Superior Immunogenicity of Inactivated Whole Virus H5N1 Influenza Vaccine is Primarily Controlled by Toll-like Receptor Signalling

[Anne]

http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000138




Superior Immunogenicity of Inactivated Whole Virus H5N1 Influenza Vaccine is Primarily Controlled by Toll-like Receptor Signalling

Felix Geeraedts¹, Nadege Goutagny², Veit Hornung², Martina Severa², Aalzen de Haan¹, Judith Pool¹, Jan Wilschut¹, Katherine A. Fitzgerald², Anke Huckriede¹^*
1 Department of Medical Microbiology, Molecular Virology Section, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands, 2 Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
Abstract

In the case of an influenza pandemic, the current global influenza vaccine production capacity will be unable to meet the demand for billions of vaccine doses. The ongoing threat of an H5N1 pandemic therefore urges the development of highly immunogenic, dose-sparing vaccine formulations. In unprimed individuals, inactivated whole virus (WIV) vaccines are more immunogenic and induce protective antibody responses at a lower antigen dose than other formulations like split virus (SV) or subunit (SU) vaccines. The reason for this discrepancy in immunogenicity is a long-standing enigma. Here, we show that stimulation of Toll-like receptors (TLRs) of the innate immune system, in particular stimulation of TLR7, by H5N1 WIV vaccine is the prime determinant of the greater magnitude and Th1 polarization of the WIV-induced immune response, as compared to SV- or SU-induced responses. This TLR dependency largely explains the relative loss of immunogenicity in SV and SU vaccines. The natural pathogen-associated molecular pattern (PAMP) recognized by TLR7 is viral genomic ssRNA. Processing of whole virus particles into SV or SU vaccines destroys the integrity of the viral particle and leaves the viral RNA prone to degradation or involves its active removal. Our results show for a classic vaccine that the acquired immune response evoked by vaccination can be enhanced and steered by the innate immune system, which is triggered by interaction of an intrinsic vaccine component with a pattern recognition receptor (PRR). The insights presented here may be used to further improve the immune-stimulatory and dose-sparing properties of classic influenza vaccine formulations such as WIV, and will facilitate the development of new, even more powerful vaccines to face the next influenza pandemic

 

[gsgs]

Re: Superior Immunogenicity of Inactivated Whole Virus H5N1 Influenza Vaccine is Primarily Controlled by Toll-like Receptor Signalling

how much better are the whole-virus-vaccines in unprimed people ?

I remember, that with seasonal vaccine, split virus was better in adults
while whole virus was better in children.

But not so much as to become excited (AFAIR)

 

[Anne]

Re: Superior Immunogenicity of Inactivated Whole Virus H5N1 Influenza Vaccine is Primarily Controlled by Toll-like Receptor Signalling

Taken together our observations show that the superior immune response to WIV, relative to that to SV or SU vaccines, is driven primarily by TLR-dependent mechanisms. Herein the presence of the viral RNA in the vaccine seems to play a crucial role. In contrast to SV and SU vaccines WIV contains substantial amounts of viral RNA. Removal of ssRNA from WIV by detergent solubilization and ultracentrifugation followed by reconstitution of the viral membrane envelopes to virosomes abolishes the capacity of the vaccine to induce production of IFNα by pDCs in vitro (Text S3 and Figure S1A) and type 1 immune responses in vivo [15]. On the other hand, ssRNA purified from WIV and condensed with polyethylenimine (PEI) did induce IFNα production in vitro (Text S3 and Figure S1B). Obviously, exposure of the viral RNA to β-propiolactone in the course of virus inactivation leaves the RNA intact to trigger TLR7-mediated signaling pathways (Figure 4), which translates into a strong and Th1-skewed antibody response to WIV in wild-type mice. In addition, the viral RNA may contribute to the TLR-independent part of the response to WIV since TLR7-independent production of IFNα could only be induced in pDCs by WIV and not by formulations (SV, SU, or reconstituted viral envelopes) which lack viral RNA (Figure 4B) [15]. These lines of evidence point to the ssRNA in WIV as the key component that enhances and steers the adaptive immune response by involvement of innate immune mechanisms.

Hi gsgs, I ve problem with my keyboard.. It dont work well .. I don't remember what split vaccin was.
what sort of " split" ? A question : why some 1918 people have immunity against 1918's avian flu, 90 years after the event, and why people don't have ( or have bad immunity ) immunity against ordinary flu vaccine.. ?

 

[gsgs]

Re: Superior Immunogenicity of Inactivated Whole Virus H5N1 Influenza Vaccine is Primarily Controlled by Toll-like Receptor Signalling

split virus (SV) = normal seasonal vaccine

the 1918-immunity was strain-specific, seasonal flu mutates