Efficacy and safety of live attenuated persistent and rapidly cleared Mycobacterium tuberculosis vaccine candidates in non-human primates

Abstract

Tuberculosis (TB) remains a global health burden for which safe vaccines are needed. BCG has limitations as a TB vaccine so we have focused on live attenuated Mycobacterium tuberculosis mutants as vaccine candidates. Prior to human studies, however, it is necessary to demonstrate safety in non-human primates (NHP). In this study, we evaluate the safety and efficacy of two live attenuated M. tuberculosis double deletion vaccine strains mc26020 (ΔlysA ΔpanCD) and mc26030 (ΔRD1 ΔpanCD) in cynomolgus macaques. In murine models, mc26020 is rapidly cleared while mc26030 persists. Both mc26020 and mc26030 were safe and well tolerated in cynomolgus macaques. Following a high-dose intrabronchial challenge with virulent M. tuberculosis, mc26020-vaccinates were afforded a level of protection intermediate between that elicited by BCG vaccination and no vaccination. BCG vaccinates had reduced tuberculosis-associated pathology and improved clinical scores as compared to saline and mc26030 vaccinates, but survival did not differ among the groups.

Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials

“…1073/pnas.1214188109/-/DCSupplemental. mice, guinea pigs, or monkeys (21,22). This strain has been deemed to be safe for use in BSL2 laboratories by the Institutional Biosafety Committees of the Albert Einstein College of Medicine and Weill Cornell Medical College, as approved by the US National Institutes of Health.…”

Comparative Analysis of Monkeypox Virus Infection of Cynomolgus Macaques by the Intravenous or Intrabronchial Inoculation Route

“…i.b. inoculation was chosen because it (i) has been reported to be effective for other pathogens (4,23,27), (ii) may prove to be more reliable and accessible than aerosol inoculation, and (iii) more closely resembles the natural route of infection (respiratory exposure) than i.v. inoculation (15).…”

“…The i.b. inoculation of NHPs has been reported to be an effective method for the delivery of simian varicella virus, adenovirus vectors, and Mycobacterium tuberculosis (4,23,27). Inoculation by the i.b.…”

The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection

“…While a number of vaccine efficacy studies have been published using the high-dose cynomolgus or rhesus macaque models of infection (8,37,41,42), to our knowledge this is the first vaccine trial in which both low- and high-dose M. tuberculosis challenges were performed. The H56 booster vaccine gave similar outcomes in the two models, and in particular very low levels of the inflammation marker ESR and low infection-driven responses to CFP10 were striking observations in both experiments and indicated efficient control of bacterial replication.…”