Recalling ancestral SARS-CoV-2 variants: is it an original sin with benefits?

Immune imprinting was first described in the context of influenza as “original antigenic sin” by Thomas Francis Jr in 1960.1TF Jr, On the Doctrine of Original Antigenic Sin.Proc Am Philos Soc. 1960; 104: 572-578Google Scholar Influenza imprinting might nudge the immune response towards conserved regions of currently circulating influenza virus strains, rather than the most immunogenic region of the dominant strain of the future influenza epidemics. Similar concerns have been raised for SARS-CoV-2, in particular, whether previous vaccination or infection with pre-omicron variants might impair responses against currently circulating strains. Have we committed an original sin by vaccinating with the spike protein of a now outcompeted variant of SARS-CoV-2, that will henceforth stunt our immune response to the variants and vaccines of the future, leading to higher morbidity and mortality? In other words, is this a scenario for us to overcome, as Hoffmann and colleagues2Hoffmann M Behrens GMN Arora P et al.Effect of hybrid immunity and bivalent booster vaccination on omicron sublineage neutralisation.Lancet Infect Dis. 2023; 23: 25-28Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar conclude in their recent correspondence in The Lancet Infectious Diseases? There is a lot of evidence that underpins the notion that the immune response to viruses is guided by previous exposure to similar antigens. This response is also the case for SARS-CoV-2, whereby previous exposure to other human coronaviruses, such as HKU-1, appears to guide the antibody response towards epitopes that are conserved, rather than novel and SARS-CoV-2 specific epitopes.3Ladner JT Henson SN Boyle AS et al.Epitope-resolved profiling of the SARS-CoV-2 antibody response identifies cross-reactivity with endemic human coronaviruses.Cell Rep Med. 2021; 2100189PubMed Google Scholar Several studies examined the immune response to infections with omicron variants, and these, too, revealed evidence of immune imprinting. In individuals primed with ancestral strains of SARS-CoV-2 through infection or vaccination, titres of neutralising antibodies, an established marker of protection, are boosted against ancestral strains and to a lesser degree against omicron itself.4Kaku CI Bergeron AJ Ahlm C et al.Recall of preexisting cross-reactive B cell memory after Omicron BA.1 breakthrough infection.Sci Immunol. 2022; 7eabq3511Crossref PubMed Scopus (30) Google Scholar Infections with omicron variants did not transition the immune response towards proficient neutralisation of newer variants of omicron, such as BA.2.75.2 and BQ.1.1, while upholding strong titres against wildtype SARS-CoV-2.2Hoffmann M Behrens GMN Arora P et al.Effect of hybrid immunity and bivalent booster vaccination on omicron sublineage neutralisation.Lancet Infect Dis. 2023; 23: 25-28Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar The upholding of strong titres is despite all omicron variants sharing only a small minority of unaltered neutralising B-cell epitopes with the earliest variant of SARS-CoV-2.5Muik A Lui BG Diao H et al.Progressive loss of conserved spike protein neutralizing antibody sites in Omicron sublineages is balanced by preserved T-cell recognition epitopes.bioRxiv. 2022; (published online Dec 15.) (preprint)https://doi.org/10.1101/2022.12.15.520569Google Scholar A similar observation can be made for bivalent vaccine boosters containing the spike of omicron variants BA.5, in addition to wildtype SARS-CoV-2. Wildtype SARS-CoV-2 is neutralised most effectively, even though a broadening of the immune response towards newer omicron variants also occurs, but in a much lesser magnitude.6Davis-Gardner ME Lai L Wali B et al.Neutralization against BA.2.75.2, BQ.1.1, and XBB from mRNA Bivalent Booster.N Engl J Med. 2023; 388: 183-185Crossref PubMed Scopus (29) Google Scholar If this broadening of the immune response offers long-lived improved protection from infection, especially by emerging omicron variants, remains to be seen. But the insights gained through studies of neutralising antibodies do not seem to translate into higher mortality. Priming with wildtype SARS-CoV-2 through three vaccine doses upholds efficacy against the most important outcomes of vaccination, severe disease, and death in the case of an omicron infection,7Tsang NNY So HC Cowling BJ Leung GM Ip DKM Effectiveness of BNT162b2 and CoronaVac COVID-19 vaccination against asymptomatic and symptomatic infection of SARS-CoV-2 omicron BA.2 in Hong Kong: a prospective cohort study.Lancet Infect Dis. 2022; (published online Dec 12.)https://doi.org/10.1016/S1473-3099(22)00732-0Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar potentially aided by upheld T-cell immunity. And priming with pre-omicron variants of SARS-CoV-2, before an infection with the first omicron variants BA.1 or BA.2, reduced the risk of re-infection, rather than promoted it.8Chemaitelly H Ayoub HH Tang P et al.Immune imprinting and protection against repeat reinfection with SARS-CoV-2.N Engl J Med. 2022; 387: 1716-1718Crossref PubMed Scopus (12) Google Scholar Considering that infections with omicron variants were associated with less, albeit still considerable, serious adverse outcomes than the ancestral delta variant,9Lauring AS Tenforde MW Chappell JD et al.Clinical severity of, and effectiveness of mRNA vaccines against, covid-19 from omicron, delta, and alpha SARS-CoV-2 variants in the United States: prospective observational study.BMJ. 2022; 376e069761PubMed Google Scholar it appears to be a beneficial population strategy to maintain high memory B-cell immunity against ancestral strains. The action of immune imprinting, by upholding high neutralising antibody titres against ancestral SARS-CoV-2 strains in the population, might help eradicate ancestral strains, in favour of attenuated strains circulating in consecutive waves. A novel (hypothetical) strain derived from the delta variant that shares the predisposition to cause lethal outcomes might be the worst-case scenario going forward in the pandemic in regions with high population-immunity. And immune imprinting might help protect us from this prospect. We agree with Hoffmann and colleagues that overcoming immune imprinting might be needed to optimise vaccine efficacy against reinfection with omicron variants emerging today and in the future. We can learn from the observation that the response towards newer omicron variants is enhanced in magnitude and breadth through previous infection,10Kurhade C Zou J Xia H et al.Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1 and XBB.1 by parental mRNA vaccine or a BA.5 bivalent booster.Nat Med. 2022; (published online Dec 5.)https://doi.org/10.1038/s41591-022-02162-xCrossref PubMed Scopus (50) Google Scholar which exposes the immune system to wider range of non-neutralising epitopes. The frequency of vaccination and the time intervals between them also play an important role. Alternative strategies, such as mucosal vaccines, might also help in broadening the immune response. Meanwhile, it should be considered that immune imprinting might be offering a wall of protection from even more severe variants derived from ancestral strains. SC reports once being a part of a clinical advisory board of BioNTech in 2020. SH and SC received study support from Roche diagnostics.