Tropical Disease Foundation

The swift development of coronavirus disease 2019 (COVID-19) vaccines marked a monumental effort in global coordination and collaboration; however, there remained major disparities in vaccine access and research capacity across countries. Unequal participation in vaccine development studies from low- and middle- income countries (LMICs) clearly signaled an urgent need to strengthen health research infrastructure in those regions. With funding from the Gates Foundation (GF), this site readiness initiative carried out rapid capacity enhancement activities to enable large-scale, Phase 3 pivotal clinical trial conduct in LMICs. The International Vaccine Institute (IVI) worked with site partners in four countries (Mozambique, Ghana, Nepal, and the Philippines) after conducting feasibility assessments for site selection. Site-specific gaps were identified, and capacity building activities focused on staff training, site infrastructure, and resource mobilization were carried out over roughly 7 months from October 2020 to May 2021. Despite pandemic-related challenges such as supply chain shortages, by the end of the capacity building efforts all sites were either contracted to or in discussions with trial sponsors to conduct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine studies. This article provides an overview of the site selection process, critical components of site establishment, and final site readiness evaluations carried out amidst a global health emergency. This experience illustrates the value of research capacity enhancement as essential to both pandemic preparedness and global health equity. The lessons learned are being carried into an ongoing initiative across West Africa, currently underway as the "Advancing Research Capabilities in West Africa (ARC-WA)."

This study evaluated the safety and immunogenicity of the PIKA-adjuvanted recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein subunit vaccine as a booster dose for healthy adults who had previously received two or more doses of an inactivated coronavirus disease 2019 (COVID-19) vaccine. The study was a phase II multicenter, double-blinded, comparator-controlled, randomized trial. Participants were randomly assigned to receive either the PIKA COVID-19 vaccine booster dose or an inactivated COVID-19 vaccine (Sinovac, China). Safety was assessed based on adverse events, while immunogenicity was measured by neutralizing antibodies against SARS-CoV-2 and serum immunoglobulin G (IgG) levels. Data on safety and immunogenicity were collected in the short-term (within 14 days after the booster dose) and long-term (from 90 to 365 days after the booster dose). The PIKA-adjuvanted vaccine demonstrated a significant increase in neutralizing antibodies against the Omicron variant (geometric mean ratio [GMR]=2.0 on day 7, p-value <0.001; GMR=2.7 on day 14, p-value <0.001) and the wild type SARS-CoV-2 virus (GMR=2.3 on day 7, p-value <0.001; GMR=2.8 on day 14, p-value<0.001) in the early post-vaccination period when compared to the inactivated vaccine. Additionally, the PIKA COVID-19 vaccine showed higher seroconversion rates for neutralizing antibodies against both variants during the first 14 days post-vaccination. However, there were no significant differences in neutralizing antibody levels between the two vaccines from day 90 to day 360 post-vaccination. Serum IgG antibody levels for the PIKA COVID-19 vaccine were also higher throughout the study period. The incidence of adverse events was slightly higher in the PIKA COVID-19 group, with the most common events being pain at the injection site and headache. All adverse events were mild or moderate, with no reports of severe or life-threatening adverse events in either group. The PIKA COVID-19 vaccine, when administered as a booster dose, showed promising short- and long-term immunogenicity with no emergent safety issues identified. The booster dose of the PIKA COVID-19 vaccine elicited a robust immune response against various SARS-CoV-2 variants and provided some seroprotection for up to 360 days (ClinicalTrials.gov registration number: NCT05463419).

Abstract BackgroundIndividuals with bacteriologically confirmed pulmonary tuberculosis disease (TB) that do not report symptoms (subclinical TB) represent around half of all prevalent cases of TB, yet their contribution to Mycobacterium tuberculosis (Mtb) transmission is unknown, especially compared to individuals who report symptoms at time of diagnosis (clinical TB). Relative infectiousness can be approximated by cumulative infections in household contacts, but such data are rare.Methods and FindingsWe reviewed the literature to identify studies where surveys of Mtb infection were linked to population surveys of TB disease. We collated individual population data for analysis and used literature on the relative durations of subclinical and clinical TB to estimate relative infectiousness through a cumulative hazard model, accounting for sputum-smear status. Relative prevalence of subclinical and clinical disease in high burden settings was used to estimate the contribution of subclinical TB to global Mtb transmission.We collated data on 414 index cases and 789 household contacts from three prevalence surveys (Bangladesh, Philippines, Viet Nam) and one case-finding trial in Viet Nam. The odds ratio of household infection prevalence was 1.2 (0.6-2.3, 95% Confidence Interval). Adjusting for duration of disease, we found a per-unit-time infectiousness of subclinical TB relative to clinical TB of 1.93 (0.62-6.18, 95% Prediction Interval (PrI)). 14 countries across Asia and Africa provided data on relative prevalence of subclinical and clinical TB, suggesting an estimated 68% (27-92%, 95% PrI) of global transmission is from subclinical TB.ConclusionsOur results suggest that subclinical TB contributes substantially to transmission and needs to be diagnosed and treated for effective progress towards TB elimination.

We analysed national TB prevalence surveys from eight countries individually and in pooled multicountry models. Socio-economic level (SEL) was measured in terms of both relative household position and absolute wealth. The outcome of interest was whether or not an individual had TB disease. Logistic regression models were used to control for putative risk factors for TB disease such as age, sex and previous treatment history. Overall, a strong and consistent association between household SEL and individual TB disease was not found. Significant results were found in four individual country models, with the lowest socio-economic quintile being associated with higher TB risk in Mongolia, Myanmar, Tanzania and Viet Nam. TB prevalence surveys are designed to assess prevalence of disease and, due to the small numbers of cases usually detected, may not be the most efficient means of investigating TB risk factors. Different designs are needed, including measuring the SEL of individuals in nested case-control studies within TB prevalence surveys or among TB patients seeking treatment in health care facilities.

ProblemNew drugs for infectious diseases often need to be evaluated in low-resource settings. While people working in such settings often provide high-quality care and perform operational research activities, they generally have less experience in conducting clinical trials designed for drug approval by stringent regulatory authorities.ApproachWe carried out a capacity-building programme during a multi-centre randomized controlled trial of delamanid, a new drug for the treatment of multidrug-resistant tuberculosis. The programme included: (i) site identification and needs assessment; (ii) achieving International Conference on Harmonization – Good Clinical Practice (ICH-GCP) standards; (iii) establishing trial management; and (iv) increasing knowledge of global and local regulatory issues.Local settingTrials were conducted at 17 sites in nine countries (China, Egypt, Estonia, Japan, Latvia, Peru, the Philippines, the Republic of Korea and the United States of America). Eight of the 10 sites in low-resource settings had no experience in conducting the requisite clinical trials.Relevant changesExtensive capacity-building was done in all 10 sites. The programme resulted in improved local capacity in key areas such as trial design, data safety and monitoring, trial conduct and laboratory services.Lessons learntClinical trials designed to generate data for regulatory approval require additional efforts beyond traditional research-capacity strengthening. Such capacity-building approaches provide an opportunity for product development partnerships to improve health systems beyond the direct conduct of the specific trial.

BackgroundThe reasons that patients with multidrug-resistant tuberculosis (MDR TB) miss treatment are multi-factorial and complex. Identifying patterns of treatment interruption that predict poor outcomes can be used to target program activities aiming to improve treatment adherence.ObjectiveTo characterize patterns of treatment interruption among MDR TB patients and determine the association between patterns and treatment outcomes.MethodsRetrospective analysis of MDR TB patients. A treatment interruption was defined as any time that a patient missed a prescribed dose of treatment for at least 1 day but for a period of less than 2 consecutive months. Patients were characterized by the number, length and variability of interruptions, variability of time between interruptions, and percent of missed doses. Final treatment outcome was dichotomized as a successful (cured or completed) or poor outcome (defaulted, failed, or died). Risk ratios were calculated to determine the association between characteristics of treatment interruption and treatment outcomes. All analyses were conducted in 6 month treatment intervals.ResultsOnly 7.0% of 583 patients completed treatment without interruption. Of the remaining 542 patients, the median time to the first interruption was 2 ½ months (70 days). In multivariate analysis, patients who had longer interruptions with sporadic variability during the 6–12 month or the 12–18 month treatment period had a significantly increased risk for poor outcomes compared to patients who had short, regular interruptions (RRadj 4.37, 95% CI 1.2–15.8; = 0.03 and RRadj 3.38, 95% CI 1.6–7.1; p = 0.001, respectively). In addition, missing 10% or more of the prescribed doses during any 6 month period in the initial 18 months of therapy significantly increased the risk for poor outcomes (RRadj range 1.55–2.35; p-value range 0.01–0.005).ConclusionPatients that miss more consecutive days of treatment with sporadic interruption patterns or a greater proportion of treatment are at an increased risk for poor treatment outcomes.