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The value of influenza aerosol transmission experiments

The Value of Influenza Aerosol Transmission

Saturday, July 05, 2014 at 06:45 AM EDT

A Harvard epidemiologist has been on a
crusade to curtail aerosol transmission experiments on avian influenza H5N1
virus because he believes that they are too dangerous and of little value.
Recently he has taken his arguments to the Op-Ed pages of the New York Times. While Dr.
Lipsitch is certainly entitled to his opinion, his arguments do not support his

In early 2013 Lipsitch was the subject of a piece in Harvard Magazine about
avian influenza H5N1 virus entitled The Deadliest Virus. I have previously criticized this article in which Lipsitch calls
for more stringent H5N1 policies. More recently Lipsitch published an opinion in PLoS
in which he called for alternatives to experiments with potential
pandemic pathogens. We discussed this piece thoroughly on This Week in Virology #287. The arguments he uses
in both cases are similar to those in the OpEd.

The Times OpEd is entitled Anthrax? That’s not the real
. The title is a reference to the possible exposure to anthrax
bacteria of workers at the Centers for Disease Control. Even worse than
anthrax, argues Lipsitch, would be accidental exposure to a pathogen that could
transmit readily among humans. He then argues that such a pathogen is being
created in laboratories that study avian influenza H5N1 transmission.

Lipsitch tells us ‘These experiments use flu strains like H5N1, which
kills up to 60 percent of humans who catch it from birds.’ As an epidemiologist
Lipsitch knows that this statement is wrong. The case fatality ratio for avian
H5N1 influenza virus in humans is 60% — the number of deaths divided by the
cases of human infections that are diagnosed according to WHO criteria. The
mortality rate is quite different: it is the number of fatalities divided by
the total number of H5N1 infections of humans. For a number of reasons the H5N1 mortality ratio in humans has
been a difficult number to determine.

Next Lipsitch incorrectly states that the goal of experiments in which avian
influenza H5N1 viruses are given the ability to transmit by aerosol among
ferrets is ‘to see what gives a flu virus the potential to create a
pandemic.’ The goal of these experiments is to identify mechanistically what is
needed to make an avian influenza virus transmit among mammals. Transmission of
a virus is required for a pandemic, but by no means does it assure one. I do
hope that Lipsitch knows better, and is simply trying to scare the readers.

He then turns to the experiments of Kawaoka and colleagues who recently
reconstructed a 1918-like avian influenza virus and provided it with the
ability to transmit by aerosol among ferrets. These experiments are
inaccurately described. Lipsitch writes that the reconstructed virus was
‘both contagious and comparably deadly to the 1918 flu that killed tens
of millions of people worldwide’. In fact the reconstructed virus is less
virulent in ferrets than the 1918 H1N1 virus that infected humans. In the same
sentence Lipsitch mixes virulence in ferrets with virulence in humans —
something even my virology students know is wrong. Then he writes that
‘Unlike experiments with anthrax, creating such flu strains in the lab
presents a danger that affects us all, because once it is out, such a strain
would be extremely hard to control.’ This is not true for the 1918-like avian
influenza virus assembled by the Kawaoka lab: it was shown that antibodies to
the 2009 pandemic H1N1 influenza virus can block its replication. The current
influenza virus vaccine contains a 2009 H1N1 component that would protect
against the 1918-like avian influenza virus.

The crux of the problem seems to be that Lipsitch does not understand the
purpose of influenza virus transmission experiments. He writes that ‘The
virologists conducting these experiments say that by learning about how flu
transmits in ferrets, we will be able to develop better vaccines and spot
dangerous strains in birds before they become pandemic threats.’ This
justification for the work is wrong.

Both Kawaoka and Fouchier have suggested that identifying mutations that
improve aerosol transmission of avian influenza viruses in ferrets might help
to detect strains with transmission potential, and help vaccine manufacture. I
think it was an error to focus on these potential benefits because it detracted
from the real value of the work, to provide mechanistic information on what
allows aerosol transmission of influenza viruses among mammals.

In the Kawaoka and Fouchier studies, it was found that adaptation
of H5N1 influenza virus from avian to mammalian receptors lead to a decrease in
the stability of the viral HA glycoprotein. This property had to be reversed in
order for these viruses to transmit by aerosol among ferrets. Similar
stabilization of the HA protein was observed when the reconstructed 1918-like
avian influenza virus was adapted to aerosol transmission among ferrets. It is
not simply coincidence when three independent studies come up with the same
outcome: clearly HA stability is important for aerosol transmission among
mammals. This is one property to look for in circulating H5N1 strains, not
simply amino acid changes.

Lipsitch mentions nothing about the mechanism of transmission; he focuses on
identifying mutations for surveillance and vaccine development. He ignores the
fundamental importance of this work. In this context, the work has tremendous

The remainder of the Times OpEd reminds us how often accidents
occur in high security biological labortories. There are problems with these
arguments. Lipsitch cites the emergence of an H1N1 influenza virus in 1977 as
‘escaped from a lab in China or the Soviet Union’. While is seems clear
that the 1977 H1N1 virus probably came from a laboratory, there is zero
evidence that it was a laboratory accident. It is equally likely that the virus
was part of a clinical trial in which it was deliberately administered to

Lipsitch also cites the numerous incidents that occur in American
laboratories involving select agents. I suggest the reader listen to Ron Fouchier explain on TWiV #291 how a computer crash must
be recorded as an incident in high biosecurity laboratories, but does not lead
to the release of infectious agents.

Lipsitch clearly feels that the benefits of aerosol transmission research do
not justify the risks involved. I agree that the experiments do have some risk,
but it is not as clear cut as Lipsitch would suggest. Although ferrets are a
good model for influenza virus pathogenesis, like any animal model, they are
not predictive of what occurs in humans. An influenza virus that transmits by
aerosol among ferrets cannot be assumed to transmit in the same way among
humans. This is the assumption made by Lipsitch, and it is wrong.

I agree that transmission work on avian H5N1 influenza virus must be done
under the proper containment. Before these experiments can be done they are
subject to extensive review of the proposed containment and mitigation procedures. There is no justification for the
additional regulation proposed by Lipsitch.

In my opinion aerosol transmission experiments on avian influenza viruses
are well worth the risk. We know nothing about what controls aerosol
transmission of viruses. The way to obtain this information is to take a virus
that does not transmit by aerosol, derive a transmissible version, and
determine why the virus has this new property. To conclude that such
experiments are not worth the risk not only ignores the importance of
understanding transmission, but also fails to acknowledge the unpredictable
nature of science. Often the best experimental results are those which were
never anticipated.

Lipsitch ends by saying that ‘There are dozens of safe research
strategies to understand, prevent and treat pandemic flu. Only one strategy
— creating virulent, contagious strains — risks inciting such a
pandemic.’ Creating a virulent strain is not part of the strategy. Lipsitch
conveniently ignores the fact that Fouchier’s H5N1 strain that transmits by
aerosol among ferrets is not virulent when transmitted by that route. And of
course we do not know if these strains would be transmissible in humans.

I am very disappointed that the Times chose to publish this OpEd without
checking Lipsitch’s statements. He is certainly entitled to his own opinion,
but he is not entitled to his own facts.

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