PNAS: Testing An IL-15 Adjuvanted Vaccinia-Based `Universal’ Flu Vaccine (In Mice)




# 8422


The headlines this afternoon – particularly those coming out of Hong Kong – are proclaiming a `Breakthrough’  that may eventually  lead to a universal flu vaccine.  The key word is `eventually, as so far this breakthrough has only been tested in mice . . . and as we’ve seen before in medical research, mice are sometimes terrible liars.


The excitement is over a study, published yesterday in PNAS,  where researchers from the University of Hong Kong, described how they piggy-backed a broadly protective flu vaccine onto a live vaccinia virus, and in it, incorporated a human cytokine (interleukin-15) adjuvant.


First a link to the study, then some excerpts from the HKU press release, after which I’ll be back with a bit more. (NOTE: If all of this sound vaguely familiar, there is a good reason for that, which I’ll go into also).


IL-15 adjuvanted multivalent vaccinia-based universal influenza vaccine requires CD4+ T cells for heterosubtypic protection

Sophie A. Valkenburg, Olive T. W. Li, Polly W. Y. Mak, Chris K. P. Mok, John M. Nicholls, Yi Guan, Thomas A. Waldmann, J. S. Malik Peiris, Liyanage P. Perera, and Leo L. M. Poon



We present a novel vaccine that elicits protective immune responses against many different influenza viruses belonging to both group 1 and 2 lineages. The vaccine uses a live vaccinia virus that expresses multiple H5N1 influenza viral proteins and the cytokine IL-15 to stimulate the immune system. The vaccine was able to induce T-cell immune responses that recognize different influenza viruses and these immune responses were augmented when exposed to a challenge virus, resulting in protection against a lethal disease. Vaccine-induced CD4+ T cells that coordinate immune responses were found to be more important than CD8+ T cells in conferring protection. Our vaccine provides a promising strategy for universal protection against novel and emerging influenza viruses.

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While not used much today, the vaccinia virus is the mild `pox’ virus that was used to eradicate smallpox back in the 1970s.  It has been investigated as potential `carrier’ for recombinant vaccines for at least 20 years, partially because it is relatively easy to quickly manufacture, and because -  with `billions already served’ - it has an enviable safety record.


While fairly benign for those with good immune systems, the standard vaccinia virus could pose a risk to those with immunocompromised systems, so a highly attenuated  Modified vaccinia Ankara (also known as MVA), might be substituted to reduce the risk.


Unlike conventional flu vaccines, which sometimes require traditional adjuvants (like squalene, oil & water, and other proprietary formulas) to increase the immune response (particularly for hard to defend against avian H5 & H7 strains), this experimental vaccine uses a gene for interleukin-15 (IL-15) to stimulate the immune system.


This paper has an impressive pedigree, including such familiar names as Dr. Leo Poon, Malik Peiris, and Yi Guan. Details are provided via the following press release:


April 1, 2014

HKU develops a universal influenza A vaccine that can elicit protective immune responses against viruses of multiple HA subtypes

A research team, led by Dr Leo Poon, Associate Professor of the School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong (HKU), in collaboration with the National Cancer Institute, National Institutes of Health, United States of America (USA), has developed a novel influenza A vaccine that can induce protective responses against distinctly different influenza A viruses in mice, including the avian H7N9 virus. The study has been published this morning (April 1, 2014) in an international scientific journal, Proceedings of the National Academy of Sciences of the United States of America.

Research Implications
The research team has developed a novel vaccine against influenza A viruses. In the vaccine, a live recombinant vaccinia virus (Wyeth/IL-15/5Flu) that expresses multiple H5N1 influenza viral proteins and the cytokine IL-15 is used to stimulate robust immune responses. The vaccinia virus is useful as it is also used as a vaccine for smallpox, and is therefore already licensed for human use with over a billion doses given so far. The vaccine can be adapted for mass production in case of a worldwide influenza outbreak.

The novel influenza A vaccine is able to induce T-cell immune responses against influenza A viruses of different hemagglutinin (HA) subtypes, overcoming the limitations of the current seasonal vaccines. These immune responses can provide protection against lethal challenge of influenza A viruses by reducing the amount of viruses and the duration of illness. In addition, vaccine-induced CD4+T cells that coordinate immune responses are found to be more important than CD8+T cells in inducing protection. These results reveal an important yet underappreciated role of CD4+T cells in initiating cross-reactive protection against influenza A viruses. Overall, this vaccine provides a promising strategy for universal protection against new and emerging influenza viruses.

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Essentially, in hundreds of lab tests, and challenged by a number of virulent flu strains, this vaccine provided between 80% and %100% protection . . . in mice.


While a promising strategy for someday producing a `universal’ flu vaccine, lead researcher, Dr Leo Poon Lit-man, told the South China Morning Post today, “ . . . it might take years before the vaccine is tested in human clinical trials.”


If all of this sounds familiar, it is because many of these same researchers published a similar study back in 2009 in the Journal of Immunology.


Vaccinia Virus-Based Multivalent H5N1 Avian Influenza Vaccines Adjuvanted with IL-15 Confer Sterile Cross-Clade Protection in Mice

Leo L. M. Poon, Y. H. Connie Leung, John M. Nicholls, Pin-Yu Perera, Jack H. Lichy, Masafumi Yamamoto, Thomas A. Waldmann, J. S. Malik Peiris,and Liyanage P. Perera


Today’s study builds on this previous research, which was pretty much H5N1-centric.  The author’s explain in today’s press release:


In this study, the use of this unique vaccine was extended to mediate heterosubtypic immunity towards viruses of different subtypes. The vaccine protected mice against the fatal attacks by the most recent human H7N9, seasonal H3N2, pandemic H1N1/2009, and highly pathogenic H7N7 influenza A viruses


Of course, the standard caveats apply:


  • What works well in mice doesn’t always always work well in humans.
  • There are a good many unknowns when it comes to boosting the human immune system, even when using a `human cytokine’ gene, so much more study is required.
  • Most of those alive before 1970 were vaccinated with the vaccinia (smallpox) vaccine, and it isn’t really known how much that will affect this vaccine’s ability to deliver its recombinant payload. 


It has literally been 5 years since the first study was published, and it may well be another five years before human clinical trials can be conducted on this novel vaccine technique. 


While it is unknown whether we have five years before the next pandemic, in complex research projects such as this one, sometimes there are no alternatives but to take the long view.