Tweet
Commentary
Vaccine Development for an Imminent PandemicWhy We Should Worry, What We Must Do
David S. Fedson
Received 01/29/06; Accepted 01/29/06
Previously published as a
KEY WORDS
pandemic, influenza, vaccine, vaccination, H5N1,
reverse genetics, antigen sparing, adjuvant, alum, WHO
ABSTRACT
The avian H5N1 virus continues to evolve and poses an imminent pandemic threat. Pandemic vaccine development, however, has progressed slowly. For it to succeed, it must be based on a public health perspective that reflects the arithmetic of pandemic vaccine demand, especially by countries without vaccine companies. Clinical trials ofH5N1 vaccines have been discouraging, and we must understand why the H5N1 virus is so poorly immunogenic. Antigen-sparing pandemic vaccines will be required, and future trials must identify the most effective adjuvant and determine whether whole virus vaccines will be needed. Problems related to intellectual property and concerns about several regulatory issues must be resolved. Public funding for clinical trials must be provided and firm leadership and coordination exercised by national and international (WHO) public health officials. Vaccination for an imminent pandemic requires a global perspective not only for vaccine development but also for vaccine production and distribution.
Avian A/H5N1 influenza first appeared in poultry markets in Hong Kong in 1997 and infected 18 people, six of whom died. The virus returned to Hong Kong in 1999 and 2003, reemerged in several countries in Southeast Asia in 2004 and recently spread to Europe.
1 Among diagnosed patients in Southeast Asia, approximately 50% have died. Health officials everywhere are deeply concerned that events such as these will inevitably lead to a new influenza pandemic, and many have said it is imminent. When a new pandemic virus emerges, vaccination will be central to pandemic response. For this reason, we mustbe concerned about developing an effective pandemic vaccine.2
WHY WE SHOULD WORRY ABOUT AN IMMINENT PANDEMIC
This year, 3 million people will die of AIDS, but the death toll from the next influenza pandemic could be much higher. Historians now estimate that 50?100 million people died in the 1918?1920 pandemic?2 1/2 to 5% of the world?s population.
2 Given the more than 3-fold increase in population since then, a 1918-like pandemic today could kill 175?350 million people. This is 1000 times more people than were swept away by the 2004 tsunamis. It is more than the number of people killed in all wars and by the most murderous governments throughout the 20th Century. These people would die not in100 years, but in 1 or 2. A pandemic caused by an H5N1 virus with undiminished virulence would be far worse. Since 1997, many influenza scientists have felt that sooner or later the H5N1 virus will
eventually develop the capacity to not only infect humans and cause disease, but also acquire the ability to be transmitted efficiently from one person to the next. Almost nine years have passed and this has not happened, but no one should think the pandemic threat is receding. The H5N1 viruses isolated in recent years are more virulent for birds than they were in 1997, and they have spread to several mammalian species in addition to man.3
Virologists have convincingly shown that the virus of the 1918 pandemic was of avian origin, a finding that emphasizes the threat posed by evolutionary changes in the genome of the H5N1 virus.
The precise molecular requirements for efficient human-to human transmission of the H5N1 virus have yet to be defined, but changes in only a few amino acids in a few key gene products might be sufficient.4 For example, a strain-specific difference in hemagglutinin (HA) receptor binding specificity between two different 1918 viruses has been shown
to be due to a single amino acid substitution at position 190.5 Similarly, in a mouse model of A/Hong Kong/97 (H5N1) infection, substitution of glutamine for lysine at position 627 of the PB2 protein converted a nonlethal to a lethal infection.6 Recent gene sequencing
www.landesbioscience.com Human Vaccines 39
Pandemic Vaccine Development
studies of two H5N1 isolates obtained from fatal human cases in
Turkey have shown that their PB2 proteins also have this amino acid
substitution at position 627. In addition, their HAs have a substitution
at position 223 that is associated with increased affinity for sialic acid
receptors on human cells. 7,8 These two human isolates are the first
to show both of these mutations. Although the mutations have not
been associated with efficient human-to-human transmission, they
provide a sobering reminder of the continuing H5N1 pandemic threat.
Several years ago, a respected influenza expert cautioned against
what he called influenza ?extrapolitis?; that is, the assumption that
the next pandemic will be as severe as the one in 1918.9 No one can
know how severe the next pandemic will be, nor which influenza
virus will be its cause?it could be an H2, H7, H9 or another subtype.
However, given the alarming experience with human H5N1 influenza,
it would be prudent to prepare for the ?worst-case? scenario.
WHY WE SHOULD WORRY ABOUT DEVELOPING
A PANDEMIC VACCINE
No influenza vaccine was available for the 1918 pandemic and
very little was used for the last pandemic in 1968. Things are vastly
different now. In virtually all countries where influenza vaccines are
used, the level of use is increasing; currently, almost 300 million people
are being vaccinated worldwide each year.
10 Nonetheless, the global vaccine supply is fragile. In 2004, contamination of vaccine produced in the U.K. led to the loss of half the normal U.S. supply. Because the U.S. has only one domestic influenza vaccine producer, intense efforts were undertaken to obtain supplies from other countries. Only a few million doses could be found.
We have not paid attention to the arithmetic of pandemic vaccine
supply.
In 2003, more than 95% of the world?s influenza vaccines
were produced in only nine countries, and more than 65% of all
doses came from five Western European countries.10 Overall, the
nine-vaccine producing countries used 62% of world?s vaccines, yet
they accounted for only 12% of the world?s population. The remaining
38% of all doses were used in countries that have little or no capacity
to produce influenza vaccines on their own. These ?have not? countries
had to rely on Western European companies for 99% of their
vaccines. Because influenza vaccination is increasing rapidly in these
countries, they soon will account for half of the global use of seasonal
vaccines. If the ?have not? countries are to have adequate supplies of
vaccines for the next pandemic, we must ensure that effective vaccines
are developed and that they can be quickly produced and equitably
distributed to all countries that want to use them.
Anticipating the number of doses of pandemic vaccine the world
will demand involves some common sense and a bit of arithmetic.
Because few people will have had previous exposure to the pandemic
virus, most will require two doses to ensure adequate protection.
Given the world?s current vaccine production capacity (300 million
doses of trivalent vaccine in ~6 months),2 if a monovalent pandemic
vaccine were produced according to the formulation of seasonal
influenza vaccines (15 μg hemagglutinin [HA] per dose), only
450 million people could be vaccinated (300 x 3/2 = 450). This will
not begin to meet the needs of even the vaccine-producing countries.
Consequently, their governments, having decided to vaccinate most
if not all of their populations, will probably not allow the export of
pandemic vaccines to ?have not? countries until their own needs have
been met.2 This is the arithmetic of pandemic vaccine supply, and it
is unforgiving.
We have been slow to recognize that an antigen-sparing pandemic
vaccine will be essential.
If the global supply of pandemic vaccines
is to be sufficient to meet world demand, its formulation must be
?antigen-sparing?; in other words, each dose must contain a much
smaller amount of HA antigen.2,11 Intradermal (ID) vaccination using
a very low (e.g., 1/10th) dose of antigen has been proposed, but there
has been very little experience with ID vaccination of immunologically
na?ve individuals, and ID vaccine administration would be
difficult to implement in large-scale vaccination programs. Most
efforts to date have focused on developing traditional inactivated
vaccines that can be administered intramuscularly. Many studies
have shown that in unprimed individuals, whole-virus vaccines are
more immunogenic than split-virus or subunit vaccines. But
whole-virus vaccines alone will not be sufficiently antigen sparing;
an adjuvant will have to be used.2,11,12
The arithmetic of global pandemic vaccine supply will be less
unforgiving if the next pandemic is caused by an H2 or H9 virus.
Seed strains for formulating pilot lots of H2 or H9 vaccines have been
produced using conventional genetic reassortment techniques.
2,11-13
Preliminary clinical trials have shown that two doses of alumadjuvanted,
whole virus H2 and H9 vaccines are adequately
immunogenic when formulated with 3.75 and even 1.875 μg HA
per dose. If globally produced, such vaccines could theoretically
immunize (with two doses) as many as 1.8 billion (3.75 μg HA) or
3.6 (1.875 μg HA) billion people.2
Clinical trials of H5N1 vaccines have been disappointing.
Developing pandemic vaccines against H5 (or H7) viruses will be
much more difficult. Until recently, no commercially viable human
vaccine against an H5N1 virus could be produced because these
highly pathogenic viruses are lethal for embryonated eggs. However,
virologists can use reverse genetics (RG) to remove the polybasic
amino acid sequence at the HA cleavage site that is responsible for
H5N1 virulence. 2,12,13 Within 10?20 days, a high-growth, 6:2
reassortant virus can be prepared that can be safely used for
egg-based vaccine production. The first RG-engineered H5N1 virus
was prepared in early 2003, and a similar virus prepared in early
2004 is being used by most vaccine companies to produce pilot lots
of H5N1 vaccines for clinical trials.
Clinical trials to assess the immunogenicity and safety of several
candidate H5N1 vaccines are underway, and preliminary (but as yet
unpublished) results of two studies have been announced. In the
U.S., the NIH tested a nonadjuvanted, split virus H5N1 vaccine
produced by Sanofi Pasteur (U.S.). In healthy adults, two doses of
this vaccine induced acceptable levels of antibody only at 90 μg HA
per dose.14 In France, two doses of an alum adjuvanted, split virus
H5N1 vaccine produced by Sanofi Pasteur (France) have been shown
to be acceptably immunogenic at 30 μg HA per dose.15
The implications of the H5N1 vaccine trial results for pandemic
vaccine supply are extremely discouraging, even for vaccine-producing
countries. Take the U.S., for example. Given the usual 6-month
vaccine production cycle and current U.S. production capacity (60
million doses of trivalent vaccine), the supply of a nonadjuvanted
H5N1 vaccine formulated at 90 μg HA per dose would be sufficient
to vaccinate (with two doses) only 15 million Americans. An alumadjuvanted
H5N1 vaccine formulated at 30 μg HA per dose would
vaccinate only 45 million people. These numbers are far short of the
public health needs of a country that is moving steadily toward
routine universal influenza vaccination every year. For the world as
a whole, supplies of these two vaccines would be sufficient to vaccinate,
with six months? production, only 75 or 225 million people,
respectively. Although several companies are planning to conduct
additional trials of adjuvanted H5N1 vaccines, the results of these
trials might not be much better.
Pandemic Vaccine Development
40 Human Vaccines 2006; Vol. 2 Issue 1
We have not managed to coordinate the development of pandemic
vaccines by all companies.
If we are worried about the H5N1
vaccine trial results, we should be equally concerned about the
process by which the vaccines are being developed. It is worth remembering
that in 1976, the last time a pandemic threat was perceived,
the U.S. conducted publicly funded clinical trials of four different
swine flu vaccines produced by four companies in more than 6000
healthy adults, children and older adults.16,17 The trials provided
information on the swine flu vaccine formulation and vaccination
schedule. They were completed in 4?5 months. In contrast, an
RG-engineered H5N1 virus was prepared in early 2003 and a vaccine
could have been quickly produced and introduced into clinical trials.
This was not done. Three years later, the most important thing we
have learned is that we will be totally unable to produce supplies of
effective H5N1 vaccines that will be large enough to meet global
needs for an imminent pandemic.
WHAT WE MUST DO TO DEVELOP PANDEMIC VACCINES
The threat of an H5N1 pandemic has been present for nine years,
and nothing suggests it is going to disappear. The need to develop
vaccines to meet this threat is understood by all. If we could be
certain that the pandemic would not arrive for another ten years, we
would then be able to call on several new vaccines; cell cultureproduced
vaccines, well established live-attenuated vaccines, new
adjuvanted vaccines and perhaps universal vaccines containing crossprotective
antigens.
13,18 Nonetheless, we cannot count on the
pandemic virus waiting this long to emerge. Common sense tells us
we must take the threat of an imminent pandemic seriously. In many
ways, we have been living on borrowed time because vaccine development
has proceeded so slowly. Several things must be done to
change this.
We must view pandemic vaccine development as a public health
problem, not as a vaccine problem.
Thus far, vaccine companies
have been allowed to develop their own H5N1 vaccine formulations,
and there has been no overarching public health strategy for coordinating
their efforts. Yet, development of pandemic vaccines must be
based on the needs of public health, not vaccine companies, and it
must pay special attention to the needs of ?have not? countries. Much
of the delay in developing vaccines for an imminent pandemic can
be traced to a widespread failure to appreciate the implications of
this public health perspective.
We must understand why the H5N1 virus is poorly immunogenic.
Investigators who first studied vaccines directed against the H5N1
virus were forced to use a vaccine that contained a non-pathogenic
surrogate H5N3 virus because reverse genetics was not yet available.
In mice, inactivated whole-virus and alum-adjuvanted subunit
H5N3 vaccines were protective against lethal H5N1 challenge.
12 Ina small clinical trial of a surface antigen H5N3 vaccine, an acceptable
neutralizing antibody response was achieved only with two doses of
an MF59 adjuvanted preparation (7.5 to 30 μg HA per dose).12
More recent studies in mice
19 and ferrets20 of whole-virus adjuvanted
(incomplete Freund?s adjuvant) H5N1 vaccines prepared with reverse
genetics have shown protection again lethal challenge with homologous
and heterologous H5N1 viruses. Moreover, serologic studies in
man suggest that a current adjuvanted H5N1 vaccine could be used
for priming against a future H5N1 pandemic virus.21
What is worrisome is that clinical trials of the H5N1 vaccines
have shown that higher amounts of HA have been required to elicit
an immune response when compared with responses to the HAs of
other influenza virus subtypes.
12 In addition, vaccine companies
have found that the amounts of HA antigen they obtain in their
production processes are 30?40% of what they normally expect.
Little is known about the molecular basis for the poor immunogenicity
and poor yields for the H5 hemagglutinin, and, in particular,
whether crucial epitopes are modified during the preparation of
reverse genetics reassortants, during inactivation or during the process
of preparing split virus vaccines. Successful development of an effective
H5N1 vaccine may depend on the answers to these questions.
We must use an adjuvant if we are to have an antigen-sparing
vaccine.
Although the pace of pandemic vaccine development in the
U.S. has recently picked up, the NIH program for H5N1 vaccine
initially began with a trial of a nonadjuvanted formulation. Yet U.S.
policy for pandemic vaccination requires that 600 million doses be
produced within at least 6 months. Given a domestic production
capacity of only 180 million doses of monovalent 15 μg HAcontaining
vaccine (60 x 3), the arithmetic should have informed
government scientists early on that producing a number of doses
sufficient to meet public health needs would require that each dose
contain no more than 4.5 μg HA per dose. Thus, from the outset the
NIH should have focused on developing an antigen-sparing H5N1
vaccine formulation by comparing low-dose adjuvanted and nonadjuvanted
H5N1 vaccines in the same set of clinical trials. Testing
only a non-adjuvanted H5N1 vaccine first wasted at least one year
and probably more.
Vaccine companies in other countries have not made the same
mistake; they understand better the arithmetic of pandemic vaccination,
not only for their own countries but also for the countries they
supply with seasonal vaccines. For this reason, they have compared
or will compare non-adjuvanted with adjuvanted vaccines in their
clinical trials.
We must include whole virus vaccines in clinical trials.
Given the known superiority of whole virus vaccines in unprimed individuals,11,12
clinical trials of H5N1 adjuvanted vaccines should have includedwhole virus, not just split virus or subunit preparations. The clinical
trials of adjuvanted H5N1 vaccines planned by GlaxoSmithKline in
Germany and by four companies in Japan will test alum-adjuvanted
whole-virus formulations.
22 However, the clinical trial of CSL
currently underway in Australia and other trials planned by Sanofi
Pasteur in the U.S. and by Chiron will only test adjuvanted split
virus or subunit preparations. Remarkably, despite discouraging
results from its alum-adjuvanted split-virus H5N1 vaccine trial,
Sanofi Pasteur in France has said it will ?not look at whole virus vaccines?.
23
From the perspective of a company, this is understandable.
Some companies depend on the splitting process to contribute to
virus inactivation, although influenza viruses can be inactivated
without splitting. Adopting a new inactivation process risks regulatory
uncertainty, something that companies producing split virus or
subunit seasonal vaccines want to avoid. Yet, adjuvanted whole-virus
H5N1 vaccines might be better able to meet the public health need
for antigen-sparing vaccines. Company decisions not to test whole
virus formulations ignore this need.
We must not let intellectual property issues and regulatory
concerns cause further delay.
Several nonvirological issues have
delayed clinical trials of candidate pandemic vaccines.2 Initially,
uncertainty over intellectual property (IP) rights for reverse genetics
was a troubling issue for several European vaccine companies. Now
that RG patent rights have been consolidated in the hands of one
company (MedImmune),24 uncertainties over RG-IP have receded.
MedImmune has indicated that it will allow reverse genetics-engineered
www.landesbioscience.com Human Vaccines 41
Pandemic Vaccine Development
viruses to be used for pandemic vaccine development without
payment of royalties. 25 It has also stated that it ?will waive royalties
on its intellectual property for any and all pandemic influenza vaccines
that are offered free of charge in the interest of public health.?
However, intellectual property issues could still be important if
clinical trials demonstrate that proprietary adjuvants such as MF59
are better able to meet the need for an antigen sparing pandemic
vaccine.26
European regulatory officials are also concerned about the safety
of RG-engineered viruses, despite reassurance from WHO experts
that this should not be a problem.
27 In one European country, regulations
that consider RG-engineered viruses to be ?genetically
modified organisms? have prevented its vaccine company from
undertaking H5N1 vaccine development. Moreover, in the U.S., the
FDA until recently required that a license for an adjuvanted pandemic
vaccine could be obtained only if a company presented evidence of
the clinical efficacy of a similarly adjuvanted seasonal influenza
vaccine. Although this requirement has been lifted, it undoubtedly
influenced the initial decision by the NIH to test only a nonadjuvanted
H5N1 vaccine.
We must obtain public funding for clinical trials of pandemic
vaccines.
Several countries have negotiated contracts for supplies of
pandemic vaccines, Canada being the first in 2000, and many more
are attempting to do so. However, with the exception of the U.S.,
Australia and Japan, pandemic vaccine development itself has
received little if any financial support from governments.2 In
Europe, vaccine companies have had to pay for clinical trials of their
?pandemic-like? vaccines, and consequently each of the few trials that
have been conducted has enrolled only a small number of subjects.
No European country has yet provided the public funding needed for
clinical trials of H5N1 vaccines, and neither has the European
Union. In contrast, the U.S. has understood that pandemic vaccine
development requires public funding (although the NIH has had
trouble knowing what should be done), whereas European investigators
have known what to do but have had no public funding to do it.
Why European governments have chosen not to fund the development
of something essential for their national health security is unclear; it
is difficult to imagine they would similarly expect industry to fully
fund the development of weapons systems deemed vital for their
national defence. The U.S. and Europe (and other vaccine-producing
countries and even non vaccine-producing countries) must find a
way to collaborate and publicly fund this urgently needed research.
We must have firm leadership for pandemic vaccine development
at the international level.
WHO has done a remarkable job of
calling attention to the global threat of pandemic influenza.
However, its contributions to pandemic vaccine development have
been less impressive. WHO has convened several meetings that have
allowed companies and national health officials to share information,
but WHO has only ?encouraged companies to test vaccine formulations
that include an adjuvant?.28 Like national governments, WHO
has let companies decide what kinds of pandemic vaccines they will
develop. In doing so, and in the face of what could be an imminent
pandemic, the critical needs of ?have not? countries for the timely
development of antigen sparing vaccines have received little attention.
PANDEMIC VACCINATION REQUIRES A GLOBAL PERSPECTIVE
Preparing for pandemic vaccination will require solutions to
many problems that go beyond vaccine development.
2 Governments
will have to assume legal liability for vaccine-associated adverse
events. The international community must decide how to forecast
the vaccine demands of all countries and determine how ?have not?
countries will be able to obtain vaccine supplies from countries
whose political leaders have ?nationalized? their own vaccine companies.
No one should under-estimate how difficult it will be to solve these
problems, but everyone should recognize that not solving them
beforehand could lead to an extraordinary humanitarian and political
crisis worldwide. Everyone must also recognize that managing this
crisis will be less difficult if the global supply of pandemic vaccine is
large instead of small.
Vaccine companies are already doing much to develop pandemic
vaccines, but they could certainly do more. However, final responsibility
for pandemic vaccine development rests with public officials.2
The 2004 tsunamis and Hurricane Katrina have reminded us of
the dreadful suffering people experience when public officials fail to
make adequate preparations for future emergencies. Vaccine development
for an imminent pandemic requires similar preparation.
29 In its absence, the political and moral fallout can and will be profound.30,31
Winston Churchill once wrote, ?It is no use saying, ?We are doing
our best.? You have got to succeed in doing what is necessary.? If
public officials fail to do what is necessary to develop effective
antigen-sparing pandemic vaccines and a highly virulent pandemic
virus emerges within the next few years, the consequences of their
failure will be all too evident, and they will haunt us for years to come.
References
1. Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, Lochindarat S, Nguyen
TK, Nguyen TH, Tran TH, Nicoll A, Touch S, Yuen KY; Writing Committee of the World
Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A
(H5N1) infection in humans. N Engl J Med 2005; 353:1374-85.
2. Fedson DS. Preparing for pandemic vaccination: An international policy agenda for vaccine
development. J Public Health Policy 2005; 26:4-29.
3. Webster RG, Peiris M, Chen H, Guan Y. H5N1 outbreaks and enzootic influenza. Emerg
Infect Dis 2006; 12:3-8.
4. Taubenberger JK, Morens DM. 1918 influenza: The mother of all pandemics. Emerg
Infect Dis 2006; 12:15-22.
5. Glaser L, Stevens J, Zamarin D, Wilson IA, Garcia-Sastre A, Tumpey TM, Basler CF,
Taubenberger JK, Palese P. A single amino acid substitution in 1918 influenza virus hemagglutinin
changes receptor binding specificity. J Virol 2005; 79:11533-6.
6. Shinya K, Hamm S, Hatta M, Ito H, Ito T, Kawaoka Y. PB2 amino acid at position 627
affects replicative efficiency, but not cell tropism, of Hong Kong H5N1 influenza A viruses
in mice. Virology 2004; 320:258-66.
7. WHO. Avian influenza - Situation in Turkey - Update 4. Sequencing of human virus 2006,
(http://www.who.int/csr/don/2006_01_12/en/index.html).
8. Butler D. Alarms ring over bird flu mutations. Nature 2006; 439:248-9.
9. Dowdle WR. Striking the balance. In: Osterhaus ADME, Cox N, Hampson AW, eds.
Options for the control of influenza IV. Amsterdam: Elsevier BV, 2001:3-7.
10. Macroepidemiology of Influenza Vaccination (MIV) Study Group. The macroepideimiology
of influenza vaccination in 56 countries, 1997-2003. Vaccine 2005; 23:5133-43.
11. Wood JM. Developing vaccines against pandemic influenza. Philos Trans Roy Soc London
B Biol Sci 2001; 1953-60.
12. Stephenson I, Nicholson KG, Wood JM, Zambon MC, Katz JM. Confronting the avian
influenza threat: vaccine development for a potential pandemic. Lancet Infect Dis 2004;
4:499-509.
13. Luke CJ, Subbarao K. Vaccines for pandemic influenza. Emerg Infect Dis 2006; 12:66-72.
14. Lambert LC. Update on NIH H5N1 vaccine trials. National Vaccine Advisory Committee,
2005, (http://www.hhs.gov/nvpo/nvac/nov05.html).
15. Sanofi Pasteur announces preliminary trial results for a first H5N1 prepandemic influenza
vaccine candidate with an adjuvant. Lyon: 2005, (http://www.sanofipasteur.com).
16. Parkman PP, Hopps HE, Rastogi SC, Meyer Jr HM. Summary of clinical trials of influenza
virus vaccines in adults. J Infect Dis 1977; 136(Suppl):S722-30.
17. Wright PW, Thompson J, Vaughn WK, Folland DS, Sell SHW, Karzon DT. Trials of
influenza A/New Jersey/76 virus vaccine in normal children: An overview of age-related
antigenicity and reactogenicity. J Infect Dis 1977; 136(Suppl):S371-41.
18. Palese P. Making better influenza virus vaccines? Emerg Infect Dis 2006; 12:61-6.
19. Lipatov AS, Webby RJ, Govorkova EA, Krauss S, Webster RG. Efficacy of H5 influenza
vaccines produced by reverse genetics in a lethal mouse model. J Infect Dis 2005; 191:1216-20.
20. Hoffmann E, Lipatov AS, Webby RJ, Govorkova FA, Webster RG. Role of specific hemagglutinin
amino acids in the immunogenicity and protection of H5N1 influenza virus vaccines.
Proc Natl Acad Sci USA 2005; 102:12915-20.
Pandemic Vaccine Development
42 Human Vaccines 2006; Vol. 2 Issue 1
21. Stephenson I, Bugarini R, Nicholson KG, Podda A, Wood JM, Zambon MC, Katz JM.
Cross-reactivity to highly pathogenic avian influenza H5N1 viruses after vaccination withnonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a
potential priming strategy. J Infect Dis 2005; 191:1210-5.
22. R&D for avian/pandemic influenza vaccines by IFPMA Influenza Vaccine Supply
International Task Force (IVSITF) members (updated 24 Jan 2006). (http://www/ifpma.org/).
23. MacKenzie D. Tests dash hopes of rapid production of bird flu vaccine. New Scientist
2005; 16 December 2005.
24. MedImmune expands patent estate for reverse genetics with new rights from Mount Sinai
School of Medicine, 12/07/05. (http://phx.corporate-ir.net/phoenix.2html?c=83037&p=
irol-newsArticle%ID=793603).
25. Statement of MedImmune, Inc. regarding reverse genetics technology. In: Knobler SL,
Mack A, Mahmoud A, Lemon SM, eds. The threat of pandemic influenza. Are we ready?
Washington: The National Academies Press, 2005:196-7.
26. Singh M, Ugozzoli M, Kazzaz J, Chesko J, Soenawan E, Mannucci D, Titta F, Contorni
M, Volpini G, Guidice GD, O'hagan DT. A preliminary evaluation of alternative adjuvants
to alum using a range of established and new generation vaccine antigens. Vaccine 2005;
In press.
27. World Health Organization. Production of pilot lots of inactivated influenza vaccine from
reassortants derived from avian influenza viruses. Interim biosafety risk assessment,
(http:www.who.int/csr/disesase/avian_influenza/guidelinestopics/en/index5.html).
28. World Health Organization. Vaccine research and development: Current status. 2005,
(http://www.who.int/csr/disease/avian...11_03/en/inde).
29. Milstien J, Lambert S. Emergency response vaccines?A challenge for the public sector and
the vaccine industry. Vaccine 2002; 21:146-54.
30. Hamilton DS, Smith BR. Atlantic storm. EMBO Rep 2006; 7:4-9.
31. Benatar SR. Moral imagination: The missing component in global health. PLoS Medicine
2005; 2:e400.