Pandemic Influenza: An Inconvenient Mutation

Abstract

Seasonal influenza affects 10% of the population annually, killing up to one million persons worldwide. Pandemic viruses have even greater potential for mortality. We have several defenses, including personal and public health protective measures, vaccines immunologically matched to circulating

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20 MARCH 2009 VOL 323 SCIENCE www.sciencemag.org
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CREDIT: PAUL WEIN
LETTERS IBOOKS IPOLICY FORUM IEDUCATION FORUM IPERSPECTIVES
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COMMENTARY
Benefits from biodiversity
LETTERS
Pandemic Influenza: An Inconvenient Mutation
SEASONAL INFLUENZA AFFECTS 10% OF THE POPULATION ANNUALLY, KILLING UP TO ONE
million persons worldwide. Pandemic viruses have even greater potential for mortality. We
have several defenses, including personal and public health protective measures, vaccines
immunologically matched to circulating strains, and two classes of antiviral drugs (neu-
raminidase inhibitors and adamantane ion-channel blockers). Our preventive options are lim-
ited by viral genetic diversity and a rapid viral mutation rate. Currently, two human influenza A
subtypes (H1N1 and H3N2) and two influenza type B lineages cocirculate. About 425 million
doses of trivalent influenza vaccine are produced annually, enough to protect less than 7% of
the world’s population. In the event of a pandemic, well-matched protective vaccines against a
novel agent would not be available for at least several months, highlighting the importance of
therapeutic options.
By 2009, however, 98% of circulating influenza A/H1N1 strains in North America have
become resistant to the frequently prescribed and widely stockpiled neuraminidase inhibitor
oseltamivir (Tamiflu), and 98% of A/H3N2 strains are resistant to the adamantanes. The alter-
native neuraminidase inhibitor zanamivir and the two approved adamantanes—amantadine
and rimantadine—are all in short supply, and the
adamantanes have substantial side effects. Influ-
enza therapeutic options are clearly unraveling at a
time when public health officials are appropriately
concerned about pandemic emergence.
The spread of high-level oseltamivir resistance
in A/H1N1 strains is puzzling, as it appears to have
occurred without antiviral selective pressure (1).
Whether such levels of resistance will continue or
diminish is unknown. Is high-level resistance an
unfortunate byproduct of (still unknown) polygenic
factors that confer viral fitness, such as balancing
hemagglutinin and neuraminidase activity? Does
resistance in influenza A/H1N1 imply a chance that
resistance will develop in highly pathogenic avian
A/H5N1 viruses, which bear the same neu-
raminidase subtype? Two past pandemic viruses
(1957 and 1968) emerged after circulating human
viruses reassorted with avian influenza viruses;
emergence of a future pandemic strain by the same
mechanism, but incorporating either an antiviral-
resistant H1N1 neuraminidase or A/H3N2 matrix
gene, is a possibility that cannot be ignored.
Pandemic planning envisions that if a virus with
pandemic potential emerges, initial human-to-
human transmission can be spotted quickly and
contained by nonpharmaceutical interventions and
by rapid community administration of antiviral
agents and vaccines (2, 3). If this strategy fails, a
edited by Jennifer Sills
conceivable consequence, however unlikely,
is accidental creation of a drug-resistant pan-
demic strain, a manmade analog of the feared
naturally arising reassortant alluded to above.
Most national stockpiles have appropri-
ately favored neuraminidase inhibitors (mainly
orally administered oseltamivir) over ion-
channel blockers (oral adamantanes) for
pandemic preparedness, given the well-
recognized rapid emergence of resistance to
the latter when used in treatment (4). Now, as
noted, transmissible oseltamivir resistance in
human A/H1N1 strains makes this strategy
problematic on many levels, including con-
cern about efficacy in a pandemic, as well as
emergence of a pandemic reassortant contain-
ing resistance genes (1). A complicating fac-
tor is increasing appreciation that secondary
bacterial pneumonias have caused most
deaths in past pandemics (5). Circulation of
clinically aggressive community-acquired
methicillin-resistant Staphylococcus aureus is
an additional factor to be considered in plan-
ning for pandemic response. Taken together,
these several developments suggest a need to
continually examine and periodically recon-
firm or update pandemic response strategies.
Whatever strategies are adopted, it is clear
that additional anti-influenza therapeutics
are urgently needed. So far, vaccines and
antivirals have targeted three influenza
envelope proteins: hemagglutinin, neu-
raminidase, and the matrix 2 ion channel pro-
tein. We need new classes of antivirals that
interfere with other necessary viral processes
(e.g., polymerase complex activity, inter-
feron antagonist activity, and viral assem-
bly). The desired outcomes of existing and
future therapies (reduced severity, mortality,
Letters to the Editor
Letters (~300 words) discuss material published
in Science in the previous 3 months or issues of
general interest. They can be submitted through
the Web (www.submit2science.org) or by regular
mail (1200 New York Ave., NW, Washington, DC
20005, USA). Letters are not acknowledged upon
receipt, nor are authors generally consulted before
publication. Whether published in full or in part,
letters are subject to editing for clarity and space.
Preparing for a virus storm.
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viral shedding, and transmission) should be
considered with respect to both seasonal and
pandemic influenza.
The unpredictable nature of influenza
presents a challenge for both research and
pandemic preparedness planning. Our ability
to anticipate pandemic events is poor, and our
anti-pandemic armamentarium is weak. In an
ever-shifting landscape of influenza evolu-
tion, we need to be farsighted and forceful in
optimizing pandemic response capacity.
SCOTT P. LAYNE,1* ARNOLD S. MONTO,2
JEFFERY K. TAUBENBERGER3
1Department of Epidemiology and Center for Rapid
Influenza Surveillance and Research, University of
California Los Angeles School of Public Health, Los Angeles,
CA 90095, USA. 2Department of Epidemiology, University
of Michigan School of Public Health, Ann Arbor, MI 48109,
USA. 3Laboratory of Infectious Diseases, National Institute
of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD 20892, USA.
*To whom correspondence should be addressed. E-mail:
scott.layne@ucla.edu
References and Notes
1. N. J. Dharan et al., JAMA, 10.1001/jama.2009.294,
published online 2 March 2009.
2. M. E. Halloran et al., Proc. Natl. Acad. Sci. U.S.A. 105,
4639 (2008).
3. A. S. Monto, Clin. Infect. Dis. 48, 397 (2009).
4. The United States has stockpiled 81 million doses of
oseltamivir—one dose each for 25% of the population.
5. D. M. Morens, J. K. Taubenberger, A. S. Fauci, J. Infect.
Dis. 198, 962 (2008).
6. This research was supported in part by the Intramural
Research Program of the NIAID and the NIH.
Romanian Expatriates Face
Career Obstacles
IN HIS NEWS FOCUS STORY “REACHING FOR
the stars in Romania” (21 November 2008, p.
1183), M. Enserink gives a realistic descrip-
tion of some important problems of Romanian
science. I would like to add another important
issue: Successful expatriated Romanian sci-
entists should be encouraged to return to
Romania to hold important positions, and they
should be appropriately compensated for
doing so. In theory, expatriated scientists are
encouraged to return and take leadership
roles. In practice, these scientists have trouble
securing their place in the applicant pool. To
qualify for consideration, the expatriated sci-
entists must demonstrate that the position they
hold abroad is equivalent to the Romanian
position immediately subordinate to the open
position. The legal process to determine
equivalency is cumbersome, and there is no
definite authority who can certify equiva-
lence. These ambiguous requirements often
serve as an obstruction to expatriate scientists.
ZENO SIMON
Institute of Chemistry, Romanian Academy, Bd. Mihai
Viteazul, 24, Timisoara 300223, Romania. E-mail: zsimon@
acad-icht.tm.edu.ro
Reversible Exploration
Not Worth the Cost
C. P. MCKAY (“BIOLOGICALLY REVERSIBLE
exploration,” Policy Forum, 6 February,
p. 718) makes an impassioned case for so-
called biologically reversible exploration of
Mars. However, such a strategy will impose
additional costs on an already strained pro-
gram (1), and it is neither feasible in the con-
text of a robust Mars exploration program nor
necessary to ensure the fidelity of future in
situ scientific endeavors. The concept of bio-
logically reversible exploration is focused on
potential effects of forward contamination—
the transport of terrestrial microorganisms to
other planetary bodies. Using real options the-
ory (2), we can evaluate the ability to preserve
future decision paths (such as the ability to
“reverse” biological incursions) with present
investments [such as spacecraft sterilization
and constraints put in place on “special
regions” (3)]. An accounting of present and
future scientific costs and benef its must be
made to critically assess this idea. In the near
term, additional costs will result from space-
craft preparation regimes, compliance, and
possibly reduced mission capability due to
constraints on instrumentation and landing
site restrictions. The suggestion that even
human exploration should achieve “biologi-
cal reversibility” will impose an enormous
burden on such missions in terms of both
direct costs and curtailed science from restric-
tions on access to the subsurface. In contrast,
the supposed benefits are only potential bene-
fits, mostly in the event of terraforming, and
extremely long-term in nature. The exchange
of meteorite material between Earth and Mars
(4), the flotilla of existing landed missions,
and the fleet of orbiters that will eventually
crash into the surface already determine both
the past and near-future two-way exchange of
biological material between Earth and Mars.
Special regions of scientific interest on Mars
do call for prudent measures to reduce con-
tamination, but the extreme measures advo-
cated by McKay will not yield sufficient ben-
efits to justify their high costs.
SAMUEL C. SCHON
Department of Geological Sciences, Brown University,
Providence, RI 02912, USA. E-mail: samuel_schon@
brown.edu
References
1. A. Lawler, Science 322, 1618 (2008).
2. A. K. Dixit, R. S. Pindyck, Investment Under Uncertainty
(Princeton Univ. Press, Princeton, NJ, 1994).
3. COSPAR, “Report on the 34th COSPAR Assembly,”
COSPAR Inform. Bull. No. 156, 24 (April 2003).
4. B. J. Gladman, J. A. Burns, M. Duncan, P. Lee,
H. F. Levison, Science 271, 1387 (1996).
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CORRECTIONS AND CLARIFICATIONS
News of the Week: “NSF restores data on minority Ph.D.s” by J. Mervis (27 February, p. 1161). The National Science
Foundation estimates that its new policy on reporting small numbers of minorities will suppress data on 3.7% of the new Ph.D.s
in the Survey of Earned Doctorates. The original story incorrectly reported that 4% of the 280 subfields would be affected.
News Focus: “Tales of a prehistoric human genome” by E. Pennisi (13 February, p. 866). The story mischaracterized James
P. Noonan’s mouse experiment that used an enhancer showing human-specific activity. In that study (published in the 5
September 2008 issue of Science, p. 1346), the enhancer drove the expression of a reporter gene in the mice, but the
researchers did not examine its effect on thumb development.
News Focus: “On the origin of art and symbolism” by M. Balter (6 February, p. 709). Ochre expert Ian Watts was cited as
saying that there was little sign that ochre found at Twin Rivers, Zambia, was ground into powder, as needed for decoration.
This incorrectly states Watts’s view. Although only a small percentage of the approximately 300 pieces of ochre found at Twin
Rivers show signs of grinding or other use, nearly all those that do are a dark, sparkly red. This leads Watts to conclude that
they might have been preferentially chosen for symbolic purposes, although that is not certain.
Reviews: “Darwin’s originality” by P. J. Bowler (9 January, p. 223). On page 226, reference 8 should read as follows:
J. Browne, Charles Darwin: The Power of Place (Jonathan Cape, London, 2002). In reference 22, Transmutation Notebook D
should have been Notebook B. Also in reference 22, two page numbers were missing: Natural Selection, p. 36, and Charles
Darwin’s Notebooks, p. 180.
Reports: “Observation of pulsed γ-rays above 25 GeV from the Crab pulsar with MAGIC” by The MAGIC Collaboration (21
November 2008, p. 1221). The e-mail address for N. Otte was incorrect. The correct address is nepomuk@scipp.ucsc.edu.
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