Monday, September 30, 2013

There May Be Hope for a Universal Flu Shot

A recent study suggests that the development of vaccines that protect against multiple strains of Influenza A Virus (IAV) on a long-term scale is possible.1

If you have ever stayed home from school or work with a sudden fever, cough, sore throat, and generally achiness, you probably had the flu. You may have even gotten the flu shot, but influenza still got the best of you. Vaccination for the flu is difficult, because the virus mutates and develops different strains all the time.2 The flu shot or nasal mist that we use to prevent influenza is typically trivalent, which means it has the ability to protect against three specific flu strains.3 These strains change depending on what scientists predict will be the most dangerous strains to the public that year.3 Obviously, an ideal vaccine would protect against any form of the flu. For this reason, research that shows how CD8 T cells can be cross-protective against heterosubtypic infections is especially promising.

The goal of the study was to better understand the effects of vaccination on the way the immune system responds to infection with IAV. Influenza A virus is found in both animals and humans. It is also generally responsible for seasonal flu epidemics in humans.4 The most at risk individuals are children, the elderly, and other people with weakened immune systems. Influenza is responsible for between three thousand and forty-nine thousand deaths per year, as well as up to two hundred thousand hospital visits.4

In order to understand the methods and
results of the experiment, one must have a basic understanding of certain components of the immune system, as well as specific terms and phrases that are important in the study.

CD8 T cells are cytotoxic cells that specifically terminate the acute influenza infection and contribute to long-term memory of the virus.1 Virus-like particles (VLP) are developed from influenza virus proteins, but they do not contain IAV genomic material.1 This means that resemble the actual virus, but they are replication deficient. Because of this characteristic, VLPs have a greater potential for use in the vaccination of high influenza risk individuals.1 Lung-draining lymph nodes (dLNs) are the part of the body in which naïve CD8 T cells are primed. The cells then leave the dLNs when they migrate to the lungs (the site of infection with IAV).

The study conducted by Hemann, Kang, and Legge made many comparisons between control mice and mice that were vaccinated with VLPs prior to IAV infection. The experiment was broken up into several different parts in order to show how different aspects of immunity contributed to their overall determination.

The first part was conducted to prove that VLP vaccination for IAV led to an increase in HA533-specific CD8 T cells in the lungs. It found that the overall number of CD8 T cells in the lungs did not change, but the percentage of cells that were HA533-specific CD8 T cells significantly increased. (Figure 1)1

Next, the study aimed to prove that the proliferation of the HA533-specific CD8 T cells occurred at increased levels. The number of these cells did not change in the dLNs after seven and fourteen days, which is attributed to the migratory patterns of the cells from the dLNs to the lungs before the one and two week testing times. However, when levels were tested earlier (by three or four days), increased proliferation and migration was observed.

Another aspect of the study focused on the levels of HA533-specific CD8 T cells in the dLNs and the lungs after IAV infection. Compared to mice infected with IAV who never received a vaccine, vaccinated mice showed a significant increase in this specific cell type in the lungs. This increase was observed starting at only one day after the IAV challenge.

After determining that VLP vaccination did indeed cause increased levels of HA533-specific CD8 T cells in the mice, the scientists sought proof that the presence of these cells led to increased immune defense against lethal amounts of IAV. To do this, anti-CD8α depletion was used to completely ablate IAV-induced CD8 T cell immunity in some of the mice. The mice were exposed to IAV fourteen days after the end of the depletion process, and mice without HA533-specific CD8 T cell immunity showed only sixty percent survival rates compared with control vaccinated mice that did not undergo depletion before infection. This indicates that the depleted cells are necessary for complete protection from lethal influenza A.

The next thing to test was whether or not the effects of VLP vaccination protect against homosubtypic as well as heterosubtypic strains of IAV challenges (homo-same; hetero-different). First, a survival rate of just over eighty-six percent was found for mice exposed to lethal A/PR/8/34 strain when vaccinated with VLPs of this same strain. The survival then needed to be compared with a heterosubtypic strain. This was achieved by observing the survival of A/PR/8/34 vaccinated mice infected with IAV strain A/Japan/305/57. In this strain, a modified, cross-reactive version of the HA533 epitope is still present. (Table 1)1 Survival rate for mice infected with this strain was ninety percent. This shows that the same VLP vaccination can greatly protect against two different strains of virus, as long as the crucial HA533 epitope is still present. Subsequently, when infected with a strain in which the HA533 epitope was not present (A/HK/1/68), no mice survived.

Overall, the findings of this study indicate that vaccines that elicit CD8 T cell responses show potential for protecting more broadly against influenza viruses. The creation of a universal influenza A vaccine should employ VLPs to increase CD8 T cell proliferation and to allow for protection against heterosubtypic strains of the virus. This could hopefully combat the constant need to create new and very strain-specific shots and mists every year as well as broaden the scope of flu vaccines. One of the biggest limitations of this study is that its results show the effects of vaccinating mice, not humans. However, as research progresses, similar results may be found if a version of the study were applied to humans. (Of course, ethically, no humans could be given lethal doses of IAV).

For more information on influenza or details from the relevant study, see the primary and secondary citations.


Primary Source:

      1. Hemann, E. A., Kang, S-M., & Legge K. L. (2013). Protective CD8 T Cell-Mediated Immunity against Influenza A Virus Infection following Influenza Virus-like Particle Vaccination. Journal of Immunology. 191: 2486-2494.

Secondary Sources:

2. Preventing Influenza. (2013). American Lung Association. Accessed on 28 September 2013. <http://www.lung.org/lung-disease/influenza/preventing-influenza.html>. 

      3. Key Facts About Seasonal Flu Vaccine. (2013). Centers for Disease Control and Prevention. Accessed on 28 September 2013. <http://www.cdc.gov/flu/keyfacts.htm>.

      4. Types of Flu. (2013). Cold, Flu, and Cough Health Center. WebMD. Accessed on 28 September 2013. <http://www.webmd.com/cold-and-flu/flu-guide/advanced-reading-types-of-flu-viruses>.

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