The Norwegian Institute of Public Health is reporting sporadic occurrences of a mutation in a portion of the flu virus that is involved with the process by which it attaches to cells. I use the word “sporadic” because at this point there is no evidence that the cases where the genetic change has been found are epidemiologically linked. Therefore we don’t see it spreading from person to person but rather arising in people after they have been infected. At least that’s how it appears from reports, but we have only preliminary information at this point. According to WHO, the mutation has been seen before, again sporadically and as early as April, in Brazil, China, Japan, Mexico, Ukraine, and the US. Should we be worried about it?
For me that’s not exactly the right question because I worry about everything when it comes to influenza. Just like auto accidents, flu infections come in a huge range of severity from barely visible scratches to fender benders to whip lash to multiple disabling injury to death. I don’t take the potential of being hit by a car lightly either. Any instance could kill me or someone I love. The right question is whether I am especially worried about this report. Not yet. As more information becomes available I might get more worried or dismiss it entirely as the kind of change we see when a virus isn’t very fastidious about how it reproduces. Because it’s not about the specific mutation but about the biology and we don’t know how to read the biology from the genetic sequence. Much of what we thought was important with respect to transmissibility or virulence or something else has been shown wrong by the virus itself. Every time we think we have a fix on it, it shows us otherwise. Here’s what we wrote two months ago when the Dutch found the E627K mutation in PB2 in one of their isolates:
Even though this virus has been described as relatively stable genetically, individual viruses, even within the same patient, often have small differences in the thousands of letters that make up their genetic code. Influenza A virus is a very sloppy reproducer, and while its only objective in life is to make a copy of itself it often does single task very badly. But it’s like the guy who was asked how he could sell his gasoline for a penny less than he paid for it, his answer was, “volume.” The flu virus makes so many copies of itself when it infects a host cell that it can afford to make a lot of mistakes. Usually those mistakes are disastrous for the copy and it doesn’t replicate any more. Very many of the little mistakes are just little mistakes and don’t affect the virus at all. And some of them turn out to be good for the virus and possibly bad for the host in that they allow the virus to replicate faster, infect more and different kinds of cells and increase its ability to transmit from one host organism to another (transmissibility). (Effect Measure, October 1, 2009)
The Dutch mutation was thought to strongly determine whether the virus would be more avian or more human, but swine flu went ahead and infected humans all over the globe with the version thought to be more avian. It apparently hadn’t read that it needed this mutation to be adapted to humans and so far E627K hasn’t taken root. In the case of the Norwegian mutation (D225G) we don’t even have a theory about its significance, although it is in the part of the virus that binds to the host cell for entry.
What are the possibilities? This change isn’t likely to make this virus more transmissible. It’s already transmissible as hell and doesn’t need any help in that department. It isn’t in the part of the viral protein that the vaccine is directed against, so I doubt it would make the vaccine unusable. The same is true for antiviral activity, even though resistance to antivirals is likely to emerge via other mutations. CDC and the UK are both reporting some instances of Tamiflu resistant virus spreading from person to person. What the virus means for virulence, however, is unknown. The Norwegians speculated it could make the virus more prone to infect the lower respiratory tract but they are speculating. That would seem to be the major concern at the moment but there isn’t much to go on.
Having said these somewhat reassuring things, however, I don’t want anyone to be reassured. We are in the early stages of a pandemic with a dangerous virus and there is just too much we don’t know to be able to be either alarmed or reassured by any particular piece of news. In our view focussing on particular mutations is not especially valuable in the current state of our knowledge. The flu virus isn’t especially big but it is still too complicated for us to understand. There are eight genetic segments, each of which undergoes both mutation and reassortment, i.e., some of the internal segments mix and match between viruses and new combinations emerge.
The best way to think about this is that these eight functional segments act as a team. When one member of the team acquires a new skill, the value of that skill depends upon how the whole team works together. Sometimes a superstar isn’t the best thing, but a group of less talented but smoothly working players is what is needed. But there’s no rule about this. Some years teams make it to the Superbowl because of having one or two outstanding athletes (“stars”) while other years it’s the team that makes the fewest mistakes and works best together that wins out. We don’t know how to predict this for sports teams, an easier problem than for the team of eight in the influenza virus.
The mutation is being widely reported to be D222G (this is H1 numbering; it is 225 in H3 numbering). What this designation means is that in the spikes of hemagglutinin protein on the outside of the virus (parts of which elicit the primary immune response), the amino acid 222 places in from one end has changed from “D” (aspartate) to “G” (glycine). Does this change in one of the team members make the virus operate much better? Does it change the biology in any way, and if so, in what way. We don’t know. And what does “better” mean in terms of the virus? We aren’t sure of that either. The bottom line for the virus is that it make more copies of itself, but the factors that allow it to do that (e.g., should it become more virulent or less virulent?) are unpredictable and largely unknown. This is what this statement by WHO means:
The significance of the mutation is being assessed by scientists in the WHO network of influenza laboratories. Changes in viruses at the genetic level need to be constantly monitored. However, the significance of these changes is difficult to assess. Many mutations do not alter any important features of the virus or the illness it causes. For this reason, WHO also uses clinical and epidemiological data when making risk assessments.
In other words, when it comes to genetic sequences, it’s not what the sequence says but what the sequence does. And we can only know that by watching. This is the first time we have watched a pandemic unfold in real time and we still don’t know how to interpret many of the things we are seeing.
The virus will tell us, eventually. We’ll just have to stay tuned.
Addendum: For those with a more technical interest, there is a good rundown of previous experience with this mutation over at the Flu Wiki Forum by SusanCC here. Recommended. If you want to know more about the Stevens paper she cites, we posted on it here and the general subject here and here and the complexity of it here.