Immune history and influenza virus susceptibility

Abstract

Antibody responses to influenza viruses are critical for protection, but the ways in which repeated viral exposures shape antibody evolution and effectiveness over time remain controversial. Early observations demonstrated that viral exposure history has a profound effect on the specificity and magnitude of antibody responses to a new viral strain, a phenomenon called 'original antigenic sin.' Although 'sin' might suppress some aspects of the immune response, so far there is little indication that hosts with pre-existing immunity are more susceptible to viral infections compared to naïve hosts. However, the tendency of the immune response to focus on previously recognized conserved epitopes when encountering new viral strains can create an opportunity cost when mutations arise in these conserved epitopes. Hosts with different exposure histories may continue to experience distinct patterns of infection over time, which may influence influenza viruses' continued antigenic evolution. Understanding the dynamics of B cell competition that underlie the development of antibody responses might help explain the low effectiveness of current influenza vaccines and lead to better vaccination strategies.

Figure 1. The development of antibody response to drifted influenza virus strains

(A) The population begins completely susceptible to strain 1, which has two epitopes in this example. Upon infection, individuals in cohort A generate antibodies against the red and purple epitopes. The strain then acquires a mutation in the purple epitope (and becomes strain 2). New susceptible hosts (cohort B) that become infected with strain 2 develop antibodies to the red and green epitopes. In contrast, older individuals (cohort A) that are exposed to strain 2 develop an antibody response focused primarily on the red epitope that was conserved in strain 1. Older individuals likely experience mild infections with strain 2 since these individuals possess cross-reactive antibodies against the red epitope. Eventually, immune pressure at the red epitope selects for a virus (strain 3) that possesses a red→blue mutation. Older individuals (cohort A) regain susceptibility since they have an antibody response focused on the former red epitope, and younger individuals (cohort B) are protected against this strain because they possess antibodies against the green epitope conserved in strain 2. (B–C) After exposure to strain 2, antigenic cartography based on the sera from cohort A (B) and cohort B (C) reveals different patterns. Antibodies from individuals in cohort B recognize the red and green epitopes and perceive all strains as identical, whereas antibodies from individuals in cohort A recognize the red epitope and perceive strain 3 to be distinct from strains 1 and 2.