Academic journal article Bulletin of the World Health Organization

Influenza A Virus Recycling Revisited(*)

Academic journal article Bulletin of the World Health Organization

Influenza A Virus Recycling Revisited(*)

Article excerpt

Voir page 826 le resume en francais. En la pagina 826 figura un resumen en espanol.


Influenza pandemics and the emergence of new haemagglutinin antigen (HA) subtypes of the influenza A virus have become synonymous in modern day virology. With little or no population immunity to the novel surface antigen(s), the virus spreads rapidly, resulting in increased morbidity and excess mortality (1) worldwide. Epidemics and pandemics in the pre-virology era are more difficult to recognize. Historic pandemics are characterized as periods of excess mortality that coincided with global accounts of disease that are epidemiologically and clinically compatible with influenza A. Six pre-virology influenza A pandemics are listed by Potter (2) for the last 300 years: 1729-33, 1781-82, 1830-33, 1889-91, 1900 and 1918-20. Vivid descriptions of the devastating effects of influenza-like disease worldwide leave little doubt that the first four were true pandemics, separated from each other by about 50 years. During the 1889-91 pandemic, morbidity and mortality were greater than had been seen in decades, with three successive waves occurring through most parts of the world (3). The 1918-20 pandemic, also with three successive waves, was unequalled in recorded history (4). The outbreak in 1900 was deemed a pandemic only in retrospect (5). Excess mortality was reported in North America (Massachusetts) and in England and Wales during the winter of 1900-01, but historic accounts of influenza epidemics occurring elsewhere in the world are absent. On the basis of the criteria for all other pre-virology pandemics, 1900 would not qualify (2, 3).

The pandemics of 1889-91, "1900", and 1918-20 occurred prior to the isolation of the first influenza virus type A from humans in 1933 (6), and were linked to subtypes on the basis of retrospective studies of sera from the elderly, or "seroarchaeology" (5, 7, 8-13). The concept of influenza A virus subtype recycling arose from these reports. For nearly 30 years, textbooks and reviews have stated that subtype H2 first appeared in about 1889, H3 in about 1900 and H1 in 1918, and that H2 also appeared in 1957 and H3 in 1968. This suggests that the number of subtypes capable of infecting humans is finite. Since H1 reappeared in 1977, whatever its origin, some workers feel that H2 may be the next pandemic candidate. This article critically reviews the data on which the concept of influenza A virus recycling is based and the implications of recycling for pandemic planning.

Principles of seroarchaeology

The "doctrine of original antigenic sin" (14) states that the first infection with an influenza virus leaves a lifelong immunological imprint, reinforced by later infections with antigenically related strains. That is, the highest antibody titres in an age group appear to reflect the dominant antigens of the virus responsible for the childhood infections of the group. Antibody reinforcement or heterologous anamnestic antibody responses within a subtype depend on the existence of cross-reactive determinants on the original priming haemagglutinin and the secondary stimulating haemagglutinin (15, 16). Heterotypic anamnestic antibody responses between H2 and H3 subtypes have been attributed to shared neuraminidase (N2) antigens (17-19).

In practice, seroarchaeology is not an exact science. Spurious haemagglutination inhibition (HI) heterotypic responses between subtypes often occur for which there are no obvious immunological explanations (9, 13, 20, 21). Age-related HI seroprevalence patterns may be influenced by a number of conditions, including immunological experience with influenza viruses, the presence of non-specific serum inhibitors, the choice and quality of treatment to destroy inhibitors, "avidity" of the influenza virus test strain for antibody, and the minimum titre selected as baseline. In addition, the higher the selected baseline antibody titre, the sharper the seroprevalence peak. …

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