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

 

 

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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

 

Significance

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.

PNAS: H1N1 Vaccination Produced Antibodies Against Multiple Flu Strains

 

Photo Credit – CDC PHIL

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In January of 2011 we saw a report out of Emory University and the University of Chicago that found that some people infected with the 2009 H1N1 virus appeared to have developed antibodies against other flu strains as well (see H1N1 And The Road To A Universal Flu Vaccine). 

 

An unusual and unexpected result, leading researchers to wonder if receiving the inactivated H1N1 vaccine (as opposed to being infected with the virus) produced a similar response.

 

Yesterday, the results of another study (from the same researcher centers) were published in PNAS that looked at the B cell responses of 24 healthy adults immunized with the inactivated pandemic 2009 H1N1 vaccine.  

 

 

And much like the earlier study, they found that a majority of vaccinated subjects had produced broadly cross-reactive B cells (antibodies).

 

First a link to the study and abstract, followed by excerpts from the press release.

 

Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells

Gui-Mei Li, Christopher Chiu, Jens Wrammert, Megan McCausland, Sarah F. Andrews, Nai-Ying Zheng, Jane-Hwei Lee, Min Huang, Xinyan Qu, Srilatha Edupuganti, Mark Mulligan, Suman R. Das, Jonathan W. Yewdell, Aneesh K. Mehta, Patrick C. Wilson, and Rafi Ahmed

 

 

Public release date: 21-May-2012

Emory University

Pandemic 2009 H1N1 vaccination produces antibodies against multiple flu strains

Discovery brings researchers closer to goal of 'universal' flu vaccine

The pandemic 2009 H1N1 vaccine can generate antibodies in vaccinated individuals not only against the H1N1 virus, but also against other influenza virus strains including H5N1 and H3N2. This discovery adds an important new dimension to the finding last year that people infected with pandemic 2009 H1N1 virus produced high levels of antibodies that were broadly cross-reactive against a variety of flu strains.

 

<SNIP>

 

The researchers analyzed B cell (antibody) responses in 24 healthy adults immunized with the inactivated pandemic 2009 H1N1 vaccine. Vaccination caused a rapid increase in production of monoclonal antibodies that were capable of neutralizing multiple flu strains. Three of the antibody types also were able to stick to the "stalk" region of the virus that does not change as much as other regions and thus could provide a basis for a vaccine with broader and more reliable protection.

 

Antibodies that are broadly reactive against multiple influenza strains are rarely seen in people after infection or vaccination with seasonal flu, the authors note. In the 24 vaccinated individuals in the current study, the majority of flu antibodies neutralized more than one influenza strain and also seemed to be the result of B-cell memory resulting from previous exposure to other flu strains.

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The generation of broadly cross-reactive antibodies after either infection with, or vaccination against, the 2009 H1N1 virus is an unusual outcome and scientists are working to determine exactly why this occurred.

 

Although flu viruses mutate constantly, it is known that there are parts of the flu virus (notably in the `stalk’) that change little over the years and are common across multiple strains. 

 

One of the strategies being employed in the creation of a universal vaccine is to target these stable regions of the virus, and hopefully create protection against a wide range of flu strains over multiple years with just one shot.

 

According to an MSNBC report, researchers involved in this study speculate that because H1N1 was such a "new" strain of flu, it forced the body to activate a rare type of B cell that produced antibodies that targeted this stable region in the `stalk’ of the virus.

 

While test subjects showed signs of antibody cross-reactivity against  H1N1, H3N2, and even H5N1, it isn’t certain whether these antibody responses are vigorous enough to prevent infection or illness, or how long they may last.

 

Still, one can’t help but wonder if the relatively mild flu season of 2011-12 might not have been due - at least in part – to some lingering levels of protection derived from the 2009 H1N1 pandemic vaccine or virus.

 

No doubt fodder for another study as scientists continue to work to understand the mysteries of influenza.

 

While the goal of creating a universal flu vaccine is still a ways off, it is hoped that these latest results will one day assist in the development of that holy grail of influenza virology.

H1N1 And The Road To A Universal Flu Vaccine

 

 

 

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A remarkable and unexpected finding stemming from the examination of antibodies derived from a small group of people who contracted the 2009 `swine flu’ virus may eventually lead to the creation of a `universal’ flu vaccine.

 

At least that is the hope of researchers whose findings will be published in the January 10th edition of Journal of Experimental Medicine.

 

It turns out that some of those who were tested developed a number of antibodies that conferred broad immunity against a variety of influenza viruses, not just the novel H1N1 flu strain.

 

We get the details from from a couple of press releases.  First from the University of Chicago Medical Center.

 

H1N1 pandemic points to vaccine strategy for multiple flu strains

Although the 2009 H1N1 influenza pandemic infected an estimated 60 million people and hospitalized more than 250,000 in the United States, it also brought one significant benefit—clues about how to make a vaccine that could protect against multiple strains of influenza.

 

In the Jan. 10, 2011, issue of the Journal of Experimental Medicine, researchers from the University of Chicago and Emory University report that people who were infected with pandemic H1N1 and recovered had an extraordinary immune response, producing antibodies that are protective against a variety of flu strains.

 

The 2009 H1N1 virus matched typical influenza strains only in the components that are absolutely critical for the virus to function. It induced an immune response to those components that overlapped with prior influenza exposures. Incorporating these defenses--focused on the virus's most essential molecules--into a vaccine could put an end to the yearly scramble to predict coming flu strains and quickly mass produce a different vaccine each fall.

 

"The result is something like the Holy Grail for flu-vaccine research," said study author Patrick Wilson, PhD, assistant professor of medicine at the University of Chicago. "It demonstrates how to make a single vaccine that could potentially provide immunity to all influenza. The surprise was that such a very different influenza strain, as opposed to the most common strains, could lead us to something so widely applicable."

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Next, from Emory University.

 

Pandemic flu strain could point way to universal vaccine

The search for a universal flu vaccine has received a boost from a surprising source: the 2009 H1N1 pandemic flu strain.

 

Several patients infected with the 2009 H1N1 strain developed antibodies that are protective against a variety of flu strains, scientists from Emory University School of Medicine and the University of Chicago have found. The results were published online Monday in the Journal of Experimental Medicine.

 

"Our data shows that infection with the 2009 pandemic influenza strain could induce broadly protective antibodies that are only rarely seen after seasonal flu infections or flu shots," says first author Jens Wrammert, PhD, assistant professor of microbiology and immunology at Emory University School of Medicine and the Emory Vaccine Center.

 

"These findings show that these types of antibodies can be induced in humans, if the immune system has the right stimulation, and suggest that a pan-influenza vaccine might be feasible."

(Continue . . .)

 

 

Additional coverage of this story today includes:

 

H1N1 pandemic flu points to vaccine strategy for multiple flu strains Science Daily

Universal flu shot that vaccinates for life a step closer Telegraph.co.uk

 

While enticing, this is just a step forward in the quest for a universal flu vaccine.   More of a clue or a strategy on how to proceed, than an actual solution.

 

A safe, effective, and commercially available formula is still years away.

 

But this is how progress is measured.  One small scientific discovery at a time.

NIH: Commentary On Universal Flu Vaccines

 

 

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World War I was brought to a halt, in part, due to the massive wave of pandemic influenza that – by November of 1918 - had crippled the ability of soldiers and sailors to fight on both sides of the conflict.

 

Nearly 25 years later, when WWII broke out, concerns arose that once again putting hundreds of thousands of troops in close quarters might spark another global influenza epidemic (it didn’t). 

 

This time, a decade after the influenza virus had finally been isolated, scientists had a new, experimental vaccine that – starting in 1943 -was widely used on servicemen. 

 

This first vaccine was reportedly effective during the 1943-44 and the 1944-45 flu seasons, but suffered an almost complete failure during the 1946-47 season (see doi: 10.1073/pnas.162366899) when the predominate influenza strain shifted sharply antigenically. 

 

First detected on US military bases in Japan in 1946, this new virus spread quickly around the world, but is little remembered today because it produced few excess deaths.

 

What this did demonstrate was that to be effective, influenza vaccines have to be updated each year to keep up with the rapidly evolving influenza virus.

 

More than sixty years later, scientists are still scrambling to stay one-step ahead of the  multiple strains of influenza in circulation, by trying to guess what strains will be infecting people more than 6 months in advance.

 

Some years, they get it right.  Some years . . .  well, it isn’t easy when nature’s lab is open and experimenting 24/7.

 

The Holy Grail for flu vaccine researchers is a universal vaccine – one that would protect against multiple (even antigenically shifted/drifted) strains and that would remain protective for many years.

 

This would solve two huge problems.  

 

First, it would end (or at least greatly reduce) the constant game of playing catch-up with evolving and mutating viruses.

And second, if a shot could be good for 5 or more years, you could vaccinate a much larger portion of the world’s population over time.

 

We could conceivably stop the next global pandemic in its tracks, by already having `herd immunity’.  

 

We aren’t there, of course.   But the NIH, and many other researcher entities are hard at work on finding the breakthrough that will make this a reality.

A few past blogs on this hunt, include:

 

Towards A Universal Flu Vaccine

NIH: Progress Towards A Universal Flu Vaccine

Uncovering Influenza's Achilles Heel

 

 

This week Anthony S. Fauci, M.D., NIAID director, and Gary J. Nabel, M.D., Ph.D., director of the NIAID Vaccine Research Center, have published a commentary on the prospects for a universal vaccine in Nature Medicine.

GJ Nabel and AS Fauci. Induction of unnatural immunity: Prospects for a broadly protective universal influenza vaccine. Nature Medicine DOI: nm.2272 (2010).

 

While this is (alas) behind a pay wall, we can get a pretty fair idea of the contents from this NIH press release.

 

A Flu Vaccine that Lasts

NIH Scientists Consider Prospects for a Universal Influenza Vaccine

WHAT: 
The costly, time-consuming process of making, distributing and administering millions of seasonal flu vaccines would become obsolete if researchers could design a vaccine that confers decades-long protection from any flu virus strain. Making such a universal influenza vaccine is feasible but licensing it may require innovation on several fronts, including finding new ways to evaluate the efficacy of vaccine candidates in clinical trials, conclude scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

 

In a Nature Medicine commentary, authors Anthony S. Fauci, M.D., NIAID director, and Gary J. Nabel, M.D., Ph.D., director of the NIAID Vaccine Research Center, contrast the envisioned universal influenza vaccine with today’s seasonal influenza vaccines. Current seasonal flu vaccines prompt immune responses that mimic those made following natural exposure to the flu virus. Both exposure and vaccination elicit antibodies directed at the roundish head portion of a lollypop-shaped flu protein called hemagglutinin (HA). But the composition of HA’s head changes from year to year, gradually becoming unrecognizable to previously made antibodies. Thus, vaccination—which induces antibodies tailored to that year’s HA head region—must be repeated annually to maintain immunity to the virus.

 

A universal flu vaccine would have to elicit a type of immune response that rarely occurs naturally, note Drs. Fauci and Nabel. A detailed understanding of flu virus structure may make such a vaccine possible, they add. For example, scientists have identified a region of HA’s stem that is shared among diverse strains, and a research group at NIAID’s Vaccine Research Center recently created influenza vaccines that elicit antibodies aimed at this shared region, rather than at the quick-changing head. Animals that received the experimental vaccines were protected from a diverse array of flu virus strains.

 

In essence, say the authors, thanks to the growing body of knowledge about flu viruses and their interactions with the cells of humans and animals they infect, it may one day be possible to make a universal flu vaccine that improves on nature. They also outline how such a vaccine might proceed through stages of clinical testing and on toward licensing. For example, they sort the 16 known influenza virus subtypes into three tiers based on their likelihood of causing widespread disease in humans. Drs. Fauci and Nabel suggest that vaccine development might be prioritized to produce first-generation universal influenza vaccine candidates that protect against multiple virus strains within the highest priority group.

 

For more information about NIAID research on influenza, visit the NIAID flu Web portal.