Study: Limited cross-variant immunity from SARS-CoV-2 Omicron without vaccination. Image Credit: Naeblys / Shutterstock

Weak and short-lived natural immunity in unvaccinated after Omicron infection

In a recent study published in the journal Natureresearchers showed that Omicron infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) without SARS-CoV-2 vaccination conferred low cross-variant neutralization abilities.

Study: Limited cross-immunity against SARS-CoV-2 Omicron without vaccination. Image Credit: Naeblys / Shutterstock

Background

Many waves of infection have occurred since the start of the CoV disease 2019 (COVID-19) pandemic, with concerning new variants of SARS-CoV-2 (COV) continuing to emerge and outcompete previous variants. SARS-CoV-2 Omicron and Delta variants are VOCs of international importance compared to Gamma, Beta and Alpha VOCs, which spread more regionally. While Delta infection can lead to severe lung disease, Omicron infection usually presents with milder symptoms, especially in vaccinated people. The current concern is whether widespread Omicron infections will lead to subsequent cross-immunity, hastening the end of the COVID-19 pandemic.

About the study

In the current study, scientists analyzed infections of SARS-CoV-2 strains Omicron, Delta and WA1 in mice. The team used transgenic mice that overexpressed human angiotensin-converting enzyme 2 (hACE2), called K18-hACE2 mice, since the Delta and WA1 variants cannot infect conventional laboratory mice. These mice were infected intranasally with the three SARS-CoV-2 isolates for one week, and their weight and body temperature were monitored for disease progression.

The authors measured viral ribonucleic acid (RNA) production and infectious particle formation in the lungs and airways of infected mice over time to determine viral replication dynamics. Additionally, they assessed SARS-CoV-2 replication patterns in virus-infected human cell lines and lung organoids.

The team assessed T cell phenotypes and cytokine expression in the lungs of infected mice. Additionally, single-cell suspensions from the lungs of mice infected with scythes and viruses were generated. Additionally, time-of-flight (CyTOF) mass spectrometry cytometry was performed on them before and after activation with cross-linked 15-mer peptides spanning the entire spike (S) protein to assess whether the The observed pro-inflammatory response was related to T cell depletion in late infection.

Researchers sourced sera from mice a week after infections and examined their neutralization efficiency against SARS-CoV-2 isolates Omicron, Delta, Alpha, and WA1 to assess humoral immune responses caused by infection with the three isolates analyzed. They estimated 50% neutralization titers (NT50) by measuring plaque-forming units at various serum dilutions. Similarly, humoral immunity in unvaccinated/vaccinated and convalescent Omicron/Delta against COVID-19 against Omicron, Delta, Alpha and WA1 variants was analyzed. Additionally, serum samples from COVID-19 naïve and unvaccinated subjects were also tested against all four SARS-CoV-2 variants.

Results

Study results showed that mice infected with SARS-CoV-2 WA1 and Delta exhibited progressive hypothermia and significant weight loss. In contrast, mice infected with Omicron showed mild symptoms, such as a slight increase in body temperature and no weight loss. While all Omicron-infected animals survived the one-week trial, 60% of Delta-infected mice and 100% of WA1-infected mice exhibited humane endpoint traits.

Animals infected with WA1 and Delta had higher SARS-CoV-2 infectious titers in upper respiratory tract, brain and lung at all time points compared to Omicron. Similar results were found in human airway organoids and the alveolar epithelial cell line. Pro-inflammatory markers of severe COVID, such as CC-motif chemokine ligand 2 (CCL2) and CXC-motif chemokine ligand 10 (CXCL10), were easily elicited by WA1 and Delta infections compared to Omicron. The induction of interleukin 1 (IL1) did not differ significantly between the three viral isolates. However, there was a trend for reduced IL1 expression in Omicron-infected mice two days post-infection.

Delta, WA.1 and Omicron infections caused phenotypic alterations of T cells, but this was lower in mice infected with Omicron. Additionally, scientists found that Omicron induced lower levels of pro-inflammatory cytokines and depleted lung T cells. Therefore, animals infected with Omicron exhibited reduced pathogenicity of Omicron and a two to three log decline in Omicron replication.

Sera from mice infected with Omicron and overexpressing the hACE2 receptor only neutralize Omicron but not other COVs, while SARS-CoV-2 Delta and WA1 infections result in significant cross-neutralization. Sera from Omicron-infected patients who had not been vaccinated showed the same restricted neutralization of Omicron only as in mice. On the other hand, breakthrough infections of Omicron and Delta resulted in broader overall neutralization titers against all SARS-CoV-2 COVs.

conclusion

In conclusion, the study results showed that infection with Omicron elicited a modest humoral immune response in humans and mice without vaccination against COVID-19. Unlike the Delta and WA1 variants, Omicron multiplies to a small extent in the brain and lungs of infected animals, resulting in mild disease with reduced activation of lung-resident T cells and production of pro-cytokines. inflammatory.

Omicron showed weak neutralization of crossover variants compared to other isolates tested in human and unvaccinated mouse serum samples. This was likely due to its significantly altered protein S or lower replication potential. Although they possess identical inflammatory and replicative capacities, WA1 and Delta had distinct neutralization patterns. This inference highlighted the importance of S proteins in triggering cross-variant neutralization. Interestingly, breakthrough infections of Delta and Omicron enhanced vaccine-induced immunity, resulting in hybrid immunity that protected not only against themselves, but also against other SARS-CoV-2 variants.

Collectively, the present work has illustrated that Omicron infection boosts pre-existing immunity evoked by COVID-19 vaccinations, but may not provide widespread protection against non-Omicron variants of SARS-CoV-2 in people. not vaccinated. Additionally, current findings have supported the incorporation of Omicron- and Delta-based immunogens into future multivalent/heterologous COVID-19 vaccination approaches for broader protection against SARS-CoV-2 variants. .

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