Expert Commentary & Five-year View
TB is transmitted by the respiratory route and role of mucosal immunity against MTB infection is becoming of increasing interest in the development of new TB vaccine strategies. Future delivery of new vaccines by the inhaled or intranasal routes aiming at stimulating mucosal immunity in the lungs might induce the proper catalog of innate and cell-mediate immune responses that could virtually protect during the course of MTB infection. However, potential risks of live vaccine dissemination to the brain or extensive lung inflammation inherent with respiratory routes require rigorous preclinical and clinical characterization. Given the consistent efficacy data with mucosal delivery of new subunit vaccines, the success of future boosting vaccination may lie in switching to mucosal delivery.
In addition to conferring protection against severe forms of childhood TB, observational studies have suggested that BCG may have non-specific beneficial effects on overall survival. Recent studies showed that BCG vaccination results in training of innate immunity against non-mycobacterial infections and unrelated bacteria (Staphylococcus aureus) and fungi (Candida albicans) offering a potential immunological explanation for BCG's non-specific effect on overall mortality. Moreover, BCG vaccination has been associated with induction of potent Th1-type immunity at birth that can enhance immune responses to other neonatal vaccines.
Concerning the inconsistent efficacy of BCG against common forms of TB disease responsible for transmission, epidemiological data[21,134] provide evidence that a new BCG-replacement strategy effective against all forms of TB is necessary. Experience with currently utilized whole-cell vaccines indicates that using the human pathogen is the optimal approach for inducing efficient protection and live-attenuated strategies are the best approach to confer durable T-cell immune responses. New live-attenuated MTB could present a successful vaccination approach to replace BCG. In addition, the close genealogy of MTB and M. bovis suggests that live-attenuated MTB vaccines could share the live-saving benefits observed with BCG, but they should be addressed in preclinical and clinical studies. Also, a more effective intradermal vaccine at birth, capable of inducing adequate immune memory holds potential to effectively respond to subunit (potentially mucosal) regimens.
The current animal models are imperative for selection and progress of new TB vaccines to clinical development in the global pipeline. However, new models for TB transmission, latency and neonatal disease are required to allow better vaccine appraisal and help predict outcome of clinical trials. Moreover, new candidates should be able to offer efficacy against different clinical isolates of MTB. New BCG-replacement approaches should be inexorably tested in neonatal animal models not only to assess their safety profile in this population, but also to test their vaccine efficacy in an animal model with an immature immune system.
Innovative reliable models are needed to mimic as close as possible the real clinical setting and to be able to predict outcome of long and expensive efficacy trials. An ideal trial design requires a population with a high incidence of TB and a competent immune system where specific endpoints are easily determined. However, countries with the highest TB burden are usually the poorest and face the problems of malnutrition, co-infection with other pathogens (helminths, malaria, HIV) and poor sanitation, which can severely impact on immune status and on the individual's response to a potentially promising vaccine. The current models for screening utilize healthy specific pathogen-free animal models, where even BCG leaves little room for improvement. And efficacy data observed in these models are normally extrapolated to predict outcome of clinical trials in poor endemic areas. The use of novel animal models able to predict vaccine efficacy (or lack of efficacy) in such scenarios would be of major relevance in the design of future clinical trials in poor TB endemic settings.
Biomarkers in clinic are needed for prediction of vaccine efficacy against TB vaccine evaluation and to shorten costly efficacy trials. For accelerating successful vaccine development, new human immunology-based clinical research initiatives need to be implemented with the goal of elucidating and more effectively generating vaccine-induced protective immune responses. Regarding concerns with false-positive results to ESAT-6 IGRA assays in clinic, it appears that such data would not halt development of promising vaccine candidates. When planning new vaccine clinical trials, early regulatory contacts are of extreme importance in high-burden developing countries where the regulatory and ethics expertise required for approving TB vaccine trials is limited.
Very substantial efforts have been made over the past decade to develop vaccines against TB and R&D should continue to ensure that the robust pipeline continues to expand and strengthen. Since the global economic crisis has negatively impacted the funding of health research, it is critical that researchers and advocates unite to educate policy makers about the need for new TB vaccines and the role they can play in supporting TB vaccine research and clinical development in poor socio-economic conditions. In the coming years, the first human efficacy data will be available from different viral-vectored vaccines expressing a limited set of antigens. Robust safety and immunogenicity data are imperative for conduct of future Phase IIb safety and efficacy trials of new BCG-replacement regimens such as MTBVAC and VPM1002 in neonates. Such trials are central to demonstrate whether these vaccines confer superior protection to BCG and surveillance of vaccinated neonates would demonstrate whether protection is long lasting.
Expert Rev Vaccines. 2013;12(12):1431-1448. © 2013 Expert Reviews Ltd.