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>.
i Images:
http://thestayathomemother.com/node/314
http://hplusmagazine.com/2009/08/21/gene-discovery-reveals-critical-proteins-function-hearing/
http://blog.resumebear.com/hot-topics/flu-tips-2013/
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