I know very little about the
demographic of the readers of this blog, however, I would fancy my chances
betting that the majority of readers haven’t recently received an influenza
vaccination, I certainly haven’t. The main group of people that receive the
vaccine (here in the UK anyway) are those considered most “at risk” – these
predominantly being the very young and old or those with underlying health
problems.
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| Illustration of an influenza viral particle and an enlargement of the HA spike |
Vaccination largely works by
stimulating the production of antibodies that target a specific part of a pathogen.
In the case of influenza, the main target for these antibodies is the
hemagglutinin (HA) spike, which is exposed on the surface of viral particles.
As you can see in the picture, the spike is made up of a ‘head’ and a ‘stalk.’ The
vast majority of antibodies produced are against the head. However, this has
issues because the head can easily mutate and become unrecognizable to the antibodies
we produce. As such, a new influenza vaccine must be given every year so to
generate novel antibodies against the newly mutated virus. Annual vaccination has
issues in the fact that the vaccine must be produced in advance of the “’flu
season,” necessitating a degree of guesswork about the viruses that will be
circulating in the coming winter months. Furthermore, should a completely new
virus emerge, there will be no protection provided by the current vaccine – as
was the case in 2009 with the Swine Flu pandemic (a H1N1 virus), and as is
feared for Bird Flu viruses (either H5N1 or H7N9).
The best solution to the
issues of the current vaccine is to develop a ‘universal’ vaccine. In an ideal
world, this would be a single shot vaccine that would provide life-long
protection against all influenza
viruses. If this could be achieved, there would be no need to give new vaccine
doses every year and there would be substantially less fear about pandemic
spread of a new virus. A universal vaccine would need to produce antibodies
against part of the virus that is conserved between all influenza stains (e.g.
is the same in a H1N1 virus and a H7N9 and a H16N10 and so on) and, by
extension, does not easily mutate. A vaccine fitting these criteria will
produce a ‘cross-protective’ response. Fortunately, the HA stalk has these
properties and could, in principle, be used as a universal vaccine that would provide
protection against all influenza viruses. The only problem is no vaccines have
been able to produce antibodies targeting the stalk.
This brings me onto the main
topic for this blog; a paper recently published in the journal Nature Immunology from the labs of Paul Thomas and Maureen McGargill. I felt the need
to blog about this paper based on some very interesting findings about the
immune response to influenza. In essence, their work found that treatment with
an immunosuppressive drug, known as rapamycin, is able to cause a
cross-protective response, thus enhancing the prospect of generating a universal
vaccine.
In their study, the
vaccination was of mice using a weakened H3N2 virus and then subsequently
infecting with a H5N1 virus to test the efficacy of the vaccine. The team found
that if the mice were treated with rapamycin prior to the vaccine, they would
be protected against the H5N1 virus. In contrast, the mice not given rapamycin
mostly died within 2 weeks of H5N1 infection. Importantly, they also showed
that treatment with rapamycin and then infection with H5N1 (without the H3N2
vaccine) did not provide any protection. Therefore, something about the primary
infection with H3N2 virus was being modulated to provide better protection
against H5N1.
This led the team down a
path to try and find the culprit for this protection, which turned out to be B
cells (the immune cells responsible for producing antibodies). Without B cells,
and therefore antibodies, mice had no protection against H5N1 following the
H3N2 vaccination. Additionally, it was seen that, following rapamycin
treatment, the antibodies produced were targeting the HA stalk, instead of the
head. Therefore, the question to ask is: how is rapamycin altering the antibody
response?
Antibodies fall into 5
classes known as Ig (immunoglobulin) M, G, A, D and E. When the immune response
is first triggered, for example by the H3N2 virus, the vast majority of
antibodies produced are of the IgM class. Over time a process of ‘class
switching’ occurs that produces an improved immune response. Against a viral
vaccine, most class switching from IgM produces IgG antibodies that have a
higher affinity for the virus and therefore improve the protection. It was
found that rapamycin treatment inhibited class switching, causing an excess of
IgM antibodies in the rapamycin treated, vaccinated animals.
The reason I wanted to blog
about this study is that it raises some interesting points about evolution.
Class switching is important, if we didn’t have it, our immune system would be
nowhere near as effective at protecting us from pathogenic infection. It wasn’t
looked at, but I would speculate that any rapamycin treated mice that were
vaccinated with the weakened H3N2 and then infected with a H3N2 virus would have
a slightly weaker immune response against the re-infection compared to animals
that could class switch. However, blocking class switching has the advantage of
producing a cross protective response. Since we have class switching, it
appears that animals have evolved to produce the strongest, and most specific
immune response they can, in the most specific manner possible – all the eggs
are in one basket as it were. Evolution has no foresight so only selects for
the animal that has the best protection. Furthermore, it would seem to
suggest that in evolutionary history there may have been less circulating
influenza viruses as the production of a cross protective response was not actively
selected for. The final point to make is that this may explain why the stalk
region of the HA spike is highly conserved between influenza viruses, compared
to the head. If the best immune response produced is by targeting the head
region of HA spikes, then it is advantageous for the virus to mutate this. If
our immune system rarely targets the stalk, there is no evolutionary pressure
for this to rapidly mutate.
In the vast majority of
cases, producing a very strong immune response is essential to our survival
from infection. However, this study points towards a potential new avenue to
boost our search for a universal influenza vaccine, by counter-intuitively
blocking the evolutionarily advantageous process of class switching.
