Via the Clinician's Biosecurity Network Report we learn of a new study from the Webster St. Jude laboratory in Memphis showing that H5N1 can mutate to oseltamivir (Tamiflu) resistance without any loss in genetic fitness. Tamiflu resistance has been seen but infrequent and there was considerable evidence that the resistant strains were handicapped in some way, thus making them either less virulent or less transmissible. The hope was this was a built-in limitation. Now we know it isn't:
To investigate the fitness (pathogenicity and replication efficiency) of NAI-resistant [neuraminidase inhibitor resistant] H5N1, Yen and colleagues used reverse genetics to create recombinant H5N1 influenza viruses with either wild-type neuraminidase (NA) or one of four single amino acid changes found in nature and known to be associated with NAI resistance: E119G, H274Y, R292K, and N294S. For comparison, they created recombinant H1N1 viruses with the same mutations.1The researchers found that two of the four mutations (E119G and R292K) resulted in H5N1 and H1N1 viruses that did not grow well in vitro and could not be stably maintained. The other two mutations (H274Y and N294S) resulted in viruses that replicated as efficiently in vitro as wild-type H5N1 and H1N1 viruses. H274Y resulted in markedly reduced susceptibility to oseltamivir but not zanamivir in both H5N1 and H1N1. N294S resulted in moderately reduced susceptibility to oseltamivir in both viruses but also slightly reduced susceptibility to zanamivir.
The H5N1 viruses with either of the two mutations were just as lethal to mice as wild-type H5N1; however, the H1N1 viruses with either mutation did show decreased lethality. The explanation for this may be that although both mutations resulted in decreased NA enzymatic activity in both H5N1 and H1N1, the NA enzymatic activity of the wild-type H5N1 was significantly higher than that of the wild-type H1N1. Therefore, the reduced NA function did not affect the H5N1 virus fitness but did affect that of the H1N1. The function of NA is to enable release of the newly created virus from the host cell; therefore, reduced NA activity would be expected to lead to a reduced ability to replicate and cause disease. (CBN Report)
We recently did an exhaustive set of posts (here) on a mathematical model that made the assumption a fully or mostly fit resistant strain was possible. The modeling paper, by Lipsitch et al., showed that even if resistance develops, use of Tamiflu prophylactically and therapeutically was still a winning strategy in the first wave, but the resistance would eventually spread and dominate the circulating strains. From the Lipsitch paper:
Important predictions that we believe to be robust to model structure are that (1) antiviral use will favor the spread of resistance even if such use rarely generates de novo [spontaneously arising] resistant strains; (2) despite the spread of resistance, prophylaxis and treatment can both delay and reduce the size of the epidemic; (3) nondrug interventions (if effective) and antiviral use - which will likely be used together in the response to a pandemic - generally have synergistic benefits, despite the fact that nondrug interventions may promote resistance; and (4) relatively minor differences in fitness cost may make large differences in outcomes, even when emergence probabilities are low (Figure 4). These results extend those of previous models, which showed (like our model) that the fitness cost of resistance strongly influences the ability of resistant strains to spread during an epidemic. (Lipsitch et al., PLoS Medicine)
Oseltamivir (Tamiflu) seems to be more affected than zanamivir (Relenza), but the former can be taken orally in capsule form while the latter uses an inhaler for administration. A handful of patients with either H274Y or N294S mutations have been reported in the literature. Not good news, but not unexpected.
Source paper: Yen HL, Ilyushina NA, Salomon R, et al. Neuraminidase inhibitor-resistant recombinant a/vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and in vivo. J Vir 2007:81(22); 12418-12426. http://jvi.asm.org/cgi/content/full/81/22/12418.
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Fantastic.
Is there much hope for a vaccine that will retain its usefulness?
Huh, I wrote this prediction in a letter to the NEJM after de Jong et al first published their results in late 2005. They didn't bite. We'll have to see whay Hayden has to say.
Now what? Marissa points out that this has likely knocked out a good part of the prophylactic protection for H5N1. It also explains a lot in Indon and other places. Is it because they have been feeding Tamiflu to their poultry that is starting to go out of date or is it a natural progression? Think about how much money that was spent on Tamiflu and now its...worthless?
Tom DVM I think posted something up about this about a year ago and I think he posited that it was inevitable that this would happen.
Ah crap.
http://www.newstarget.com/022214.html
Many virologists are amazed at the speed at which H5N1 mutates. Most viruses do not mutate that much--but influenza, like the immunodeficiency virus (HIV), is a notorious exception. Influenza viruses have a high rate of mutation, which means they are very flexible genetically.
The studies I have read seem to indicate that Tamiflu, Relenza, etc. is a joke. They will not stop this virus, if it becomes efficient at human to human contagion. It is a waste of millions of dollars by governments.
The reason is, the virus mutates too rapidly for these medicines to stop it during a pandemic, because everybody and his dog will be inhaling and swollowing these medicines, giving the virus the perfect opportunity to mutate. And because chickens in Asia have been given tons of the stuff, so they will not contact the disease, we have a slight problem.
And as for a vaccine for bird flu, for how long have they been trying to produce a vaccine for Aids? But again, because it mutates so rapidly, no luck. And the same applies to a virus for an influenza virus like H5N1, it just mutates so rapidly, the vaccine may not work, because the strain of H5N1 in the vaccine may not match the strain that is circulating. Please remember, after the pandemic hits, it will take months to produce the vaccine. By that time I may already be dead from the bird flu. If I die in that way, I intend to write a letter to my congressman in protest.
During the 1918 pandemic, blood from survivors was used as an effective treatment for other patients. And recent experiments, giving blood from infected mice to other mice, seemed to protect the other mice.
But how do you obtain enough blood to help during a pandemic?
During a pandemic, I will probably swallow and inhale anything I can get my hands on to try to stay alive. But guess what, the speed of the H5N1 mutation will probably defeat all my frenetic efforts, and I will probably die if I become infected. So goodbye for now, and hello eternity.
I wouldn't give up on a vaccine just yet.
A vaccine is much more likely to be efficacious over a long period of time. The problem with trying to slow down an active infection is that a huge amount of replication (and, of course, mutation) has already occurred. If replication is prevented from the get-go by an already primed immune response, the likelihood of a resistant bug arising is pretty low. Of course, there's always the possibility of a reservoir, asymptomatically breeding the flu of doom...
In any case, we're just going to have to be more creative in our vaccine-development. The way we develop and produce influenza vaccines currently just isn't going to cut it, especially for those with egg allergies (scary flu death, or scary anaphylactic death?)
Has anyone been following the adenovirus-based vaccine research? It's much more easily produced, may be more effective at inducing the correct immune response, can be raised against a specific strain in a shorter amount of time, and could be modified to include many different antigens at a time.
Of course, it's been a while since I've read up on all this - stupid lab work. Anyone here know the latest scoop?
Wisaakah: If you click on "Vaccines" in the category listin the left sidebar you will find a number of posts we have done on vaccines. You'll have to go back a ways. We also deal with DNA vaccines. Take a look.
Revere,
That sounds like an excellent way to procrastinate: I'll take a look.
Wisaakah: "That sounds like an excellent way to procrastinate"
No problem. That's what we're here for.
Tamiflu was never more than the most convenient antiviral.
We hear about Biocryst and the $100 million they got to develop an injectable peramivir,,... which isn't going well, but why isn't injectable zanamivir, so promising in the late 90's, being trialed?