Yesterday one of the questions we asked was whether swine H1N1 would replace seasonal viruses this season. In previous pandemics one subtype completely replaced its seasonal predecessor: in 1957 H2N2 replaced the H1N1 that had been coming back annually at least since 1918; only 11 years later, in 1968, a pandemic with H3N2 replaced the H2N2. H2N2 is no longer circulating but in 1977 an H1N1 returned and has been co-circulating with H3N2 since then. This was a new situation. We could ask why this hadn’t happened before with H2N2 and H1N1 or H2N2 and H3N2 or all three together; or we could ask why it happened after 1977 with H1N1 and H3N2. We still aren’t sure of the answer, but the question has special pertinence at this point because it bears on whether we will be seeing three viruses this fall in the north (swine H1N1, seasonal H1N1, seasonal H3N2) or just the seasonal viruses or just the swine virus, or the swine virus and one of the others. We have a vaccine to cover some of the seasonal virus (there is a lingering question of a good match for the H3N2 component) but not yet one for swine flu. We can’t wait to find out and I, for one, will be getting the seasonal vaccine as soon as it’s my turn (which will be shortly at my medical center) and then get the swine flu vaccine when it’s my turn in the queue as it becomes available. To me that seems the most prudent way to cover my bets, although I won’t know until later whether it was the right choice. Meanwhile there is science to be done to help us understand all this, and within hours of yesterday’s post appearing there was a paper published in PLoS Currents/Influenza [PLoS Currents: Influenza. 2009 Aug 25 [revised 2009 Aug 27]:RRN1011] that provided a tantalizing data point on the subject of the dynamics of infection with combinations of swine flu and the seasonal flu A subtypes.
Researchers at the University of Maryland and colleagues tested combinations of swine flu and seasonal flu in ferrets. As most readers here know, the ferret is considered a reasonable animal model for transmission and infection for human flu, better in many ways than more traditional lab animals like mice or rats. This was a very small study but the results were clear cut enough that they provide a reasonable (although not ironclad) way to interpret them. The design was straightforward. A ferret was inoculated with swine flu virus (the original California isolate) or one of the seasonal H1N1 or H3N2 (Brisbane) viruses, or a combination of swine flu and each of the seasonal viruses (no ferret got all three or just the two seasonal ones). So that’s
three five inoculated ferrets. Then two more “naive” ferrets (i.e., not inoculated) were housed with each of the infected ones, one in the same cage area, the other separated from the infected and direct contact by a wire mesh wall that allowed respiratory droplets but no direct contact. The idea was to see if the viruses alone or in combination could be transmitted. The number of animals is a bit unclear as the write-up is not very good, so I am not sure exactly what groups there were or how many. But the basic idea is obvious and the initial results are very interesting.
First, the swine virus is very contagious, at least as or more so than seasonal influenza. It also seems to have a shorter incubation period (look at Figure 1, top) and the authors state the animals developed higher viral titers, although this isn’t obvious from the data (there are no statistical tests given and the figures are only slightly suggestive). All the inoculated animals got infected by all three viruses, both one at a time and swine with each of the seasonal viruses, and shed virus for the usual 5 – 7 days. There was some evidence that swine flu infected more of the respiratory tree and the authors and evidence from the photomicrographs (Figure 2) show a more severe pathology for swine flu. There is also a suggestion that the combination of swine flu and seasonal H3N2 co-infection might be a bad combination, but this requires a great deal of further study. All of the animals inoculated with two viruses were infected with both. Swine H1 did not prevent infection an animal with season H1 or seasonal H3. What is happening within the tissues isn’t known, however. Can two viruses infect the same host cell? This happens with seasonal flu and is the way reassortment happens. But on an initial look there was no evidence of reassortment in this small experiment. We’ll come back to that in a moment. But as of now, each subtype stayed the same and there was no mixing and matching of the genetic segments.
So if co-infection is possible, how is it that swine seems to be crowding out the seasonal viruses? In this set-up, the evidence suggests it is happening at the level of transmission. If the animal is infected with swine and seasonal virus, it can infect other animals but it in this case only with the swine flu virus. There was transmission from inoculated animals to contact and respiratory droplet animals caged with them (as described), but the transmitted cases were only swine virus. In other words, although an inoculated animal was infected with two viruses, only the swine virus is passed on. How this works we don’t know yet. The authors only say that the swine virus is more genetically fit, giving it a competitive advantage, but this is only a description of what they are seeing, not an explanation of how it works. We need to understand this much better to know how general it is. What is quite clear is that the swine virus is fully adapted to humans and, as the authors remark, is less likely to reassort because the combination it has is better than the seasonal viruses. That may be why we have yet to see a change in virulence. A more virulent virus would only be selected for if it was more transmissible and this virus seems to be plenty transmissible without any help. A change in virulence could even decrease transmissibility by decreasing contact rates.
Finally, about the virulence (clinical severity) of the swine virus, which in this ferret model seems to be worse than the seasonal viruses. Not by a lot but by a noticeable amount. As the authors point out, the ferrets did have evidence of a small amount of pre-existing immunity to both H1 and H3. It wasn’t a lot and wasn’t enough to prevent the animals from being fully infected. There remains a chance that it somehow modulated either the transmission or severity of the infection. But as the authors also observe, this is also a good model of the situation the human population finds itself in. There is quite a lot of background immune experience with H1 and H3 viruses, and this may be the reason that swine H1N1 has a competitive advantage. With a contagious and rapidly replicating virus like flu, it may be that this is just enough of an edge to tip the disease dynamics to allow swine flu to trump seasonal flu. That’s speculation. There’s still a lot to figure out here.
This is not one of the better written papers I’ve seen, but it is extremely pertinent to the current situation and the work is well done by very experienced investigators. We’re learning a lot but most of our knowledge will probably not come in time to affect how we handle whatever swine flu has in store for us over the next year. As Hippocrates said, the Art is long, but life is short.