The Problem of Original Antigenic Sin

by Gertrud U. Rey

Image created in BioRender.

Once the innate immune system senses a never-seen-before pathogen as new, it engages elements of the adaptive immune response. These adaptive immunity elements coordinate over time to develop a response that protects from re-infection and disease upon a second exposure to the same pathogen. The second exposure will immediately lead to activation of the adaptive immune system to eliminate the intruder. Pathogens that are very different from those encountered previously are recognized as completely new and undergo a similar sequential innate/adaptive immune response process. But what about pathogens that are just slightly different?

It turns out that small antigenic differences between pathogens can lead to a phenomenon known as “original antigenic sin,” where the immune system mounts a particularly strong response to the variant of a pathogen encountered first in life. In other words, an initial infection with an “original” strain will prime your immune system to preferentially remember and form antibodies to that strain. Later infections with similar (but slightly different) strains will successively enhance the antibodies to the original strain and suppress formation of new antibodies to the new strains, often leading to immune evasion and prevention of effective immune memory.

The concept of original antigenic sin was initially described in a 1960 commentary by Thomas Francis in the context of influenza virus infection. When analyzing the sera of individuals of different age groups, Francis noted that the majority of influenza virus antibodies in any particular person were specific for whichever strain was circulating within that person’s first decade of life. He also observed that people generally had lower antibody levels against influenza virus strains encountered later in life. This phenomenon was exemplified during a 1957 pandemic caused by a supposedly new influenza virus, when people aged 70 or more had antibodies that bound this virus and appeared to be protected from disease. This finding ran contrary to the usual presumption that older people have “weaker” immune systems and are more susceptible to severe influenza disease, and it further suggested that the causative virus was not new but had likely circulated and infected this cohort during a legendary 1890 pandemic.

Similar observations were made during subsequent pandemics. A notable example is the 2009 influenza pandemic caused by H1N1, a strain of influenza virus similar to the virus that caused the 1918 pandemic and that continued circulating until 1957. Individuals who were 52 years or older in 2009 experienced less severe disease because they had likely been exposed to H1N1 between 1918 and 1957. In contrast, people younger than 52 suffered more severe infections because they had probably never encountered that virus before. Consistent with these findings, the 1918 flu caused unusually high mortality among young adults in 1918, and low disease incidence and mortality among older individuals, suggesting that in 1918, older people had been exposed to an earlier version of the H1N1 virus.

Original antigenic sin is a particular problem with influenza viruses, which routinely accumulate small mutations that lead to new strains not recognized by antibodies to previous strains. However, it also seems to exist in the context of COVID-19, where natural SARS-CoV-2 infection may boost antibodies specific for seasonal endemic coronaviruses OC43 and HKU1. In addition, the bivalent booster SARS-CoV-2 vaccines are relatively ineffective against the Omicron variant in patients who were previously vaccinated with one of the original (pre-Omicron) vaccines – an observation that can also be attributed to original antigenic sin. That is, because a person was immunized with the original SARS-CoV-2 vaccine, they may have “original antigenic sin” – a robust response to the virus spike sequence included in the original vaccine, and poorer response to the Omicron (or subsequent) spike variants. Dengue virus infections lead to similar manifestations. An initial infection with any of the four dengue virus serotypes provides life-long immunity against the infecting serotype; however, a second infection with a different serotype skews the memory response toward the original type, often leading to enhanced disease coupled with severe complications that can often be fatal.

Although the concept of original antigenic sin is relatively clear, its underlying mechanisms are not. The phenomenon has critical implications in the design of vaccines against influenza virus and other rapidly evolving viruses. Some strategies to overcome this dilemma have involved the use of adjuvants (substances that enhance the magnitude and longevity of an immune response to an antigen), repeated boosting regimens with long time intervals between boosts, and broadly reactive vaccines that target most or all strains of a particular pathogen. However, each of these approaches presents its own challenges. I look forward to learning about new mechanistic insights and methods for overcoming these challenges as technologies and our general understanding of the problem improve.

[Original antigenic sin is also referred to as immunological imprinting, antigenic imprinting, back-boosting, negative interference, primary addiction, and antigenic seniority.]

4 thoughts on “The Problem of Original Antigenic Sin”

  1. So, there is a database inside us?.

    I wonder if it is SQL or Oracle and how many instances can be stored therein.

    Maybe there are space saving algorithms involved too, certainly made of atoms … or psychons?

    There seems to be a similar system that “knows” about atomic structures of genetic material (The Advent Of The Sulfur Atom – 4)?

  2. Which is why many balked at taking a vaccine specific to the S protein rather than the N protein. OAS was predictable.

  3. @UCT: Can you name an effective vaccine that is specific for the N protein? It doesn’t seem logical to balk at something that exists and is effective, for something that doesn’t exist. Even if a perfect vaccine might exist in the future, people live in time and avoiding disease and death in the present increases the probability that they will even have a future.

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