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One last flu shot?

I was inspired by a mix of watching Contagion and listening to a talk from Rafi Ahmed, the Director of the Emory Vaccine Center, to look into current vaccine literature and I stumbled upon a new, extremely interesting idea: the possibility of pan-influenza vaccine, or a vaccine that can promote immunity against multiple flu viruses.

This would mean no more annual flu shots and potential immunity against a future emerging pandemic influenza strain. But is it possible?

To answer this question we have to understand the biology of flu virus and the immunology behind flu vaccines.

What makes annual flu vaccines different from each other?

Flu can be caused by a variety species and strains of influenza virus, and some of these species/strains can die out within a season while others move on to take down small villages (epidemics) or induce worldwide panic (pandemics, or CNN’s money makers). Generally Influenzavirus A is the genus that gets the most attention due to their high transmission between species (pig to bird, bird to human) and severe symptoms/disease. A few of these bad boys are: H1N1 (Spanish Flu in 1918 and Swine Flu in 2009), H5N1 (Bird Flu in 2004), H2N2 (Asian Flu in 1957).

Side note: if you’d like to know why they’re named H_N_ refer to my earlier blog post on The Original Antigenic Sin.

New viruses are made constantly, and the variety of strains is due to evolution (a genetic mutation) or by genetic reassortment. Genetic mutations are generally seen in the viral surface proteins hemagglutinin (HA) (purple proteins, left) and neuraminidase (N) (orange proteins, left). Mutations lead to small variability between flu strains, therefore the virus produces slightly modified antigens (proteins on the virus that the host makes antibodies against) and creates an “antigenic shift”. This helps the virus evade the host immune system.

Additionally, flu is highly susceptible to genetic reassortment (pic below, right)– this is due to the fact that flu has 8 different RNA strands that encode its genome, whereas most viruses contain only 1 RNA strand for the entire viral genome. Therefore, one or more of these RNA strands in Flu-alpha can mingle with one or more strands of RNA from Flu-beta to make Flu-pocalypse. This is where shit hits the fan. Genetic reassortment can lead production of entirely new antigens (everyone is susceptible) and possibly increased transmission, tropism (the ability to infect different cell types or entirely different species), or BOTH. In a world I never want to be a part of, there is chance that H1N1 (spreads very easily) could combine with H5N1 (high morbidity and morality) – this is where Contagion would be plausible.

Due to these two attributes there are many different types of flu vaccines, and they are not all created equal, seasonal vaccines protect against antigens seen on seasonal flu viruses and pandemic vaccines protect against antigens seen on pandemic vaccines.

Ok, so if influenza is constantly mutating and trading pieces of their genome, how could there possibly be a vaccine against ALL strains?

We’d have to find a virus that induced production of an antibody that could bind and neutralize all flu strains. This is harder than it sounds, but luckily Rafi Ahmed’s group found that we can take advantage of the ever-changing influenza virus, and find one mutant virus that promotes neutralizing antibodies (these are antibodies that are aptly named, they bind to the virus and tag them for destruction by killer immune cells, so they neutralize the virus) that can protect against all strains.

What virus? H1N1.

Why is H1N1 so special (aside from the fact Sanjay Gupta got it)?

Rafi’s group found that unlike other seasonal flu, the majority of antibodies produced by H1N1 infection bound to conserved regions in the HA stalk region. This is important because the HA protein has a head and stalk region, and generally flu antibodies are against the head region. The head region is commonly the area of mutation during antigenic shift, and the stalk region is highly conserved among flu strains – therefore, if you make antibodies against the stalk region, they should be cross-reactive with all flu viruses.

And EUREKA they were right! The antibodies against the H1N1 HA stalk region was broadly cross-reactive with all recent annual H1N1 strains AND the highly pathogenic 1918 H1N1 virus AND avian H5N1 strains (AND H3N1 strains – this wasn’t published, but he told me this, because I’m special). These are all Influenza A strains (this also includes some seasonal viruses), they have not tested if they are cross-reactive against Influenza B strains (responsible for some seasonal flu viruses).

My question is, if all flu viruses have this HA stalk region, why don’t they induce production of antibodies against the stalk region? Why is H1N1 the only capable virus?

I don’t know the answer to this question, but it’s interesting to imagine that H1N1 probably has a very distinct and different genetic composition because it infects primarily young, healthy adults.

Additionally, Rafi’s group found that exposure to pre-existing flu strains, or flu vaccines can protect you against H1N1. Therefore, when you get flu shots or the flu you will produce antibodies that can cross-react with H1N1, which is probably why most people didn’t get VERY sick when they contracted the virus.

This is the opposite of the hypothesis I discussed in an early post about The Original Antigenic Sin (linked above).

AND this is why people are still not sure if it’s better to get seasonal flu vaccines every year or if they hurt you some how. I still wont get flu shots, but I would never recommend that to anyone, however it’s always better to be educated about these things than blindly taking shots at CVS!


Wrammert J, Koutsonanos D, Li GM, Edupuganti S, Sui J, Morrissey M, McCausland M, Skountzou I, Hornig M, Lipkin WI, Mehta A, Razavi B, Del Rio C, Zheng NY, Lee JH, Huang M, Ali Z, Kaur K, Andrews S, Amara RR, Wang Y, Das SR, O'Donnell CD, Yewdell JW, Subb (2011). Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection J Exp Med. 2011 Feb 14;208(2):411, 208 (1), 183-191

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Reader Comments (7)

This is definitely off-topic, but I'd be really interested in what you thought about the portrayal of the CDC, in particular, and the science in general, in Contagion!

October 4, 2011 | Unregistered CommenterAnn

I thought the science was amazing! The only really nit-picky thing that has been brought to my attention is when they were showing the structure of the virus on the computer screen - there's no way they would be able to determine that structure of the viral proteins that quickly, however they could thread the viral genome and make an estimated guess - but not well enough to make antibodies against it... ALTHOUGH, you don't need the definitive structure to make antibodies, SO I CAN SEE PAST THAT.

Aside from that it was magnificent! The science advisers for that film were fantastic. I thought the portrayal of the main character (Kate Winslet) was excellent, because she looked like a PhD. Also, the way the virus spread was striking familiar to the way SARS was initiated and spread, it just started from a civet instead of a bat.

I could go on, but I will just say it was great!

October 4, 2011 | Unregistered CommenterBrooke N.

I loved Contagion. And I want to be a PhD who looks like Kate Winslet.

This stalk thing is a really interesting idea. It's interesting how dependent knowledge like this is on data visualization.

Once again, as after all your posts, I feel evolutionarily unfit.

October 4, 2011 | Unregistered CommenterSarah Scoles

Cool post Brooke - I think this paper really only showed that it was possible for some people to make antibodies that could neutralize a range of influenza's, the real problem is getting everyone in a population to make them. Those people could have made them in extremely small amounts, which may not have actually been effective in vivo.

Maybe vaccinating with only the H1N1 HA stalk will do.. but I think flu vaccines are only good when they're 'live'

October 5, 2011 | Unregistered CommenterConnor

I took from the paper that the 'live' vaccine did not vaccinate as well as the HA stalk vaccine. It looks like that the 'live' vaccine might be too much for the immune system.

The immune system sees the whole virus, therefore all of the viral proteins and makes antibodies to a miriad of proteins, but all you need is the anti-HA stalk protein to clear the virus. Therefore, in this instance just the HA stalk protein alone can mount a better antibody response than the whole 'live' virus.

Why do you believe that only 'live' vaccines are good?

October 5, 2011 | Unregistered CommenterBrooke N.

Apologies - I didn't realise that was the case. I'm used to other viruses where the 'live' ones elicit much better protection (paramyxoviruses). If you used another virus vaccine as a vector (measles vaccine) and inserted the gene for the HA stalk domain, would that improve the vaccine?

October 7, 2011 | Unregistered CommenterConnor

That's an excellent question, I have no idea. That would be an interesting study. I can ask Rafi if he has tested that the next time I run into him and let you know.

October 11, 2011 | Unregistered CommenterBrooke N.

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