Risk Wise

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patients, the use of combinations of drugs may have to be considered

in these patients from the start of symptoms. These events also raise

questions about the risk that a future pandemic influenza virus could

become resistant to stockpiled antiviral drugs. Therefore stockpil-

ing of more than one antiviral drug would be advisable for pandemic

preparedness plans.

Vaccination and stockpiling of influenza vaccines

Vaccination is the most cost-effective medical intervention to combat

seasonal influenza.

More than half a century ago classical vaccines

against seasonal influenza were introduced and ever since vaccina-

tion coverage for seasonal influenza has increased. The first influenza

vaccines were produced by inoculating embryonated chicken eggs

with the virus strains of choice and harvesting the allantoic fluid

from which the virus was partially purified and inactivated. This

basic method of producing inactivated seasonal influenza vaccines

has essentially remained unchanged. These vaccines are updated bi-

annually for the northern and southern hemisphere, based on

epidemiological data collected by the abovementioned WHO-led

influenza surveillance network.

Currently the total global production capacity for seasonal

influenza vaccines has increased to more than 400 million doses of

trivalent vaccine per season. In spite of all the technologic advances

that would allow for newer methods of influenza vaccine produc-

tion, current practice is still entirely dependent on the use of

embryonated chicken eggs. The formulations for these vaccines

include whole inactivated virus, split virus, viral subunits or surface

antigens and live attenuated virus (LAIV).

In the context of a pandemic, seasonal influenza vaccine produc-

tion capacity would have to be used for the production of a pandemic

vaccine. This results in three major problems that would have to be

solved: the long response time, the limited production capacity and

the lack of efficacy of vaccines produced with the current platform

used for seasonal vaccine production. In addition, safety issues and

regulatory processes would have to be addressed in advance. The

current response time between the seasonal influenza virus strain selec-

tion and production of the first vaccine doses is more than six months.

This would be too long in the situation that a pandemic virus starts to

spread globally. The overall world seasonal influenza vaccine produc-

tion capacity is approximately 700 million doses of trivalent vaccine

and with the current production platform using split vaccine, more

than ten times the amount of vaccine would need to be administered

in a two-dose regimen to induce adequate protection. Thus, the imple-

mentation of techniques that allow dose sparing have become a major

priority in the field of pandemic vaccine development.

These considerations have prompted academic groups and

influenza vaccine manufacturers to develop new generation vaccine

formulations and production technologies that would solve these

problems. Among the smaller changes that are relatively easy to

implement are the development of novel cell culture based produc-

tion systems, as well as improved methods to prepare vaccine seed

viruses. Novel production systems based on the use of continuous

cell lines, rather than embryonated chicken eggs would make the

production systems more flexible, although it should be realized that

the continued availability of these production substrates should also

be planned well in advance. Furthermore, it should be realized that

if LAIV pandemic vaccine could be produced, the vaccine produc-

tion capacity would increase dramatically, since lower viral vaccine

doses could be used.

In the field of vaccine virus strain selection consid-

erable progress has been made over the past decade.

Novel mathematical techniques of antigenic mapping

that were originally developed to determine the best

seasonal influenza vaccine strain candidates can now

also be employed for the measurement of differences

between newly emerging avian influenza A viruses that

infect humans, like the HPAI-H5N1 viruses. This will

have important and direct consequences for the iden-

tification and preparation of the best matching seed

virus, using a repository of recently collected avian

influenza A viruses and state-of-the-art molecular tech-

niques.

In the past few years, considerable progress has been

made in the improvement of the efficacy of influenza

vaccine candidates, by using novel adjuvants, without

a major negative impact on their safety profile. An adju-

vant is a substance that is added to a vaccine to stimulate

the immune system in a non-specific way, in addition to

the specific stimulation provided by the vaccine proper.

Thus the adjuvanted vaccine may induce a more potent

and broader protective immune response than the non-

adjuvanted vaccine.

The first adjuvanted avian influenza A vaccine has

now been licensed, and has demonstrated promise for an

avian or pre-pandemic influenza vaccine by allowing

vaccine sparing and by inducing broader immunity. It

may be expected that the registration of several adju-

vanted vaccines for pre-pandemic use will follow and

that such vaccines will also form the basis for the even-

tual use of pandemic vaccines that will be prepared with

the actual pandemic seed virus strain. Finally, the use

of several novel molecular techniques has shown great

promise by yielding candidate vaccines inducing broad

protective immunity in relevant animal models. It may

be expected that influenza vaccines based on these tech-

nologies will also enter into clinical trials soon and that

these approaches may also result in the use of novel

generations of human vaccines to combat seasonal, avian

and pandemic influenza.

Conclusion

Facing the burden of disease currently caused by

seasonal influenza and the pandemic threat that looms

like a sword of Damocles over humanity, the real ques-

tion today is how to use the currently available tools

most efficiently to reduce the future impact and disease

burden of influenza on mankind. The use of vaccines

and antivirals against seasonal influenza is currently

limited to a small fraction of people in the high-risk

groups who would benefit from it the most. Therefore

too many people are unnecessarily suffering and dying

from seasonal influenza every year. Finally, although we

now have the tools to prepare the world to efficiently

combat a future influenza pandemic that may be immi-

nent, most countries have so far failed to develop

effective pandemic preparedness plans, leaving their

populations unprepared for such a major catastrophe

that will cost the lives of many millions of people.