Epidemiologic and Immunologic Significance of Age Distribution of Antibody to Antigenic Variants of Influenza Virus

Abstract

The effects on the antibody content of the population which result from repeated exposure to antigenic variants of influenza viruses have been studied by measuring, with many strains, the antibody content of lots of gamma globulin prepared in different years and the patterns of antibody found in sera collected in 1 year from various age groups. In all samples of gamma globulin collected from 1943 through 1951, high levels of antibody were found with strains of Type A and Type B influenza viruses isolated prior to 1941. The highest levels were found in the more recent collections of gamma globulin. Antibodies to A-prime, and to B strains of 1945 and 1952, were present at low levels in gamma globulin collected prior to the isolation of these viruses. A moderate increase in antibody was observed in the gamma globulin of recent years. The pattern of distribution of antibody by age found with most A-prime strains in serum pools exhibited high levels in infancy and childhood, but after the age of 20, little or no antibody was detected. With Type A strains antibody was usually not observed until the 11th year of age. Thereafter, high levels were present until age 20, when the amount of antibody declines to a moderate and relatively constant level which persists throughout life. Antibody against swine influenza virus did not become detectable until the 29th year. The intermediate antigenic character of a few A-prime isolates was reflected in the antibody pattern obtained with them. Antibody was not found until age 13 with the Lee (1940) strain of Type B influenza virus, but thereafter the level was high. With the type B isolates of 1945 and 1952, antibody became measurable at earlier ages. The present data clearly demonstrate that in the early years of life the range of the antibody spectrum is narrow, and that it becomes progressively broader in later life. A striking correlation was found between what is known of the periods of prevalence of certain strains of influenza viruses and the age of the people in whom strain-specific antibodies are currently found. It has been observed that the age at which antibodies to certain strains are first detectable has progressively advanced with the passage of time. From these data the following immunologic thesis is formulated. The antibody which is acquired during the initial infections of childhood is of limited scope and reflects the dominant antigens of the prevailing strains. The immunity conferred by the initial experiences with influenza is also limited. Successive experiences later in life with viruses of related but differing antigenic make-up result in a composite of antibody which is oriented toward a larger number of the common antigens which comprise influenza virus. These experiences confer a broader immunity which limits infection with, and antibody response to, the more recently encountered strains. The antibody-forming mechanisms appear to be oriented by the initial infections of childhood so that exposures later in life to antigenically related strains result in a progressive reinforcement of the primary antibody. The highest cumulative antibody levels detectable in a particular age group tend, therefore, to reflect the dominant antigens of the virus responsible for the childhood infections of that group. Hence the pattern of antibody distribution determined currently in different age groups provides a serologic recapitulation of past infection with antigenic variants of influenza viruses.

Serological epidemiological studies with influenza A viruses

“…1). This general age distribution of influenza antibodies thus supports the doctrine formulated by Davenport et al in 1953. Figure 4 shows the distribution of antibodies to swine virus. These were not found in children aged 11 the proportion of sera with antibody rose rapidly and peak titres were found in the age group 51-60 years where approximately 100 % of sera contained antibody.…”

“…At the same time the lack of decrease in the mean titres to both A and A1 viruses between 1952 and 1963 in the group of forty persons just described is evidence of the remarkable stability of antibodies to former influenza viruses in the adult population as a whole. It seems that the hypothesis of antigenic recall of antibodies acquired in childhood formulated by Davenport et al (1953) is supported by these findings, but that evidence also exists in favour of the view that minor antigens shared by serologically different virus families also influence the antibody levels found in the population.…”

Antibody response to immunization with influenza A/USSR/77 (H1N1) virus in young individuals primed or unprimed for A/New Jersey/76 (H1N1) virus

“…Volunteers who had not been primed for A/NJ/76 virus showed no or minor responses against this virus after immunization with A/USSR/77 virus. This phenomenon of immune response after immunization with an antigen (A/USSR/77) directed against a related antigen (A/NJ/76) to which the individual has already been exposed during preceding years, was described for the first time by Francis and co-workers, who called it 'original antigenic sin' (Davenport, Hennessy & Francis, 1953;Francis, 1955;Davenport & Hennessy, 1956).…”

Epitope analysis for influenza vaccine design

“…When the antigenic drift between the vaccine and circulating strain epitopes is modest (0.23 < p epitope < 0.6), our theory predicts that memory response may be worse than the naive response (the solid curve lies below the dashed curve in Figure 1), which means that the immunological memory from the vaccine exposure actually gives worse protection, i.e., a lower affinity constant, than would no vaccination whatsoever. This result is the original antigenic sin phenomena for influenza: vaccination creates memory sequences that for some mutation rates of influenza may increase susceptibility to future exposure [15,16]. Parenthetically, not every infectious disease exhibits original antigenic sin, with measles one such example.…”