The Doctrine of Original Antigenic Sin: Separating Good From Evil

Abstract

The term "original antigenic sin" was coined approximately 60 years ago to describe the imprinting by the initial first influenza A virus infection on the antibody response to subsequent vaccination. These studies did not suggest a reduction in the response to current antigens but instead suggested anamnestic recall of antibody to earlier influenza virus strains. Then, approximately 40 years ago, it was observed that sequential influenza vaccination might lead to reduced vaccine effectiveness (VE). This conclusion was largely dismissed after an experimental study involving sequential administration of then-standard influenza vaccines. Recent observations have provided convincing evidence that reduced VE after sequential influenza vaccination is a real phenomenon. We propose that such reduction in VE be termed "negative antigenic interaction," given that there is no age cohort effect. In contrast, the potentially positive protective effect of early influenza virus infection later in life continues to be observed. It is essential that we understand better the immunologic factors underlying both original antigenic sin and negative antigenic interaction, to support development of improved influenza vaccines and vaccination strategies.

Keywords: Influenza; immune response.

Figure 1.

Prevalence of antibody to type A influenza viruses in unvaccinated individuals to prior to the 1957 influenza A(H2N2) pandemic, demonstrating the absence of antibody in younger individuals to strains that circulated earlier and the persistence of antibody in older individuals. Data are adapted from findings in the report by Francis [1]. HAI, hemagglutination inhibition.

Figure 2.

Antibody response to monovalent adjuvant influenza virus vaccine in children, military recruits, and persons aged >30 years. Test antigens in the hemagglutination inhibition (HAI) test are those used in each of the vaccines. Homologous combinations of vaccine and antigen are indicated by an asterisk. Data are adapted from findings in the report by Davenport and Hennessy [8].

Figure 3.

Effect of prior 2013–2014 season influenza vaccine receipt on current 2014–2015 adjusted influenza vaccine effectiveness (VE) for A(H3N2) in Canada, comparing those not vaccinated in either year (reference) to those vaccinated in both years and, separately, those vaccinated in only 1 of 2 years. Data are adapted from findings in the report by Skowronski et al [29]. Abbreviation: CI, confidence interval.