Intranasal Vaccination Promotes Detrimental Th17-Mediated Immunity against Influenza Infection

Abstract

Influenza disease is a global health issue that causes significant morbidity and mortality through seasonal epidemics. Currently, inactivated influenza virus vaccines given intramuscularly or live attenuated influenza virus vaccines administered intranasally are the only approved options for vaccination against influenza virus in humans. We evaluated the efficacy of a synthetic toll-like receptor 4 agonist CRX-601 as an adjuvant for enhancing vaccine-induced protection against influenza infection. Intranasal administration of CRX-601 adjuvant combined with detergent split-influenza antigen (A/Uruguay/716/2007 (H3N2)) generated strong local and systemic immunity against co-administered influenza antigens while exhibiting high efficacy against two heterotypic influenza challenges. Intranasal vaccination with CRX-601 adjuvanted vaccines promoted antigen-specific IgG and IgA antibody responses and the generation of polyfunctional antigen-specific Th17 cells (CD4+IL-17A+TNFα+). Following challenge with influenza virus, vaccinated mice transiently exhibited increased weight loss and morbidity during early stages of disease but eventually controlled infection. This disease exacerbation following influenza infection in vaccinated mice was dependent on both the route of vaccination and the addition of the adjuvant. Neutralization of IL-17A confirmed a detrimental role for this cytokine during influenza infection. The expansion of vaccine-primed Th17 cells during influenza infection was also accompanied by an augmented lung neutrophilic response, which was partially responsible for mediating the increased morbidity. This discovery is of significance in the field of vaccinology, as it highlights the importance of both route of vaccination and adjuvant selection in vaccine development

Cytotoxic T cell vaccination with PLGA microspheres interferes with influenza A virus replication in the lung and suppresses the infectious disease

“…PLGA MS themselves also help to circumvent toler ance as they are specifically taken up by professional antigen presenting cells. A study by Maroof et al showed, that intranasal vaccination with a TLR4 agonist and a detergent split influenza antigen promotes antigen specific antibody responses but also polyfunctional antigen specific Th17 cells leading to increased weight loss and morbidity during the early stages of disease [43]. The utilization of CpG ODN and polyI:C in our vaccination protocol, in contrast, generates a strong Th1 polarizing condition, which in combination with the usage of a peptide exclusively presented on HLA A*0201 to CD8 + cytotoxic T cells, limits the danger of the induction of an unwanted Th17 cell mediated, vaccine induced IL 17 response.…”

Current prospects and future challenges for nasal vaccine delivery

“…Mice immunized with an influenza vaccine adjuvanted with a synthetic TLR-4 agonist via the nasal route, exhibited a transient, enhanced IL-17A pathology, characterized by weight loss and morbidity, which was significantly greater than observed in mice given no-adjuvanted antigen. 41 The effect of adjuvants on induction of tolerance has also been noted; an intranasal co-administration of hen egg lysozyme with a TLR2 ligand enhanced Th1-type antibodies in one case, 118 while another TLG2 ligand, Pam3Cys, was shown to increase the risk of developing autoimmune disease 119 PLGA nanoparticles have been shown to boost tolerance in suppression of arthritis 120 and further research by the same group has shown that they are responsible for generation of enhanced Treg cell induction. 68 …”

“…40 Later research has indicated that the response is more nuanced, with some contradictory evidence regarding advantages and disadvantages of IL-17A induction. 41,42,43 Predominance of one set of cytokines over the other is generally indicative of polarization of Th responses, for example the presence of IL-4 and absence of IFN-g indicate a classical Th-2 polarized immune reaction 44 although these cytokines can also be released at the same time. 45,46,47 The varying cytokine profiles related to CTL and antibody production are fundamental in affording protection against a specific pathogen.…”

“…Many studies have investigated these abilities and ascribed immune boosting response to one, other or both qualities. 26 Mucosal adjuvants that have been tested for intranasal vaccine delivery including: MF59 emulsion (containing squalene oil, the surfactants Span 85 and Tween 80 and citrate buffer), 105,106 lipopolysaccharide, 84,107 TLR agonists, 41,108,109 chitosan, 110 trimethylchitosan, 91,110 bacterial outer membrane protein 111 and cholera toxin 112 or heat-labile enterotoxin (LT) from E.coli. 113 Some side effects have been found with the use of bacterial toxin when given intranasally, including Bell's palsy (Facial paralysis) and other adverse events related to disorders of the facial nerves.…”

Activation of the aryl hydrocarbon receptor during development enhances the pulmonary CD4+ T-cell response to viral infection

“…Less is known about the role of Th17 cells during respiratory infections. They are important effector cells at mucosal sites, including the lung, and are detected in severe influenza virus infections, suggesting a role in tissue pathology (11,14,19,27). Another subset of effector CD4…”