Ferrets, Morley’s Ghost, and Viral Immunity

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“I wear the chain I forged in life,” replied [Morley’s] Ghost. “I made it link by link, and yard by yard.” Our immune system, like those chains, contains our immunologic memories. Ferrets can teach us, that like Morley’s chains, our immunologic memory is forged by experience. Sometimes, a current viral illness may, later on, protect us from a similar viral infection; but we may not be as protected as we hope.

The research was done using ferrets, which have both susceptibilities to seasonal influenza viruses that affect us and have similar respiratory transmission patterns. While the study was done using the H1N1 and H3N2 influenza virus specifically, the underlying behavior may well carry over to the virus du jour, COVID-19, and its variants. 

Original Antigenic Sin

Simply put, when you are first exposed to a novel antigen, you develop a robust immune response. Subsequently, suppose you are exposed to a similar but not the same antigen. Your immune system relies on its memory rather than go through the process of defending against a new antigen. That immunologic response may or may not be as effective as the response to the original antigen. It is not surprising that how this original sin impacts a common respiratory viral disease, seasonal flu, is relatively unstudied. COVID-19 focused our interests. 

The study involved ferrets who, like us, are both susceptible to influenza viruses and share them by transmitting viral particles through the air. The researchers were readily able to infect them with two different influenza strains, H1N1, the virus responsible for the 2009 pandemic that primarily affected those 5 to 24; and the H3N2 virus from 2017 that, like COVID-19, impacts mostly those over age 65. [1] As the numbering suggests, these viruses are similar but not the same. 

Both viruses easily spread from the infected to the susceptible, as quickly as a few hours or as long as a typical work week. Half of the ferrets initially infected with H1 were infected with H3 (H1-to-H3), and half of the ferrets initially infected with H3 were similarly infected with H1 (H3-to-H1); in both instances, three months later to mimic a new infection. 

  • The H1-to-H3 and H3-to-H1 ferrets were then used to infect the remaining ferrets that had only been infected with one of the subtypes.
  • The H3-to-H1 “donor” ferrets readily infected the remaining H3 ferrets with the H1 virus – H3 prior exposure conferred no immunologic advantage - the original antigenic sin was at work.
  • But this was not the case for the  H1-to-H3 “donor ferrets, the remaining H1 ferrets developed no infections at all – no original antigenic sin for them.

“Taken together, these results indicate that airborne transmission of H3N2 cannot overcome the barrier imposed by H1N1 immunity but transmission of H1N1 can overcome H3N2 immunity …” 

Subsequent molecular investigation showed that the immunity provided was unrelated to cross-reactive neutralizing antibodies or antibodies specific for neuraminidase (N) variation. The immunity came from the H, hemagglutinin protein component. 

What does this have to do with me?

We know that exposure to foreign antigens prompts an immune defense, both immediately by our innate immune system and longer-term by our adaptive immune response. But what the study shows is that the order of our antigenic exposure plays a more subtle role. Original antigenic sin means that our immune system is a bit fuzzy in its identification. Similar antigens can prompt similar but inadequate responses. 

This may well explain why viruses can find more susceptible hosts in certain age groups whose antigenic history makes them incompletely protected. Like Morley’s Ghost, our immune system seems to carry our antigenic history. What is different is that a prior antigenic exposure is not the guarantee of an adequate immune defense that we had thought. 

Will original antigenic sin return to haunt us as COVID-19 continues to evolve? That is only answerable with time.


[1] Seasonal flu involves two influenza viruses A and B, predominantly. H1N1 and H3N2 are both influenza A viruses subtypes, differing in the surface structure of the two proteins, hemagglutinin (H) and neuraminidase (N)


Source: Pre-existing heterosubtypic immunity provides a barrier to airborne transmission of influenza viruses PLOS Pathogens DOI: 10.1371/journal.ppat.1009273