Tuesday, 24 December 2013

Protection from suppression

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.

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.

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