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

May 12, 2009Vaccine

TLR9 activator reduces vaccine-linked disease worsening, but TLR7/8 does not; both increase disease severity when used during first RSV infection

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Abstract

Administration of TLR9 agonists during FI-RSV immunization reduced disease severity, while TLR7/8 agonists increased symptoms during RSV infection.

CpG administered during immunization decreased lung pathology, illness, and cytokine levels following RSV challenge.
TLR7/8 agonists had minimal impact on disease outcomes during immunization.
Administering TLR agonists during primary infection resulted in increased clinical symptoms and pulmonary inflammation.
Type 2 cytokine responses were reduced, while type 1 cytokines and MIP-1-alpha/beta levels increased with TLR agonist treatment during infection.
The findings indicate that the timing of TLR agonist administration is crucial for their immunomodulatory effects.

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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 MIP-1-alpha/beta 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 with 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.

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