Abstract
BackgroundWith the exception of some live vaccines, e.g. BCG, subunit vaccines formulated with “classical” adjuvants do not induce similar responses in neonates as in adults. The usual neonatal profile is characterized by lower levels of TH1-associated biomarkers. This has hampered the development of new neonatal vaccines for diseases that require early protection. Tuberculosis is one of the major targets for neonatal immunization. In this study, we assessed the immunogenicity of a novel candidate vaccine comprising a mycobacterial fusion protein, Ag85B-ESAT-6, in a neonatal murine immunization model.Methods/FindingsThe Ag85B-ESAT-6 fusion protein was formulated either with a classical alum based adjuvant or with the novel IC31® adjuvant. Following neonatal or adult immunization, 3 parameters were studied in vivo: (1) CD4+ T cell responses, (2) vaccine targeting/activation of dendritic cells (DC) and (3) protection in a surrogate mycobacterial challenge model. Conversely to Alum, IC31® induced in both age groups strong Th1 and Th17 responses, characterized by multifunctional T cells expressing IL-2 and TNF-α with or without IFN-γ. In the draining lymph nodes, a similarly small number of DC contained the adjuvant and/or the antigen following neonatal or adult immunization. Expression of CD40, CD80, CD86 and IL-12p40 production was focused on the minute adjuvant-bearing DC population. Again, DC targeting/activation was similar in adults and neonates. These DC/T cell responses resulted in an equivalent reduction of bacterial growth following infection with M. bovis BCG, whereas no protection was observed when Alum was used as adjuvant.ConclusionNeonatal immunization with the IC31®- adjuvanted Ag85B-ESAT-6 subunit vaccine elicited adult-like multifunctional protective anti-mycobacterial T cell responses through the induction of an adult pattern of in vivo DC activation.
Highlights
Tuberculosis (TB) continues to be a global disease burden despite the widespread use of Bacillus Calmette Guerin (BCG) immunization
Neonatal immunization with the IC31H- adjuvanted Ag85B-ESAT-6 subunit vaccine elicited adult-like multifunctional protective anti-mycobacterial T cell responses through the induction of an adult pattern of in vivo dendritic cells (DC) activation
C57Bl/6 mice were primed at 1 week of age (i.e. at the stage of immune maturation that most closely reflect that of human neonates [16] with Ag85B-ESAT-6 (5 mg) formulated in IC31H or aluminum hydroxide (Alum, control) via the subcutaneous (s.c.) route
Summary
Tuberculosis (TB) continues to be a global disease burden despite the widespread use of Bacillus Calmette Guerin (BCG) immunization (www.who.int/mediacentre/factsheets/fs104/en). Considerable efforts are aiming at the development of novel, safer and more efficacious vaccines against tuberculosis [1,2]. A major limitation towards the achievement of this goal is a lack of reliable biomarkers of protective immunity against M. tuberculosis (Mtb). Both CD4+ and CD8+ T cells may contribute to protection, a central role for CD4+ T cells being suggested by the disease patterns in HIV-1 infected patients [3]. The usual neonatal profile is characterized by lower levels of TH1associated biomarkers. This has hampered the development of new neonatal vaccines for diseases that require early protection. We assessed the immunogenicity of a novel candidate vaccine comprising a mycobacterial fusion protein, Ag85B-ESAT-6, in a neonatal murine immunization model
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