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Here is another great post by Dissimulo on TB2K:
Influenza mutation, immunity, and vaccine efficacy
There have been a lot of questions around here about mutations and vaccine, such as whether there is any point in getting the vaccine when the virus will mutate, whether a particular mutation has made the vaccine worthless, and whether or not someone can still get H1N1 when they have had the vaccine. I've tried to answer a lot of these questions piecemeal over the past few months, but I am going to take a swing at one comprehensive answer that I can point back to in the future.
How influenza infects, mutates, and evolves
Influenza is a negative-sense RNA virus. RNA is much like DNA, but composed of only a single strand, while DNA is two intertwined strands. It is a set of instructions for building the virus. Your cells use RNA to copy instructions from DNA and provide those instructions to the parts of the cell that make proteins. Your cells can't tell the difference between RNA that has been copied from your DNA and RNA that has been delivered by a virus. The whole purpose of the virus is to deliver its RNA into one of your cells so that your cell will use those instructions to build more virus.
Upon entering your body, the virus will come into contact with your cells. Some of those cells have proteins that that virus can recognize and connect to. You may encounter the term "tissue tropism" which is the tendency of a virus to favor one type of tissue over another. Influenza usually likes cells that make up lung tissue. Once connected, the virus is able to inject its RNA into the cell.
Influenza is a negative-sense virus, which means that its RNA is not encoded in the same way your cells encode RNA, so your cells can't follow the instructions. The RNA must be transcribed into a different form (positive-sense RNA) within your cells and the transcription provides an opportunity for mistakes (mutation). Once the positive-sense RNA has been formed, ribosomes (little machines within the cell that create proteins based on RNA instructions) begin to build virus parts instead of cell parts. This step, where the RNA is translated to protein, is another opportunity for mistakes (mutation).
While DNA has some fairly robust error checking, RNA does not, and errors occur, on average, about once per replication of the influenza genome. So, we expect a mutation in just about every influenza virus that is produced. Most of those mutations won't result in any noticeable change because the coding of RNA is designed in such a way that the most likely mutations still result in your cells building the same proteins. It takes a less probable mutation to result in a structural change and, even then, a change is most likely to make the virus less fit to "survive," not more. So, the virus mutates frequently, but a lot of those mutations are neutral, a lot are unsuccessful, and even those that are successful often need to accumulate with other successful mutations before a medically important structural change occurs. Mutation by error is generally a slow process, but it is also relentless and unfailingly results in significant changes to the virus over long periods of time.
In addition to mutating, influenza viruses can recombine and/or reassort when two different versions of the virus infect the same cell. A recombination occurs when a segment of RNA from one virus is joined to a segment from another. A reassortment occurs when an entire piece of RNA is assembled into the other co-infecting virus. Each influenza virus injects eight pieces of DNA that together make up a full set of instructions for building the virus. When mixed together in the cell, one (or more) of the pieces of RNA for one virus may be mixed with the RNA pieces of the other virus. The end result is a virus that has had 1/8, 1/4, 3/8, or 1/2 of its RNA exchanged with another virus. The result of this reassortment is a new virus that is significantly (at least 1/8th) different that the "parent" viruses. Reassortment is not as common as mutation, but it produces more significant changes.
Because influenza mutates a lot, the influenza viruses in any given person really represent a genetic spectrum - a lot of viruses that have small genetic differences. When a successful mutation occurs (meaning one that makes the virus better able to replicate), the processes of recombination and reassortment make it likely that the mutation will quickly be shared and the competitive advantage means that viruses containing the new mutation will replicate faster than their counterparts. So, while it can take a long time for a virus to produce a successful mutation, that mutation can spread very quickly from the initial host once it has arisen, given its competitive advantage and the fast rate of viral replication.
How the immune system responds
Influenza has two large proteins on its surface, hemagglutinin (HA or H) and neuraminidase (NA or N). Influenza viruses are named based on which combination of the versions of these two proteins that they bear. This is because these two proteins are very medically important, as they are the primary structures by which your immune system recognizes the influenza virus. The HA protein is used by the virus to attach to the types of cells it can best infect. The NA protein appears to primarily play a role in breaking open infected cells to release newly assembled viruses.
Here, I present a very simplified version of immune response because, well, it's really complicated and not fully understood. This will suffice for a primer, but I'm leaving out a lot of important details.
One of the first immune cells an influenza virus is likely to come in contact with in the body is a dendritic cell. Dendritic cells are most concentrated at the body's interfaces with the environment - mouth, nose, skin, lungs, etc. The dendritic cell does a basic "friend or foe" check and when it doesn't recognize the invader, it engulfs it and travels to a lymph node.
Upon reaching the lymph node, the dendritic cell finds some naive (meaning, essentially, unprogrammed) T cells that are waiting to be given the description of an invader. The dendritic cell gives them a sample of the influenza surface protein (either HA or NA, generally) and, like a bloodhound given a scent, the T cell becomes activated. In response, several events take place. The T cell releases cytokines, which cause the formation of more T cells of two classes: cytotoxic T cells and helper T cells. The cytotoxic T cells head off to find and destroy infected cells (by destroying infected cells, the ability of the virus to replicate is limited). The helper T cells then help to manage the immune reaction by producing cytokines.
Cytokines help to drive the response of a different category of immune cells, known as B cells, which do not directly attack invaders as cytotoxic T cells do, but instead produce antibodies that attach to and neutralize foreign material. Not all of the B and T cells expire in the process of fighting the virus. Some remain after the infection, and form the body's immune memory. The next time the body is infected, rather than go through the process of identifying the invader, traveling to a lymph node, presenting the antigen to T cells, and manufacturing the necessary immune response, the process is short-cut directly to the T and B memory cells that already match the invader.
Vaccines vs. mutations
So, we have briefly looked at how the virus works and how the immune response works and we're now ready to look at vaccines. The purpose of an influenza vaccine is to produce the same immune response and resulting immune memory as an influenza infection without producing illness at the same time. There are two routes to this destination - the live, attenuated virus vaccine and the viral antigen (or "killed" virus) vaccine. I'm not going to cover how vaccines work in any detail, since that has been discussed elsewhere and is not particularly important to the question of how mutations change vaccine effectiveness.
As described above, most mutations are insignificant. The body recognizes influenza based on the structure of those two surface proteins HA and NA. So, there are two kinds of mutations we need to be concerned about: those that change the surface proteins so that the immune system doesn't recognize them and those that change something about the virus that allow it to defeat the immune system.
In the first case, we worry most about a reassortment. As you may recall, in reassortment a whole piece of viral RNA is replaced and this piece of RNA may contain the code for the HA or NA protein. When this occurs, the type of the virus can change (say H1N1 to H3N1). Suddenly, the virus has a new immune profile. If one of the two proteins remains unchanged, there may still be some immune reactivity, but it will be much weaker. If both change, there is very little to match with immune memory for the parent virus. This is why reassortment is a bad thing - it can suddenly produce a new form of the virus for which there is no prepared immune defense.
In the second case, where we have an accumulation of smaller mutations, the immune system will still recognize the virus, but the response can change. Some of the things that may change are ability of the virus to confuse or resist the immune response and ability of the virus to replicate with great speed and simply overpower the immune response. In the former case, there are a number of small ways that influenza can evade some stages of immune response. One of those changes is a change in shape of part of one of the surface proteins. The protein may still look the same from most perspective, but have a new bend or coil in one region. If a dendritic cell encounters this changed region when trying to identify the influenza virus, it may respond to it as a new invader, rather than one already recognized by the immune system. Instead of triggering an immediate immune memory response, there is a delay until another dendritic cell "sees" the antigen from the proper perspective and recognizes it as a previous invader. There are a number of other genetic changes that can help influenza to evade elements of the immune response, but these are generally mild adaptations and describing how they work would take a lot of work, so I'm going to leave it at that.
It is the latter case, speed of replication, where we see the most likely cause of reduced vaccine effectiveness. Many people conceive of a vaccine as providing a protective shield, so that the vaccinated are no longer infected by the virus, however, this is a gross simplification. In fact, the vaccine produces immune memory, which enables the body to more quickly produce those T and B immune cells when infection is detected. Usually, with that head start, the immune system is able to producing a number of immune cells that can overwhelm the virus early in its replication and prevent it from opening a breach in the defenses. However, if the virus is particularly aggressive in replication, two things may occur. Firstly, the host that transmits the infection to you may be producing huge numbers of viruses and may deliver a much greater dose than normal. Secondly, this aggressively replicating virus may produce copies more quickly than the immune system is able to reproduce even the prepared immune cells. These two factors in combination, large infectious dose and fast replication, can result in the virus overwhelming even a prepared immune system. Usually, the immune system is going to catch up and halt the infection, but illness may not be avoided as is usually the case when immune memory exists.
So, in summary, we are worried about a few cases of viral evolution when it comes to vaccine efficacy:
* Reassortment that changes the surface proteins (antigens). This can result in an ineffective vaccine in one step.
* Mutation that produces a virus that is better at avoiding the immune system. The vaccine is still effective in such cases, but mild illness may still result, or even severe illness in people with particularly ineffective immune systems.
* Mutation that produces a more robustly replicating virus that simply overpowers the immune response. Again, the vaccine is still effective, but illness can overwhelm the body's defenses, particularly in the early stages of infection. Every person will be different, in that some will have produced more or less immune memory cells in response to the vaccination and some will mount a more effective response to the new infection than others.
It is worth noting that, under these circumstances, the vaccine protects the vaccinated, but not the unvaccinated. The vaccine may allow the host to mount an immune response that prevents serious illness, but that still allows the virus to replicate, which means that they can still become infectious. Herd immunity may be difficult to achieve if a virus is able to replicate so aggressively that it overwhelms the initial immune response.
Most of the mutations you will hear about in the news have some bearing on the effectiveness of the vaccine, but most also will not make the vaccine ineffective. Be concerned about vaccine ineffectiveness when you hear "reassortment". Short of reassortment, the vaccine should remain effective, but efficacy will vary from person to person and from strain to strain.
On a related note, here is a post that describes how viruses reassort and why reassortment is more of a concern within a strain of virus than between different strains:
(1st post above)
There are several factors that go into the answer [ how long does immunity last from a flu vaccine? ], but one I basically addressed above. The vaccine remains effective until the virus changes so much that the immune system no longer recognizes it. So, the vaccine remains effective against the same virus probably for your entire life, however, that virus may no longer be found anywhere in the wild after a few years.
The second major factor is flu circulation. As the population becomes resistant to one flu (which will happen with vaccination and people getting the flu and recovering) that flu is at a significant disadvantage. Any flu to which the population has had less exposure will be better able to replicate and travel. So, we rarely see the same flu for more than a few years in a row, since either a mutation will occur that results in, effectively, a new flu virus or another virus will be pulled off the bench and given a turn at bat.
Finally, your body does play some role. Immune memory declines to some degree with time. I'm not sure anyone has figured out exactly how much. People who lived through the 1918 flu appear to have some lingering immunity to H1N1. So, we know you can retain immune memory for a very long time, but we don't really know how effective it is or what goes into determining how effective it is. Immune response tends to degrade with age in general, so it is possible immune memory is just as strong after 90 years but that the immune system is weak in general.
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