Tableau 1 / Table 1 : Impact de la grippe / Impact of influenza

The influenza of 1958 (Asian) then 1968 (Hong Kong) spread over all continents. During this last pandemic, the virus was better known and a vaccine had been developed, but it became clear that the capabilities of this virus had been underestimated. The vaccine, which was used only to a limited extent, contained an H2N2 strain, whereas the pandemic virus was an H3N2, with a new haemagglutinin. The results of vaccination were disappointing therefore (table 2), but the vaccine was not totally deprived of effect: its efficacy was only 35%, compared with between 60% and 95% with appropriate strains, but it was nevertheless better to be vaccinated.

Tableau 2 / Table 2 : Essais cliniques du vaccin anti-grippal : 1956-1977 / Influenza vaccine clinical trials : 1956-1977

The 1968 pandemic prompted research, which led to a better understanding of viral mechanisms of variation.

Antigenic variation

Antigenic variations of surface glycoproteins are an important factor in viral mechanisms of escape from immune defences. Variability is a major feature of the epidemiology of influenza virus, and must be considered when developing strategies to control the disease.

Antigenic drift results from a high rate of mutations that affect specific parts of surface glycoproteins. The virus population permanently shows a high degree of heterogeneity. Variations affect in particular the gene encoding the structure of haemagglutinin, the surface protein to which immune responses are most often made. The emergence and spread of a mutant strain are facilitated by a low level of immunity against it. Selected mutants become dominant for a few months or years and are then in turn subject to variations and replaced by others.

Antigenic shift, which is rarer, has different causes. Segmentation of the influenza virus genome facilitates genetic recombination between strains of human or animal origin. A cell that is infected simultaneously by two strains of type A virus with haemagglutinins or neuraminidases of different serotypes produces hybrid viruses. All combinations are theoretically possible and lead to more radical changes than those associated with antigenic drift. For an antigenic shift to occur, infection of the same cell by two viruses is necessary. Experimental culture models have shown that recombinations also take place in nature and have been responsible for pandemics. Isolation on several occasions of two viruses of different subtypes in a given individual (e.g. H1N1 and H3N2) has shown that double infections are not rare in humans and that recombination is possible.

Understanding of these mechanisms required a new strategy for vaccine development. The antigenic composition of influenza vaccine is updated annually to cope with the incessant drift of viral antigens. This new approach does not solve the problem of shift, which remains unpredictable and unavoidable in the short term.

New Jersey porcine influenza, a pandemic false alert.

The threat of another influenza pandemic emerged in 1976 when a young military recruit died following infection with a porcine influenza virus thought to be similar to the agent that caused the 1918 pandemic. A programme of accelerated vaccine production and mass vaccination was undertaken hastily in the United States but was hampered by neurological complications (Guillain-Barré syndrome) attributed to the vaccine. The fear of a pandemic had abated by this time, and the programme was stopped after 40 million vaccinations (1).

Pandemic planning: Berlin 1993

A meeting of a French influenza study group, the GEIG (Groupe d'Etude et d'Information sur la Grippe) held in Berlin in September 1993 gathered experts, representatives of industry and health care authorities of several interested countries, and a representative of the World Health Organization to consider existing plans for responses to an influenza pandemic. They adopted guidelines that outlined control milestones and suggested steps to be taken in research, vaccine production, the use of antivirals, and organisation of strategies (2). This meeting drew the attention of European authorities and public opinion and stimulated decision making in this area.

These experts concluded that a future pandemic was likely and that the conditions will certainly differ in detail from those of the past but will share the same basic principles. However, the date of onset cannot be predicted. Workshops devoted to the problem have led to the development of plans of action in several countries.

Pandemics

A pandemic can be defined as a marked increase in time and space in the number of cases of influenza with or without virological confirmation, associated with a number of severe cases and abnormally high mortality, following detection of a virus with a new antigenic composition against which the immunity of the population is low or nil.

From an operational standpoint, several phases can be defined in the progression of a pandemic in Europe:
Phase 0: Interpandemic period.
Phase 1: Emergence somewhere in the world of a new strain or resurgence of an old strain that had hitherto disappeared. This is a pandemic alert.
Phase 2: Confirmed pandemic outside Western Europe.
Phase 3: The pandemic reaches a neighbouring country.
Phase 4: The pandemic affects the country.
Phase 5: The pandemic ends in the country.

Principles of action

WHO has drafted a report defining the general principles for preparing national plans and adapting them in response to local conditions. Several European countries have prepared such plans, including Belgium, Great Britain, France, the Netherlands, and Slovakia. WHO's guidelines for these plans address several principles that are discussed below.

National plans are intended to foresee the creation of a national crisis unit responsible first for preparing control plans and monitoring their application.

Plans should emphasise the need for very precise virological surveillance in order to detect the emergence of atypical viral strains quickly. These systems already exist, but their widespread use and adaptation to new situations have been detailed. Worldwide surveillance is necessary since it is impossible to predict where new viruses will appear. Countries that do not yet have surveillance systems must be given technical assistance. This is currently being developed in China, Africa, and Latin America through the initiatives of Reference Centres and bilateral programmes. Surveillance in China is very important, being the country where most new influenza viruses have appeared for the first time, for reasons unknown.

During phase 0, a database must be created to identify:
- addresses of those concerned in the application of the plan;
- public or private bodies that may be involved;
- type and number of individuals for priority vaccination or treatment;
- resources available for hospital admissions and treatment.

Vaccine producers cannot start vaccine production without guarantees that the vaccine will actually be used. The investment required is enormous. An international and governmental decision making mechanism is needed, which must also define the number of doses required of a monovalent vaccine specifically appropriate in the situation.

Vaccine production itself is another key factor of the various plans. Mechanisms of distribution of seeding strains have been established through international influenza reference centres set up by WHO. Strains suitable for seeding must have an adequate antigenic structure, provide good culture yields, and not expose the staff who handle them to risks of contamination. The large number of chicken embryos requested is a practical constraint. Measures to enable the speeding up of marketing authorisation procedures are also being studied.

The setting up of an immunisation campaign will depend on the amount of vaccine available, according to the production schedule foreseen, and on the definition by health authorities of the priority groups to be vaccinated. Several categories have already been designated (medical staff, security staff, transport and communication staff, volunteers, high risk individuals etc.) but the list of high risk individuals can be finalised only when certain characteristics of the new virus are known (e.g. attack and severity rates according to age and existence of underlying conditions).

The use of available antiviral agents must also be considered. Currently, only amantadine derivatives (amantadine and rimantadine) fulfil this need. These drugs have never been used extensively and caution is recommended. In the event of a pandemic threat and without available vaccines, however, antiviral agents are likely to be used as the only effective treatment. In this situation, adequate supply is also a problem, since they are not produced to any great extent in Europe. Priority indications for their use will have to be defined. Other drugs, with very different modes of action, are currently in clinical trials but are not yet available.

General measures of temporary protection could also be envisaged, such as the closure of schools or restriction of certain international links.

Communication plans have also been prepared, to inform the public reliably about the application of the measures envisaged and avoid panic with its potentially negative consequences. A communication unit is an essential structure for crisis management during a pandemic.

H5N1 avian influenza in Hong Kong.

The preparation of a national plan against an influenza pendemic is not just a strictly theorical exercise, as the recent H5N1 outbreak has shown in Hong Kong (3). This outbreak corresponded exactly to the possible start of a pandemic - a move to phase 1, and national working groups began planning (4), in close liaison with WHO and international reference centres.

1. Neustadt RE, Fineberg HV, Califano JA. The swine flu affair. Decision-making on a slippery disease. Washington : United State Department of Health, Education, and Welfare, 1978.
2. GEIG. L'Europe face au risque d'une pandémie grippale. VIIth European Meeting on Influenza and its Prevention, Berlin September 1993. Eur.J.Epid 1994; 10:449-526.
3. Lavanchy D, Eurosurveillance 1998; 3: 23-5
4. Desenclos JC, Eurosurveillance 1998; 3: 25-6