Changing the evolutionary dynamics of Influenza?

by levien on di 08 februari 2011 // Posted in misc // under

An interesting news-article appeared today, claiming a possible breakthrough in the development of a universal influenza vaccine. It describes the development of a new influenza vaccine at the Jenner Institute. Traditional influenza vaccines prime the adaptive immune system against the hemagglutinin (HA) and neuraminidase (NA) proteins (the H and N used to characterise influenza subtypes) that are on the outside of the virus particles. The problem with this approach is that these HA and NA proteins mutate rapidly in order to to escape immunity, making that a new vaccine has to be developed for each new strain that evolves. The new vaccine however targets two proteins that are on the inside of the virus particle, the matrix protein (M1) and the nucleoprotein (NP). According to the AFP news article (e.g. on Yahoo) “the two proteins within the virus are similar across strains and less likely to mutate, meaning new vaccines would not have to be developed for each new strain of the illness.” Another article goes on to explain that “the immunization could provide protection against all known strains of the flu, which will protect billions more against the flu virus. The vaccine hits a different part of the flu virus and does away with costly yearly reformulations to match vaccines to the prevalent virus during the time of epidemic. It takes approximately four months to develop a seasonal flu vaccine.”

That sounds like a great step forward, but to be honest I doubt whether it will be very effective in the long run. The problem is already apparent in the first quote. It is true that the internal proteins of influenza do not change much over time and do not differ much between strains. In evolutionary terms, we would say that these proteins are fairly well conserved, making them excellent targets for vaccination. However, this high degree of conservation is not because these proteins cannot mutate. Rather, there is not much pressure for the internal proteins to mutate, as the immune system of the host mainly (and rather effectively) targets the external virus proteins HA and NA. In the case of influenza it does this primarily by producing antibodies that bind to free virus particles in the body and disables them before they can infect new cells.

Human influenza mainly infects the upper respiratory tract, and humans are therefore mostly infected by inhaling tiny droplets (aerosols) containing virus particles. Within about six hours after infection, these virus particles (virions) start replicating in the layer of cells (epithelium) that lines your throat. The first time that a new virus strain is encountered, it takes your adaptive immune system a few days to start producing sufficient antibodies to effectively combat the virus. This response lag gives the virus ample time to infect as many cells as it can. Your body does respond to this by producing signal-chemicals (cytokines) that switch the tissue around the infection to a kind of alert-state, making the cells more difficult to infect. This so-called innate immune-response is also what causes fever, by raising the “thermostat” that controls your body temperature. Both the rapid spread of the infection and the alert-state induced by the innate response cause the virus to run out of fresh cells to infect within about two or three days. During the infection your body will try to remove as many infected cells and free virus particles as it can, among other ways by producing a lot of mucus. This is actually convenient for the virus, as it means that you will continually be spreading free virions into your environment, which in turn are capable of infecting others around you.

As virus-growth is quickly limited by the number of infectable cells, the amount of virus in your body will slowly decline over the course of a week or so. By that time, your adaptive immune system will have started producing loads of antibodies, which aid in getting rid of the last bits of virus. The adaptive immune-system is equipped with a kind of “memory”, so that it can quickly start producing large amounts of antibody the next time the same virus is encountered. Generally this will prevent a second viral infection from expanding in an early stage, so that you won’t get sick a second time.

The trick with immunisation is to inject “disabled” virus particles (or proteins), which will trigger the production of antibodies and immune-“memory”, so that you’ll be protected by adaptive immunity without having to go through a full-blown infection. But unfortunately the influenza-virus has a few tricks up its sleeve as well. One of its internal proteins called NS1 is capable of partially suppressing innate immune response of the host. Moreover, rapid mutation of the external HA and NA proteins makes that after a while (which can be in the order of just a few months), the virus has changed so much that it is no longer recognised by the adaptive immune system. Finally, influenza is a segmented virus, which means that its “genome” (the RNA molecules that code for viral proteins) consists of separate RNA-fragments. These fragments can be exchanged between different virus strains if they infect the same host. This exchange is called reassortment, and together with mutation it is responsible for a constant stream of new virus variants.

Now as was already mentioned in the news articles, the nice thing about the new vaccine is that it “teaches” the adaptive immune system to recognise the two well-conserved proteins M1 and NP that are inside the virus particles. The antibodies generated by the adaptive immune system form the humoral response, which can only react to external virus proteins. However the so-called cell mediated response can also respond to internal virus proteins. A complex process called the antigen presentation pathway enables the T-cells (T-lymphocytes) of the immune system to look “inside” infected cells, and kill them if needed. The new vaccine seems capable of boosting the T-cell response to the M1 and NP proteins, which is good news as it means that the adaptive immune system may stop infection in an early stage, regardless of the influenza-strain involved.

However, there is no reason why M1 and NP could not mutate as well. Mutation of viral proteins is an undirected process, caused by errors in the translation from viral RNA to viral proteins. Usually a mutation in one of the internal virus proteins will lead to a decrease in virus production, causing the mutated viruses to be outcompeted by non-mutated ones. A mutation in the external HA or NA proteins on the other hand may confer an advantage. Although it may reduce the efficiency with which these proteins function, it also reduces the chance that the virus particles are neutralised by antibodies. Therefore viruses that acquire mutations in their HA or NA proteins may quickly outcompete the original virus. This causes the rapid mutation of the HA and NA proteins, which in turn enables influenza viruses to bypass the adaptive immune response and reinfect people that had been infected (or vaccinated) before.

Now it is to be expected that if one would start vaccinating against M1 and NP on a large scale, a mutation in these proteins would also begin to confer a benefit to the virus. This benefit may outweigh the slight reduction in replication efficiency that normally accompanies such a mutation. No doubt the vaccine will be effective at first. But within months it should be possible for new influenza strains to evolve, with slightly modified M1 and NP proteins that render the original vaccine useless.

Unless it would succeed in eradicating human influenza completely (which is highly unlikely), a universal vaccine against influenza would presumably lead to the emergence of new influenza strains with an increased diversity and mutation rate of M1 and NP (in addition to HA and NA). Does this mean it is pointless to develop such a vaccine? Actually, I don’t think so. Although in the end this new vaccine alone probably won’t do much to improve public health, it will certainly be very interesting to see what happens. A change in the evolutionary dynamics of the virus would be an interesting result in itself, at least scientifically speaking. Moreover, vaccinating against more virus proteins at once may enable us to more effectively combat future pandemic strains of influenza. For the reasons outlined above, I very much doubt that it is possible to attain the holy grail of “lasting” vaccines against highly adaptable RNA-viruses such as influenza and HIV. But especially when combined with viral protein inhibitors, it should certainly be possible to give the little buggers a hard time, and prevent a lot of unnecessary deaths in the process.

Bring on the vaccine. Perhaps I’ll be proven wrong, after all my expectation is “merely” based on theory. But I for one am curious to see what will happen. And I guess in the end, that’s what science is all about…

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