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1. Influenza

2. Avian Influenza

3. Virology

4. Pathogenesis and Immunology

5. Pandemic Preparedness

6. Vaccines

7. Laboratory Findings

8. Clinical Presentation

9. Treatment and Prophylaxis

10. Drugs

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Amedeo Influenza


  

 

Vaccines

Stephen 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, Edward 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 μg 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 β-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 β-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, Cooper 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 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 (IFNα). If a wild-type influenza virus infects a person, the NS1 protein antagonises IFNα, 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 (Joseph 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)
    • All persons over the age of 65 years
    • Persons with chronic pulmonary or chronic cardiac disease
    • Immunosuppressed persons
    • Pregnancy - women who will be in the second or third trimester during the winter season. Vaccination is contraindicated in the first trimester.
    • 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 Torres 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,
    • safety in asthma sufferers and patients with underlying medical conditions that put them at risk for wild type influenza infections has not been established.
    • safety regarding teratogenicity and breast milk excretion has not been established in pregnant women, who should receive inactivated vaccine instead.
    • parenteral administration is contraindicated - mucosal administration via nasal spray is the correct usage.
    • 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

GlaxoSmithKline

Fluarix

Link

Link

Chiron
Vaccines

Fluvirin

Link

Link

 

Enzira

 

Link

Wyeth

Agrippal

 

Link

Solvay Healthcare

Influvac Sub-Unit

 

Link

 

Invivac

 

Link

MASTA

MASTAFLU

 

Link

SmithKlineBeecham

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 μg antigen given intradermally produces a response similar to the full dose given intramuscularly (Belshe 2004, Cooper 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 (Stephenson 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, b) 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-b).

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

Online reading sources

Sources

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