Credit NIAID
#18,007
The term Original Antigenic Sin (OAS) was first coined in 1960 by Thomas Francis, Jr. in his article On the Doctrine of Original Antigenic Sin, which postulated that when the body’s immune system is exposed to - and develops an immunological memory - to one virus, it may be less able to mount a defense against a subsequent exposure to a slightly different version of that virus.
We see the impact of OAS often with Dengue, which has 4 closely related serotypes. Regardless of the serotype of one's first infection, that illness is generally mild or moderate. Subsequent dengue infections (with different serotypes) often produce more severe illness, and sometimes death.
And if mistakenly sending the wrong antibodies into the fray isn’t bad enough, sometimes non-neutralizing antibodies can actually enhance a virus’s ability to enter a host’s cells via a process called ADE or Antibody-dependent enhancement.Why? The body's immune system mistakenly recognizes the new infection as a repeat of the first, and sends cross reactive, but non-neutralizing (read: ineffective) antibodies to the field of battle.
With influenza, it is increasingly being recognized that one's first exposure makes a significant, and lasting, impression on your immune system (see Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression).
Up until relatively recently, we thought of influenza viruses as being grouped primarily by HA subtype; H1, H3, H5, H7, etc. But, as the chart above shows, the 18 known subtypes are divided into two basic groups; Group 1 and Group 2.
And recent evidence suggests that the first HA group you are exposed to may determine your ability to fight infection by viruses from the other group. A few past blogs include:
And recent evidence suggests that the first HA group you are exposed to may determine your ability to fight infection by viruses from the other group. A few past blogs include:
This childhood imprinting may help to explain why (HA Group 2) H7N9 cases in China skewed heavily to those > 50, while (HA Group 1) H5N1 cases generally affected those under the age of 40 (see chart below).PLoS Path.: Childhood Immune Imprinting to Influenza ANature Comms: Middle-Aged Individuals May Be in a Perpetual State of H3N2 Flu Virus Susceptibility
The more diverse a family of viruses, the more problematic OAS becomes. And when it comes to diversity, COVID is hard to beat.
A little over two years ago (before Omicron swept the world), in Science: Heterologous Infection and Vaccination Shapes Immunity Against SARS-CoV-2 Variants, we looked at a lengthy study by researchers from Imperial College London and Queen Mary University of London, that looked at the long-term immune impacts of a person's 1st exposure (via infection or vaccination) to SARS-CoV-2.
From the Press release:
New research shows that the first SARS-CoV-2 spike protein a person encounters, be it by vaccination or infection, shapes their subsequent immune response against current and future variants. That is, it imparts different properties that have an impact on the immune system’s ability to protect against variants, and also affects the rate of decay of protection.
There are some studies that suggest that Repeated Omicron exposures override ancestral SARS-CoV-2 immune imprinting, but there are no guarantees we won't seen another seismic shift in the virus down the road.
Given the growing diversity of novel flu viruses, and the continued expansion of COVID variants, it is imperative that we get a better handle on the impact and mechanisms behind OAS, and find ways to mitigate its effect.
All of which brings us to a new preprint, which looks at the impact of OAS on Omicron infection, and finds it can occur either through vaccination or natural infection. I've reproduced the abstract below, but those up for a deeper diver will want to follow the link to read it in its entirety.
Immune imprinting revealed by SARS-CoV-2 Omicron infection prior to vaccination
Ravindra Gupta, Adam Abdullahi, James Onyemata, Sam Turner, Martin Edun, and 13 more
This is a preprint; it has not been peer reviewed by a journal.
https://doi.org/10.21203/rs.3.rs-4186317/v1
This work is licensed under a CC BY 4.0 License
Abstract
Immune imprinting or original antigenic sin (OAS) originally referred to a phenomenon of suboptimal immune response to a repeat exposure to a virus that was antigenically distinct from the original virus infection. OAS has been implicated in higher mortality in young people during the 2009-10 H1N1 pandemic where the elderly (H1N1 exposure in childhood) appeared relatively well protected compared to younger individuals whose first influenza infection was not H1N1.
Immune imprinting is part of a rapid recall system and is highly effective against a slowly evolving virus (drifting) but not antigenically shifting viruses such as influenza and SARS CoV-2. As predicted by OAS, suboptimal neutralization responses to the highly divergent SARS-COV-2 lineage Omicron have been observed in animal models and individuals previously vaccinated with primary course of ancestral (Wu-1) vaccine.
Due to the rapid scale up of vaccine before emergence of the antigenically distinct Omicron variant, it is unknown whether immunological imprinting for occurs in the context of SARS-COV-2 infection itself. We longitudinally assessed humoral responses to primary two dose Ad26.COV2.S Wu-hu-1 based vaccination in a Nigerian population following the global emergence of Omicron.
At study entry in Jan 2023, we found 93% and 58% of pre-vaccination participants previously exposed to ancestral Wu-1 and Omicron virus respectively by anti-N IgG and anti-receptor binding domain (RBD) IgG Wu-1 and Omicron -specific antibodies. In participants with no evidence of prior exposure to Omicron, neutralisation against Wu-1 was significantly higher than Omicron variants as expected. However, serum neutralisation titres in participants who were anti-RBD Omicron IgG positive were paradoxically 2-fold lower for Omicron BA.1 as compared to Wu-1.
This is clear evidence for imprinted immunity from the ancestral pre-omicron lineage viruses, and remarkably these old responses to Wu-1 were able to dominate over more recent, likely multiple, Omicron lineage infections. Furthermore, in these participants with prior exposure to Omicron and evidence of imprinting, we observed that further Omicron infection and Wu-1 based vaccine was associated with boosting of responses across variants with equalisation of neutralisation titres for Wu-1 and Omicron variants.
However, omicron responses did not surpass ancestral responses, suggesting persistence of imprinting and only partial mitigation. However, serum neutralisation titres in participants who were anti-RBD Omicron IgG positive were paradoxically 2-fold lower for Omicron BA.1 as compared to Wu-1.ion. Although neutralization responses at high titres were observed post dose 1 vaccination against ancestral and Omicron variants BA.1, BA.2, BA.4 in nearly all participants, neutralisation against the highly immune evasive XBB recombinant variant remained substantially lower, with a second vaccine dose providing very modest boosting. only partial mitigation
These data highlight immune imprinting against SARS-CoV-2 prior to vaccination and its persistence thereafter. In present day unvaccinated populations where serum neutralisation responses to pre-Omicron variants dominate, use of an omicron variant based vaccine should be used in preference to Wu-1 based vaccine to override imprinting and provide broader protection for vulnerable populations such as the elderly or those with compromised immunity.
Not surprisingly, this is all very complicated and only partially understood, but the development of a Pan-COV vaccine or a `Universal Flu Vaccine' likely hinges on our gaining a better understanding of immune imprinting and OAS.
