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.

Novel approaches to enable equitable access to monoclonal antibodies in low- and middle-income countries.

Monoclonal antibodies (mAbs) are revolutionizing management of non-communicable diseases in high-income countries and are increasingly being advanced for a range of infectious diseases (IDs). However, access to existing mAbs is limited in low- and middle-income countries (LMICs), and investment in developing fit-for-purpose mAbs for IDs that disproportionately affect LMICs has been limited. Underlying these access barriers are systemic challenges, including a lack of commercial incentives to target LMIC markets and complexity in manufacturing and regulatory processes. Novel strategies are needed to overcome systemic access barriers for mAbs. We outline key areas where new approaches could address these barriers, based on a multistakeholder consultation in March 2023. Three disease-market archetypes are identified to guide thinking about business models tailored to different contexts. New business models are needed to incentivize development and manufacturing of ID mAbs and to ensure mAbs are optimized with a target product profile and cost of goods that enable use in diverse LMIC settings. Lessons can be applied from voluntary licensing strategies and product development partnerships that have shown success in catalysing development and affordable supply for a range of infectious diseases. Technology transfer will be key to expand LMIC research and manufacturing capacity and to enable sustainable and diversified supply. Improved market intelligence, demand aggregation mechanisms, and portfolio-based manufacturing models could be used to de-risk commercial investment and establish a sustainable manufacturing ecosystem for affordable mAbs. Novel regulatory approaches and robust technology transfer may reduce data requirements and timelines for biosimilar approvals. Trailblazer products, with coordinated "end-to-end" support from funders, can demonstrate proof of concept for pathways to accessible mAbs across a broader range of LMICs. Research funders; local, regional, global health agencies; and, private sector partners should commit to implementing innovative partnerships and end-to-end strategies that enable equitable access to mAbs for infectious diseases in LMICs.

Short report: modulation of Mycobacterium tuberculosis infection by Plasmodium in the murine model.

A large proportion of people with latent tuberculosis live in malaria-endemic areas, so co-infection with these two organisms is likely to be common. To determine whether there might be a biologic interaction between these two pathogens in vivo, we infected mice with Mycobacterium tuberculosis and then with a non-lethal strain of Plasmodium yoelii eight weeks later. Mice chronically infected with M. tuberculosis simulate the equilibrium between pathogen and host thought to exist in human latent infection. Co-infected mice were less able to contain growth of M. tuberculosis in lung, spleen, and liver (mean +/- SEM log10 colony-forming units = 5.50 +/- 0.11 versus 5.12 +/- 0.08, 4.58 +/- 0.07 versus 4.13 +/- 0.10, and 2.86 +/- 0.10 versus 2.49 +/- 0.10, respectively) and had increased mortality. In populations where both diseases are endemic, there may be implications for increased incidence of clinically detectable tuberculosis.

Emergence of fluoroquinolone resistance in Mycobacterium tuberculosis during continuously dosed moxifloxacin monotherapy in a mouse model.

Fluoroquinolone resistance in tuberculosis may rapidly emerge. Mice infected with high titers of aerosolized Mycobacterium tuberculosis and treated for 8 weeks with four concentrations of moxifloxacin (0.125, 0.25, 0.50, and 1.0%) mixed into the diet had drug concentrations of 2.4, 4.1, 5.3, and 17.9 microg/ml, respectively, in blood. Selection of fluoroquinolone-resistant mutants occurred in all surviving mice.

Naturally attenuated, orally administered Mycobacterium microti as a tuberculosis vaccine is better than subcutaneous Mycobacterium bovis BCG.

Mycobacterium microti is phylogenetically closely related to Mycobacterium tuberculosis and is a member of that complex of organisms. It is a curved, acid-fast bacillus that is naturally attenuated with a narrow host range for Microtus species only. In this study, we confirm the unique susceptibility of voles to infection with M. microti and the relative resistance of mice with a significantly lower organism burden after 8 weeks of infection. In addition, histopathologic examination of lungs reveals a lack of cellular, granulomatous aggregates characteristically seen in murine M. tuberculosis infection. In the past, M. microti has been used successfully in humans as a vaccine against tuberculosis but was associated with cutaneous reactions. In an attempt to circumvent this adverse effect, we report the efficacy of aerosol and oral vaccination with M. microti. High-dose orogastric vaccination with M. microti resulted in a statistically significant improvement in protection against aerosol challenge with virulent M. tuberculosis in the murine model compared with subcutaneous M. bovis BCG Pasteur vaccination.

Comparison of C(18)-carboxypropylbetaine and standard N-acetyl-L-cysteine-NaOH processing of respiratory specimens for increasing tuberculosis smear sensitivity in Brazil.

Techniques to improve the sensitivity of smear microscopy would facilitate early tuberculosis (TB) diagnosis and disease control, especially in low-income countries where the positive predictive value is high. C(18)-carboxypropylbetaine (CB-18) is a zwitterionic detergent that helps to compensate for the innate buoyancy of mycobacteria, potentially enhancing recovery by centrifugation. Previous data suggest that CB-18 may increase the sensitivity of smear, culture, and molecular amplification diagnostic testing. The goal of the present study was to evaluate if the sensitivity of the smear technique using light microscopy could be improved by treating respiratory samples with CB-18. In the first phase, respiratory specimens were collected consecutively from patients with suspected pulmonary tuberculosis in a tertiary-care hospital in Rio de Janeiro, Brazil (236 specimens were analyzed). After protocol modifications, another 120 respiratory specimens were evaluated. The standard technique was N-acetyl-L-cysteine with sodium hydroxide (NALC-NaOH) treatment, smear concentration with centrifugation, and Ziehl-Neelsen staining. Culture on Löwenstein-Jensen slants was performed on all specimens for use as the "gold standard." No specimens from patients undergoing active TB treatment were included. The initial protocol for CB-18 processing resulted in a sensitivity of 59.6% and specificity of 96.8% compared to standard processing with a sensitivity of 66.0% and specificity of 96.8%. Using the modified protocol, the sensitivity of CB-18 increased to 71.4% with a specificity of 97.0% versus standard processing with a sensitivity of 61.9% and a specificity of 99.0%. The diagnostic yield of acid-fast bacillus smear with CB-18 in the absence of fluorescence microscopy and PCR compared to standard processing with NALC-NaOH was not significantly different, although the power to detect a difference by the modified assay was low.