Influenza - The need for new pharmaceuticals to eminent threats

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6.2: Pandemic Influenza


6.2
-
1



Priority Medicines for Europe and the World

"A Public Health Approach to Innovation"





Background Paper







Preparing for Pandemic Influenza:

A Research Agenda for the European Union
During the Interpandemic Period






This chapter has been compiled
by David S. Fedson, M.D.

in collaboration with the Global Influenza Programme


11 October
2004


6.2: Pandemic Influenza


6.2
-
2



Table of Contents


1.

Executive Summary

................................
................................
................................
..............................

3

2.

Background

................................
................................
................................
................................
............

6

3.

Burden of Disease

................................
................................
................................
................................
.

8

3.1.

The Influenza Virus

................................
................................
................................
....................

8

3.2.

Interpandemic Influenza: The Burden of Disease

................................
................................
..

8

3.3.

Avian Influenza: Increasing the Risk for a Pandemic

................................
............................

9

3.4.

Pandemic Infl
uenza and its Potential Impact on Europe and the World

..........................

10

4.

Prevention and Control of Influenza

................................
................................
..............................

11

4.1.

The Current Control Strateg
y and its Effectiveness

................................
.............................

11

4.1.1.

Influenza Vaccination

................................
................................
................................
.......

11

4.1.2.

Antiviral Agents

................................
................................
................................
...............

11

4.1.3.

Use of Vaccines and Antivirals During a Pandemic

................................
.........................

12

4.1.4.

Non
-
Medical Interventions

................................
................................
...............................

13

4.2.

Current Implemen
tation of the Control Strategy

................................
................................
.

14

4.2.1.

The Interpandemic Use of Influenza Vaccine in Europe and the Rest of the World

.........

14

4.2.2.

Th
e Interpandemic Use of Antivirals in Europe and the Rest of the World
......................

18

4.2.3.

Affordability of the Interventions

................................
................................
......................

18

5.

Constraints

to a Better Control

................................
................................
................................
.........

19

5.1.

Interpandemic Period

................................
................................
................................
...............

19

5.2.

Pandemic Period

................................
................................
................................
.......................

20

5.2.1.

Limitations of the Vaccination Strategy

................................
................................
............

20

5.2.2.

Limitations of the Antiviral Strategy

................................
................................
................

21

6.

Lessons Learned from Res
earch into Pharmaceutical Interventions

................................
........

22

6.1.

Vaccination Strategies

................................
................................
................................
...............

22

6.2.

Reverse Genetics
................................
................................
................................
........................

25

6.3.

Existing Research Resource Flows

................................
................................
..........................

26

7.

Pipeline of Products

................................
................................
................................
...........................

27

7.1.

Pipeline for Influenza Vaccine
s

................................
................................
...............................

27

7.2.

Pipeline for Antiviral Agents
................................
................................
................................
...

29

7.3.

About Safety and Efficacy of Products in the Pipeline

................................
........................

30

8.

Research into New Pharmaceutical Interventions

................................
................................
........

31

8.1.

Vaccines with Broad Spectrum and Long Lasting Immunity

................................
.............

31

8.2.

Newer Antiviral Agents

................................
................................
................................
...........

33

8.3.

Other Pharmaceuticals

................................
................................
................................
.............

33

8.4.

Institutions and Human Resources

................................
................................
........................

34

9.

Gaps and Opportunities for Pharmaceutical Research

................................
................................

34

9.1.

Research to Be Carried Out in 5 Years

................................
................................
...................

35

9.1.1.

Vaccines

................................
................................
................................
.............................

35

9.1.2.

Antiviral Agents

................................
................................
................................
...............

35

9.1.3.

Non
-
Pharmaceutical Research

................................
................................
..........................

36

9.1.4.

Translational Research

................................
................................
................................
......

38

9.2.

Research to be Carried Out in the Longer Term

................................
................................
...

38

9.3.

Rese
arch in Need for Increased Support

................................
................................
...............

39

9.4.

The Comparative Advantage of the EU

................................
................................
.................

40

10.

References

................................
................................
................................
................................
............

42


Appendix

6.2: Pandemic Influenza


6.2
-
3


1.

Executive Summary

The threat of a new influenza pandemic, its potential impact on health and the social and
economic life of nations are clearly recognized by World Health Organization and the
Euro
pean Union. The key strategies to prepare for a pandemic have been adopted by the
Member States of both organizations. Although all agree that vaccines and antiviral agents
will be the only reliable interventions for reducing the morbidity and mortality of

a
pandemic, current vaccines and antivirals and have several disadvantages and supplies of
both will be severely limited.


Annual outbreaks of influenza are due to minor changes in the virus that enable it to evade
the immunity humans have developed foll
owing previous infection or vaccination. For this
reason, the vaccine needs to be reformulated each year and vaccination must be repeated.
Occasionally, one or more genes will be replaced by the genes of another (often avian)
influenza virus. When this occ
urs, most people will have little or no immunity to this new
virus. If it can be efficiently transmitted from one person to the next, a new pandemic will
emerge.


Outbreaks of influenza in animals, especially when they occur simultaneously with annual
out
breaks in humans, increase the chance that genes from the two viruses will reassort and
produce a new pandemic virus. During the past few years, the world has experienced
several outbreaks of avian influenza that have resulted in human infections. These ev
ents
remind us that the arrival of the next pandemic is just a matter of time.


The impact of the next pandemic will depend on the infectivity and virulence of the
pandemic virus. Mortality estimates for the next pandemic have ranged from 2
-
7 million
deat
hs, and for a 1918
-
like pandemic could reach 175 to 350 million. Even with the most
conservative estimates, millions of people will become seriously ill or die. Compared with
the relatively small number of cases of SARS and their focused social and economi
c impact,
one can expect the worldwide impact of the next influenza pandemic to be far greater.


The main strategy for controlling seasonal epidemics of influenza is yearly vaccination of
high
-
risk individuals. Although vaccination is considered cost
-
effec
tive in developed
countries, vaccine uptake remains low in many of these countries. In developing countries,
basic information on the burden of disease does not exist, making it difficult for
policymakers to justify programmes for influenza prevention and
control. Low vaccine
uptake is mirrored by the world’s vaccine production capacity. Approximately 300 million
doses of the current inactivated trivalent influenza vaccine are produced each year, two
-
thirds of them by companies located in the European Union
. These European companies
provide virtually all of the doses of influenza vaccine used in countries that do not have
influenza vaccine companies.


Antiviral agents reduce severity and duration of influenza but due to high prices they are
little used. As
a result, the current supply and production capacity for these agents is
severely limited.


6.2: Pandemic Influenza


6.2
-
4


These shortcomings in vaccine and antiviral supply will become evident when the next
pandemic emerges. It will take several months before full
-
scale pandemic vacc
ine production
can begin. Because countries with influenza vaccine companies can be expected to delay or
prohibit the export of pandemic vaccines until their domestic needs have been met, countries
without vaccine production facilities will be unable to ob
tain supplies of pandemic vaccines.
Unlike vaccines, antiviral agents could be stockpiled in advance, but stockpiles will be
limited because of their high cost and uncertainty regarding the effectiveness of these agents.
Interventions other than vaccines a
nd antivirals might delay transmission of a pandemic
virus, but would unlikely interrupt its global transmission.


In order to overcome limitations in the supply of pandemic vaccines, several options have
been explored. The results show that compared with

current trivalent inactivated vaccines,
monovalent pandemic vaccines formulated with a low antigen dosage and including a
commonly available adjuvant could increase the number of doses of pandemic vaccine that
could be produced by 12
-

to 24
-
fold. These fi
ndings offer the best hope for producing an
adequate supply of pandemic vaccines for Member States of the European Union and for
other countries throughout the world.


Reverse genetics provides a rapid and safe alternative to traditional genetic reassortme
nt for
preparing seed strains for pandemic vaccine production. However, the use of reverse
genetics is constrained by issues regarding intellectual property rights and public concern
about the use of ‘genetically modified organisms’. In order to take full
advantage of this
important technology, these issues must be resolved as soon as possible.


In order to guarantee rapid licensing of pandemic vaccines, the European Medicines
Evaluation Agency (EMEA) has issued guidelines for vaccine manufacturers on how
to
prepare a pandemic vaccine dossier. The dossier is based on a ‘mock
-
up’ vaccine that could
contain the highly pathogenic avian H5N1 influenza strain currently causing widespread
disease in Asia. Although a reverse genetics
-
engineered vaccine seed strain

has been offered
free
-
of
-
charge to all manufacturers, the companies have little or no incentive to invest in
costly clinical trials of a vaccine they will never market. In the United States, the NIH is
currently providing public funding for such clinical
trials. Although the vaccine formulations
the NIH will test will not allow for greatly expanded production of pandemic vaccines to
meet global demand (they will not be low
-
dose, adjuvanted preparations), Europeans should
recognize that public funding will
be necessary if clinical trials of pandemic vaccines are to
be undertaken in Europe.


The recent introduction of an intra
-
nasally administered live
-
attenuated influenza vaccine in
the US (but not yet in Europe) is promising, but this vaccine is unlikely to

have much impact
on the influenza vaccine market in Europe for several years. A more long
-
term research
strategy should include studies of vaccines targeting one of several highly conserved virus
antigens that induce broad spectrum and long
-
lasting protec
tion.


The EU currently provides modest support for the d
eveloping human influenza vaccines:
€2.1 million for FLUPAN and €1.76 million for NOVAFLU. The US government has
committed a far larger amount (at least $50
-
100 million, if not more) to this research.
6.2: Pandemic Influenza


6.2
-
5


However, even in the US investment in pandemic vaccine
development is modest compared
with investments in developing vaccines for other diseases.


In the field of antivirals, there is little commercial investment in research. Public funding to
support research on current or new antiviral agents is largely limi
ted to the US.


In the European Union, priorities for pharmaceutical research on influenza vaccines and
antiviral agents should focus on short
-

and long
-
term research. Moreover, pharmaceutical
research should go hand
-
in
-
hand with translational research tha
t will provide the basis for
implementing programs for using newer vaccines and antivirals.


Short
-
term research (within the next five years) should focus on evaluating the
immunogenicity and safety of low
-
dose, adjuvanted ‘pandemic
-
like’ vaccines. Intelle
ctual
property rights and regulatory issues related to the use of reverse genetics to prepare seed
strains for pandemic vaccine production need to be resolved. The benefits of expanded use
of existing vaccines (including live attenuated influenza vaccines)

and expanding vaccine
manufacturing capacity should be further explored.


For antiviral agents, their effects on reducing serious complications of influenza should be
further explored. Studies on the effectiveness of a lower dose and shorter duration of
treatment with anti
-
neuraminidase agents could increase their availability during a
pandemic. More important, there is an urgent need for research on newer antiviral agents,
some of which might target new virus antigens.


Research is also needed on the po
ssible impact of commonly available medications such as
statins on the clinical course of influenza
-
related illness.


Long
-
term research should focus on developing broad spectrum vaccines that provide long
lasting protection. In addition, the development
of new antiviral agents that overcome the
disadvantages of current agents is urgently needed. Support for research on the basic
immunology of the response to vaccination, the molecular pathophysiology of influenza
virus infection and the role of biological

response mediators in host defense should go hand
-
in
-
hand with research on influenza vaccines and antiviral agents.


The ability of Europeans to respond to the next influenza pandemic will in considerable
measure depend on the willingness of the European

Union to provide public support for a
research agenda on pandemic vaccines and antiviral agents in interpandemic years.
Successful implementation of this agenda will allow the European Union to fulfil its
obligations to all Europeans and meet its responsi
bilities to people in other countries
throughout the world.

6.2: Pandemic Influenza


6.2
-
6



2.

Background

Despite a considerable increase in our knowledge of influenza viruses, major breakthroughs
in the prevention and control of annual epidemics and influenza pandemic preparedness
have n
ot been made. This is especially worrying as an influenza pandemic becomes more
and more likely. The last pandemic occurred more than 35 years ago and the recent years'
outbreaks of avian influenza in poultry in Asian countries have heightened global conce
rn
that a new human pandemic could follow.
1


The World Health Organization (WHO) has historically focused its influenza activities on
virological surveillance to support annual vaccine strain selection. Recently, WHO expanded
its focus to address new chall
enges. In May 2002, WHO convened a consultation of influenza
experts, virologists, epidemiologists and public health officials. The consensus that was
achieved led to the publication of the first Global Agenda on Influenza Surveillance and
Control
2
.
(See
Appendix

6.2.2
)

The Global Agenda responds to the challenges posed by poor
understanding of the impact of influenza, especially in developing countries, the long time
frame
needed to manufacture influenza vaccines, persisting inadequate vaccine coverage in
most countries, and the need for surveillance activities to be more closely related to control.
It encourages collaboration among all those in the public and private sector
s who can
contribute to better influenza surveillance and control, and maps out a strategic plan for
doing so. The Global Agenda identifies 17 priority activities judged necessary to reduce the
burden of epidemics and prepare the world for the next pandemi
c. They are listed according
to four main objectives: (i) strengthen surveillance; (ii) improve knowledge of the health and
economic burden of influenza; (iii) increase influenza vaccine usage, and (iv) accelerate
national and international action on pande
mic preparedness. Each priority activity is further
defined in a series of recommended activities for researchers, industry, governments, and
WHO. Among the priorities are research on pandemic viruses, vaccines, antiviral agents and
other control measures.


The Global Agenda has been widely accepted by scientists all over the world. It gained
strong political backing in May 2003 when the World Health Assembly (WHA) adopted a
resolution on the “Prevention and Control of Influenza Pandemics and Annual Epidemi
cs”.
3

(See
Appendix

6.2.3
)
In this resolution, Member States acknowledged that influenza affects
millions of people worldwide and causes fatal complications in up to 1
million people each
year. Many of these deaths could be prevented by increasing the use of existing vaccines,
particularly in high
-
risk groups. Member States expressed concern about “the general lack of
national and global preparedness for a future influen
za pandemic, especially in view of the
recurrence of such pandemics and the high mortality, social disruption, and economic costs
they invariably cause, which may now be exacerbated by rapid international travel, the
recent worldwide increase in the size o
f at
-
risk populations, and the development of
resistance to first
-
line antibacterial drugs.” They recognized the need to improve vaccine
formulations, increase manufacturing capacity for vaccines, ensure more equitable access to
antiviral drugs, and streng
then disease surveillance as part of national and global pandemic
preparedness. The WHA resolution called for Member States ”to support research and
development on improved influenza vaccines, particularly concerning their suitability for
use in developing

countries, in order to develop and produce an influenza vaccine
6.2: Pandemic Influenza


6.2
-
7


formulation capable of conferring long
-
lasting and broad protection against all influenza
virus strains.” WHO was asked ”to search jointly with other international and national
partners, incl
uding the private sector, for solutions to reduce the present global shortage of,
and inequitable access to, influenza vaccines and antiviral drugs, both for epidemic and
global pandemic situations.”


The event that marks the beginning of European plannin
g for the next influenza pandemic
was the EU
-
sponsored conference “Pandemic Preparedness in the Community” that was
held in Brussels on 27 November 2001. In its preliminary conclusions, the conference noted:


The next pandemic is imminent. EU Member States

are not prepared. Vaccine availability is not
secured. Antiviral stocks do not exist and will not be under the current market forces. In the event of a
pandemic millions of people could die, economies will be affected and services (medical, civil) could
c
ollapse. Members of the public will not excuse authorities, who will be held responsible for not having
put in place up
-
to
-
date preparedness
.”
4


In March 2004 the European Commission published a working document on “Community
Influenza Pandemic Preparednes
s and Response Planning”.
5

(See
Appendix

6.2.1
)

The
document noted that "
current vaccine production capacity is not deemed to be sufficient to
meet the demands of the Commun
ity in the event of a pandemic. Manufacturers’ reserve
capacity is not likely to be enough to support a sudden increase in demand. Availability of
vaccines or antivirals to populations most at risk may, in critical situations, be further limited
by measure
s imposed by Member State authorities to provide maximum protection to their
own population. Measures should, therefore, be considered with a view to ensuring equity
of access.
" The Commission emphasized that research performed during the inter
-
pandemic
pe
riod would be vital for preparing an effective pandemic response, noting that "
research
leading to the development of new vaccine technology should remain a priority and be
linked to routine and fast
-
track licensing procedures for influenza vaccines. Curre
nt and
emerging anti
-
viral drug resistance developments in influenza need to be addressed through
coordinated research at the European level. Furthermore, in the process of early recognition
of the identity and origins of pandemic strain, the role of inter
national scientific cooperation
is key. The Commission will therefore continue to develop its collaborative research
networks to integrate partners in third countries, as was the case in the past with similar
threats, such as Ebola and Lassa fever and more

recently SARS
. "


Since these reports were published, considerable progress has been made in formulating
plans for pandemic preparedness within the European Union and outsite.
6

The research
components for various Community actions had already been identif
ied in the Community’s
5
th

and 6th Framework Programmes. Two projects for developing new influenza vaccines are
currently being funded and a call was recently issued for proposals for post genomic
research in the field of influenza vaccines. In addition, i
n April 2004 the European Agency
for the Evaluation of Medicinal Products (EMEA) published guidelines for developing and
registering pandemic influenza vaccines through a procedure that will be based on ‘mock
-
up’ dossiers for candidate pandemic vaccines su
bmitted by individual vaccine companies.
7


Nonetheless, there has been limited progress in developing new interventions to prevent or
delay a pandemic and that are accessible by the majority of the world’s population. This can
be remedied only through grea
ter investment by the public sector. This need was strongly
emphasised in the report of a recent WHO Consultation on “Priority Public Health
6.2: Pandemic Influenza


6.2
-
8


Interventions Before and During a Pandemic” that was held in March 2004.
8

This report can
and should be used as an
inspiration to all the readers of this document.

3.

Burden of Disease

3.1.

The Influenza Virus


Influenza viruses are negative
-
stranded RNA viruses, of which type A is the most
pathogenic for humans.
9

The influenza virus genome consists of eight RNA segments that

code for 10 proteins: two envelope glycoproteins
-

the hemagglutinin (HA) and
neuraminidase (NA) antigens, matrix protein (M1), nucleoprotein (NP), three polymerases
(PB1, PB2 and PA), an ion channel protein (M2) and two non
-
structural proteins (NS1 and
N
S2). The type A viruses that cause epidemics in man are classified according to their HA
(H1, H2 and H3) and NA (N1 and N2) antigens. Point mutations in the HA and less
frequently NA antigens lead to the antigenic drift characteristic of interpandemic year
ly
epidemics. Sudden substitutions of whole genes from one subtype to another, by mixing
human and animal influenza viruses in animal hosts, lead to the antigenic shifts that
uniquely characterize new pandemics.


3.2.

Interpandemic Influenza: The Burden of Dise
ase


Influenza affects people of all ages in all parts of the world, and each year 5 to 20% will
develop symptomatic illness
9
. Epidemics of varying degrees of severity occur each winter.
Although difficult to a
ssess, these annual epidemics are thought to result in between three
and five million cases of severe illness and up to 1,000,000 deaths worldwide. Most deaths
associated with influenza in industrialized countries occur among people over 65 years of
age.


Although most cases of influenza are self
-
limited, they are responsible for an enormous
amount of work absenteeism, additional medical care and economic loss. In England and
Wales, for example, hospital admissions for influenza
-
related conditions have caus
ed major
problems for health service delivery each winter, especially for older people,
10

and this
experience is duplicated in other countries.
11

Moreover, in England and Wales, an estimated
6200 to almost 30,000 people died of influenza
-
related illnesses du
ring each of the epidemics
between 1975 and 1989,
12

an experience common to other countries where influenza morality
has been studied.
13

In the United States, estimates put the economic costs of annual influenza
epidemics at several billion dollars per year.
14

There have been few studies of the health and
economic burden of influenza in tropical and developing countries. However, a recent report
from Hong Kong for the period 1998
-
2001 documented rates of excess influenza
-
related
hospital admissions for pneumon
ia, chronic obstructive pulmonary disease and heart failure
that were comparable to those reported in developed countries.
15

In the developing countries
of Madagascar and the Democratic Republic of Congo, recent outbreaks have been extensive
and case
-
fatali
ty rates have been 3
-
4%, rates similar to those experienced in developed
countries during the 1918 pandemic. The mortality impact of these outbreaks has been
especially severe in children.


In developed countries, infection rates are higher in children tha
n in any other age group,
and children are the principle disseminators of influenza throughout communities. Influenza
6.2: Pandemic Influenza


6.2
-
9


is a major cause of acute otitis media
16

and in children < 2 years of age hospitalization rates
approach those seen in elderly adults.
17

Se
veral studies from European countries have
documented the impact of childhood influenza on ambulatory care visits
18

19

20
and
hospitalizations.
21

22

23

24
Recently, attention has been drawn to influenza
-
associated
complications such as febrile seizures and acute i
nfluenza
-
associated encephalopathy, a
condition that is either fatal or causes serious neurological sequelae in more that half of
cases.
25

Influenza is also an important cause of respiratory illness and hospitalization for
acute cardiopulmonary conditions i
n pregnant women, although adverse effects on perinatal
outcomes have not been noted.
26


In most European countries there are no estimates of excess influenza
-
associated mortality
nor are there measures of influenza’s impact on the economic life of communit
ies and
nations. Several studies have documented aspects of the burden of influenza in European
children, but compared with other countries, less is known about rates of hospitalization,
specific complications such as acute encephalopathy, and the effects
of influenza on
pregnant women and perinatal outcomes. Accurate assessment of the health and economic
impact of influenza in different populations will enable policy
-
makers to set priorities
and justify budgets for programs for influenza prevention and con
trol.


3.3.

Avian Influenza: Increasing the Risk for a Pandemic


Avian influenza viruses do not normally infect species other than birds and pigs. However,
in 1997, avian H5N1 influenza appeared in the poultry markets of Hong Kong and infection
spread to 18 pe
ople, six of whom died
27
. Little, if any, inter
-
human spread was recorded.
Human cases of H5N1 influenza reappeared in 1999 and again in early 2003. In late 2003 and
early 2004, an unprecedented outbreak of avian H5N1 influenza swept through poultry
flocks

in many countries in East and Southeast Asia. Again, human cases of H5N1 infection
occurred, and this time 24 (68%) of the 34 people who were infected died.
28

Avian influenza
has persisted in poultry flocks in several of the counties affected, and in Augus
t 2004 three
additional fatal cases of human H5N1 influenza were reported from Vietnam.
29




Europeans have also had recent experience with avian influenza. In early 2003 a highly
pathogenic avian influenza H7N7 outbreak affected commercial poultry farms in

The
Netherlands and infection was transmitted to humans. As a result, more than 400 poultry
workers and their family members developed conjunctivitis and influenza
-
like illness and
one person, a previously healthy veterinarian, died.
30

This is not the only

documented
instance of the transmission of an avian influenza virus to mammals. In the early 1980s, an
H7N7 avian virus infected seals on Cape Cod in New England, and within two months 25%
had died.
31



The persistence of highly pathogenic avian influenza
viruses in poultry flocks in Asian
countries provides continuing opportunities for the direct infection of humans. As more
humans become infected, the likelihood increases that humans might be concurrently
infected with human and avian influenza strains. O
ne of these persons could serve as the
“mixing vessel” for the emergence of a novel influenza virus subtype possessing the genetic
phenotype that permits efficient person
-
to
-
person transmission, the essential requirement for
a new pandemic virus
32
. Another
possible and alarming scenario, and different from the
“mixing vessel” mechanism, is that of an avian virus mutating at a critical site to allow for a
6.2: Pandemic Influenza


6.2
-
10


stronger binding of the virus to cells in the human respiratory tract and therefore speeding
up viral rep
lication and facilitating a more efficient man
-
to
-
man transmission


The World Health Organization and infectious disease experts throughout the world are
concerned that events such as the recent avian influenza outbreaks in Asia could lead to a
new human
influenza pandemic.
1

33



3.4.

Pandemic Influenza and its Potential Impact on Europe and the World


The influenza pandemic of 1918 was one of the most significant disease outbreaks in all of
recorded history
.
34

Within
a two
-
year period, it killed an estimated 50
-
100 million people
worldwide, far more than died in World War I.
35

Two later pandemics
-

Asian influenza in
1957
-
59 and Hong Kong influenza in 1968
-

were much milder, but nonetheless caused
widespread social dis
ruption and substantial excess mortality.
34



No one can know with certainty how severe the next pandemic will be. Several years ago, a
respected influenza expert cautioned against what he called ‘influenza extr
apolitis’; that is,
the assumption that the next pandemic will be as severe as the one in 1918.
36

Epidemiological
models from the Centers for Disease Control and Prevention, Atlanta, USA project that today
a pandemic could result in 2 to 7.4 million deaths
worldwide. In high income countries that
account for 15% of the world’s population, epidemiological models project a demand for
134

233 million outpatient visits and 1.5

5.2 million hospital admissions.
37

Many regard
these estimates as very conservative and

believe that the burden of pandemic disease will be
more severe, especially in developing countries.


If the next pandemic is as severe as the one in 1918, the situation could be much worse.
Given the more than 3
-
fold increase in the world’s population s
ince 1918, a reappearance of a
1918
-
like pandemic could also kill as many as 175 to 350 million people. This is more than
the number of people killed in all wars and by the most murderous governments throughout
the 20th Century.
38

These people would die not

in 100 years but in 1 or 2.


In early 2004, 68% of the human cases of avian H5N1 influenza seen in Vietnam and
Thailand died. The case
-
fatality rate was far worse than what was seen in 1918. If a
pandemic virus with this degree of virulence were to acqui
re the transmission
characteristics of a usual pandemic influenza virus, the health consequences for human
populations everywhere could be catastrophic. No country will be spared.


In addition to their consequences for health, influenza outbreaks can have

a huge impact on
the social and economic life. Recent experience with SARS has shown that an emerging
disease that causes a small number of cases in a region can rapidly spread to distant
countries and create anxiety in the community. Medical facilities c
an be easily overwhelmed,
and anxiety can quickly disrupt community life. Compared with the SARS experience, a
severe influenza pandemic can be expected to be far worse. Widespread illness may result in
significant shortages of personnel who provide essent
ial community services and public fear
may put immense political pressure on decision makers. Thus, in making plans for
responding to the next pandemic, it would be prudent to anticipate the ‘worst case scenario’,
remembering that, “the only thing more dif
ficult than planning for an emergency is having
to explain why you didn't".
39


6.2: Pandemic Influenza


6.2
-
11


4.

Prevention and Control of Influenza

4.1.

The Current Control Strategy and its Effectiveness


4.1.1.

Influenza Vaccination

Influenza vaccines are the mainstay of influenza prevention and cont
rol.
9

The trivalent
inactivated vaccines currently available are immunogenic and safe. Following vaccination,
serological responses to the hemagglutinin (HA) antigen of the influenza virus correlate well
with cl
inical protection.
40

Vaccination also stimulates an increase in anti
-
neuraminidase
antibodies,
41

42

and these antibodies protect against both influenza itself
43

and secondary
bacterial pneumonia [J. McCullers, personal communication, 16 June 2004]. Provided th
ere is
a close match between the vaccine virus and the virus causing disease, the protective efficacy
of vaccination is up to about 70% against disease and even more so against adult
hospitalizations and death.
44

In addition to being clinically effective, i
nfluenza vaccination
has also been shown to be cost
-
effective in European countries.
45



Vaccination of children is also clinically effective
46

and high levels of coverage among
schoolchildren induce herd immunity and prevent deaths in older adults.
47

Pregnan
t women
are at increased risk of hospitalization for influenza
-
related illness,
48

and vaccination during
pregnancy has the potential to benefit not only mothers themselves but also their newborn
infants.
49



There are relatively few European studies on the e
ffectiveness of influenza vaccination
preventing influenza
-
associated hospitalizations and death in adults, children and
pregnant women.


WHO recommends the use of influenza vaccine in nationally defined risk groups.
50

People at
risk include
residents of in
stitutions for the elderly or the disabled, persons (> 6 months of
age) with chronic cardiovascular, pulmonary, metabolic or renal disease, persons who are
immunocompromised and individuals who are above a nationally defined age limit
irrespective of their

medical risk status (most countries define the age limit as

≥ 65 years).
The WHA resolution on influenza in 2003 recommended that Member States undertake the
following:
3




where national influenza vaccination policies exist: increase vaccination coverage of
all high
-
risk

groups, including the elderly and persons with underlying chronic
disease, and establish appropriate strategies for doing so, with the goal of attaining
vaccination coverage in the elderly population of at least 50% by 2006 and 75% by
2010;



where no natio
nal influenza vaccination policies exist: assess the health and economic
impact of annual influenza epidemics as a basis for developing and implementing
influenza prevention policies within the context of other national health priorities.


4.1.2.

Antiviral Agents


Currently, four antivirals have proven efficacy in treatment and prophylaxis of influenza A
infections: two M2 inhibitors (amantadine and rimantadine) and two neuraminidase
inhibitors (zanamivir and oseltamivir).
9

The therapeutic efficacy of all of these agents was
6.2: Pandemic Influenza


6.2
-
12


established in clinical trials conducted in adults and children who received treatment within
two days of the onset of the symptoms. There are few data on their efficacy in high
-
risk
individuals.
53

Antivirals reduce virus shedding and thus infectivity of treated infected
persons.


Early treatment with M2 inhibitors reduces the duration of symptoms and the time to
recovery by one to two days. When M2 inhibit
ors are used in treatment, antiviral resistance
develops rapidly, limiting their use. Moreover, the avian H5N1 viruses isolated in Asia have
not been inhibited by these agents. All influenza type A and B viruses, including the avian
viruses, are sensitive
to the anti
-
neuraminidase agents oseltamivir and zanamivir. Zanamivir
is administered by inhaler and its use has been limited. Oseltamivir has been more widely
used, and when given within the first 48 hours of the onset of symptoms, it shortens the
course
of clinical illness, reduces antibiotic use and reduces rates of pneumonia and hospital
admissions.
51

Thus far, antiviral resistance has not become an important clinical problem
with oseltamivir.
9
,
52



There are
no European data on the effectiveness of neuraminidase inhibitors in
preventing influenza
-
associated hospitalizations and death in adults, children and
pregnant women.


4.1.3.

Use of Vaccines and Antivirals During a Pandemic

Influenza vaccines and antiviral agent
s are the two essential components of a comprehensive
pandemic response. Other components include adequate supplies of antibiotics and other
resources for providing hospital and outpatient care to populations affected by the pandemic.
Most countries will h
ave limited or inadequate resources to manage a pandemic. Given this,
national authorities must address the question of which citizens should

be given priority for
receiving the limited supplies of pandemic vaccines and antiviral agents.


Considerations fo
r establishing priority groups for vaccination will be different for each
country, not only because of differences in vaccine availability and resources but also
because of differences in population structure and the organization of essential services.
Dec
isions as to who should be included in priority groups will depend on the primary goals
of the vaccination programs. Possible target groups for pandemic vaccination include the
following:
53

(See
Appendix

6.2.4
)




Essential service providers including health care workers (to maintain essential
services)



Groups at high risk of death and severe complications (to prevent or reduce death
and hospital admissions)



Persons without ri
sk factors or complications (to prevent or reduce morbidity).


Options for the use of antiviral agents will depend on their availability, the size of the target
groups and the specific goals to be achieved. The main options include:
53




Long term prophylaxis (prevention) of defined populations for the duration of a
wave of pandemic activity (minimum of 4 weeks)



Prophylaxis during outbreaks in closed institutions (usually lasting about 2 weeks)

6.2: Pandemic Influenza


6.2
-
13




Protection of indivi
duals for the period between vaccination and the development
of

protection, ranging from 2

6 weeks depending on whether one or two doses of
vaccine

is recommended



Prophylaxis of individuals following exposure to pandemic influenza (approximately
one

week p
er course)



Treatment of ill persons for whom treatment can be initiated within the first 48 hours
of illness



Treatment of exposed persons for whom influenza vaccination is contraindicated


In general, prophylaxis is more likely that treatment to prevent se
rious complications from
influenza because it prevents influenza virus infection itself. However, early treatment
represents a more efficient use of resources than prophylaxis, which requires a prohibitively
large stockpile.
8

Vaccination should still be the primary method of prophylaxis.


4.1.4.

Non
-
Medical Interventions

In the early stages of a pandemic, antiviral agents will be in very short supply and vaccines
will not be available for many months. During this perio
d other non
-
medical interventions
could delay the national and international spread of the pandemic. This strategy of ‘buying
time' was discussed during the WHO Consultation on”Priority Public Health Interventions
Before and During an Influenza Pandemic” t
hat was held in March 2004.
8


A wide range of non
-
medical interventions


from personal hygiene and wearing masks to
quarantine and screening travellers


could potentially limit the transmission of the
pandemic

virus. Although many of these interventions were tested during the response to
the SARS outbreak, their use under the very different conditions of an influenza pandemic
has not been systematically evaluated. Their effectiveness will depend on the transmis
sibility
of the virus, its virulence, its attack rate in different age groups, the duration of virus
shedding, and the susceptibility of the virus to antiviral agents. In addition to their
effectiveness, the choice of non
-
medical interventions will be driv
en by their availability, cost,
ease of implementation and likelihood of acceptance by the public. Mathematical modelling
suggests that early detection of the first chains of human
-
to
-
human transmission might
provide a unique opportunity to prevent or at l
east delay further virus transmission. Because
the window of opportunity will close quickly, prior guidance on the most appropriate
interventions will be particularly important.


More than 30 non
-
medical public health interventions for controlling a pande
mic have been
suggested. It is unlikely that any single measure would have a meaningful impact on its own.
However, as all regions of the world are unlikely to be affected simultaneously during the
first wave of infection, opportunities for preventing the
spread of the pandemic virus to
these regions will probably remain open even after the pandemic has begun. During this
phase, simple measures such as hand washing, the use of masks and voluntary quarantine
for symptomatic persons could help reduce transmis
sion. Travel
-
related measures such as
exit screening of persons departing from affected areas might limit or delay international
spread. Knowing that a pandemic has emerged, the general public will probably be strongly
motivated to adopt personal preventiv
e behaviours, even though some of them might have
limited effectiveness. Some behaviours such as avoiding travel to affected areas will
probably be followed regardless of official recommendations. In all instances, implementing
6.2: Pandemic Influenza


6.2
-
14


these measures may require c
hanging public health laws at both national and international
levels.


Once efficient and sustained human
-
to
-
human transmission is established in a region,
containment of the virus will become virtually impossible and opportunities for averting
the pandem
ic or appreciably slowing its spread will end. Thus non
-
medical interventions
may be important 'additional control measures', but by themselves they will not be able to
stop or control a pandemic.


4.2.

Current Implementation of the Control Strategy


4.2.1.

The Interp
andemic Use of Influenza Vaccine in Europe and the Rest of the World

Supplies of influenza vaccine for the next pandemic will be critically dependent on the levels
of vaccine use during the interpandemic period. Thus, planning for pandemic vaccine
supply
requires an ongoing understanding of the global epidemiology of influenza
vaccination
54
.


An overview of the global production and distribution of influenza vaccines during the
interpandemic period has been provided by the Influenza Vaccine Supply (IVS) Int
ernational
Task Force. The IVS Task Force is sponsored by the International Federation of
Pharmaceutical Manufacturers Associations (IFPMA). Its report for the period 2000
-
2003 was
recently submitted to WHO (
see Table 6.2.1)
. In 2000, 230 million doses of
influenza vaccine
were distributed worldwide, 162 million (70%) of which were distributed in Canada, the U.S.,
Western Europe, Australasia and Japan. In 2004, vaccine distribution increased to 292 million
doses, of which 207 million (71%) were used in thes
e same countries. During this four
-
year
period, vaccine distribution increased 18% in Western Europe, 20% in Canada and the US,
25% in Australasia and 134% in Japan. For the rest of the world, vaccine distribution
increased from 69 million doses to 85 mill
ion doses, a 23% increase. For these other countries,
the use of influenza vaccine was largely limited to four countries in South America
(Argentina, Brazil, Chile and Uruguay), several countries in Central Europe (especially
Hungary and Poland), Russia an
d South Korea. Compared with 1994, when approximately
135 million doses of influenza vaccine were distributed worldwide, the level of vaccine
distribution ten years later had more than doubled.


6.2: Pandemic Influenza


6.2
-
15


Table 6.2.1: Global Distribution of Influenza Vaccine, 2000
-
2003


WHO Region






Total Doses Distributed (000s)*







______________________________________________






2000


2001


2002


2003


Europe





93,004


99,094


103,824 102,891

Western Europe



65,130


67,864


7
2,812


76,523


Central & Eastern


27,874


31,230


31,012


26,368


Europe


Americas




104,593 114,389 122,348 123,578


Canada




11,900


10,600



9,700


11,100


United States



68,000


78,345


82,705


84,913†

Mexico, Central



24,693


25,444


29,943


27,565

& South America




Western Pacific




29,916


39,424


41,795


61,189


Australia




3,415



3,632



4,087



4,357


Japan




12,491


17,440


20,802


29,253


New Zealand




646




627



668



715


Other countries



13,364


17,725


16,238


26,864


Southeast Asia





82



95



134



253


Eastern Mediterranean




1,043



1,201



1,163



1,540


Africa






2,291



2,530



1,298



1,230


GLOBAL TOTA
L


230,928 256,733 270,562 291,979*


*Individual reports on the numbers of doses of influenza vaccine distributed each year were
submitted by all IVS Task Force companies: Ave
ntis Pasteur, Aventis Pasteur MSD, Berna Biotech,
Ltd., Chiron/Powderject, CSL Limited, GSK Biological, Medimmune, Inc., Shire Biologicals, Solvay
Pharmaceuticals B.V. and Wyeth Vaccines. The Association of Japanese Biologicals Manufacturers
reported data
on behalf of four Japanese vaccine companies. In addition, data were gathered from
non
-
IVS Task Force companies located in Hungary, the Russian Federation and Romania. The Task
Force was unable to obtain information on doses produced and distributed in oth
er counties. The data
were reported for calendar years according to WHO Regions. For some regions, additional
information was obtained on vaccine distribution in countries within the regions.


†The data for the United States in 2003 do not include doses o
f cold
-
adapted, live
-
attenuated trivalent
influenza vaccine distributed by Medimmune. In 2003, Medimmune produced ~4
-
5 million doses of
CAIV
-
T and distributed ~830,000 doses, but only ~250,000 doses were actually sold.


Almost all of the world’s influenza
vaccine is produced in nine countries. Five of these
countries are EU Member States
-

France, Germany, Italy, The Netherlands and the UK. The
other four countries are Australia, Canada, Japan, and the US. (In Europe, a Swiss company
markets influenza vacci
ne, but it obtains its bulk virus from a vaccine company located in
Australia.) In 2003, these nine countries had only 12% of the world’s population, yet they
produced ~95% of the world’s influenza vaccine. Almost none of the doses produced in
6.2: Pandemic Influenza


6.2
-
16


Canada, Japa
n and the US were exported to other countries, and all of the 13.8 million doses
produced in Hungary, Romania and Russia were used domestically.


In 2003, companies located in five EU countries produced 190 million doses of influenza
vaccine, 65% of the w
orld’s supply. The EU companies produced 85% of the 93 million
doses used in countries outside Western Europe, Canada, the US, Australasia and Japan.


The IVS Task Force survey has provided an accurate summary of influenza vaccine
production and the distr
ibution of vaccine to different regions of the world. However, the
survey cannot provide country
-
specific information on vaccine distribution for more than a
few countries. Recently, the Macroepidemiology of Influenza Vaccination (MIV) Study
Group was esta
blished to provide this information. Individual investigators in each country
now submit data on the total number of doses of vaccine distributed each year. The data are
reported as rates of vaccine distribution per 1000 total population. Information has b
een
gathered from 40 countries and the results for 2002 are shown in Figure 6.2.1 (MIV Study
Group, unpublished observations). The largest user of influenza vaccine was Canada,
primarily because its largest province (Ontario) has a universal influenza vacc
ination
program. The Republic of Korea ranked third, in part because a vigorous vaccination
program was undertaken in the wake of the SARS outbreak in early 2003. Countries within
the European Union showed varying levels of vaccine use, with those in Weste
rn Europe
generally having higher levels than the new Member States of Central and Eastern Europe.
However, Russia and Hungary had higher levels of vaccine use that did several Western
European countries, and a few countries in South America used more vacc
ine that did some
European countries.


6.2: Pandemic Influenza


6.2
-
17


Figure 6.2.1: Rates of Influenza Vaccine Distribution in 40 Countries in 2002
1


Number of doses distributed per 1000 total population


All EU Member States and almost all other developed
and rapidly developing countries have
national recommendations to vaccinate elderly people and others with high
-
risk medical
conditions.
55

Nonetheless, ten
-
fold variations in vaccine use are still seen within the EU.



1

Member States of the European Union are shown in solid bars; non
-
EU countries are shown in the hatched bars.
No data were obtained for Cyprus, Esto
nia and Malta.

6.2: Pandemic Influenza


6.2
-
18


Factors that contribute to these variati
ons include different levels of understanding of the
health and economic consequences of influenza, the presence or absence of public programs
for vaccine delivery and vaccination reimbursement, and the views of small groups of policy
makers. In addition,
a number of underlying cultural factors are important.


The data provided by the IVS Task Force and the MIV Study Group document a reality of
enormous logistical and political importance for the Member States of the European
Union. Most countries in the
EU and virtually all non vaccine
-
producing countries in the
rest of the world are critically dependent on supplies of interpandemic influenza vaccines
produced in only five EU countries. This dependence will directly affect the availability
of supplies of
pandemic vaccines for the other 20 EU Member States and for all other
countries that do not have influenza vaccine companies of their own.


4.2.2.

The Interpandemic Use of Antivirals in Europe and the Rest of the World

There is very little epidemiological inform
ation available on the use of antiviral agents
worldwide. The M2 inhibitors have several disadvantages, have not been heavily marketed
and have fallen out of favour. The anti
-
neuraminidase agents, particularly oseltamivir, have
received more attention and
are the only agents that would be effective against the avian
H5N1 viruses. Only one company located in Switzerland produces oseltamivir, although it is
considering building one or more additional production sites in other countries. The time
needed to inc
rease production capacity in the current facility is at least 9
-
12 months, if not
longer.


There are no publicly available data on the distribution of oseltamavir in EU countries or in
the rest of the world. However, the EU and global production capacity
for this agent is
extremely limited. In 2003, approximately 7 million oseltamivir ‘treatments’ (one treatment is
a five
-
day course for an individual patient) were distributed by the manufacturer (Brown P,
Roche Pharmaceuticals, personal communication, 17 J
une 2004). Approximately half of the
treatments were used in Japan. The total number of ‘treatments’ was similar to the
population of the country where oseltamivir is produced. In the event of a pandemic, the
export of oseltamivir might be prohibited, and
consequently supplies will be available only
in countries that have stockpiled oseltamivir (at great expense) in advance.


Greater and more diversified manufacturing capacity for anti
-
neuraminidase agents is
needed, as are new and less expensive antiviral
agents.


4.2.3.


Affordability of the Interventions

Several years ago, influenza vaccines were sold in developed countries at relatively low
prices, but recent supply constraints and expanding markets have been accompanied by
increased prices. In Western Europe
, the current (2004) retail price to health care providers is
€ 5
-
16 per dose [Bertrand Verwee, personal communication, 18 August 2004]. In 2000, the
total cost of vaccinating an individual in three Western European countries was €15
-
30.
45

Despite recent price increases, the value of influenza vaccination is still regarded as very
high, even though annual revaccination is required. Cost
-
effectiveness analyses for three
Western European countries show that vaccina
ting elderly persons is highly cost
-
effective
and in some instances may even be cost saving.
45



6.2: Pandemic Influenza


6.2
-
19


There is little public knowledge about vaccine prices and the costs of vaccination programs
in the newer Member St
ates of the EU and in the rest of the world. In most developing
countries the cost of the vaccine probably puts influenza vaccination outside the range of
affordability for public vaccination programs. Nonetheless, the increase in vaccine use
documented fo
r many rapidly developing countries indicates that for large segments of the
populations in these countries, influenza vaccines are considered affordable.


Antiviral agents are considerably more expensive than influenza vaccines. Little is known
about the
ir current prices in all EU countries. However, in 2000 the cost of a five
-
day course
of anti
-
neuraminidase treatment ranged from € 30
-
40 in three Western European countries,
and a 4
-
week course of chemoprophylaxis cost € 130
-
215.
45

Chemoprophylaxis was 30
-
50
times more expensive than vaccination, although properly timed treatment of symptomatic
patients was reasonably cost
-
effective. Greater use of antivirals would eventually have the
effect of reducing their pr
ice, but it is unknown to what level prices would drop.



In the event of a pandemic, anti
-
neuraminidase agents could be stockpiled in bulk and
formulated for use when a pandemic threat is declared. Nonetheless, the basic cost of the
bulk drug for a five
-
d
ay treatment course would be at least € 7 and the cost of its formulation,
distribution and administration would add greatly to the total cost per person.


The current costs of antiviral agents represent a major obstacle to their supply and will
severely
limit their use in the control of pandemic influenza.

5.

Constraints to Better Control

5.1.

Interpandemic Period


Despite the effectiveness of global influenza surveillance, national and international
responses to influenza suffer from several weaknesses that coul
d have severe consequences
for public health in the event of a pandemic. Recent WHO
-
sponsored consultations have
identified several areas of concern.
8
,
53




There is an

urgent need for better understanding of the occurrence, epidemiology, and
health and economic burden of influenza in developing countries. Surveillance and
control activities in these countries receive little support, and as a result the WHO
surveillance
network has important geographical gaps. Health officials in these
countries have little available evidence for concluding that influenza is a significant
health problem and that policies for its control should be adopted.



Some countries in the European U
nion have made considerable progress in increasing
influenza vaccination coverage, particularly when operational targets have been set.
However, knowledge about the benefits of influenza vaccination has not been
translated into effective vaccination progra
ms in most Member States. At present,
only ~50 countries, mainly in the industrialized world, have policies for influenza
vaccination. Despite numerous studies demonstrating the safety and effectiveness of
vaccines, only 10

20% of people in high
-
risk group
s in these countries are vaccinated.
Vaccination coverage rates in developing countries are minimal. In addition,
vaccination rates among health care workers in direct contact with the elderly high
-
risk group are low, despite strong evidence that health ca
re workers contribute to
6.2: Pandemic Influenza


6.2
-
20


outbreaks in institutions caring for the elderly and are highly susceptible to infection
themselves.



No currently available influenza vaccines confer protection against all strains of the
three influenza virus subtypes that cause h
uman disease. Because each subtype
exhibits frequent antigenic drift, the vaccine formulation must be adjusted each year.
This change requires re
-
licensing of the vaccine and repeat vaccination. Thus
stockpiling influenza vaccine is not an option. In addit
ion, influenza vaccine
continues to be moderately expensive for people who live in developed countries and
its price is out of reach for most of those who live in developing countries.


Greater efforts are needed to implement current recommendations for i
nfluenza vaccination
in order to reach coverage levels specified by the World Health Assembly in its resolution on
influenza. Research on novel vaccines, vaccine delivery methods and production
technologies is needed to overcome the limitations of current
influenza vaccines.


5.2.

Pandemic Period


5.2.1.

Limitations of the Vaccination Strategy

If a new pandemic virus emerges within the next few years, several potential limitations in
the supply of pandemic vaccines immediately become apparent.
54

Pandemic vaccine
production will be totally dependent on the capacities of the existing vaccine companies in
the EU and the rest of the world. All of these companies currently produce their vaccines in
embryonated eggs.
56

If the interp
andemic use of vaccine increases in the next few years, the
production capacities of vaccine companies will increase in parallel, but the incremental
increase year
-
on
-
year will not be large. One new EU
-
based company is scheduled to enter
the market within
the next 2
-
3 years and it plans to market 40
-
50 million doses of cell culture
-
produced inactivated influenza vaccine each year. None of the other EU
-
based companies is
expected to have an appreciable capacity to produce cell culture vaccines within the nex
t five
years; it usually takes five or more years to build and obtain regulatory approval for a new
vaccine production facility. Given that five EU
-
based companies produced 190 million doses
of trivalent vaccine in 2003 (Table 6.2.1) and that an additional

40
-
50 million doses will soon
be added, the overall capacity of EU
-
based companies for pandemic vaccine production
within the next five years is unlikely to exceed the equivalent of ~250 million doses of
trivalent vaccine each year.


Because the pandemic
vaccine will almost certainly contain only the pandemic vaccine virus
(it will be a monovalent vaccine), it is possible that up to 750 million doses of same
-
strength
(15 µg HA) monovalent pandemic vaccine could be produced within the EU. However, most
if n
ot all people will not have been previously infected with a virus like the pandemic virus.
Because they will be immunologically naïve, they will require two doses of vaccine to be
fully protected
54
. Moreover, in

many if not most countries, public health authorities will want
to vaccinate everyone in their populations.
33
,,
54

This means that in the 25 EU countries, only
375 mi
llion people could be vaccinated with a ‘same strength’ monovalent vaccine, well
under the total EU population of 450 million. Further, when a pandemic virus appears,
government leaders in the five countries that have vaccine companies could be tempted to
‘nationalize’ their vaccine production facilities, citing national emergencies, to ensure that
there is enough vaccine to vaccinate their own populations.

6.2: Pandemic Influenza


6.2
-
21



If a pandemic vaccine is formulated to contain 15 µg HA, 100 million people in the 20 EU
countries
without vaccine companies will have to wait several months or more for
supplies of pandemic vaccines. Countries outside the EU that have traditionally been
supplied with interpandemic vaccines by EU
-
based companies might not be able to obtain
any supplies
of pandemic vaccines.


5.2.2.

Limitations of the Antiviral Strategy

One or more antiviral agents currently in use will likely be effective in the prophylaxis and
treatment of illness caused by a new pandemic virus. Important differences between the M2
inhibitors
and the neuraminidase inhibitors will require careful definition of their respective
roles in pandemic control. However, supplies of these agents will quickly be exhausted in the
first few weeks of the pandemic. Because these agents are relatively stable o
ver time, they
could be stockpiled. However, for most countries the cost of stockpiling will be a significant
burden.


All countries will need to consider the complementary use of vaccines and antiviral agents in
planning for various phases of pandemic co
ntrol. Vaccination will remain the primary means
of prevention once vaccines become available. Antivirals will have to be used in special
situations.
53

Countries will be able to meet their pandemic requirements
only if they make
plans for obtaining supplies of antivirals in advance. Manufacturers require regular
estimates of demand on which to base production plans, and the current market
-
based
system has limited or no surge capacity to respond to a sudden increa
se in demand. There is
currently no global estimate of the future demand for antiviral agents, and a global
distribution system for what will inevitably be limited supplies does not exist. Moreover, the
issue of liability for adverse reactions to antiviral

treatment has not been addressed.


In the event of a pandemic, supplies of antiviral agents will be available only to countries
that have stockpiled them (at great expense) in advance.

Greater and more diversified
manufacturing capacity for anti
-
neuramin
idase agents is needed, as are new and different
antiviral agents.

6.2: Pandemic Influenza


6.2
-
22


6.

Lessons Learned from Research into Pharmaceutical Interventions

6.1.

Vaccination Strategies


Within the past few years, several groups of European investigators have carefully explored
a promi
sing strategy for developing ‘pandemic
-
like’ vaccines that (1) induce protective levels
of antibodies when two doses are given to immunologically naïve subjects, and (2) could be
produced in abundant supply by vaccine companies using their existing facilit
ies
54
. The
strategy is based on using a lower dose of HA antigen and including an adjuvant. The initial
studies were conducted using a proprietary MF59 adjuvant
57

58

59

60
, but later studies have
used a simple alu
m adjuvant of the kind widely available and used by all vaccine companies
that produce childhood vaccines.
61
,
62

Vaccines against H2, H5 and H9 ‘pandemic
-
like’ viruses
have been tested. Both adjuvanted and non
-
adjuvanted vaccines have been produced using
bot
h whole virus and subunit virus preparations. The vaccines have been formulated with
HA concentrations as low as 1.875 µg per dose.
61
,

62

A single injection of one th
ese low
-
dose
vaccines primes the immune system and a second dose, usually given 3 weeks later, leads to
the development of protective levels of antibodies when measured after another 3 weeks.


How low the HA content of a pandemic vaccine can be set is unce
rtain, but an ‘antigen
sparing’ strategy has critical implications for the amounts of vaccine that could be produced
at any given time during the course of a pandemic vaccination program. For example, if the
world’s vaccine companies were told to produce a

monovalent alum
-
adjuvanted whole virus
pandemic vaccine with an HA content of 1.875 µg (i.e., 8
-
fold less than normal strength),
they could theoretically produce approximately 36 times more vaccine than normal. If
normally they would produce 130 million d
oses in a 6
-
month period, they would be able to
produce 4.68 billion doses of pandemic vaccine (130 x 3 x 1.5 x 8; see pandemic supply model

in Figure 6.2.2). This would be enough to vaccinate 2.34 billion people (2 doses), almost one
-
third the world’s pop
ulation. These estimates are hypothetical and they assume that the
pandemic virus would have similar growth/yield characteristics as current vaccine strains,
that the production facilities would be available, and that the immunogenic properties of the
pand
emic virus would be similar to those of the H2, H5 and H9 viruses already tested.
Nevertheless, this amount of vaccine would probably exceed the vaccine delivery capacities
of all of the world's health care systems. One should also consider the option of u
sing a
single low
-
dose priming strategy without a second dose. A one
-
dose strategy might be
sufficient to reduce the frequency of severe illness and death when the pandemic virus hits
an unprotected population. The clinical efficacy of these strategies cou
ld not be tested in man,
but could be evaluated using appropriate animal models.


The low
-
dose, alum
-
adjuvanted vaccine strategy is central to the thinking of all EU
vaccine companies. Most European and WHO experts consider it to be the most promising
app
roach for guaranteeing adequate supplies of pandemic vaccines for all EU Member
States and for all other countries that will depend on EU companies for supplies of
pandemic vaccines.


6.2: Pandemic Influenza


6.2
-
23


Figure 6.2.2: Pandemic Vaccine Supply Model for Global Production


0
1000
2000
3000
4000
5000
Trivalent
0
0
10
50
90
130
170
210
Monovalent
0
0
30
150
270
390
510
630
Whole virus
0
0
45
225
405
585
765
945
Adjuv. (8x)
0
0
360
1800
3240
4680
6120
7560
1
2
3
4
5
6
7
8
million D
* months
**doses / month
**
*
2 doses for 2.3 billion people
2 doses for 2.3 billion people
0
1000
2000
3000
4000
5000
Trivalent
0
0
10
50
90
130
170
210
Monovalent
0
0
30
150
270
390
510
630
Whole virus
0
0
45
225
405
585
765
945
Adjuv. (8x)
0
0
360
1800
3240
4680
6120
7560
1
2
3
4
5
6
7
8
million D
* months
**doses / month
**
*
2 doses for 2.3 billion people
2 doses for 2.3 billion people




= ten million doses per week, ● = 30 million doses per week,


= 45 million doses per
week and


㴠㌶〠浩llio渠n潳敳⁰敲⁷敥e⸠
卯畲u攺⁎ H敨浥⁥ ⁡l⸠G卋ⰠG敲浡湹m

6.2: Pandemic Influenza


6.2
-
24




Box 1: The US Approach to Developing a Pandemic Vaccine: Lessons for the EU


In June 20
04, the National Institutes of Health (NIH) in the US awarded contracts to Aventis Pasteur
(US) and Chiron Vaccines (UK) to produce pilot lots of monovalent H5N1 'pandemic
-
like' vaccines.
These vaccines will be formulated at two dosage strengths
-

15 µg an
d 45 µg of HA antigen (standard
and high
-
dose, respectively)
-

in order to comply with FDA requirements for currently licensed
influenza vaccines. They will be tested in the NIH Vaccine Trial and Evaluation Units. Public funding
will support the full costs

of this project.



The US currently has a domestic influenza vaccine production capacity of approximately 50 million
doses of trivalent vaccine per year. According to the NIH strategy, 50 million doses of domestically
produced trivalent inactivated vacci
ne would be equivalent to 150 million doses of standard
-
dose (15
µg HA) monovalent pandemic vaccine and 50 million doses of high
-
dose (45 µg HA) vaccine. For the
US to be able to offer two doses of standard
-
dose pandemic vaccine to each person (assume 300
million x 2 = 600 million vaccinations), domestic production of trivalent vaccine would have to
increase four
-
fold (and for a high
-
dose pandemic vaccine up to 12
-
fold) to reach the equivalent of 600
million doses of trivalent vaccine per year. To expect su
ch an expansion of domestic vaccine
production capacity within the next five years is not realistic.


The current NIH strategy for developing an H5N1 ’pandemic
-
like' vaccine appears to be based on (1)
the goal of determining the optimal dose of HA antigen

for an individual rather than an acceptably
immunogenic dose for a population, and (2) the assumption that a new pandemic virus will not
emerge for five or more years. The US government hopes to increase domestic capacity for producing
influenza vaccines
by accelerating the introduction of cell culture vaccine production and expanding
the supply of embryonated eggs, but these effort are almost certain to be of limited success within the
next five years.


From a global perspective, it would be more benefic
ial for pandemic vaccine development to focus on
ensuring that the largest possible supply of pandemic vaccine can be made available as quickly as
possible. A short
-
term development strategy should be based on existing egg
-
based production
capacity. Its go
al should be to determine the lowest amount of HA antigen that can be included in an
adjuvanted vaccine that will be acceptably immunogenic when given in a two
-
dose schedule to a
population. This alternative strategy would respond to the needs of people in

vaccine producing
countries and would provide millions of doses of pandemic vaccine for people in other countries.


Europeans can learn two lessons from the current US approach to developing pandemic vaccines.
First, vaccine development should focus on v
accines that are acceptably immunogenic for
populations and that can be produced in existing production facilities. Most European vaccine
experts already accept this strategy. Second, public funding is driving the development of
pandemic vaccines in the US
. Current evidence suggests that Europeans have yet to appreciate that
public funding will be essential for pandemic vaccine development in Europe.



6.2: Pandemic Influenza


6.2
-
25


6.2.

Reverse Genetics


There is a possibility that the next influenza pandemic could be caused by a highly
pa
thogenic avian virus.
1
,
32
,
33

In the first eight years following the 1997 outbreak of H5N1
avian influenza in Hong Kong,

no commercially viable human H5N1 vaccine could be
produced.

Since the early 1970s, vaccine reference strains have been prepared using the technique of
genetic reassortment. With this technique, embryonated eggs are co
-
infected with an
influenza virus co
nsidered most likely to cause epidemic disease and a high
-
growth strain of
influenza A/PR8 virus. Following subsequent cloning, a progeny genetic reassortant virus is
isolated that has two genes coding for the surface (HA and NA) antigens of the epidemic
v
irus and six genes derived from the A/PR8 virus that are associated with high growth.


Genetic reassortants have been essential to the success of influenza vaccine production for
more than 30 years, but they have disadvantages. The time needed to isolate
a genetic
reassortant suitable for commercial vaccine production can take many weeks. The
reassortants do not always grow efficiently in egg
-
based production systems. Importantly,
t
his technology cannot be used with highly pathogenic avian viruses because
the resulting
reassortants are highly pathogenic for embryonated eggs and may be capable of human
infection.

These reasons explain why no commercially viable seed strain for human H5N1
vaccine production has yet been prepared using genetic reassortment.


W
ithin the past two years,
reference strains suitable for producing human 'pandemic'
influenza vaccines have been prepared in several laboratories using the techniques of reverse
genetics (RG).
1
,
9
,
33
,
58

Using this technique, the polybasic amino acids associated with H5N1
virulence are removed from the HA cleavage site. Plasmids
containing the genes for the
avian virus HA and NA antigens are then cloned and transfected into Vero cells along with
plasmids containing the six A/PR8 genes. The progeny virus is rescued from cell culture,
purified, propagated in embryonated eggs and tes
ted for stability and pathogenicity. The
methods for preparing RG
-
engineered viruses are straightforward, the results are predictable
and the process can take as little as 10
-
20 days. Moreover, when used with avian viruses, the
resultant RG
-
engineered refe
rence strains can be used as seed strains for egg
-
based vaccine
production.


Reverse genetics has been used to prepare reference strains using human isolates of H5N1
viruses obtained during the 2003 and 2004 outbreaks of avian influenza. WHO has been
instr
umental in developing guidelines for safety testing of these reassortants and has
provided advice on risk assessment for vaccine manufacturers intending to use them
63

.


It is important that virologists working in WHO
-
affiliated laboratories and in vaccine

companies gain more experience with reverse genetics
-
engineered influenza viruses. This
will ensure that the time between the isolation of a new pandemic virus and the beginning of
full
-
scale vaccine production is minimized.


6.2: Pandemic Influenza


6.2
-
26


6.3.

Existing Research Resource
Flows


Two projects for influenza vaccine development have been funded by the EU. The 4
-
year
FLUPAN project (€ 2,100,000) was begun in January 2001. Its goal has been to develop better
methods to rapidly detect the emergence a pandemic virus in animals and

its spread in man,
and to more rapidly produce a safe and effective vaccine. The major focus of the research has
been to use reverse genetics to produce reference strains of vaccine viruses (mostly avian
viruses) to produce pilot lots of vaccines in cell
culture systems and to evaluate the
immunogenicity and safety of these vaccines in Phase I/II clinical trials. The investigators
have also produced libraries of reagents for the production and standardization of several
avian and swine virus vaccines and e
xplored the use of genetically modified mammalian
cells that express influenza virus proteins for future use in diagnostic tests. The 3
-
year
NOVAFLU project (€ 1,765,000) was begun in autumn 2002. Its goal is to develop more
effective strategies for vaccin
ation against interpandemic and pandemic influenza. The
investigators are developing better strategies for vaccine strain selection, exploring
alternative approaches for vaccine production in cell culture systems, considering several
novel vaccine candidat
es and evaluating animal model systems of influenza virus infection
to establish better laboratory correlates of clinical protection.


The EU Framework programme is currently open (until the 16
th

of November 2004) again for
new research proposals explorin
g post
-
genomic approaches to a pandemic vaccine. Studies
should focus on the development of a system that allows for rapid design of safe and
efficient vaccines and scale
-
up of production and should address the development of
improved adjuvants, standardis
ation of animal models and strategies for multi
-
centre
clinical vaccine evaluation in man.


The EU is also funding the VIRGIL project to monitor and evaluate the evolution of
resistance to antiviral agents in Europe.


In the U.S., the National Institute
of Allergy and Infectious Disease (NIAID) at the NIH
supports activities for developing and testing effective countermeasures against pandemic
influenza that range from basic and applied research to partnerships with industry. Current
NIAID projects includ
e developing a library of reference viruses and producing and
distributing reagents for vaccine standardization, research and surveillance. NIAID also
supports the production and clinical evaluation of different types of pandemic influenza
vaccines to asse
ss their safety and age
-
related immunogenicity. Inactivated and live
-
attenuated egg
-
based and non
-
egg based vaccines (e.g., DNA and recombinant protein
vaccines) are also being evaluated.

6.2: Pandemic Influenza


6.2
-
27


Recent NIAID activities include:




Evaluation of a recombinant mono
-
component (HA only) H5 vaccine in Phase I/II
clinical trials (1997 H5 strain)



Grant award to Aventis Pasteur to produce an inactivated cell culture
-
based H7
influenza vaccine



Evaluation of a Phase I inactivated subunit H9N2 vaccine (serology in process)



Aw
ard of contracts to Aventis Pasteur and Chiron to pilot lots of an inactivated 2004
H5N1 vaccine (both companies are licensed in the U.S.)



Award a contract to Chiron (Sienna, Italy) to evaluate an MF59 adjuvanted
inactivated H9N2 influenza vaccine


Suppo
rt for the development and testing of improved inactivated influenza vaccines and
new production technologies include the development of cell culture
-
based vaccine
technologies, broadly cross
-
protective influenza vaccines and the improvement of
inactivated

vaccines by assessing the role of adjuvants, alternate delivery systems and dose
range. Recent accomplishments include the production and clinical evaluation of the first
trivalent baculovirus
-
expressed influenza vaccine in a phase II clinical trail and p
hase I/II
clinical trials to enhance the effectiveness of inactivated influenza vaccines for the elderly.


NIAID also supports the development of new antiviral drugs against influenza. Activities
range from basic research to identify new drug targets,
in v
itro

and
in vivo

antiviral screening
programs, and the preclinical and clinical evaluation of new drugs.


The resources currently committed to this NIAID research program (excluding extramural
funding) are in the range of US$ 50
-
100 million. Additional fun
ding might become available
under the $ 5.4 billion Bioshield program.


There is little knowledge of funding levels for influenza research that is supported by
individual EU governments and by non
-
governmental organizations. Currently the world's
largest s
ource of non
-
governmental funding for all vaccine
-
related research is the Bill and
Melinda Gates Foundation in the US. The foundation has yet to fund research devoted to
influenza prevention and control.

7.

Pipeline of Products

7.1.

Pipeline for Influenza Vaccine
s


The most important new influenza vaccine product introduced in recent years
,

has been
Medimmune’s intranasal cold
-
adapted live
-
attenuated influenza vaccine (LAIV; FluMist).
Clinical trials have shown very promising clinical efficacy in children and you
nger adults
against infection with homotypic and heterotypic influenza viruses.
64

The LAIV product was
launched in the US in 2003
-
2004, but sales were far lower than had been planned for or
anticipated. Major reasons for this failure were the vaccine’s very

high price, the limited age
group (5 to 49 years) for which it was licensed, and the inconvenience of handling a product
that must be stored frozen. In future years, the company will market its LAIV product at a
lower price. Additional safety data will le
ad to recommendations for using it in children less
than 5 years of age. A fully liquid non
-
frozen preparation will also be forthcoming.
6.2: Pandemic Influenza


6.2
-
28


Medimmune’s LAIV is not yet being used in EU countries, but will probably be introduced
within the next few years. Howe
ver, it is unlikely that it will command a substantial share of
the European influenza vaccine market for many years to come.


All European vaccine companies are seriously considering investments in cell culture
vaccine production systems, and several hav
e built facilities that are already licensed or will
be licensed within the next few years. It is widely believed that one advantage of cell culture
production will be to free manufacturers from their dependence on supplies of embryonated
eggs.
64
,
65

In addition, it is believed that cell culture systems will allow companies to rapidly
increase vaccine production when confronted with a sudden increase in demand, as will
occur with a pandemic. Whether this anticipat
ed ‘surge capacity’ will materialize remains an
open question. Nonetheless, there can be little doubt that companies with a commercial need
to increase their vaccine production capacity will do so by building cell culture facilities. It
will take many year
s, however, before cell culture
-
produced vaccines command a substantial
share of the European or global influenza vaccine market. Vaccines produced in
embryonated eggs are likely to be the mainstay of influenza prevention for at least the rest of
this deca
de, if not longer.


Two European vaccine companies are collaborating on the development of a virosomal
influenza vaccine
.
66

Clinical trials have shown that this vaccine is safe and immunogenic, and
applications for registration are pending in at least two
countries.


In the US, a new influenza vaccine is being developed by a biotechnology company using a
recombinant baculovirus
-
expressed HA antigen that is prepared in insect cell culture
.
67

In an
early clinical trial, two doses of a monovalent H5 HA
-
contai
ning vaccine were poorly
immunogenic at relatively high doses (90 µg HA), but recent unpublished Phase II (b) dose
-
ranging studies of two doses of a trivalent HA vaccine (15, 45 and 135 µg for each HA) are
said to be more encouraging. Questions that still
must be addressed are the immunogenicity
of only one dose, the possible need for an adjuvant, the effect that the absence of an NA
antigen will have on its acceptability for registration and the cost of its production relative to
egg
-
derived vaccines.


As

mentioned earlier, several vaccine companies have been making preparations for
producing clinical lots of H5N1 and other 'pandemic
-
like' vaccines. However, progress has
been limited due to biosafety requirements, uncertainties regarding intellectual prope
rty
rights for the reverse genetics
-
engineered H5N1 reference strains and lack of public funds to
support the clinical trials.


An overview of some of the products in company pipelines is shown in Table 6.2.2.

6.2: Pandemic Influenza


6.2
-
29



Table 6.2.2: Overview of Pipeline Products
2


7.2.

Pipeline for Antiviral Agents


Little is know about pharmaceutical company pipelines for new antiviral agents. Interest in
their development may have waned as a result of the co
mmercial difficulties experienced by
companies that have already introduced anti
-
neuraminidase agents. One company has
essentially withdrawn from the market and another has discontinued its development
program. However, one pharmaceutical company in Japan
recently reported results of a
Phase I study of a long
-
acting neuraminidase inhibitor adminis
tered by inhalation.
68

Experimental studies showed complete protection of experimentally infected mice when
treated 7 days before infection, and Phase I studies in
man showed that this agent’s active
metabolite could be detected in urine up to 6 days after the inhalation of one dose. The
commercial dimensions of this company’s development program are unknown. Given its



2

Table contains information published on internet. The contents have not been checked with the companies and
may be incomplete.

Company

Sort of product/ development

Stage

Aventis

Alternative delivery system (intradermal)

Phase 1 finished


Cell culture

Long term

Chiron

Cell culture

MF59 adjuvanted subunit egg grown H5N3
vaccine

Phase 2

Phase 1 research

Protein Science

FluBlok

-

recombinant HA


Rec H5 HA vaccine

Phase 3 fall this
year

Phase 1 research


Recombinant Neuraminidase (Additive)

Phase 2 finished

Zymetx

ViraZYme: technology to be used for
diagnostics and antiviral development

Antivirals: animal
testing

Shire

Cell c
ulture


Baxter

Cell culture

Approved in NL

Crucell

Cell culture

Commercial
agreement with
Aventis

Solvay

Cell culture

Approved in NL


Virosomal influenza vaccine (with Berna)

Under approval in
NL and CH

BernaBiotech

Virosomal influenza vaccine (with S
olvay)


Under approval in
NL and CH

GSK

Subunit vaccine

Low dose subunit/whole virus alum adjuvanted
H2N2 and H9N2 vaccines

Phase 1

Phase 1 research

Biota / Sankyo

Long acting neuraminidase inhibitors

See text

EU vaccine
manufacturers

Pandemic ‘mock
-
u
p’ vaccines for EU licensing
(ie H5, H7, H9 or H2 vaccines)

Planning stage

6.2: Pandemic Influenza


6.2
-
30


simplicity of administration and its long
-
lastin
g activity, this and/or other similar antiviral
agents could have widespread applicability for the control of pandemic influenza.


7.3.

The Safety and Efficacy of Products in the Pipeline


Currently available influenza vaccines have a well
-
established record of

safety. Nonetheless,
concerns about safety are always present. The swine influenza vaccine used in the US in 1976
was associated with an increase in the occurrence of Guillain

Barre syndrome, although
vaccines used since then have been essentially free of

this association
.
69

More recently, an
inactivated vaccine produced by a Canadian company was associated with cases of an ocular
complication that was traced to a correctible change in the vaccine’s manufacturing process.
70

Also, an intranasally administered

inactivated vaccine produced by a European company
was quickly withdrawn from the market because it was associated with Bell’s palsy.
71

The
adverse effect was attributed to the adjuvant used in the vaccine, and the vaccine has not
been reintroduced into th
e market. There have been extensive safety studies of
Medimmune’s LAIV and no serious adverse events have yet been noted. The acute and long
-
term safety of vaccines still under development is not known. As with all other vaccines, rare
and delayed complica
tions of vaccination cannot be known without careful post
-
marketing
surveillance and evaluation of suspected adverse events.


Concerns have been raised about the safety of workers involved in vaccine production. One
relates to the safety of using a revers
e genetics
-
engineered vaccine strain in commercial
vaccine production facilities. A risk assessment sponsored by WHO provides reassurance on
this issue
63
.


In Europe, the EMEA has published its Note for Guidanc
e on dossier structure and content
for pandemic influenza vaccines marketing authorization applications.
7

(See appendices
6.
2.5

and
6.2.6
)
The document addresses the quality requirements, the non
-
clinical safety and
immunological requirements and the clinical requirement for ‘mock
-
up’
pandemic vaccines.
Because there will be no time to conduct clinical trials of a true pandemic vaccine,
immunogenicity and safety data should be obtained for 'mock
-
up vaccines' that are
developed and tested during the interpandemic period. These vaccines m
ust include viral
antigen(s) to which humans are immunologically naïve. Assuming the true pandemic
vaccine is similar to and is produced in the same way as the ‘mock
-
up’ vaccines, clinical data
from the core pandemic dossier can be extrapolated to the true

pandemic vaccine and it can
be quickly registered.


With few if any influenza antiviral agents in the pipelines of pharmaceutical companies,
there is no information on their safety.

6.2: Pandemic Influenza


6.2
-
31


8.

Research into New Pharmaceutical Interventions

8.1.

Vaccines with Broad Spec
trum and Long Lasting Immunity


In February 2004, WHO held a meeting on the “Development of Influenza Vaccines with
Broad Spectrum and Long
-
lasting Immune Responses”
72
. The goal of this meeting was to
identify critical scientific issues and gaps in knowled
ge that must be addressed in order to
accelerate the development of new influenza vaccines that induce broad spectrum and long
-
lasting immunity. A broadly protective vaccine that is affordable in developing countries
could be important in light of the avia
n influenza outbreak in Asia and concern that a virus
from this avian reservoir might acquire the capacity for human
-
to
-
human transmission and
result in a pandemic.


Vaccine Type

A broad spectrum influenza vaccine would offer protection against infections

caused by
divergent influenza virus types and subtypes and would also protect against infection
caused by an antigenically new virus characteristic of a pandemic. It would not need to be
updated each year because it would offer equal protection against in
fection with
antigenically drifted virus strains not perfectly matched (by HA and NA) with current
inactivated influenza vaccines. This would make the manufacturing process more flexible
and less time constrained. If the vaccine were also able to induce lo
ng
-
lasting immunity, the
current yearly vaccination strategy could be revised to one that would be easier to
implement in developing countries.


Currently available inactivated influenza vaccines cannot be used to protect children less
than 6 months of ag
e and are less than optimally protective in older adults. They must also
be reformulated and re
-
administered each year. However, they do induce a certain degree of
heterotypic immunity to infection with variants related to the vaccine virus. Increasing the

dose of HA correlates with an increasing magnitude, duration and cross
-
reactivity of anti
-
HA antibodies and these antibodies correlate with protection against disease. Increased
levels of antibody to the NA antigen also reduce the intensity of infection a
nd limit its
transmission to others. Given the importance of these two antibodies, improvements in
existing inactivated vaccines could be important. By inducing better antibody responses to
these two antigens, an improved inactivated vaccine could contribu
te to better heterotypic
immunity and provide longer
-
lasting protection against infection caused by antigenic
variants within a subtype.


In addition to anti
-
HA and NA antibodies, cytotoxic lymphocytes (CTL) also help to reduce
the intensity and duration
of viral shedding. Several invariant antigens (M1, NP, and
possibly others) induce CTL responses, and antibody to the invariant M2 protein may also
have an important role in protection. Vaccines containing these invariant antigens could
induce long
-
lasting

immunity and provide in advance significant protection against a yet
-
to
-
emerge pandemic virus.


6.2: Pandemic Influenza


6.2
-
32


Delivery Options and Adjuvants

Many of the disadvantages of current inactivated influenza vaccines could be overcome by
mucosal delivery.
72

Intranasal administration of influenza virus seems promising because
administration of antigens to the mucosa is required for optimal IgA antibody responses.
This route stimulates both mucosal and systemic immune responses. Muco
sal vaccine
delivery could facilitate vaccine use, especially in developing countries. However, several
obstacles stand in the way, including the need to develop an optimal delivery system,
overcoming concern about inducing immune tolerance, achieving a pr
oper balance between
IgA and IgG antibodies, and defining the need for adjuvants to improve antibody responses.
Despite a recent setback, the potential value of mucosal vaccination is sufficient reason to
continue research on this approach to vaccine deliv
ery.


Several adjuvants are available for improving immune responses to vaccines.
72

The choice of
adjuvant depends on the proposed antigen, the type of immune response required and the
target population for vacc
ination. Virosomal vaccines containing IL

2 or CpG as an adjuvant
have induced enhanced immune responses in clinical trials. In mice, cationic liposomes
containing antigens are highly immunogenic without added adjuvants. ISCOMS can induce
TH1 and TH2 respo
nses and have induced long
-
lasting immunity and increased immune
responses in both young and elderly subjects.



Several potential new conjugated vaccines prepared with the ectodomain of the influenza
M2 protein have induced homotypic and heterotypic immun
ity to infection by antigenic
variants within a subtype and by different influenza A subtypes
73
. Preclinical studies of this
‘universal’ influenza A vaccine in experimental animal models of infection have

been
promising
.
74



DNA vaccines that induce antibody

responses to surface antigens have been shown in
animal models to induce homologous protection, while DNA vaccines against conserved
internal proteins (NP, M1) induce broad, heterotypic protection against infections by
influenza A viruses of different sub
types.
72


Influenza virus infections can induce both broad spectrum and long
-
lasting immunity
against reinfection with an influenza virus within a subtype. This suggests that live
-
attenuated influenza vaccines (
LAIV) could induce similar protection and that this would be
due to immunity to viral components other than the hemagglutinin
75
. In mice, ferrets and
humans, LAIV have induced potent protection against both homotypic and antigenically
drifted viruses. Chil
dren benefit from LAIV but evidence for the superiority of LAIV over
inactivated vaccines in adults is mixed.


Regulatory Issues

Several difficult regulatory issues will have to be addressed before a new vaccine that
promises to induce cross
-
protective an
d long
-
lasting immunity can be licensed. Regulatory
authorities must be convinced that laboratory correlates of immunity provide reliable
evidence of protection. It is unlikely that a clinical trial to demonstrate true long
-
lasting
protection (e.g., more t
han five years) would be undertaken. Consequently, regulatory
officials will probably have to accept evidence of heterotypic protection over fewer years, as
was shown in the clinical trials of live
-
attenuated influenza vaccine.

6.2: Pandemic Influenza


6.2
-
33



More important will be the

decision on whether to regard a new cross
-
protective vaccine as a
replacement for or as a supplement to the current inactivated influenza vaccines. If regarded
as a replacement vaccine, licensure will likely depend on a Phase III clinical efficacy trial.
A
placebo
-
controlled trial could be conducted in healthy younger adults in whom serious
consequences of infection in the placebo group would not be expected. Such a trial would
not be able to determine whether the new vaccine would prevent hospitalization
and death.
A placebo
-
controlled trial in older adults could not be justified because infections would
have to occur in the placebo group to demonstrate the efficacy of the new vaccine, and they
could be severe or fatal. (None of the evidence for the effect
iveness of current inactivated
vaccines in preventing hospitalisation and death has come from placebo
-
controlled trials
conducted in community
-
dwelling older adults.
44

If evidence of efficacy were to be required

in older, high
-
risk individuals, the clinical trial would have to be structured to demonstrate
non
-
inferiority of the new vaccine compared with the inactivated vaccine. Such a trial would
be large, costly and difficult to justify. A placebo
-
controlled cli
nical trial in high
-
risk
individuals might be possible if the trial were conducted in a developing country where
there is little chance the inactivated vaccine could be introduced.


If a new vaccine is to be regarded as a supplemental vaccine, a clinical
trial designed to
demonstrate a significant degree of incremental improvement over the current inactivated
vaccine alone would also be large and costly. If laboratory correlates of protection were
convincing, such a vaccine might be licensed and incrementa
l and (more important) long
-
lasting protection demonstrated in long
-
term observational studies. Currently there is no
consensus on how a candidate vaccine that promises broad spectrum and long
-
lasting
protection is to be evaluated, but sooner or later this

question will have to be addressed.


8.2.

Newer Antiviral Agents



One new approach to the treatment of influenza focuses on short interfering RNAs (siRNAs).
RNA interference has been shown to suppress influenza virus replication
in vitro
. In
experimental in
fluenza infection in mice, siRNAs specific for highly conserved regions of the
nucleoproein (NP) of acidic polymerase molecules inhibit virus replication in the lungs and
protect against lethal challenge
.
76
,

77

Protection is not mediated by interferon. Impor
tantly,
siRNA protects against lethal challenge with highly pathogenic H5 and H7 avian influenza A
viruses.


Another possible approach to antiviral treatment and prophylaxis involves the NS1 protein.
H5N1 influenza is lethal because the NS1 protein makes
the virus resistant to the antiviral
effects of interferons and tumor necrosis factor alpha.
78
,
79

The NS1 protein could be evaluated
as a target for newer antiviral agents.


8.3.

Other Pharmaceuticals


Few laboratory and clinical investigators are currently st
udying the molecular
pathophysiology of influenza virus infection and the role of the innate immune system in the
response to infection
80
. Yet such understanding could help us develop new ways of reducing
the morbidity and mortality caused by interpandemic

and pandemic influenza. Recent
6.2: Pandemic Influenza


6.2
-
34


studies suggest that the biological basis for severe influenza in humans is associated with
virus
-
induced cyotokine dysregulation
81
. Avian H5N1 influenza viruses are potent inducers
of proinflammatory cytokines (e.g., TNF
-
alp
ha and interferon beta). High serum
concentrations of the chemokines interferon induced protein
-
10 (IP
-
10) and monokine
induced by interferon gamma (MIG) have also been reported in patients with H5N1 disease.


In addition to these laboratory findings, epi
demiologists recognize that influenza is
associated with an increased risk of hospitalizations for cardiovascular and cerebrovascular
diseases. Observational studies have documented reductions in hospitalization for
congestive heart failure, recurrent myoc
ardial infarction and stroke following influenza
vaccination.
44

Given these findings, new advances in the understanding of cardiovascular
treatments could have important implications for the prophylaxis and ther
apy of
interpandemic and pandemic influenza.


Much attention has been given recently to the positive effects of high intensity statin
treatment for coronary heart disease. These effects seem to be due to their anti
-
inflammatory
effects rather than their e
ffects on low
-
densit
y cholesterol lipoproteins. Whether prophylaxis
and/or treatment with statins or other commonly available therapeutic agents that affect the
innate immune system could modify the clinical course of human influenza is unknown.
However, i
n the event of a pandemic, antiviral agents will be largely unavailable and vaccine
supplies will be delayed. In these circumstances, it will be essential to know whether
commonly used treatments could affect, positively or negatively, the clinical course
of
pandemic virus infection.


8.4.

Institutions and Human Resources


In the last seven years, most of the European research on pandemic influenza vaccines has
been conducted by a few groups of dedicated investigators using funds obtained from either
commercia
l sources or national governments. The budgets for these projects have been
limited. Most of the world’s influenza vaccine is produced in the European Union and a
regulatory framework for pandemic vaccine development has been created by the EMEA.
There are

adequate numbers of European investigators and institutions to continue work on
improving existing influenza vaccines and developing new vaccines and antiviral agents.
However, if they are to be successful, they will have to have adequate and stable fundi
ng for
their research.

9.

Gaps and Opportunities for Pharmaceutical Research

The primary objectives of supporting new pharmaceutical research in the field of influenza is
to reduce the burden of yearly epidemics, to be better prepared to limit the health an
d
socioeconomic burden of the next pandemic and to ensure equal access to vaccines and
antiviral agents used in prevention and control. These objectives cannot be met by
pharmaceutical research alone. The success of these interventions will also depend gre
ater on
understanding of the burden of disease and the health and economic benefits of these
interventions.


Reducing the burden of pandemic influenza will not be possible by medical interventions
alone. In the early weeks after a pandemic virus emerges,
non
-
medical interventions may be
6.2: Pandemic Influenza


6.2
-
35


are the only interventions affordable in most countries. Slowing the spread of a pandemic
will depend on the available infrastructure for surveillance and early warning and
possibilities for the quick determination of the c
ausative agent. Although there are many
research opportunities in this area, this chapter has focused on medical interventions only.


The research agenda outlined below is divided into studies that should be carried out over
the next five years and studie
s that should be carried out over a longer period. A sharp
distinction cannot be drawn between the two. Because we do not know when the next
pandemic will occur, it is essential that both short
-

and long
-
term research be conducted
simultaneously. The three

most important priorities in this research agenda are outlined in
bold.


9.1.

Research to Be Carried Out in 5 Years



9.1.1.

Vaccines

The research agenda for vaccine development is based on the identified gaps in current
knowledge, as outlined earlier.




Evaluate dif
ferent types of monovalent inactivated influenza vaccines (whole
virus/split and subunit, adjuvanted/non
-
adjuvanted, and egg
-
derived/ cell culture
derived) and different vaccination schedules (one/two doses, different dose ranges)
using vaccines directed a
gainst different hemagglutinin (HA) subtypes considered
to have pandemic potential, especially H5N1, H7N7, H9N2 and H2N2. To ensure
the most economical use of limited vaccine supplies, the evaluation of a low
-
dose
priming strategy should be emphasized.



Eva
luate the safety and effectiveness of using reverse genetics to prepare reference
strains of these ‘pandemic
-
like’ viruses that can be used as seed strains by vaccine
companies in Europe and elsewhere to produce pilot lots of ‘pandemic
-
like’ vaccines.



Cont
inue to prepare libraries of reagents specific for a range of potential ‘pandemic
-
like’ viruses that can be used to test a future pandemic virus ahead of the time when
specific reagents directed against the pandemic virus become available.



Evaluate new me
thods of vaccination, including mucosal and "needle free" vaccine
delivery methods, that might offer improved immunogenicity and be more suitable
for mass vaccination programs.



Explore the use of different adjuvants and other new approaches (e.g., higher
doses
of HA antigen) to improving the antibody response to inactivated influenza vaccines
among elderly persons and those with immunocompromise.



Evaluate the role of maternal vaccination and the transplacental transfer of
neutralizing antibody in protecti
ng newborn infants against influenza.


9.1.2.

Antiviral Agents

The research agenda for antiviral agents is based on identified gaps in knowledge as
identified earlier.




Determine the minimally effective dose and duration for antiviral therapy using anti
-
neuramin
idase and other antiviral agents.

6.2: Pandemic Influenza


6.2
-
36




Determine whether use antiviral treatment reduces the occurrence of serious
consequences of influenza, such as hospital admission for pneumonia and other
influenza
-
related complications.



Evaluate the comparative effective
ness of the M2 inhibitors and neuraminadase
inhibitors and the importance of antiviral resistance when they are used in treatment
and prophylaxis.



Determine the minimally effective dosages and side effects of antiviral agents when
used in selected high
-
ri
sk populations, such as infants, pregnant women,
immunocompromised persons, and elderly persons with underlying disease.



Develop long
-
acting anti
-
neuraminidase agents that can be easily administered and
are much less expensive to produce.



Further explore t
he mechanisms of antiviral resistance to both classes of antiviral
agents and assess the biological consequences of resistance for transmissibility and
virulence.



Develop new and improved antiviral agents directed at the M2 and NA antigens
and explore pos
sibilities for developing other classes of antiviral agents directed at
other targets such as the NS1 and HA antigens


9.1.3.

Non
-
Pharmaceutical Research

The research agenda for non
-
pharmaceutical research is based on identified gaps in basic
knowledge of the im
mune response to vaccination, the molecular pathophysiology of
influenza virus infection and the role of the innate immune system in the host response to
infection.




Continue to explore how different components of the innate and adaptive immune
systems co
nfer protection against influenza following vaccination, giving special
attention to factors that determine heterotypic and heterosubtypic protection and the
contributions of CTL

based immunity.



Evaluate the molecular response to influenza virus infection

in cell culture systems
and the role of cytokines and other biological response mediators in determining the
outcome of infection. Evaluate also these responses in experimental infections in mice,
ferrets and primates.



Explore the effects of commonly avai
lable pharmaceutical agents that are known to
affect biological response mediators on the response to influenza virus infection both
in vitro

and
in vivo
.

6.2: Pandemic Influenza


6.2
-
37




Box 2: Reverse Genetics, Intellectual Property and Influenza Vaccination


Reverse genetics (RG) is

a promising technique for the rapid and safe production of influenza vaccine seed
strains. The practical advantages of reverse genetics over genetic reassortment are well known. However, there is
one essential difference between the two techniques: revers
e genetics is associated with patents. The intellectual
property (IP) rights for RG are held by at least two academic institutions and one pharmaceutical company, all
three of which are located in the United States. The patent holders have agreed that RG c
an be used to prepare
reference strains for research purposes. However, if RG
-
engineered seed strains are to be used for commercial
vaccine production, patent holders expect to be paid royalties.


The recent award of NIH contracts to Aventis Pasteur and Ch
iron to prepare pilot lots of H5N1 vaccine for
clinical testing highlights several problems related to intellectual property rights for reverse genetics. If we were
now facing a true H5N1 pandemic threat, an H5N1 pandemic vaccine would be needed, but most
vaccine
companies would be uncertain about the precise ownership of the IP rights for the RG
-
engineered seed strains
they would be called upon to use. A few companies have probably already undertaken their own RG patent
analyses, but no one should expect t
hem to disclose their findings. The US Department of Health and Human
Services recently conducted a patent search of its own and has formulated its future policy options, but they are
not publicly known. Even if they were, the US patent rights would apply
only to the US, since patent rights in
Europe and Japan are independent of those in the US. The status of European patents is not publicly known.


In the absence of knowing who owns the intellectual property for RG, it will be difficult for a vaccine comp
any to
enter into negotiations on royalty payments for pandemic vaccine production. If one company attempts to open
negotiations with only one patent holder, litigation by the other patent holders could follow. Moreover, if
presented with a pandemic threat
, the governments of countries with vaccine companies would probably exercise
compulsory use licenses. Royalty payments for using RG would be determined by governments and would not
be negotiated between patent holders and patent users. Even if there were
no problems with RG
-
IP, companies
with no previous experience using RG
-
engineered viruses might have difficulty obtaining regulatory approval for
the using them in their production facilities.


A strong argument can be made for resolving RG
-
IP ownership
be
fore

the next pandemic threat appears
54
,
82
. This
would allow companies to determine whether using RG
-
engineered seed strains would offer advantages for
vaccine production when compared with genetic reassortants.

Companies would have time to respond to
regulatory requirements to upgrade their production facilities. Since some European countries regard RG
-
engineered viruses as ‘genetically modified organisms’, there would be time for European vaccine companies to
r
esolve uncertainties over GMO issues with national regulatory authorities and with the public. Royalty
payments could be negotiated with the RG patent holders, avoiding litigation. However, several obstacles still
stand in the way.


Experts in intellectua
l property describe the influenza RG
-
IP issue as a classic example of market failure. Unless
the public sector provides a framework for RG
-
IP negotiations during interpandemic years, companies will not be
prepared to produce pandemic vaccines using RG
-
engi
neered reference strains. Moreover, because IP issues are
governed by national patent laws, any negotiating framework that is established must be international in scope.
The need for an international solution has been acknowledged by WHO
8
, but WHO can address the technical but
not the IP issues related to RG.


Because of its importance to the European and global supply of pandemic vaccine, efforts must be undertaken
immediately to solve the intellectual property
issues related to reverse genetics. An international solution is not
readily apparent. Political and technical support might be sought not only from EU Member States but also from
other institutions such as the Organization for Economic Cooperation and Dev
elopment (almost all countries
with vaccine companies are OECD Member States). The technical support of the World Intellectual Property
Organization and the WIPO Arbitration and Mediation Center could be especially helpful
83
. Whatever process is
chosen, ac
hieving a solution to the problem of intellectual property for reverse genetics represents an important
criterion for judging the world’s ability to achieve ‘good governance’ for global public health.
84


6.2: Pandemic Influenza


6.2
-
38


9.1.4.

Translational Research

The research agenda for trans
lational research is based on gaps identified in current
knowledge.




Remove obstacles to the use of reverse genetics to prepare seed strains for producing
‘pandemic
-
like’ vaccines and accelerate the introduction of this technology into the
production of i
nterpandemic vaccines. These obstacles include the status of
intellectual property rights, regulatory requirements (e.g., biosafety) for using these
viruses in vaccine production facilities and the acceptability of using these
‘genetically modified organis
ms’ by regulatory authorities and the public.



Conduct burden of disease studies in several EU Member States to determine the
impact of interpandemic influenza on influenza
-
related hospitalizations and death.
Special attention should be given to the elderl
y, young children and pregnant women.



Conduct yearly observational studies (case
-
control studies) in several EU Member
States on the effectiveness of influenza vaccination in reducing the occurrence of
influenza
-
related complications and death, following
an internationally designed
WHO protocol for such studies.



Explore the legal and political issues regarding liability for adverse events associated
with pandemic vaccination.



Undertake case
-
control studies during the next influenza season (or during past

influenza seasons where appropriate administrative databases exist) to determine
whether common treatments for cardiovascular and cerebrovascular diseases are
associated with reductions or increases in all influenza
-
related hospitalizations and
deaths, no
t just those associated with underlying cardiovascular or cerebrovascular
diseases. In addition, analyse the databases of large prospective randomized
controlled trials of cardiovascular therapies to determine whether subjects in the
treatment groups exper
ience reductions or increases in influenza
-
related events that
are independent of the effects of influenza vaccination.



Undertake studies of influenza virus infection in experimental animals to determine
whether treatment with commonly available medicatio
ns that affect the innate
immune system alter clinical illness and/or virus shedding. Special attention should
be given to the effects of treatment on the development of secondary bacterial
pneumonia.



Undertake
in vitro

cell culture studies to determine w
hether specific treatments before
or shortly after infection with influenza viruses affect the subsequent production of
proinflammatory cytokines and other biological response mediators.


9.2.

Research to be Carried Out in the Longer Term


The long
-
term researc
h agenda for vaccines, antiviral agents and non
-
pharmaceutical
research is based on identified gaps in current knowledge.




Continue to explore the potential for developing and clinically testing influenza
vaccines that provide heterotypic (broad spectrum)

and long
-
lasting protection,
including vaccines directed at the ectodomain of the M2 protein and other
conserved influenza proteins.

6.2: Pandemic Influenza


6.2
-
39




Conduct clinical studies comparing the efficacy of LAIV and IIV vaccines in children
and adults, including assessments of

potential correlates of immunity other than
serum anti
-
HA antibody and of the value of each type of vaccine for induction of
heterotypic immunity in the different age groups
85
.



Reassess efficacy and safety of DNA
-
based influenza vaccines using adjuvants an
d
new delivery systems. These vaccines have shown efficacy in pre
-
clinical studies and
are an attractive alternative to the current vaccines because large
-
scale production of
DNA vaccines would be easy, fast and inexpensive.



Continue to evaluate the short
and long
-
term occurrence of adverse events following
influenza vaccination and antiviral treatment.


9.3.

Research in Need of Increased Support


Most of the elements of the pharmaceutical and translational research agenda outlined above
are not included in or l
ikely to be included in pharmaceutical research traditionally carried
out by companies. Therefore, implementing this research strategy will require financial
support from public sources.


The current pipeline for new vaccine and antiviral agents is limit
ed because there are few
incentives for companies to develop a wider variety of new products. Several factors are
responsible for this:



No one knows when the next pandemic will occur. It is not commercially attractive
for a company to invest in the develop
ment of a product that may never be sold or a
technique that is of limited use during the interpandemic period.



Even if a potential pandemic vaccine could be of use in the interpandemic period (for
example, vaccinating poultry workers in Southeast Asia wit
h an H5N1 vaccine), it
would probably not be affordable in countries at greatest risk.



The current inactivated interpandemic vaccine needs to be re
-
administered every
year. Replacing the current vaccine with a long lasting vaccine would dramatically
decrea
se profits for the current manufacturers.



Currently one antiviral agent is superior to other antivirals regarding its effectiveness
and limited development of antiviral resistance. However, since there is only one
manufacturer and potentially a very great
demand, this company has little incentive
to look for alternative (cheaper) ways to make its product affordable to larger
populations.



There may be limited interest on the part of other pharmaceutical companies to
explore the possible impact of existing p
roducts or new antiviral agents because the
profits expected from their sale during the interpandemic period may be limited.


However, several factors might serve as positive incentives to drive the research agenda:




With an increasing interest in vaccinat
ing children, the development of influenza
vaccines that are more easily administered could be commercially attractive.



There is increasing interest in using reverse genetics during the interpandemic period.
This technique might increase a company’s capaci
ty to produce vaccine, reducing
production costs and increasing profit margins. In 2003, the circulating A/Fujian
strain could not be included in the Northern Hemisphere’s trivalent vaccine because
6.2: Pandemic Influenza


6.2
-
40


a high
-
growth genetic reassortant seed strain that could b
e used for vaccine
production was unavailable. However, an A/Fujian
-
containing seed strain was
produced using reverse genetics. This experience should serve as a stimulus to solve
intellectual property rights issues for reverse genetics during the interpan
demic
period.


All of the research gaps that have been identified meet the requirements for public support
by the European Union.


9.4.

The Comparative Advantage of the EU


Most of the world’s largest influenza vaccine companies are located in the EU and ther
e is
a global dependence on the influenza vaccines produced in the EU.

This constitutes a
compelling argument for EU support for the research agenda described in this

proposal.

The research will require a level of public funding beyond that which can be ex
pected from
individual EU Member States. Such support will bring added value to the EU because it:




Specifically addresses gaps in knowledge within Europe,



Responds to European legislation, and



Should result in findings that will benefit to all Member St
ates within the European
Union


Currently, most of the public support for developing pandemic vaccines and antiviral agents
is being provided by the US government. There may be additional (political) arguments for
obtaining public support for this research

agenda in order to ensure that European citizens
also benefit from the progress being made.


Among the many topics outlined in the research agenda above, three should be given
highest priority:




Evaluate different types of monovalent inactivated influen
za vaccines (whole
virus/split and subunit, adjuvanted/non
-
adjuvanted, and egg
-
derived/ cell culture
derived) and different vaccination schedules (one/two doses, different dose ranges)
using vaccines directed against different hemagglutinin (HA) subtypes c
onsidered
to have pandemic potential, especially H5N1, H7N7, H9N2 and H2N2. In particular,
to ensure the most economic use of a limited vaccine supply, a low
-
dose priming
strategy should be investigated.



Continue to explore the potential for developing inf
luenza vaccines that provide
heterotypic (broad spectrum) and long
-
lasting protection, including vaccines
directed at the ectodomain of the M2 protein and other conserved influenza
proteins.



Develop new and improved antiviral agents directed at the M2 and
NA antigens
and explore possibilities for developing other classes of antiviral agents directed at
other targets such as the NS1 and HA antigens.


Public funding provided by the European Union to support this research agenda will ensure
that Member States
are better able to conduct programs for the prevention and control of
6.2: Pandemic Influenza


6.2
-
41


interpandemic and pandemic influenza. By supporting this research, the European Union
will fulfil its responsibilities for maintaining the health and economic wellbeing of all
Europeans
and contribute to the health and wellbeing of people in other countries
throughout the world.

6.2: Pandemic Influenza


6.2
-
42


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