Influenza virus-like particle vaccine

influenza-vlpA new type of vaccine against influenza, made with virus-like particles, has been shown to protect ferrets from infection with the 2009 H1N1 swine-origin strain. What is a virus-like particle, and how is it produced?

If you have been taking influenza 101, you know that new virus particles are produced in infected cells by budding. During this process, the membrane bulges from the cell and is eventually pinched off to form a free particle. These virus particles contain the viral RNA segments, and an assortment of viral proteins including PA, PB1, PB2, NP, M1, M2, HA, and NA. But not all of those viral proteins are needed to produce an influenza virus particle. When only the viral HA, NA, and M1 proteins are synthesized in cells, particles are released from cells that look very much like influenza virions (illustrated). These are called ‘virus-like particles’ because they resemble influenza viruses, but lack the viral genome and many viral proteins.

Influenza virus-like particles are not infectious, but they are immunogenic: when injected into animals, they induce the production of anti-viral antibodies that can block infection. In one study, virus-like particles were produced in cultured insect cells by using an insect virus vector – a baculovirus – to deliver genes encoding the influenza HA, NA, and M1 proteins. Mice inoculated with these virus-like particles were protected after challenge with infectious virus. More recently, mice vaccinated with virus-like particles produced with proteins from an H5N1 avian strain were protected against challenge with lethal H5N1 viruses.

These findings suggest that virus-like particles could be used in humans to protect against influenza infection. They offer a number of advantages over the current influenza virus vaccines, most of which are prepared by growing virus in embryonated chicken eggs. Viral infectivity is destroyed with formalin, and the virions are then disrupted with detergents. Virus-like particle vaccines would not require these treatments, and would be available to individuals with egg allergies. Some influenza virus vaccines are produced in cell culture, but these are also treated to eliminate infectivity.

Another important advantage of the virus-like particle vaccine is that it can be produced relatively rapidly: within weeks, compared to months for egg-produced vaccines. This property would be especially useful when new pandemic strains emerge. For example, the swine-origin H1N1 influenza virus emerged in the spring of 2009, and vaccine manufacturers are scrambling to have a product ready for the fall.

Because an influenza virus-like particle vaccine is a new type of vaccine, many years of testing in animals and in humans will be required before it can be used. Some of the questions that must be addressed include the safety of the vaccine in humans, whether the anti-viral antibody repertoire induced by the vaccine is sufficiently broad, and of course whether immunization confers efficient protection against challenge in the majority of recipients.

I am particularly curious about how an influenza virus-like particle vaccine would compare with the infectious, attenuated influenza vaccine, Flumist. This intranasally-administered vaccine mimics a natural infection and has been shown to be more effective in preventing influenza than inactivated vaccine. While virus-like particle vaccines are an attractive option, they are not infectious and therefore might not induce the same antibody repertoire as would an infectious virus. A disadvantage of Flumist is that it is produced in eggs. If influenza virus-like particles prove safe and efficacious in humans, they could replace the egg-grown, inactivated vaccines.

Pushko, P., Tumpey, T., Bu, F., Knell, J., Robinson, R., & Smith, G. (2005). Influenza virus-like particles comprised of the HA, NA, and M1 proteins of H9N2 influenza virus induce protective immune responses in BALB/c mice Vaccine, 23 (50), 5751-5759 DOI: 10.1016/j.vaccine.2005.07.098

Bright, R., Carter, D., Crevar, C., Toapanta, F., Steckbeck, J., Cole, K., Kumar, N., Pushko, P., Smith, G., Tumpey, T., & Ross, T. (2008). Cross-Clade Protective Immune Responses to Influenza Viruses with H5N1 HA and NA Elicited by an Influenza Virus-Like Particle PLoS ONE, 3 (1) DOI: 10.1371/journal.pone.0001501

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  • Russ 19 August 2009, 1:19 pm

    I came across an interesting article related to this post. It is about a vaccine production for Norwalk virus using “virus-like” nanoparticles in tobacco plants. I sent you an e-mail to TWIV and have posted the link here as well.


  • mdubuque 21 August 2009, 9:49 am

    Perhaps my question is caused by a failure to understand this posting.

    Is it possible that these types of virus particles are produced by cells as part of a yet undiscovered subsequent strategy for immunizing and defending ourselves against the larger virus particles?

    Alternatively stated, we know that some of these virus particles are immunogenic. Is it possible that our immune systems are capitalizing on this capacity via unknown pathways?

  • profvrr 21 August 2009, 5:58 pm

    While 'empty' virus particles – lacking a viral genome – are probably
    produced in all virus infections, they are the vast minority. In this
    study, the authors specifically engineered viruses that lack the
    genome. I don't believe such 'empty' particles play a role in defense
    against natural infections.

  • profvrr 21 August 2009, 5:58 pm

    Got your email to TWiV, Russ. Great story which we'll cover next week.
    Thanks very much.

  • guenter stertenbrink 22 August 2009, 9:36 am

    viruses dying naturally, from heat or UV or chemicals – aren't they
    also somehow virus-like particles and thus give some immunity
    without infecting ?

    flumist is better for children, but worse for adults, I had read

  • edrybicki 26 August 2009, 10:59 am

    It is therefore very interesting that plant-made H5 HA (and H1, thought is is not published) also buds to form particles, which are more immunogenic than purified HA protein ((D'Aoust et al., Plant Biotechnol J. 2008 Dec;6(9):930-40).

    And MUCH cheaper to make than any other way….

  • edrybicki 26 August 2009, 11:04 am

    Ummmmmm….hate to argue, but in HBV infections, virus-like and genome-free 22 nm particles way outnumber the “Dane particles” which are the infectious virions – and were the basis of vaccines made from human serum before recombinant subunit vaccines became the norm?

  • profvrr 26 August 2009, 9:58 pm

    Thanks Ed. Arguing is always welcome here. You are absolutely right about HBV.

  • profvrr 27 August 2009, 10:16 am

    Would it really be easier to homogenize tons of plant leaves to make suitable amounts of vaccine? Isn't simply harvesting VLPs from the cell culture medium far easier from a production standpoint? Someone with production savvy should weigh in on this…

  • Technicalbuy 1 September 2009, 10:07 pm

    Medicago does just that with tobacco plants. 1 square meter of the plants can produce about 30,000 doses of vaccine at under $0.20/dose. It's shown full protection at very low doses and also cross protection with different H5N1 strains.

  • Technicalbuy 1 September 2009, 10:10 pm

    Oh and I forgot that they were the first in the world to produce the H1N1 vaccine. Took them 2wks

  • Ed Rybicki 3 September 2009, 6:19 am

    Yes, well, I could paste my recent review in here…(shameless self-advertising B-) – but I won't.

    Suffice it to say that conventional vaccine production requires LARGE amounts of stainless steel and sterile manufacturing conditions just to produce the raw material – and production of the raw material for a plant-produced vaccine does not. My lab has made equivalent products – virus-like particles composed of Human papillomavirus L1 proteins – via baculovirus/insect cell culture, and via transgenic and transient expression in plants, and I can vouch for it costing a LOT less for the infrastructure to produce the plants than it did for all the insect cell culture facilities and media.

    And “simply harvesting VLPs from culture medium” requires filtration, centrifuges possibly, columns…which is exactly what the downstream processing for a plant-produced vaccine would need.

    Interesting thing about the Medicago HA proteins, and the ones that we have experimented with: they localise to the apoplastic space in leaves – which can be flushed out in intact leaves infused with simple buffer by vacuum infiltration, by low-speed centrifugation without damaging the leaves. You end up with some straw-coloured liquid rich in HA protein, with VERY few contaminants. Pretty much equivalent to harvesting TC SN!

  • Technicalbuy 3 September 2009, 2:49 pm

    Yes I've seen the process in action…incredibly simple. Didn't even mention the surge capacity benefits of plants vs cell culture etc. Wouldn't mind reading your review if you have it handy 🙂

  • Technicalbuy 3 September 2009, 9:49 pm

    Yes I've seen the process in action…incredibly simple. Didn't even mention the surge capacity benefits of plants vs cell culture etc. Wouldn't mind reading your review if you have it handy 🙂