The arsenal of public health tools to reduce morbidity and mortality from an influenza pandemic is limited. Options include vaccines, antiviral drugs, and interventions such as respiratory protection and social distancing. In a statement The World Health Organization (WHO) described the importance of a vaccination strategy: “Influenza vaccination is the most important intervention in reducing the impact of influenza, and a key component of the WHO response and preparedness efforts for influenza of pandemic potential, including avian influenza A(H5N1), A(H9N2) and A(H7N9).” Data for seasonal influenza vaccines and the 2009 A(H1N1)pdm09 vaccines provide a basis for estimating potential effectiveness of A(H7N9) vaccines. Inactivated seasonal influenza vaccines have a pooled efficacy estimate of 59%, primarily for younger adults. A paucity of evidence exists for demonstrating protection in adults aged 65 years or older, particularly with influenza A vaccines. Three primary scenarios exist for how this A(H7N9) virus outbreak will unfold: 1. The virus could disappear in the animal reservoir, ending new human cases 2. The virus could persist in the animal reservoir, resulting in sporadic human infections. 3. The virus could, through mutation or reassortment, become readily transmissible between humans, resulting in a global pandemic.

1. VIEWPOINT
ONLINE FIRST
Major Challenges in Providing an Effective and
Timely Pandemic Vaccine for Influenza A(H7N9)
Michael T. Osterholm, PhD, MPH
Katie S. Ballering, PhD
Nicholas S. Kelley, PhD
T
HE EMERGENCE OF AVIAN INFLUENZA A(H7N9) VI-
rus in humans has public health authorities around
the world on high alert for the potential develop-
ment of a human influenza pandemic.1
As of May
8, 2013, authorities had identified 131 confirmed cases and
32 deaths among residents of 8 provinces and 2 munici-
palities in China.2
Three primary scenarios exist for how this A(H7N9) vi-
rus outbreak will unfold. First, the virus could disappear
in the animal reservoir, ending new human cases. Second,
the virus could persist in the animal reservoir, resulting in
sporadic human infections. Third, the virus could, through
mutation or reassortment, become readily transmissible be-
tween humans, resulting in a global pandemic.
The arsenal of public health tools to reduce morbidity and
mortality from an influenza pandemic is limited. Options
include vaccines, antiviral drugs, and interventions such as
respiratory protection and social distancing. According to
the World Health Organization (WHO), “Influenza vacci-
nation is the most important intervention in reducing the
impact of influenza, and a key component of the WHO re-
sponse and preparedness efforts for influenza of pandemic
potential, including avian influenza A(H5N1), A(H9N2) and
A(H7N9).”3
However, seasonal and pandemic influenza vac-
cines have significant limitations,4
including limited vac-
cine effectiveness, the inability to identify reliable corre-
lates of protection, and the need to distribute large quantities
of vaccine early in the pandemic course.
Estimated Effectiveness of A(H7N9) Vaccines
Data for seasonal influenza vaccines and the 2009
A(H1N1)pdm09 vaccines provide a basis for estimating po-
tentialeffectivenessofA(H7N9)vaccines.Inactivatedseasonal
influenza vaccines have a pooled efficacy estimate of 59%,
primarily for younger adults.4
A paucity of evidence exists for
demonstratingprotectioninadultsaged65yearsorolder,par-
ticularlywithinfluenzaAvaccines.Thepooledefficacyoflive-
attenuatedinfluenzavaccines(LAIVs)is83%inchildrenaged
6 months to 7 years, but currently available data do not sup-
port effectiveness in the population aged 8 years or older.4
The median effectiveness reported in 6 studies of adju-
vanted A(H1N1)pdm09 pandemic vaccines was 72% (range,
60%-93%).4
In a study of unadjuvanted A(H1N1)pdm09 vac-
cine conducted in the United States, effectiveness was 56%
(95% CI, 23%-75%).4
For these studies, most participants
were younger than 50 years, with approximately half younger
than 18 years.
There is no reason to believe that a yet-to-be-developed
pandemic A(H7N9) vaccine will perform any better than ex-
isting seasonal vaccines or the A(H1N1)pdm09 vaccines, par-
ticularly with regard to vaccine efficacy in persons older than
65 years. To date, the median age of H7N9 cases is 60 years.
If a pandemic occurs and this epidemiologic pattern per-
sists, a pandemic A(H7N9) vaccine, even if it includes an
adjuvant, will likely have limited to modest effects on the
overall morbidity and mortality from the novel strain.
Determining and Measuring Correlates
of Protection for A(H7N9) Vaccines
In the United States, vaccine dose for inactivated pandemic
vaccines is determined by the amount of hemagglutinin head
antigen needed to achieve a hemagglutination inhibition (HI)
titer of 1:40 in at least 70% of children and adults younger
than 65 years or, alternatively, the amount of antigen needed
to demonstrate that 40% of recipients have a 4-fold or greater
increase in HI.5
Even though HI titers have been used for de-
cades as a correlate of protection for influenza vaccines, the
US Food and Drug Administration (FDA) noted that “pro-
spectively designed studies to evaluate the effectiveness of in-
fluenza vaccines have not identified a specific HI antibody
titer associated with protection against culture-confirmed in-
fluenza illness.”5
LAIVs do not have a recognized correlate
of protection, which will create challenges for interpreting
immunogenicity of candidate H7N9 vaccines.
ThelimiteddataavailablesuggestthatforanH7N9vaccine
to provide protection, it will likely require significantly more
antigenthanseasonalvaccines,willlikelyrequireanadjuvant,
orboth.Twophase1clinicalstudiesofaninactivatedH7vac-
cinehavebeenconductedtodate.6,7
Inonestudyusinganun-
adjuvanted H7N7 vaccine, only 8 of 22 recipients receiving 2
doses of 90-␮g vaccines had at least a 4-fold HI increase; none
achieveda1:40titer.6
InanotherstudyofanH7N1vaccinewith
adjuvant, none of 13 recipients receiving 2 doses of a 24-␮g
Author Affiliations: Center for Infectious Disease Research and Policy (Drs Os-
terholm, Ballering, and Kelley), Minnesota Center of Excellence for Influenza
Research and Surveillance (Drs Osterholm and Kelley), University of Minnesota,
Minneapolis.
Corresponding Author: Michael T. Osterholm, PhD, MPH, Center for Infectious
Disease Research and Policy, University of Minnesota, 420 Delaware St, SE MMC263,
Minneapolis, MN 55455 (mto@umn.edu).
©2013 American Medical Association. All rights reserved. JAMA, Published online May 9, 2013 E1
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2. adjuvanted vaccine had a 1:40 titer.7
A single phase 1 study of
anH7N3LAIVdemonstratedsafetyandmostparticipantshad
ameasurableimmuneresponse,althougharecognizedcorre-
late of protection for LAIV has not been identified.8
Previous
studies with H5N1 vaccines required 2 90-␮g doses for 50%
ofadultstodevelop1:40HItiters;however,anadjuvantedvac-
cine using 3.8 ␮g showed improved results.
Timely Availability of A(H7N9) Vaccines
ForA(H7N9)vaccinestobebeneficialduringanemergingpan-
demic, vaccines must be made available quickly. Factors de-
termining availability include time to develop and distribute
vaccine and global manufacturing capacity. Both factors will
beinfluencedbytheminimumimmunogenicantigendosage.
Efforts are under way to develop seed strains for A(H7N9)
vaccines,manufactureclinicalstudyvaccinelots,andconduct
phase1clinicalstudies.TheUSDepartmentofHealthandHu-
man Services anticipates that these efforts will be completed
within5months.However,actualvaccinemanufacturinglikely
will not occur until an A(H7N9) pandemic is considered im-
minent. Since it typically takes 17 to 22 weeks from prepara-
tionoftheseedstrainuntilvaccinecanbeshipped,thebest-case
scenarioisatimeframeof4monthsfromplacementofvaccine
orderstoavailabilityofproductionlotsfordistribution.Recent
federal investments in potency testing may reduce this time.
Dependingonwhenvaccinesareordered,themanufacturers’
ability to convert from seasonal vaccine to pandemic vaccine
production, and how quickly the pandemic spreads, it is pos-
siblethatvaccineswillarriveinlimitedquantitiesbutafterthe
criticalpointwhentheywillsignificantlyaffectmorbidityand
mortality, as occurred in 1957, 1968, and 2009.4
The 2009 A(H1N1)pdm09 illustrates the potential chal-
lenges of vaccine availability during an A(H7N9) pan-
demic. In late April 2009, public health officials deter-
mined that the A(H1N1)pdm09 pandemic was under way.
Within weeks, the first vaccine seed strains were made avail-
able to manufacturers. At the same time, government agen-
cies in a number of countries placed large orders for pan-
demic vaccine. Phase 1 clinical studies and the early
manufacturing of bulk vaccine antigen occurred in paral-
lel. Despite these efforts, most pandemic vaccine was not
available in the United States until late October, almost 2
months after the second wave peaked.4
This same situation
occurred in 1957 and 1968; vaccine was too little, too late.
Current annual global capacity for manufacturing hema-
gglutinin-headinfluenzavaccineisapproximately4.54billion
monovalent 15-␮g doses.9
The antigen concentration for an
H7N9 vaccine is currently unknown, but if 90 ␮g is required,
global annual manufacturing capacity will be approximately
757milliondosesofmonovalentinfluenzavaccines.Thisisless
than15%oftheglobalneedandmuchofitwillnotbeavailable
until6ormoremonthsaftermanufacturingbegins.Adjuvants
mayaugmentvaccinecapacity,butdevelopmentofanadequate
globalvaccinesupplywillremainanunprecedentedchallenge.
Regulatory Approval Process for A(H7N9) Vaccine
A(H7N9) pandemic vaccine, if needed in the near future,
will require a different regulatory process compared with
the 2009 pandemic vaccine. Because A(H7N9) influenza vi-
rus is a novel human virus strain and limited data are avail-
able for H7 strains, manufacturers will not be able to apply
to the FDA for license approval of an A(H7N9) vaccine un-
der the provisions of a “strain change” request. Rather, the
FDA will likely need to review data from the planned clini-
cal studies and determine whether to issue Emergency Use
Authorizations for A(H7N9) vaccines; this would be the first
such authorization for vaccines.10
Toward the Future
Another influenza pandemic is inevitable. Even with re-
cent additional vaccine manufacturing capacity and im-
provements in potency testing, the global public health com-
munity remains woefully underprepared for an effective
vaccine response to a pandemic. To be successful in meet-
ing the challenge of a severe pandemic, the influenza vac-
cine enterprise must move forward with the development
of novel antigen influenza vaccines that protect most indi-
viduals from multiple strains of influenza.
Published Online: May 9, 2013. doi:10.1001/jama.2013.6589
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE
Form for Disclosure of Potential Conflicts of Interest and none were reported.
Funding/Support: This work has been funded in part with federal funds from the
National Institute of Allergy and Infectious Diseases, National Institutes of Health,
Department of Health and Human Services, under contract HHSN266200700007C.
Role of the Sponsor: The National Institute of Allergy and Infectious Diseases had
no role in the preparation, review, or approval of the manuscript or in the decision
to submit the manuscript for publication.
Disclaimer: The contents of this article are solely the responsibility of the authors
and do not necessarily represent the official views of the National Institutes of Health.
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VIEWPOINT
E2 JAMA, Published online May 9, 2013 ©2013 American Medical Association. All rights reserved.
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