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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 Details and advances noted now will be outdated tomorrow.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

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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

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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