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Natural immunity weak and short-lived in unvaccinated after Omicron infection

In a recent study posted to the journal Nature, researchers showed that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron infection without SARS-CoV-2 vaccination conferred poor cross-variant neutralizing capacities.

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


Numerous waves of infection have occurred since the start of the CoV disease 2019 (COVID-19) pandemic, with novel SARS-CoV-2 variants of concern (VOCs) continuing to emerge and out-compete prior variants. The SARS-CoV-2 Omicron and Delta variants are internationally significant VOCs compared to the Gamma, Beta, and Alpha VOCs, which spread more regionally. While Delta infection can lead to severe lung illness, Omicron infection usually has milder symptoms, particularly in those who have been vaccinated. The current concern is whether extensive Omicron infections will result in subsequent cross-variant immunity, hastening the COVID-19 pandemic’s termination.

About the study

In the present study, the scientists analyzed the SARS-CoV-2 Omicron, Delta, and WA1 strains infections in mice. The team employed transgenic mice overexpressing human angiotensin-converting enzyme 2 (hACE2), named K18-hACE2 mice, since Delta and WA1 variants cannot infect conventional laboratory mice. These mice were infected intranasally with the three SARS-CoV-2 isolates for a week, and their weight and body temperature were monitored for illness progression.

The authors measured viral ribonucleic acid (RNA) production and infectious particle formation in infected mice’s lungs and respiratory tracts with time to determine viral replication dynamics. Further, they assessed the SARS-CoV-2 replication patterns in virus-infected human cell lines and lung organoids. 

The team evaluated T-cell phenotypes and cytokine expression in infected mouse lungs. Besides, single-cell suspensions from the lungs of mock- and virus-infected mice were generated. Additionally, cytometry by time of flight (CyTOF) mass spectrometry was performed on them before and after activation with intersecting 15-mer peptides spanning the entire spike (S) protein to assess if the pro-inflammatory response observed was connected with T-cell depletion in late infection.

The researchers procured sera from mice one week following infections and examined their neutralization efficacy against the SARS-CoV-2 Omicron, Delta, Alpha, and WA1 isolates to evaluate humoral immune responses caused by infection with the analyzed three isolates. They estimated the 50% neutralization (NT50) titers by measuring plaque-forming units at various serum dilutions. Similarly, humoral immunity in COVID-19 non-vaccinated/vaccinated and Omicron/Delta convalescent individuals against the Omicron, Delta, Alpha, and WA1 variants were analyzed. Furthermore, sera samples from COVID-19 naive and non-vaccinated subjects were also tested against the four SARS-CoV-2 variants.


The study results depicted that the SARS-CoV-2 WA1- and Delta-infected mice had gradual hypothermia and significant weight loss. In contrast, Omicron-infected mice showed mild symptoms, such as a modest rise in body temperature and zero weight loss. While every Omicron-infected animal survived the one-week trial, 60% of Delta- and 100% of WA1-infected mice exhibited humane end-point traits.

WA1- and Delta-infected animals had higher infectious SARS-CoV-2 titers in the upper airways, brain, and lungs at all timepoints relative to Omicron. Similar results were found in the human airway organoids and the alveolar epithelial cell line. Pro-inflammatory markers of severe COVID, like C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 10 (CXCL10), were readily triggered by WA1 and Delta infections versus Omicron. Interleukin 1 (IL1) induction did not differ substantially among the three viral isolates. However, there was a tendency toward reduced IL1 expression in Omicron-infected mice two days after infection.

Delta, WA.1, and Omicron infections caused phenotypic alterations in pulmonary T cells, but this was lower in Omicron-infected mice. In addition, the scientists found that Omicron induced lower degrees of pro-inflammatory cytokines and exhausted pulmonary T cells. Hence, the Omicron-infected animals had reduced Omicron pathogenicity and a two to three log drop in Omicron replication.

Sera from mice infected with Omicron and overexpressing the hACE2 receptor neutralize just Omicron but not other VOCs, whereas SARS-CoV-2 Delta and WA1 infections result in significant cross-variant neutralization. Sera from Omicron-infected patients who had not been vaccinated displayed the same restricted neutralization of solely Omicron as in mice. On the other hand, Omicron and Delta breakthrough infections resulted in overall broader neutralization titers towards all SARS-CoV-2 VOCs.


To conclude, the study findings showed that infection with Omicron caused a modest humoral immune response in humans and mice without COVID-19 vaccination. Unlike the Delta and WA1 variants, Omicron multiplies to a low extent in infected animals’ brains and lungs, resulting in mild illness with reduced lung-resident T cell activation and pro-inflammatory cytokine production.

Omicron showed poor cross-variant neutralization than other tested isolates in non-vaccinated human and mice sera samples. This was probably due to its significantly altered S protein or lesser replicative potential. Despite possessing identical inflammatory and replicative capabilities, WA1 and Delta had distinct neutralization patterns. This inference highlighted the importance of S proteins in triggering cross-variant neutralization. Interestingly, Delta and Omicron breakthrough infections enhanced vaccination-induced immunity, resulting in a hybrid immunity that protected against not just themselves but also additional SARS-CoV-2 variants.

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

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