From The Influenza Report - Vaccines

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From The Influenza Report - Vaccines

http://www.influenzareport.com/ir/vaccines.htm

better formatting of charts at webpage

Vaccines

Korsman

Introduction

Vaccines are apathogenic entities that cause the immune system to respond

in such a way, that when it encounters the specific pathogen represented by

the vaccine, it is able to recognise it - and mount a protective immune

response, even though the body may not have encountered that particular

pathogen before.

Influenza viruses have been with mankind for at least 300 years, causing

epidemics every few years and pandemics every few decades. They result in

250,000 - 500,000 deaths, and about 3-5 million cases of severe illness

each year worldwide, with 5-15 % of the total population becoming infected

(WHO 2003). Today, we have the capability to produce 300 million doses of

trivalent vaccine per year - enough for current epidemics in the Western

world, but insufficient for coping with a pandemic (Fedson 2005).

The influenza vaccine is effective in preventing disease and death,

especially in high risk groups, and in the context of routine vaccination,

the World Health Organization reports that the " influenza vaccine is the

most effective preventive measure available " (WHO 2005e). With regard to

the present fear of an imminent influenza pandemic, " Vaccination and the

use of antiviral drugs are two of the most important response measures for

reducing morbidity and mortality during a pandemic. " (WHO 2005d).

Vaccine Development

History

The concept of vaccination was practiced in ancient China, where pus from

smallpox patients was inoculated onto healthy people in order to prevent

naturally acquired smallpox. This concept was introduced into Europe in the

early 18th century, and in 1796, Jenner did his first human

experiments using cowpox to vaccinate (vacca is Latin for cow) against

smallpox. In 1931, viral growth in embryonated hens' eggs was discovered,

and in the 1940s, the US military developed the first approved inactivated

vaccines for influenza, which were used in the Second World War (Baker

2002, Hilleman 2000). Greater advances were made in vaccinology and

immunology, and vaccines became safer and mass-produced. Today, thanks to

the advances of molecular technology, we are on the verge of making

influenza vaccines through the genetic manipulation of influenza genes

(Couch 1997, Hilleman 2002).

Yearly Vaccine Production

All vaccines in general use today are derived from viruses grown in hens'

eggs, and contain 15 ?g of antigen from each of the three strains selected

for that year's vaccine - two influenza A strains (H1N1 and H3N2) and one

influenza B strain. From the selection of the strains to be used in the

vaccine, all the way to the final vaccine, is a lengthy process that may

take up to 6-8 months.

Selection of the yearly vaccine strain

Throughout the year, 110 national influenza surveillance centres and 4 WHO

collaboration centres in 82 countries around the world watch the trends in

circulating strains of influenza. Genetic data is collected, and mutations

identified. The WHO identifies the strains that are likely to most resemble

the strains in circulation during the next year's winter seasons, and this

information is shared with vaccine producers, who begin preparation for

vaccine production.

This decision is made each year in February for the following northern

hemisphere winter and September for the following southern hemisphere

winter. Details of the planned February 2006 meeting can be seen on the WHO

website (WHO 2005k).

For the northern hemisphere winter season from the end of 2004 to the

beginning of 2005, the recommendations were as follows (WHO 2005h-i):

* an A/New Caledonia/20/99(H1N1)-like virus

* an A/Fujian/411/2002(H3N2)-like virus

* a B/Shanghai/361/2002-like virus

For the southern hemisphere winter season of mid-2005, the recommendations

were:

* an A/New Caledonia/20/99(H1N1)-like virus

* an A/Wellington/1/2004(H3N2)-like virus

* a B/Shanghai/361/2002-like virus

For the northern hemisphere winter season of 2005-2006, the recommendations

are:

* an A/New Caledonia/20/99(H1N1)-like virus

* an A/California/7/2004(H3N2)-like virus

* a B/Shanghai/361/2002-like virus

For the southern hemisphere winter season of mid-2005, the recommendations

are:

* an A/New Caledonia/20/99(H1N1)-like virus

* an A/California/7/2004(H3N2)-like virus

* a B/Malaysia/2506/2004-like virus

For example, A/New Caledonia/20/99(H1N1) means that it is an influenza A,

type H1N1, the 20th isolate from New Caledonia in 1999. One can see that

the H1N1 influenza A in the vaccine still represents the circulating

strain, while the H3N2 virus has changed over time. Obviously,

A/Fujian/411/2002 was not a good prediction in 2004. As a matter of fact,

the rate of vaccine failure was unusually high during the winter season

2004/2005.

Processes involved in vaccine manufacture

Shortly after the WHO announces the anticipated circulating strains for the

coming season, vaccine manufacturers start making the new vaccine strain.

If the strain chosen to be represented in the vaccine is the same as that

used in the previous vaccine, the process is faster.

First, the CDC, or other reference source, take the strains to be used and

grow them in combination with a strain called PR8 (H1N1 A/PR/8/34) which is

attenuated so that it is apathogenic and unable to replicate in humans

(Beare 1975, Neumann 2005). This allows reassortment to occur, resulting in

a virus containing six PR8 genes along with the haemagglutanin (HA) and

neuraminidase (NA) of the seasonal strain. This new virus is then incubated

in embryonated hens' eggs for 2-3 days, after which the allantoic fluid is

harvested, and the virus particles are centrifuged in a solution of

increasing density to concentrate and purify them at a specific density.

Then, the viruses are inactivated using formaldehyde or ?-propiolactone,

disrupted with detergent, and the HA and NA are purified. Finally, the

concentrations are standardized by the amount of haemagglutination that

occurs (Hilleman 2002, Potter 2004, Treanor 2004).

In about June/July, the strains are tested to ensure adequate yield,

purity, and potency. After this, the three strains - two influenza A

strains and one influenza B strain, which were all produced separately -

are combined into one vaccine, their content verified, and packaged into

syringes for distribution.

Production capacity

At present, the world has a production capacity of about 300 million

trivalent influenza vaccines per year, most of which is produced in nine

countries - Australia, Canada, France, Germany, Italy, Japan, the

Netherlands, the United Kingdom, and the United States. In 2003, only 79

million doses were used outside of these countries and Western Europe. A

further 13.8 million vaccines were produced and used locally in Hungary,

Romania, and Russia (Fedson 2005).

Approximately 4-5 million doses of the live attenuated virus vaccine are

produced per year.

Types of Influenza Vaccine

The different types of vaccines in use today for influenza can be divided

into killed virus vaccines and live virus vaccines. Other vaccines of these

two types are under development, as well as some that do not fall into

either category, where a degree of genetic manipulation is involved.

Killed vaccines

Killed virus vaccines can be divided into whole virus vaccines, and split

or subunit vaccines.

Whole virus vaccines were the first to be developed. The influenza virus

was grown in the allantoic sac of embryonated hens' eggs, subsequently

purified and concentrated using red blood cells, and finally, inactivated

using formaldehyde or ?-propiolactone. Later, this method of purification

and concentration was replaced with centrifuge purification, and then by

density gradient centrifugation, where virus particles of a specific

density precipitate at a certain level in a solution of increasing density.

Subsequently, filter-membrane purification was added to the methods

available for purification/concentration (Hilleman 2002, Potter 2004).

Whole virus vaccines are safe and well tolerated, with an efficacy of 60-90

% in children and adults.

Split vaccines are produced in the same way as whole virus vaccines, but

virus particles are disrupted using detergents, or, in the past, ether.

Subunit vaccines consist of purified HA and NA proteins, with the other

viral components removed. Split and subunit vaccines cause fewer local

reactions than whole virus vaccines, and a single dose produces adequate

antibody levels in a population exposed to similar viruses (Couch 1997,

Hilleman 2002, Potter 2004). However, this might not be sufficient if a

novel pandemic influenza virus emerges, and it is believed that two doses

will be required.

Inactivated influenza virus vaccines are generally administered

intramuscularly, although intradermal (Belshe 2004, 2004, Kenney

2004) and intranasal (mucosal) routes (Langley 2005) are being investigated.

Live vaccines

Cold-adapted live attenuated influenza virus (CAIV) vaccines, for

intranasal administration, have been available in the USA since July 2003,

and in the former Soviet Union, live attenuated influenza vaccines have

been in use for several years. The vaccine consists of a master attenuated

virus into which the HA and NA genes have been inserted. The master viruses

used are A/Ann Arbor/6/60 (H2N2) and B/Ann Arbor/1/66 (Hoffman 2005, Palese

1997, Potter 2004). The vaccine master virus is cold-adapted - in other

words, it has been adapted to grow ideally at 25 degrees Celsius, which

means that at normal human body temperature, it is attenuated. The

adaptation process has been shown to have caused stable mutations in the

three polymerase genes of the virus, namely PA, PB1, and PB2 (Hilleman

2002, Potter 2004).

The advantages of a live virus vaccine applied to the nasal mucosa are the

development of local neutralising immunity, the development of a

cell-mediated immune response, and a cross-reactive and longer lasting

immune response (Couch 1997).

Of concern in the CAIV vaccine, is the use in immunocompromised patients

(safety ?) and the possible interference between viral strains present in

the vaccine which might result in decreased effectiveness. Damage to

mucosal surfaces, while far less than with wild-type virulent influenza

viruses, may lead to susceptibility to secondary infections. Safety issues,

however, do not seem to be a problem in immunocompetent individuals. Of

greater concern for the future is the possibility of genetic reversion -

where the mutations causing attenuation change back to their wild-type

state - and reassortment with wild-type influenza viruses, resulting in a

new strain. However, studies done to test for this have not detected

problems so far (Youngner 1994).

Vaccines and technology in development

It is hoped that cell culture, using Madin-Darby Canine Kidney (MDCK) or

Vero (African green monkey kidney) cells approved for human vaccine

production, may eventually replace the use of hens' eggs, resulting in a

greater production capacity, and a less labor-intensive culturing process.

However, setting up such a facility takes time and is costly, and most

vaccine producers are only now beginning this process.

Reverse genetics allows for specific manipulation of the influenza genome,

exchanging genome segments for those desired (Palase 1997, Palese 2002b).

Based on this method, several plasmid-based methods (Neumann 2005) for

constructing new viruses for vaccines have been developed, but are not yet

in use commercially. A number of plasmids, small circular pieces of DNA,

containing the genes and promoter regions of the influenza virus, are

transfected into cells, which are then capable of producing the viral

genome segments and proteins to form a new viral particle. If this method

could be used on a larger scale, it may simplify and speed up the

development of new vaccines - instead of the cumbersome task, for the live

attenuated vaccines, of allowing reassortment in eggs, and then searching

for the correct reassortment (6 genes from the vaccine master strain, and

HA and NA from the selected strain for the new vaccine), the vaccine

producers could simply insert the HA and NA genes into a plasmid.

DNA vaccines have been tested for a variety of viral and bacterial

pathogens. The principle upon which the vaccine works is inoculation of the

virus with DNA, which is taken up by antigen presenting cells, allowing

them to produce viral proteins in their cytosol. These are then detected by

the immune system, resulting in both a humoral and cellular immune response

(Hilleman 2002).

Vaccines to conserved proteins have been considered, and among the

candidates are the M2 and the NP proteins. It is hoped that, by producing

immunity to conserved proteins, i.e. proteins that do not undergo antigenic

change like HA and NA do, a vaccine can be produced that does not need to

be " reinvented " each year. This is also on the WHO's agenda for a pandemic

vaccine (Couch 2005). Such vaccines have been shown to be effective in

laboratory animals, but data are not available for human studies. " Generic "

HA-based vaccines, aimed at conserved areas in the protein, are also being

considered (Palese 2002b).

Adjuvants have been used in a number of vaccines against other pathogens,

and are being investigated for a role in influenza vaccines. The purpose of

adjuvants is to increase the immune response to the vaccine, thus allowing

either a decrease in antigen dose, a greater efficacy, or both. Alum is the

only adjuvant registered in the United States, and MF59, an oil/water

emulsion, has been used in influenza vaccines in Europe since 1997 (Wadman

2005). A vaccine using the outer membrane proteins of Neisseria

meningitidis as an adjuvant has shown success in early clinical trials

(Langley 2005).

Attenuation by deletion of the gene NS1 or decreasing the activity of NS1

is being investigated. NS1 produces a protein that inhibits the function of

interferon alpha (IFN?). If a wild-type influenza virus infects a person,

the NS1 protein antagonises IFN?, which has an antiviral effect. An

infection with a NS1-deficient virus would quickly be overcome by the

immune system, hopefully resulting in an immune response, but with no

symptoms (Palese 2002b).

Replication-defective influenza viruses can be made by deleting the M2 or

the NS2 genes (Hilleman 2002, Palese 2002b). Only a single round of

replication can occur, with termination before the formation of infectious

viral particles. Protein expression will result in an immune response, and

there is no danger of infection spreading to other cells or people.

Efficacy and Effectiveness

Antibody response, determined by measuring haemagglutination inhibition

titers, is used as a serological marker of the immunological response to

the vaccine, or efficacy. In persons primed by previous exposure to viruses

of the same subtype, antibody response is similar for the various types of

vaccines. However, in persons without such previous exposure (either

through vaccination or through natural infection), response is poorer in

the split and subunit vaccines, where two doses are required.

In healthy primed adults, efficacy after one dose ranges from 80-100 %,

while in unprimed adults, efficacy enters into this range after two doses.

In other populations, efficacy is lower:

Table 1: Efficacy of influenza vaccination*

Population

Efficacy

Healthy adults and most children

80-100%

Renal failure (chronic)

66 %

Renal transplant

18-93%

Haemodialysis

25-100%

Bone marrow transplant

24-71%

Cancer

18-60%

HIV infection

15-80%

*adapted from Pirofzki 1998, Potter 2004, Musana 2004

Effectiveness, usually defined by prevention of illness, is generally

slightly lower, with 70-90 % effectiveness in children and healthy adults

under the age of 65. In those above 65 years of age, a lower rate of 30-40

% is seen. However, the vaccine is 20-80 % effective in preventing death

from influenza in persons older than 65 years, with revaccination each year

reducing mortality risk more than a single vaccination (Govaert 1994, Gross

1995, Nichol 1994, Partriarca 1985, Voordouw 2004). In patients with

previous myocardial infarctions (MI), a study by Gurfinkel et al. (2004)

showed a reduction in the one year risk of death (6 % in the vaccinated

group, 13 % in the control group) and combination of death, repeat MI, or

rehospitalisation (22 % versus 37 %), possibly due to a non-specific effect

of immune responsiveness. Further studies are planned to evaluate the

impact of influenza vaccination on acute coronary syndromes.

Vaccination of caregivers against influenza also reduces the exposure of

vulnerable populations to influenza.

Studies have been done on effectiveness in terms of health benefits and

cost in several healthy populations (Bridges 2000, Langley 2004, Monto

2000, Wilde 1999). They suggest that, while individual health benefits from

vaccination certainly exist, as do reductions in days absent from work,

vaccinating healthy working adults may not provide cost savings when

compared to loss of productivity and days taken off due to illness.

Vaccinating health care professionals is recommended, not only because of

health benefits and reduced days absent from work, but because it is

believed that hospital employees tend to report to work in spite of having

an acute febrile illness. Previous studies have shown that vaccinating

health care professionals reduces nursing home and hospital-acquired

influenza infections (Pachuki 1989, Potter 1997).

Side Effects

Guillain-Barré Syndrome is seen as the most dangerous side effect of

influenza vaccines, aside from manifestations of egg allergy. It is,

however, rare: the annual reporting rate decreased from a high of 0.17 per

100,000 vaccinees in 1993-1994 to 0.04 in 2002-2003 (Haber 2005).

The most frequent side effects are pain, redness, and swelling at the

injection site (10-64 %) lasting 1-2 days, and systemic side effects such

as headache, fever, malaise, and myalgia in about 5 % of vaccinees (Belshe

2005, Musana 2004, Potter 2004). These side effects are largely due to a

local immune response, with interferon production leading to systemic

effects. Local side effects are more common with whole virus vaccines than

subunit or split vaccines, and also more common with intradermal

vaccination than intramuscular vaccination.

Since the inactivated vaccines do not contain live virus, they cannot cause

influenza infection - often respiratory illness is incorrectly attributed

to influenza vaccination. Live attenuated virus vaccines do contain live

virus; however, side effects are rare, with a runny nose, congestion, sore

throat, and headache being the most commonly reported symptoms, with

occasional abdominal pain, vomiting, and myalgia (Musana 2004). They are

not recommended for use in children below the age of 5 years, although a

study by Piedra et al. (Piedra 2005) showed safety in children above the

age of 18 months. Controversies have arisen around the possibility of

exacerbated asthma in children between 18-34 months of age (Bergen 2004,

Black 2004, Glezen 2004). It should be noted, however, that these vaccines

should be avoided in immunocompromized patients.

Recommendation for Use

Indications

Groups to target

The primary groups to be targeted for vaccination can be memorized with an

easy mnemonic - FLU-A (Musana 2004).

F - facilities such as nursing homes or chronic care facilities.

L - likelihood of transmission to high risk persons - healthcare workers

and care providers can transmit influenza to patients, as can other

employees in institutions serving the high risk population groups, as well

as people living with individuals at high risk.

U - underlying medical conditions such as diabetes mellitus, chronic heart

or lung disease, pregnancy, cancer, immunodeficiency, renal disease, organ

transplant recipients, and others.

A - age > 65 years, or between 6-23 months of age

Since the risk of influenza rises linearly from the age of 50 years, some

promote the vaccination of those aged between 50 and 64 in addition to

those above 65 years of age. In a study of health professional attitudes to

such a policy in England, both sides were equally divided (ph 2005).

Vaccination for those above 50 years of age is recommended in the USA,

while all those above 6 months are offered vaccination in Canada.

In the era of a potentially pending pandemic, other groups also have

importance for targeting - poultry workers in the Far East are being

vaccinated to prevent infection with circulating human influenza strains.

This vaccine will not protect against avian influenza strains, but will

help prevent dual infection, if infection with avian influenza does occur,

thereby reducing opportunities for reassortment of two strains in one human

host. For the same reason, travelers to areas where avian influenza is

present are advised to be vaccinated against human influenza (Beigel 2005).

Guidelines

The World Health Organisation makes the following recommendations on who

should receive influenza vaccines (WHO 2005b-c, WHO 2005f):

* Residents of institutions for elderly people and the disabled.

* Elderly, non-institutionalized individuals with chronic heart or lung

diseases, metabolic or renal disease, or immunodeficiencies.

* All individuals > 6 months of age with any of the conditions listed

above.

* Elderly individuals above a nationally defined age limit,

irrespective of other risk factors.

Other groups defined on the basis of national data and capacities, such as

contacts of high-risk people, pregnant women, healthcare workers and others

with key functions in society, as well as children aged 6-23 months.

The CDC guidelines are similar, with a few additions (Harper 2004, CDC 2005) -

* Residents of nursing homes and long-term care facilities

* Persons aged 2-64 years with underlying chronic medical conditions

* All children aged 6-23 months

* Adults aged > 65 years - high risk

* Adults aged > 50 years - recommended

* All women who will be pregnant during the influenza season

* Children aged 6 months - 18 years on chronic aspirin therapy

* Healthcare workers involved in direct patient care

* Out-of-home caregivers and household contacts of children aged 0-23

months

South Africa has the following guidelines (summarised from Schoub 2005),

dividing the population into 4 groups who may receive the vaccine -

* Category 1 - At risk persons (i.e. at risk for complications of

influenza)

o All persons over the age of 65 years

o Persons with chronic pulmonary or chronic cardiac disease

o Immunosuppressed persons

o Pregnancy - women who will be in the second or third trimester

during the winter season. Vaccination is contraindicated in the first

trimester.

o Children with chronic pulmonary or cardiac diseases as well as

immunosuppressed children. Children on aspirin therapy should also be

immunised because of the risk of Reye's syndrome.

* Category 2 - Contacts of high-risk persons - healthcare workers,

caregivers of the elderly and high-risk patients, and persons living with

high risk persons.

* Category 3 - Workplace vaccination.

* Category 4 - Personal protection.

Australian guidelines (Hall 2002) -

* Everyone 65 years of age and older

* Aboriginal and Strait Islander people 50 years of age and older

* People six months of age and older with chronic illnesses requiring

regular medical follow-up or hospitalisation in the previous year

* People six months of age and older with chronic illnesses of the

pulmonary or circulatory systems (except asthma)

* Residents of nursing homes or long-term care facilities

* Children and teenagers aged six months to 18 years on long-term

aspirin therapy (because aspirin treatment puts them at risk of Reye's

syndrome if they develop a fever)

* Healthcare and other workers providing care to the high-risk groups

above.

* Other groups for whom influenza immunisation should be considered

include pregnant women, overseas travelers and persons infected with HIV.

Most countries with guidelines will have similar recommendations. Canada,

although having similar recommendations for priority groups, actively

encourages vaccination of everyone above the age of 6 months (Orr 2004).

If a pandemic becomes a reality, recommendations will likely extend to

everyone. However, frontline workers such as healthcare personnel, as well

as police forces and military personnel, might be high priority targets.

Contraindications

Contraindications to influenza vaccination are:

* egg allergy - the vaccines are made in eggs, and, although rare,

severe allergic reactions such as anaphylaxis can occur.

* acute febrile illness - vaccination should be delayed. Minor

illnesses such as mild upper respiratory tract infections or allergic

rhinitis are not contraindications.

* first trimester of pregnancy has in the past been seen as a

contraindication. However, the ACIP recommendations changed in 2004, and

currently the guidelines say that vaccination can occur in any trimester

(Bettes 2005, Harper 2004).

* previous Guillain-Barré syndrome has in the past been considered as a

contraindication, but this is now no longer a contraindication for the use

of inactivated vaccine. (Fleming 2005).

Contraindications to vaccination with live attenuated vaccine are

(Medimmune 2005):

* age < 5 or > 65 years.

* immunocompromised patients - the use of the live-attenuated vaccine

is contraindicated, and inactivated vaccines should be used instead.

Caution should be used when giving the vaccine to those who may come into

contact with immunocompromised patients, as this caused controversy in 2004

when vaccine supplies were limited (Manion 2005). HIV-infected individuals

may not have significant immune suppression in the early years of their HIV

infection, and it is accepted that certain live attenuated vaccines, such

as those for measles and varicella, can be used in these patients. Little

information is available on the use of live attenuated influenza vaccine in

HIV-infected people, but what is available suggests that this vaccine is

safe in adults who are in the CDC class A1-2, and in children who are in

the CDC class N1-2 or A1-2, i.e. asymptomatic or mildly symptomatic, with

CD4 counts higher than 200/µl in adults (King 2000, King 2001). Both

studies conclude that inadvertent vaccination or exposure to the attenuated

virus is unlikely to result in significant adverse effects. However, it

should be noted that small numbers of patients were involved, and until

sufficient data are obtained, extreme caution should be exercised.

* previous Guillain-Barré syndrome.

* children under the age of 18 years who are receiving aspirin therapy

should not receive live vaccine, as it is a risk for Reye's syndrome. They

should receive inactivated vaccine instead.

* In addition,

o safety in asthma sufferers and patients with underlying medical

conditions that put them at risk for wild type influenza infections has not

been established.

o safety regarding teratogenicity and breast milk excretion has

not been established in pregnant women, who should receive inactivated

vaccine instead.

o parenteral administration is contraindicated - mucosal

administration via nasal spray is the correct usage.

o administration with other vaccines should be avoided - within 4

weeks before or after a live vaccine, and within 2 weeks before or after an

inactivated vaccine.

Dosage / use

Inactivated vaccine

Children

* 6-35 months - 0.25 ml in anterolateral thigh (deltoid only if

adequate muscle is present)

* 3-8 years - 0.5 ml in anterolateral thigh (deltoid as above)

Adults

* 9 years onwards - 0.5 ml in deltoid muscle

Live attenuated vaccine

Children (5-8 years old)

* first vaccination - 2 doses, 60 days apart

* previous vaccination - 1 dose per season

Adults (9-49 years old)

* 1 dose per season

Companies and Products

The FDA web page on influenza vaccines can be found here:

http://www.fda.gov/cber/flu/flu.htm

Table 2 shows some of the available influenza vaccines, with links to FDA

and package insert data.

Table 2. Influenza vaccines and manufacturers.

Manufacturer

Brand name

FDA page

Package insert

Sanofi

Pasteur

Fluzone

Link

Link

Fluzone - preservative free

Link

Inactivated Influenza Vaccine (Split Virion) BP

Link

Inactivated Influenza Vaccine (Split Virion) For Paediatric Use

Link

Inflexal V

Link

Vaxigrip

Link

Mutagrip

Link

GlaxoKline

Fluarix

Link

Link

Chiron

Vaccines

Fluvirin

Link

Link

Enzira

Link

Wyeth

Agrippal

Link

Solvay Healthcare

Influvac Sub-Unit

Link

Invivac

Link

MASTA

MASTAFLU

Link

KlineBeecham

X-Flu

MedImmune Vaccines

FluMist*

Link

Link

*FluMist is the only currently available live attenuated influenza vaccine.

All others are inactivated.

Strategies for Use of a Limited Influenza Vaccine Supply

Antigen sparing methods

Several methods of reducing the amount of antigen in vaccine preparations

have been investigated. Most importantly are the use of adjuvants and the

exploitation of a part of the immune system designed to elicit an immune

response - dendritic cells.

Adjuvants are used in a number of vaccines in current use, such as those

for Diphtheria/Tetanus/Pertussis (DtaP) and Haemophilus influenzae (Hib).

Examples of adjuvants include alum (a combination of aluminum compounds),

liposomes, emulsions such as MF59, Neisseria meningitidis capsule proteins,

immunostimulating complexes (ISCOMs), and interleukin-2. They enhance the

immune response to a vaccine, allowing a lower dose to be given, while

maintaining sufficient protective response (Couch 1997, Langley 2005,

Potter 2004).

Dendritic cells can be exploited by giving vaccines intradermally, as they

induce T cell responses, as well as T cell dependent antibody formation (La

Montagne 2004, Steinman 2002). Intradermal vaccination is well established

with hepatitis B and rabies vaccines, and has recently been investigated

with considerable success for influenza vaccines (and in a study from 1948

(Weller 2005). 40 %, 20 %, and 10 % of the standard intramuscular dose of

15 ?g antigen given intradermally produces a response similar to the full

dose given intramuscularly (Belshe 2004, 2004, Kenney 2004). While

the antibody titre is protective, the levels may not be as durable as those

induced by intramuscular vaccination. Subjects over the age of 60 years

seem to have a weaker immune response with the intradermal vaccination, and

it is likely that the intramuscular injection will be preferable in this

group (Belshe 2004). Also not clear yet, is the dose-response relationship

between intramuscular and intradermal routes (Kilbourne 2005). Further

studies will clarify these matters. One drawback is that the local

reactions can be more intense, with increased pain, swelling, and redness;

however, these are still mild.

Rationing methods and controversies

In the event of a shortage of vaccine, as happened in the 2004/5 influenza

season, as well as in the event of a pandemic situation, certain

individuals, such as those working in the healthcare sector and in the

poultry industry, and those exposed on the front lines, will need to be

given priority over other groups for access to vaccines. As has happened in

the past, leaders may have identify groups for urgent vaccination in order

to allow for maximum functioning of essential services, while other groups

may have to wait until a greater supply is available (MacReady 2005,

Treanor 2004). In the event of a pandemic, this could become problematic,

but recent experience in the 2004/5 shortage showed that it was managed

well by most (Lee 2004), with some instances of companies buying up

vaccine, leaving private practices and public health services without

supply (MacReady 2005). In the UK, there have already been debates about

who should get the H5N1 pandemic vaccine first - healthcare workers, or

poultry workers - if H5N1 avian influenza were to reach Britain (Day 2005).

Pandemic Vaccine

The purpose of this section is not to be an exhaustive reference on avian

influenza vaccine development. That is a rapidly advancing field, and the

achievements of those involved will likely change the face of influenza

vaccinology, and vaccinology in general. In 10 years from now, it is likely

that we will look back on our current influenza vaccines and think of them

as primitive. Details and advances noted now will be outdated tomorrow.

This section will provide an outline of the current direction, the problems

we face at the moment, and where we can hope to be in the near future.

Development

As we have seen, vaccination against influenza is a crucial weapon, not

only in our fight against seasonal influenza, but against a pandemic that

may come tomorrow, next year, or in the next decade. We need to prepare

ourselves now.

The World Health Organisation is working with leaders of countries and

vaccine manufacturers around the world to prepare for the pandemic many

fear will arise out of the current H5N1 avian influenza scare (WHO 2005g).

Although it is an ongoing process, initial strains of H5 avian influenza,

such as A/Duck/Singapore/97 (H5N3), have been identified for use in vaccine

development (son 2005). However, it should be noted that the focus

is not solely on H5 strains - H2, H6, H7, and H9 are not being ignored,

although only H1, H2, H3, N1 and N2 have been found in human influenza

viruses (Kilbourne 1997).

Our most urgent needs are a) a stockpile of anti-influenza drugs, a

vaccine that matches the pandemic strain, c) expedited testing and approval

of this vaccine, and d) the capacity to mass-produce enough vaccine to

provide the world with a good defense. At present, all of these are still

in their infancy.

A matching vaccine will require knowledge of the pandemic strain, and until

the next pandemic begins, we will not know for certain what that strain

will be. Current efforts are working with a number of strains, mostly H5

strains, as this seems to be the most likely origin at the present time.

The technology to rapidly develop such a vaccine needs to be fully

developed. At present, there are several methods being used to develop

candidate vaccines.

* Cell culture systems, using Vero or MDCK cell lines, are in

development, and will increase our production capacity. The cells could be

grown on microcarriers - glass beads - to enable high volume culture

(Osterholm 2005). However, these will take several years to put in place,

and the cost is problematic (Fedson 2005).

* Reverse genetics is being used to design candidate vaccines - for

example, H5N1 virulence genes have been removed from a laboratory strain.

Attenuating the virulence of the virus is important, considering the

increased mortality rate of the current highly pathogenic H5N1 avian

influenza when it does enter human hosts. While the H5N1 mortality rate in

humans at present doesn't necessarily reflect the mortality rate in an

eventual pandemic, serious attention must be paid to the pathogenicity of

the current H5N1 strain before it can be used in a vaccine.

* Plasmid systems are in development - several exist, and others are

being described in the scientific literature. A generic influenza virus

would supply 6 genes in plasmid form, and once the pandemic strain is

identified, it would supply the HA and NA genes. DNA vaccine development

experiencing a limited success.

* Apathogenic H5N3 with an adjuvant is being tested - the immune

response will be against the H5 only, but the important aspect here is the

use of an attenuated strain (Horimoto 2001).

* Live attenuated cold adapted virus is being considered. This may open

even more doors for potential reassortment, however, and it may take

considerable time to demonstrate safety in certain populations, such as the

elderly and children.

* H5N2 inactivated vaccines exist for poultry, and appeared to be

protective against H5N1 from 2002 and 2004, but it is expected that human

vaccines will have to be better matched than poultry vaccines (Lipatov 2004).

Mock vaccines

In order to ensure that, when the time comes, a vaccine can be rapidly

produced, tested, and shown to be safe, immunogenic, and protective, the

WHO has asked vaccine manufacturers and scientists to start developing new

vaccines based on strains that may be related to an eventual pandemic

strain. These vaccines will likely never be used, and are being developed

to demonstrate that when the actual pandemic vaccine is needed, the

principle is sound, and the technology is in place and proven on previous

vaccines - hence the term " mock vaccine " . The important aspect is the

development of established vaccines that do not need lengthy studies before

they can enter the market. They need to contain viral antigens humans have

not had previous exposure to, such as the H5N1 antigens, and companies need

to take them through clinical trials to determine immunogenicity, dose, and

safety, and ultimately be licensed for use in the same stringent procedures

used for other vaccines.

Currently, an expedited system is in place for the inactivated influenza

vaccines against seasonal human influenza - the whole process, from the

identification of the strains to be used, to the injection in the

consultation room, takes about 6-8 months, because the vaccine is an

established one, and only certain aspects need to be confirmed prior to

release. This same system needs to be in place for a pandemic vaccine

(Fedson 2005, WHO 2004a-.

Production capacity

In an ideal world, 12 billion doses of monovalent vaccine would be

available in order to administer two doses of vaccine to every living human

being.

The reality is that we do not have this much available.

Currently, the world's vaccine production capacity is for 300 million doses

of trivalent vaccine per year. This amounts to 900 million doses of

monovalent vaccine, if all production were shifted to make a pandemic

vaccine. Considering that at least two doses will be needed, the current

capacity serves to provide for only 450 million people. This is further

complicated by the fact that the dose of antigen that will be required is

not yet known, but studies indicate that it may be higher than current

human influenza vaccines (Fedson 2005).

The world has suffered from vaccine shortages before - recently in the

2004/5 winter season, and closer to the threatening situation, in the

pandemic of 1968. Furthermore, many countries do not have their own

production facilities, and will rely on those countries that do. Will those

countries be able to share vaccine supplies?

Transition

Osterholm asks (Osterholm 2005), " What if the pandemic were to start ? "

* tonight

* within a year

* in ten years?

The New England Journal of Medicine had an interview with Dr Osterholm,

which is available online for listening to or for downloading:

http://content.nejm.org/cgi/content/full/352/18/1839/DC1

If the pandemic were to start now, we would have to rely on non-vaccine

measures for at least the first 6 months of the pandemic, and even then,

the volumes produced would not be sufficient for everyone, and some sort of

rationing or triage system would be necessary. Vaccine and drug production

would have to be escalated - for much later in the pandemic, as this will

not make a difference in the short term. The world's healthcare system

would have to plan well in order to cope with distribution when they become

available - at present, it is doubted that it could handle the distribution

and administration of the vaccines, never mind trying to handle that under

the pressure placed on it by a pandemic. Vaccines may only be available for

the second wave of the pandemic, which tends to have a higher mortality

than the initial wave.

If the pandemic starts in a year's time, it is likely that we will then

have some experience in developing mock vaccines, so that a vaccine could

be produced relatively quickly using a variety of the technologies

currently under investigation. There would still be a significant delay,

and it is likely that there would still be insufficient quantities, with

rationing required.

We don't know when a pandemic will occur - but starting preparation now is

essential. If the pandemic is delayed by a few years, we may well have the

required vaccine production capacity to minimise the disastrous consequences.

Solutions

The WHO suggests various strategies to solve these problems (WHO 2005d) and

is working with governments, scientists, vaccine and drug companies, and

other role players around the world to achieve a solution.

Strategies for expediting the development of a pandemic vaccine

Shorten the time between emergence of a pandemic virus and the start of

commercial production.

1. Candidate " pandemic-like " vaccines need to be made and put through

trials. This will require adopting a centralized evaluation team to examine

the findings of the studies and give clearance for the use of the vaccine.

It would not be feasible for each medicine's evaluation team to do this for

their own country. The vaccine needs to become established through " mock "

trials in order to be able to be expedited in this way - then, like the

current influenza vaccine, it is known, and only brief studies are required

to confirm immunogenicity and safety.

2. Increased production capacity must be developed worldwide - for

example, changing to cell culture vaccines. Another important means to

improve production is to increase consumption - using more of the current

vaccine today will not only decrease the burden of current influenza

disease, as well as helping to prevent reassortment in humans infected with

two strains of virus, but will ultimately enable production to be increased.

Enhance vaccine efficacy

1. Antigen sparing methods, such as intradermal injection, need to be

researched more thoroughly, as they provide for a potential saving in

antigen - the 1 µg of antigen (per strain) in current vaccines could be

lowered considerably. If we could use one 8th of the dose, our current 900

million monovalent doses could be expanded to 7.2 billion doses - enough

for 3.6 billion people, more than half of the world's population (Fedson

2005).

2. Adjuvants need to be evaluated - if immunogenicity can be enhanced,

less antigen would be required for a protective immune response.

3. Mock-up vaccines must be developed and tested in clinical trials to

determine the most antigen sparing formulation and the best vaccination

schedule (Fedson 2005, Kilbourne 2005).

4. Newer vaccine technology needs to be developed, e.g. reverse

genetics, and knowledge of epitopes in influenza to design more effective

vaccines.

Controversies

A number of controversies surrounding the development of a new influenza

vaccine need to be dealt with (Fedson 2005, Osterholm 2005).

Financial - patents exist for the plasmid-based methods of making virus in

cell culture and the legal implications in various countries need to be

examined and addressed. Will the owners of the intellectual property

benefit in any way? Mock vaccines need to be made, but will probably never

be sold and used. Who will fund this endeavour?

Rationing - in the event of vaccine shortage, higher risk groups will need

vaccination first, along with those working on the front lines to control

the pandemic. In such an event, the definition of " high risk group " may

need to be revised - will it include children, for instance? Who will get

the vaccine first - there is already tension over this issue in the UK:

poultry farmers or healthcare workers? (Day 2005)

Equitable access will need to be ensured - countries without vaccine

production, poorer countries, and developing countries will all want to

have their share of the vaccine supply.

Liability issues - due to increased vaccination with current vaccines,

greater attention must be paid to liability. Several countries have

legislation that limits and/or covers certain liability for vaccine

companies - encouraging such legislation will make vaccine companies feel

more free to develop new vaccines, and increase the supply of current

vaccines. When the time comes for rapid entry of pandemic vaccines into

general use, such legislation will be important.

Organising

Barnett employs a Haddon Matrix to show what sort of planning needs to be

done at different stages of the pandemic, from pre-pandemic to

post-pandemic (Barnett 2005).

The WHO will play an important role in the process. In 2001, the Global

Agenda for Influenza Surveillance and Control was established (Webby 2003,

Stohr 2005). Its role is to enhance our surveillance abilities, in order to

better detect a pandemic, and prepare for influenza seasons until then. It

is also charged with the task of increasing our knowledge of influenza, and

enhancing vaccine acceptance and use, in order to prepare us for a pandemic

(WHO 2005j).

The WHO also needs to lead the address of the problems of production

capacity, legislation and expedited vaccine availability, and research that

needs to be done in order to reach the point where these are possible. It

needs to help solve the controversies over financing, patents and

intellectual property, equity for developing countries and countries not

producing vaccine, and rationing of vaccine when supplies do not meet the

demands of a population of more than 6 billion people.

The Ideal World - 2025

" Our goal should be to develop a new cell culture-based vaccine that

includes antigens that are present in all subtypes of influenza virus, that

do not change from year to year, and that can be made available to the

entire world population. We need an international approach to public

funding that will pay for the excess production capacity required during a

pandemic. " (Osterholm 2005)

References

Useful reading and listening material

Audio

* Osterholm MT. Preparing for the next pandemic. N Engl J Med 2005;

352: 1839-42. Audio content:

http://content.nejm.org/cgi/content/full /352/18/1839/DC1

* Belshe RB. The origins of pandemic influenza--lessons from the 1918

virus. N Engl J Med 2005; 353: 2209-11. Audio content:

http://content.nejm.org/cgi/content/full /353/21/2209/DC1

Online reading sources

* US Department of Health and Human Services. The official U.S.

government Web site for information on pandemic flu and avian influenza.

http://pandemicflu.gov/research/

* Centers for Disease Control (CDC), USA. Influenza (flu).

http://www.cdc.gov/flu/

* World Health Organisation (WHO). Epidemic and Pandemic Alert and

Response Influenza.

http://www.who.int/csr/disease/influen za/en/index.html

* World Health Organisation (WHO). Epidemic and Pandemic Alert and

Response Avian Influenza.

http://www.who.int/csr/disease/a vian_influenza/en/index.html

* World Health Organisation (WHO). Responding to the avian influenza

pandemic threat. Recommended strategic actions. 2 September 2005

pandemic threat. Recommended strategic actions. 2 September 2005

http://www.who.int/entity/csr/resources/publications/influenza/WHO_CDS_CSR_G

IP_2005_8/en/inde x.html

* WHO. Recommendations for Influenza Vaccine Composition.

* http://www.who.int/csr/d isease/influenza/vaccinerecommendations1/en/

Journal of Infectious Diseases, 1997, vol 176, suppl 1, Pandemic Influenza:

Confronting a Re-emergent Threat

http://www.journals.uchica go.edu/JID/journal/contents/v176nS1.html

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--------------------------------------------------------

Sheri Nakken, R.N., MA, Hahnemannian Homeopath

Vaccination Information & Choice Network, Nevada City CA & Wales UK

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