Synergistic induction of interferon α through TLR-3 and TLR-9 agonists stimulates immune responses against measles virus in neonatal cotton rats

摘要

Immunization of neonates is problematic because of the immaturity of their immune system and the presence of maternal antibodies, both of which affect B cell responses. We tested the effects of co-administration of measles vaccine with a combination of TLR-3 (pI:C) and TLR-9 (ODN2216, optimized for human TLR-9) agonists on the ability to induce an effective immune response in neonatal cotton rats. TLR-9 expression in cotton rat lymphocytes was at the same low level as in human lymphocytes, which is in contrast to mice that express higher levels. TLR-3 expression levels were comparable between cotton rats, mice and humans. A combination of TLR-3 and TLR-9 agonists synergistically induced high levels of type I interferon in neonatal spleen cells and higher levels of IL-10 as compared to adult spleen cells. Previously, it was shown that type I interferon stimulates B cell generation and antibody secretion in vitro and in vivo, and that IL-10 has immunomodulatory effects. The simultaneous induction of both type I interferon and IL-10 indicated that this immunization regimen could be both effective and safe. Neonatal cotton rats did not generate neutralizing antibodies after measles vaccination in the first week of life (although a T cell response was detectable). However, co-administration of the TLR-3 and TLR-9 agonist combination with measles vaccine in neonatal cotton rats induced neutralizing antibody responses comparable to those after adult immunization. This immunization regimen was also effective in neonatal cotton rats in the presence of natural maternal antibodies, although antibody titers were lower than after immunization in the absence of maternal antibodies.