Original Antigenic Sin Responses to Influenza Viruses

TLDR

Original antigenic sin, a paradox to Burnet’s rule, describes how humans infected with a novel influenza strain preferentially produce antibodies to older strains, reducing responses to new antigenic determinants and worsening disease severity, a phenomenon first noted fifty years ago and recently questioned. This study aimed to assess how strongly variant influenza viruses induce original antigenic sin. Researchers sequentially infected mice with two related influenza A strains and quantified antibody responses, focusing on the impact of the first infection on immunity to the second. The results showed that original antigenic sin markedly impaired protective and recall responses to the second virus and that antibody production was almost exclusively directed against the first strain, suggesting a potential immune evasion strategy by variant influenza viruses.

Abstract

Abstract Most immune responses follow Burnet’s rule in that Ag recruits specific lymphocytes from a large repertoire and induces them to proliferate and differentiate into effector cells. However, the phenomenon of “original antigenic sin” stands out as a paradox to Burnet’s rule of B cell engagement. Humans, upon infection with a novel influenza strain, produce Abs against older viral strains at the expense of responses to novel, protective antigenic determinants. This exacerbates the severity of the current infection. This blind spot of the immune system and the redirection of responses to the “original Ag” rather than to novel epitopes were described fifty years ago. Recent reports have questioned the existence of this phenomenon. Hence, we revisited this issue to determine the extent to which original antigenic sin is induced by variant influenza viruses. Using two related strains of influenza A virus, we show that original antigenic sin leads to a significant decrease in development of protective immunity and recall responses to the second virus. In addition, we show that sequential infection of mice with two live influenza virus strains leads to almost exclusive Ab responses to the first viral strain, suggesting that original antigenic sin could be a potential strategy by which variant influenza viruses subvert the immune system.