Abstract
The search for new and improved tuberculosis (TB) vaccines has focused on IFN-γ both for selecting antigens and for evaluating vaccine delivery strategies. The essential role of IFN-γ in endogenous host protection is well established, but it is still uncertain whether this also holds true for vaccine protection. Here we evaluate the H56 fusion protein vaccine as a BCG booster in a non-human primate (NHP) model of TB that closely recapitulates human TB pathogenesis. To date, only a handful of novel adjuvants have been tested in the NHP model of TB, and therefore we administered H56 in 3 novel cationic liposome adjuvants of increasing immunogenicity (CAF01, CAF04, CAF05) and compared them to H56 in the IC31® adjuvant previously reported to promote protection in this model. The individual clinical parameters monitored during infection (weight, ESR, X-ray) all correlated with survival, and boosting BCG with H56 in all adjuvants resulted in better survival rates compared to BCG alone. The adjuvants promoted IFN-γ-responses of increasing intensity as measured by ELISPOT in the peripheral blood, but the level of vaccine-specific IFN-γ production did not correlate with or predict disease outcome. This study’s main outcome underscores the importance of the choice of adjuvant for TB subunit vaccines, and secondly it highlights the need for better correlates of protection in preclinical models of TB.
Highlights
In the past decade more than a dozen new anti-tuberculosis (TB) vaccines have entered phase 1 or phase 2 trials to evaluate safety and immunogenicity [1, 2]
H56 Efficacy against Tuberculosis in Non-Human Primates competing interests: PA, DC and EMA are coinventors of patents regarding the use of H56 (#WO0011214 (Molecular differences between species of the M. tuberculosis complex), #WO2006136162 (Tuberculosis vaccines comprising antigens expressed during the latent infection phase); PA), CAF01 (#WO0069458 (Adjuvant combinations for immunization composition and vaccines); PA), CAF04 (patent #WO2009003474 (The use of monomycolyl glycerol as an adjuvant); PA, EMA), and CAF01/CAF05 (#WO2013004234 (Methods for producing liposomes); DC)
Monkeys were infected 6 weeks after the last H56-booster by the intratracheal route with an intermediate dose [27, 28], and monitored closely for clinical parameters for a period of 71 weeks after challenge based on previous studies [7, 17], and necropsied when reaching predefined euthanasia criteria
Summary
In the past decade more than a dozen new anti-tuberculosis (TB) vaccines have entered phase 1 or phase 2 trials to evaluate safety and immunogenicity [1, 2]. The modified vaccinia virus expressing Ag85A (MVA85A) was the first new TB vaccine in almost 50 years to undergo a clinical efficacy trial [3]. During both its pre-clinical and clinical development program, this vaccine demonstrated efficient boosting of BCG-induced Th1 cells as measured by IFN-γ ELISPOT. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
