ISCOMATRIX™ adjuvant reduces mucosal tolerance for effective pulmonary vaccination against influenza

Abstract

While most pathogens infect via mucosal surfaces, most current vaccines are delivered by injection. This situation remains despite awareness of the potential benefits of mucosal delivery for inducing protection against mucosa-infecting pathogens. A major obstacle to the development of such vaccines is the paucity of safe and effective adjuvants that induce mucosal responses in non-rodents. Previously we demonstrated in sheep the potency of pulmonary-delivered influenza ISCOMATRIX™ vaccine, which induces both mucosal and systemic immunity, even with low antigen doses. In the current study, lung pre-exposure to influenza antigen alone significantly reduced the immune response to subsequent pulmonary-delivered influenza ISCOMATRIX™ vaccine. A single dose of influenza antigen, delivered to the lung without exogenous adjuvant, upregulated IL-10 expression in bronchoalveolar lavage cells and FOXP3 expression in lung tissue, suggestive of induction of a regulatory T cell (Treg) response. However, this effect was inhibited by addition of ISCOMATRIX™ adjuvant. Moreover, effective pulmonary immunization with influenza ISCOMATRIX™ vaccine was associated with a depletion of Treg markers within lung tissues. Lung exposure to influenza antigen induced a localized mucosal tolerance that reduced the efficacy of subsequent influenza ISCOMATRIX™ vaccination. An important role of ISCOMATRIX™ adjuvant in pulmonary vaccination appears to be the depletion of Treg in lung tissues. Pulmonary vaccination remains capable of inducing a strong immune response against mucosal pathogens, but likely requires an adjuvant to overcome mucosal tolerance. ISCOMATRIX™ appears to have considerable potential as a mucosal adjuvant for use in humans, a major unmet need in mucosal vaccine development.

Vaccine-induced antigen-specific regulatory T cells attenuate the antiviral immunity against acute influenza virus infection

“…In addition, the CpG adjuvant prevented the increase in the ratio of antigen-specific Treg cells upon secondary immunization in mice primed by peptide alone, but did not suppress antigen-specific Treg cells to a level as low as that induced by CpG priming. Consistent with our observation, Timothy et al 32 also found that prior vaccination in lung mucosa with unadjuvanted influenza antigen alone induces Treg cells that significantly reduce the immune response to subsequent pulmonary-delivered influenza ISCOMATRIX TM -adjuvanted vaccine. Taken together, our data suggest that antigen-specific Tregs induced by an initial suboptimal vaccination strategy have detrimental effect on the immune response induced by effective adjuvanted vaccines.…”

Construction of a Live-Attenuated Vaccine Strain of Yersinia pestis EV76-B-SHUΔpla and Evaluation of Its Protection Efficacy in a Mouse Model by Aerosolized Intratracheal Inoculation

“…time, such administration can induce both long-lasting systemic and mucosal immune responses against respiratory pathogens (Timothy et al, 2015;Perdomo et al, 2016;Wu et al, 2017;Florido et al, 2018). Therefore, pulmonary vaccine delivery has received a lot of attention in recent studies (Guillon et al, 2012;Lee et al, 2012).…”

“…The lungs have a large surface area, abundant blood flow, and highly permeable epithelium, so vaccines administered via the lung show better bioavailability and more rapid onset time than other alternative routes (Patton et al, 2004 ; Patton and Byron, 2007 ; Lee et al, 2012 ; Kunda et al, 2013 ). At the same time, such administration can induce both long-lasting systemic and mucosal immune responses against respiratory pathogens (Timothy et al, 2015 ; Perdomo et al, 2016 ; Wu et al, 2017 ; Florido et al, 2018 ). Therefore, pulmonary vaccine delivery has received a lot of attention in recent studies (Guillon et al, 2012 ; Lee et al, 2012 ).…”

Utilizing murine dendritic cell line DC2.4 to evaluate the immunogenicity of subunit vaccines in vitro

“…Adjuvants play pivotal roles in cell signaling, stimulating the innate immunity in the preamble to a robust antigen-specific adaptive immunity. Without the presence of an adjuvant, an antigen may induce immune tolerance rather than activating the immune system ( 3 – 5 ). Therefore, it is essential to co-deliver an adjuvant with an antigen to induce a desired immune response.…”