A TLR3 ligand that exhibits potent inhibition of influenza virus replication and has strong adjuvant activity has the potential for dual applications in an influenza pandemic.
The appearance and spread of the H5N1 highly pathogenic avian influenza (HPAI) raise concern of a possible pandemic. Current preventive measures include the development of a pre-pandemic influenza vaccine and stockpiling of neuraminidase inhibitors. However, their benefits can be significantly reduced by mutations in the hemagglutinin or neuraminidase resulting in antigenic changes and the appearance of drug-resistance, respectively. Drugs that target the innate immune system to achieve a 'heightened antiviral' state represent another class of antiviral agents that could contribute to the control and treatment of influenza infection. In this study, PIKA (a stabilized dsRNA) provides broad-spectrum prophylaxis against a number of influenza A viruses. In addition, when PIKA was admixed with influenza vaccine preparations, including a formalin-inactivated whole-virion H5 vaccine, significant adjuvanting effect leading to accelerated viral clearance was observed in a murine model. These biological effects appear to be mediated by the ability of PIKA to promote the maturation of dendritic cells, including up-regulation of co-stimulatory molecules, such as CD80 and CD86, and the induction of various cytokines and chemokines. Toll-like receptor 3 (TLR3) was shown to recognize PIKA in a concentration-dependent manner. The potency and versatility in its activities make PIKA an attractive candidate for use in an influenza pandemic.
Lau
Yuk-Fai
YF
Medical Countermeasures (Biological) Laboratory, Defense Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive #13-00, The Republic of Singapore, 117510, Singapore. lyukfai@dso.org.sg
Tang
Lay-Hoon
LH
Ooi
Eng-Eong
EE
D000281:Administration, Intranasal; D000818:Animals; D000914:Antibodies, Viral / Q000235:genetics / Q000276:immunology; D001717:Birds; D004196:Disease Outbreaks; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D005585:Influenza in Birds / Q000235:genetics / Q000276:immunology / Q000821:virology; D007251:Influenza, Human / Q000453:epidemiology* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012330:RNA, Double-Stranded / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000235:genetics; D015164:Vaccines, Inactivated / Q000235:genetics / Q000276:immunology; D014779:Virus Replication
D000914:Antibodies, Viral; D007252:Influenza Vaccines; D012330:RNA, Double-Stranded; D012367:RNA, Viral; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D015164:Vaccines, Inactivated