Therapeutic vaccination: hope for untreatable tuberculosis?

Although tuberculosis remains a major public health threat globally [1], promising advances have been made in the past several years in the development of new tools to control the pandemic. These include rapid diagnostic tests [2], new drug regimens that may shorten the total treatment time and improve compliance [3], and novel drug delivery systems that may allow sustained therapeutic levels with lower drug doses [4]. There are currently more than a dozen tuberculosis vaccines in human trials that are based upon a variety of platforms, including viral-vectored, recombinant bacille Calmette-Guérin, and protein/ peptide vaccines [5]. Thus, the progress made in recent years in the battle against this ancient scourge is remarkable. Unfortunately, control of tuberculosis is complicated by a number of factors, not the least of which are the interactions with human immunodeficiency infection and the development of multidrug-resistant and extensively drugresistant strains [6]. In parts of the world where these resistant strains are common, treatment of patients with tuberculosis is difficult, if not impossible, because of the paucity of effective drugs. For such patients, an immune-stimulatory therapy that effectively engages patients’ own immune systems to assist the drugs in controlling the infection would be a major asset in the clinic setting. The therapeutic vaccine described by Coler et al [7] in this issue of the Journal of Infectious Diseases appears to have many of the qualities that one would want as an adjunct to chemotherapy for tuberculosis. Although a massive effort is underway to develop and test new tuberculosis vaccines, virtually all of them are designed as prophylactic vaccines to prevent progression to pulmonary disease in newly infected individuals. In the recently published Blueprint for Tuberculosis Vaccine Development [8], nearly all of the emphasis was on the use of vaccination to prevent, not to treat, tuberculosis. The use of vaccination as an adjunct to chemotherapy for tuberculosis, however, is not a new idea. Two of the vaccines currently in human trials, RUTI [9] and Mw (Mycobacterium indicus pranii) [10], are proposed as therapeutic vaccines. Investigators have been studying the therapeutic effect of Mycobacterium vaccae for many years [11]. The results of experimental studies of such vaccines have been mixed [12, 13], likely reflecting the lack of well-standardized animal models in which to test therapeutic tuberculosis vaccines. Coler et al [7] describe the use of mouse and cynomolgus monkey models of tuberculosis in which to test the ability of a vaccine that incorporates 4 mycobacterial antigens into a synthetic nano-emulsion adjuvant containing a Toll-like receptor-4 agonist (Infectious Disease Research Institute [ID] 93/ glucopyranosil lipid A-stable water-in-oil emulsion [GLA-SE]) [14] to augment the therapeutic effect of rifampin (RIF) and isoniazid (INH). The hypersusceptible inbred mouse strain based upon a Swiss background (SWR) mouse strain was chosen for these studies because of the rapid progression to lethal disease following pulmonary infection and the inability of RIF and INH to completely eliminate bacilli from the tissues. These features gave the investigators a window within which to detect the effect of immunizing the infected, drug-treated mice 3 times with their vaccine and to measure a significant improvement in the response of the mice to the 2 drugs. Indeed, therapeutic vaccination did result in a remarkable improvement in survival, a significant reduction in lung bacillary loads and pathology, and a shortening by one-third of the treatment duration required to achieve a beneficial outcome compared with mice treated with RIF and INH alone. This latter observation is important because it suggests that therapeutic vaccination might be useful in the treatment of drug-sensitive tuberculosis to reduce the duration of Received and accepted 9 April 2012; electronically published 13 August 2012. Correspondence: David N. McMurray, PhD, Department of Microbial and Molecular Pathogenesis, College of Medicine, Texas A&M Health Science Center, 463 Reynolds Medical Building, College Station, TX 77843-1114 (mcmurray@ medicine.tamhsc.edu). The Journal of Infectious Diseases 2013;207:1193–4 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/infdis/jis429