Adult-Like Anti-Mycobacterial T Cell and In Vivo Dendritic Cell Responses Following Neonatal Immunization with Ag85B-ESAT-6 in the IC31® Adjuvant

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.

Multifunctional CD4+ T cells correlate with active Mycobacterium tuberculosis infection

“…Such ''multifunctional'' cell profiles have subsequently also been used to define correlates of vaccine-mediated protection against Leishmania [11] and M. tuberculosis [12,24,25] in mouse models of vaccination. Moreover, a similar multifunctional profile of antigen-specific T cells has been reported in adults [11] and in 10-wk-old infants routinely vaccinated with BCG at birth [8], as well as after prime-boost vaccination with BCG and modified vaccinia virus Ankara-expressing Ag85A [12], although in none of these studies direct evidence could be presented that these 31 CD4 1 T-cell responses are directly relevant to protection against M. tuberculosis, nor they were evaluated in patients with active or cured TB.…”

Contrasting Adult and Infant Immune Responses to HIV Infection and Vaccination

“…For example, cord blood B cells are able to produce polysaccharide-specific antibodies following CpG engagement of Toll-like receptor 9 (23). Moreover, the oil-in-water adjuvant MF-59 can induce robust germinal center formation in mice as young as 3 weeks of age (24), and immunization of infant mice using the adjuvant IC31 can enhance IgG1, IgG2a, and IgG2b subclass antibodies to polysaccharide antigens (25). These findings indicate that under certain circumstances, infants can develop robust responses, highlighting the need to tailor immunization strategies to pediatric populations.…”

Yersinia enterocoliticaPromotes Robust Mucosal Inflammatory T-Cell Immunity in Murine Neonates

“…Both of these approaches have shown dramatic improvements in CD4 ϩ and CD8 ϩ IFN-␥ production, mucosal IgA production, and systemic IgG1 and IgG2a antibodies to the delivered vaccine antigens. Recently, CD4 ϩ T h 17-mediated immunity has been studied in response to vaccination with rotavirus antigen in adjuvant (70) and to Mycobacterium tuberculosis antigens in the presence of non-CpG oligonucleotides (36) or cationic liposomes (37). These vaccines promoted interleukin-17A (IL-17A) levels of the same magnitude in neonatal and adult CD4…”

“…ϩ cells (36,37,70). Altogether, it has become apparent that under the proper stimulation conditions, all arms of the neonatal adaptive immune system can be induced to generate adult-like responses.…”