Development of a TB vaccine trial site in Africa and lessons from the Ebola experience

Tuberculosis is the deadliest infection of our time. In contrast, about 11,000 people died of Ebola between 2014 and 2016. Despite this manifest difference in mortality, there is now a vaccine licensed in the United States and by the European Medicines Agency, with up to 100% efficacy against Ebola. The developments that led to the trialing of the Ebola vaccine were historic and unprecedented. The single licensed TB vaccine (BCG) has limited efficacy. There is a dire need for a more efficacious TB vaccine. To deploy such vaccines, trials are needed in sites that combine high disease incidence and research infrastructure. We describe our twelve-year experience building a TB vaccine trial site in contrast to the process in the recent Ebola outbreak. There are additional differences. Relative to the Ebola pipeline, TB vaccines have fewer trials and a paucity of government and industry led trials. While pathogens have varying levels of difficulty in the development of new vaccine candidates, there yet appears to be greater interest in funding and coordinating Ebola interventions. TB is a global threat that requires similar concerted effort for elimination

Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial

Background: Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women. Methods: HPTN 084 was a phase 3, randomised, double-blind, double-dummy, active-controlled, superiority trial in 20 clinical research sites in seven countries in sub-Saharan Africa. Participants were eligible for enrolment if they were assigned female sex at birth, were aged 18–45 years, reported at least two episodes of vaginal intercourse in the previous 30 days, were at risk of HIV infection based on an HIV risk score, and agreed to use a long-acting reversible contraceptive method. Participants were randomly assigned (1:1) to either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Study staff and participants were masked to study group allocation, with the exception of the site pharmacist who was responsible for study product preparation. Participants were prescribed 5 weeks of daily oral product followed by intramuscular injections every 8 weeks after an initial 4-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF-FTC for 48 weeks. The primary endpoints of the study were incident HIV infection in the intention-to-treat population, and clinical and laboratory events that were grade 2 or higher in all women who had received at least one dose of study product. This study is registered with ClinicalTrials.gov, NCT03164564. Findings: From Nov 27, 2017, to Nov 4, 2020, we enrolled 3224 participants (1614 in the cabotegravir group and 1610 in the TDF-FTC group). Median age was 25 years (IQR 22–30); 1755 (54·7%) of 3209 had two or more partners in the preceding month. 40 incident infections were observed over 3898 person-years (HIV incidence 1·0% [95% CI 0·73–1·40]); four in the cabotegravir group (HIV incidence 0·2 cases per 100 person-years [0·06–0·52]) and 36 in the TDF-FTC group (1·85 cases per 100 person-years [1·3–2·57]; hazard ratio 0·12 [0·05–0·31]; p<0·0001; risk difference –1·6% [–1·0% to –2·3%]. In a random subset of 405 TDF-FTC participants, 812 (42·1%) of 1929 plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of the total number of person-years. Adverse event rates were similar across both groups, apart from injection site reactions, which were more frequent in the cabotegravir group than in the TDF-FTC group (577 [38·0%] of 1519 vs 162 [10·7%] of 1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1·3 per 100 person-years (0·9–1·7); no congenital birth anomalies were reported. Interpretation: Although both products for HIV prevention were generally safe, well tolerated, and effective, cabotegravir was superior to TDF-FTC in preventing HIV infection in women. Funding: National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and the Bill & Melinda Gates Foundation. Additional support was provided through the National Institute of Mental Health, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. ViiV Healthcare and Gilead Sciences provided pharmaceutical support

Sex-biased inbreeding effects on reproductive success and home range size of the critically endangered black rhinoceros

A central premise of conservation biology is that small populations suffer reduced viability through loss of genetic diversity and inbreeding. However, there is little evidence that variation in inbreeding impacts individual reproductive success within remnant populations of threatened taxa, largely due to problems associated with obtaining comprehensive pedigree information to estimate inbreeding. In the critically endangered black rhinoceros, a species that experienced severe demographic reductions, we used model selection to identify factors associated with variation in reproductive success (number of offspring). Factors examined as predictors of reproductive success were age, home range size, number of nearby mates, reserve location, and multilocus heterozygosity (a proxy for inbreeding). Multilocus heterozygosity predicted male reproductive success (p58%) and correlated with male home range size (p 44%). Such effects were not apparent in females, where reproductive success was determined by age (p <0.01, explained deviance 34%) as females raise calves alone and choose between, rather than compete for, mates. This first report of a 3-way association between an individual male's heterozygosity, reproductive output, and territory size in a large vertebrate is consistent with an asymmetry in the level of intrasexual competition and highlights the relevance of sex-biased inbreeding for the management of many conservation-priority species. Our results contrast with the idea that wild populations of threatened taxa may possess some inherent difference from most nonthreatened populations that necessitates the use of detailed pedigrees to study inbreeding effects. Despite substantial variance in male reproductive success, the increased fitness of more heterozygous males limits the loss of heterozygosity. Understanding how individual differences in genetic diversity mediate the outcome of intrasexual competition will be essential for effective management, particularly in enclosed populations, where individuals have restricted choice about home range location and where the reproductive impact of translocated animals will depend upon the background distribution in individual heterozygosity. © 2013 Society for Conservation Biology