tetano
Editor, Senior Moderator
J Virol. 2015 Jan 7. pii: JVI.03337-14. [Epub ahead of print]
[h=1]Synthetic TLR4 and TLR7 ligands as influenza virus vaccine adjuvants induce rapid, sustained and broadly protective responses.[/h] Goff PH[SUP]1[/SUP], Hayashi T[SUP]2[/SUP], Mart?nez-Gil L[SUP]3[/SUP], Corr M[SUP]4[/SUP], Crain B[SUP]2[/SUP], Yao S[SUP]2[/SUP], Cottam HB[SUP]2[/SUP], Chan M[SUP]2[/SUP], Ramos I[SUP]3[/SUP], Eggink D[SUP]3[/SUP], Heshmati M[SUP]5[/SUP], Krammer F[SUP]3[/SUP], Messer K[SUP]2[/SUP], Pu M[SUP]2[/SUP], Fernandez-Sesma A[SUP]6[/SUP], Palese P[SUP]7[/SUP], Carson DA[SUP]8[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Current vaccines against influenza virus infection rely on the induction of neutralizing antibodies targeting the globular head of the viral hemagglutinin (HA). Protection against seasonal antigenic drift or sporadic pandemic outbreaks requires further vaccine development to induce cross protective humoral responses, potentially to the more conserved HA stalk region. Here, we present a novel viral vaccine adjuvant comprised of two synthetic ligands for Toll-like receptor (TLR) 4 and TLR7. 1Z105 is a substituted pyrimido[5,4-b]indole specific for the TLR4/MD2 complex, and 1V270 is a phospholipid conjugated TLR7 agonist. Separately, 1Z105 induces rapid Th2 associated IgG1 responses, and 1V270 potently generates Th1 cellular immunity. 1Z105 and 1V270 in combination with recombinant HA from the A/Puerto Rico/8/1934 strain (rPR/8 HA) effectively induces rapid and sustained humoral immunity that is protective against lethal challenge with a homologous virus. More importantly, immunization with the combined adjuvant and rPR/8 HA, a commercially available split vaccine, or chimeric rHA antigens significantly improves protection against both heterologous or heterosubtypic challenge viruses. Heterosubtypic protection is associated with broadly reactive antibodies to HA stalk epitopes. Histological examination and cytokine profiling reveal that IM administration of 1Z105 and 1V270 is less reactogenic than a squalene-based adjuvant, AddaVax. In summary, the combination of 1Z105 and 1V270 with a recombinant HA induces rapid, long lasting and balanced Th1 and Th2-type immunity, demonstrates efficacy in a variety of murine influenza vaccine models assaying homologous, heterologous and heterosubtypic challenge viruses, and has an excellent safety profile.
[h=4]IMPORTANCE:[/h] Novel adjuvants are needed to enhance immunogenicity and increase protective breadth of influenza virus vaccines to reduce seasonal disease burden and ensure pandemic preparedness. We show here that the combination of synthetic Toll-like receptor (TLR) 4 and TLR7 ligands is a potent adjuvant for recombinant influenza virus hemagglutinin, inducing rapid and sustained immunity that is protective against influenza viruses in homologous, heterologous and heterosubtypic challenge models. Combining TLR4 and TLR7 ligands balances Th1- and Th2-type immune responses for long-lived cellular and neutralizing humoral immunity against the viral hemagglutinin. The combined adjuvant has an attractive safety profile and the potential to augment seasonal vaccine breadth, contribute to a broadly neutralizing universal vaccine formulation, and improve response time in an emerging pandemic.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25568203 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25568203
[h=1]Synthetic TLR4 and TLR7 ligands as influenza virus vaccine adjuvants induce rapid, sustained and broadly protective responses.[/h] Goff PH[SUP]1[/SUP], Hayashi T[SUP]2[/SUP], Mart?nez-Gil L[SUP]3[/SUP], Corr M[SUP]4[/SUP], Crain B[SUP]2[/SUP], Yao S[SUP]2[/SUP], Cottam HB[SUP]2[/SUP], Chan M[SUP]2[/SUP], Ramos I[SUP]3[/SUP], Eggink D[SUP]3[/SUP], Heshmati M[SUP]5[/SUP], Krammer F[SUP]3[/SUP], Messer K[SUP]2[/SUP], Pu M[SUP]2[/SUP], Fernandez-Sesma A[SUP]6[/SUP], Palese P[SUP]7[/SUP], Carson DA[SUP]8[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Current vaccines against influenza virus infection rely on the induction of neutralizing antibodies targeting the globular head of the viral hemagglutinin (HA). Protection against seasonal antigenic drift or sporadic pandemic outbreaks requires further vaccine development to induce cross protective humoral responses, potentially to the more conserved HA stalk region. Here, we present a novel viral vaccine adjuvant comprised of two synthetic ligands for Toll-like receptor (TLR) 4 and TLR7. 1Z105 is a substituted pyrimido[5,4-b]indole specific for the TLR4/MD2 complex, and 1V270 is a phospholipid conjugated TLR7 agonist. Separately, 1Z105 induces rapid Th2 associated IgG1 responses, and 1V270 potently generates Th1 cellular immunity. 1Z105 and 1V270 in combination with recombinant HA from the A/Puerto Rico/8/1934 strain (rPR/8 HA) effectively induces rapid and sustained humoral immunity that is protective against lethal challenge with a homologous virus. More importantly, immunization with the combined adjuvant and rPR/8 HA, a commercially available split vaccine, or chimeric rHA antigens significantly improves protection against both heterologous or heterosubtypic challenge viruses. Heterosubtypic protection is associated with broadly reactive antibodies to HA stalk epitopes. Histological examination and cytokine profiling reveal that IM administration of 1Z105 and 1V270 is less reactogenic than a squalene-based adjuvant, AddaVax. In summary, the combination of 1Z105 and 1V270 with a recombinant HA induces rapid, long lasting and balanced Th1 and Th2-type immunity, demonstrates efficacy in a variety of murine influenza vaccine models assaying homologous, heterologous and heterosubtypic challenge viruses, and has an excellent safety profile.
[h=4]IMPORTANCE:[/h] Novel adjuvants are needed to enhance immunogenicity and increase protective breadth of influenza virus vaccines to reduce seasonal disease burden and ensure pandemic preparedness. We show here that the combination of synthetic Toll-like receptor (TLR) 4 and TLR7 ligands is a potent adjuvant for recombinant influenza virus hemagglutinin, inducing rapid and sustained immunity that is protective against influenza viruses in homologous, heterologous and heterosubtypic challenge models. Combining TLR4 and TLR7 ligands balances Th1- and Th2-type immune responses for long-lived cellular and neutralizing humoral immunity against the viral hemagglutinin. The combined adjuvant has an attractive safety profile and the potential to augment seasonal vaccine breadth, contribute to a broadly neutralizing universal vaccine formulation, and improve response time in an emerging pandemic.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25568203 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25568203