, support tools such as alarms and phone reminders and incentives like free treatment for STIs and other illnesses during study visits. Barriers to uptake included: anxiety about the pill burden, perceptions of being too young for PrEP and fear of being labelled `prostitute’ or `HIV positive’. Poor adherence was attributed to doubt over the efficacy of PrEP as a result of beliefs that because HIV was incurable, no medicine could prevent it. Alcohol use, side effects experienced, and mobility all had a negative impact on adherence. The majority of PrEP users reported feeling safe as a result of using PrEP which had both good and negative implications on their sexual behaviour, specifically the number of sexual partners and condom use. Conclusion: Addressing community misconceptions to maximize uptake of PrEP among AGYW is important. Targeted education messages, and counselling to address misconceptions in ways that capture the attention of AGYW in communities are required.