TLR9 agonist, but not TLR7/8, functions as an adjuvant to diminish FI-RSV vaccine-enhanced disease, while either agonist used as therapy during primary RSV infection increases disease severity

Abstract

Agonists for TLR7, TLR8, and TLR9 have been shown to enhance vaccine immunogenicity. We evaluated the impact of TLR activation on RSV disease in a murine model by administering TLR7/8 and TLR9 agonists during FI-RSV immunization or RSV infection. CpG administered during immunization reduced disease following challenge as evidenced by decreased lung pathology, illness, and cytokines. In marked contrast, TLR7/8 agonist had little impact. To evaluate potential therapeutic use, TLR agonists were administered during primary infection. Although type 2 cytokine responses decreased and type 1 cytokines and MIP1-α/β increased, both TLR7/8 and TLR9 agonists increased clinical symptoms and pulmonary inflammation when administered during primary infection. Thus, TLR9-induced signaling during FI-RSV immunization reduced vaccine-enhanced disease whereas immunostimulatory properties of TLR agonists enhanced disease severity when used during RSV infection. Immunomodulation elicited by TLR9 agonist confirms the adjuvant potential of TLR agonists during RSV immunization. However, in contrast to work done HIV-1 vaccines, the inability of TLR7/8 agonist to boost type 1 vaccine-induced RSV immunity demonstrates pathogen-TLR specificity. These data reveal that the timing of administration of immunomodulatory agents is critical. Furthermore, these data underscore that amplification of anti-viral immune responses may result in immunopathology rather than immune-mediated protection.

Local cytokine response upon respiratory syncytial virus infection

“…In agreement with this observation, deletion of TLR7 was recently shown to worsen RSV-induced pathology with increased expression of IL-4, IL-13, and IL-17 in the lungs [41]. However, some TLR7 agonists have been shown to enhance disease severity in RSV infected mice [42]. Taken together, these data suggest that in response to a variety of TLR stimuli, type I IFN expression can be inhibited by host cell infection by RSV.…”

The Role of UNC93B1 Protein in Surface Localization of TLR3 Receptor and in Cell Priming to Nucleic Acid Agonists

“…This mechanism can account for the observed effect of the respiratory syncytial virus infection, which activates TLR3 and primes cells for the response to subsequent bacterial or viral infection (55). Activation of TLR3 by respiratory syncytial virus infection induces TLR3 production (21), whereas the addition of TLR9 agonist increases the disease severity (56). Enhanced expression of TLR3 has been observed in the dermis of patients with scleroderma in contrast to healthy control skin biopsies (35).…”

Selection of Adjuvants for Enhanced Vaccine Potency

“…Addition of CpG 1826 did not lead to additional immune enhancement for a peptide vaccine (complexed with an immune-enhancement dsRNA adjuvant -pI:C/E749-57) in mice [118] and for a montanide ISA720-adjuvanted opossum vaccine in rats [119]. While co-administration of CpG 1826 with a respiratory syncytial virus vaccine increased the efficacy of the vaccine, co-administration during primary infection actually enhanced the severity of the disease in mice [120].…”