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

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

In a recent study published in the journal: Natureresearchers showed that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron infection without SARS-CoV-2 vaccination conferred poor neutralizing ability between different variants.

Study: Limited Cross-variant Immunity of SARS-CoV-2 Omicron without Vaccination† ​​​​​​​Image Credit: Naeblys/Shutterstock


Since the onset of the 2019 CoV disease (COVID-19) pandemic, numerous waves of infection have occurred, with new SARS-CoV-2 variants of concern (VOCs) continuing to emerge, outpacing previous variants. The SARS-CoV-2 Omicron and Delta variants are internationally important VOCs compared to the Gamma, Beta and Alpha VOCs, which are more regionally distributed. While Delta infection can lead to severe lung disease, Omicron infection usually has milder symptoms, especially in those who have been vaccinated. The current concern is whether extensive Omicron infections will result in subsequent immunity between variants, hastening the end of the COVID-19 pandemic.

About the study

In the current study, the scientists analyzed the SARS-CoV-2 Omicron, Delta, and WA1 strain infections in mice. The team used transgenic mice that overexpress human angiotensin-converting enzyme 2 (hACE2), called K18-hACE2 mice, since Delta and WA1 variants cannot infect conventional lab mice. These mice were intranasally infected 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 the dynamics of viral replication. Furthermore, they assessed 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. In addition, single-cell suspensions were generated from the lungs of mock- and virus-infected mice. In addition, before and after activation, cytometry by time of flight (CyTOF) mass spectrometry was performed on them with crossing 15-mer peptides spanning the entire spike protein (S) to assess whether the observed pro-inflammatory response was related to depletion of T cells in late infection.

The researchers obtained sera from mice one week after infections and examined their neutralization effectiveness against the SARS-CoV-2 Omicron, Delta, Alpha, and WA1 isolates to evaluate humoral immune responses induced by infection with the three isolates analyzed. They estimated the 50% neutralization (NT50) titers by measuring plaque forming units at different serum dilutions. Similarly, humoral immunity was analyzed in unvaccinated/vaccinated COVID-19 and Omicron/Delta recovering individuals against Omicron, Delta, Alpha and WA1 variants. In addition, sera samples from COVID-19 naive and unvaccinated subjects were also tested against the four SARS-CoV-2 variants.


The study results showed that the SARS-CoV-2 WA1- and Delta-infected mice had progressive 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 each Omicron-infected animal survived the week-long trial, 60% of Delta and 100% of WA1-infected mice exhibited human endpoint characteristics.

WA1- and Delta-infected animals had higher infectious SARS-CoV-2 titers in the upper respiratory tract, brain and lungs compared to Omicron at all time points. Similar results were found in the human respiratory tract 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 readily caused by WA1 and Delta infections versus Omicron. The induction of interleukin 1 (IL1) did not differ substantially between the three viral isolates. However, there was a tendency for decreased IL1 expression in Omicron-infected mice two days after infection.

Delta, WA.1, and Omicron infections caused phenotypic changes in the lungs T cells, but this was lower in Omicron-infected mice. In addition, the scientists found that Omicron induced lower levels of pro-inflammatory cytokines and depleted lung T cells. Therefore, the Omicron-infected animals had reduced Omicron pathogenicity and a two to three log decrease in Omicron replication.

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


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

Omicron showed poor neutralization between different variants than other isolates tested in unvaccinated human and mouse sera samples. This was probably due to the significantly altered S protein or the lesser replicative potential. Despite having identical ignition and replicative capabilities, WA1 and Delta had different neutralization patterns. This inference emphasized the importance of S proteins in initiating cross-variant neutralization. Interestingly, breakthrough infections by Delta and Omicron increased vaccination-induced immunity, resulting in a hybrid immunity that protected not only against itself but also against other SARS-CoV-2 variants.

Collectively, the current work illustrated that Omicron infection enhances pre-existing immunity elicited by COVID-19 vaccinations, but may not provide widespread protection against non-Omicron SARS-CoV-2 variants in unvaccinated humans. In addition, the current findings supported the inclusion 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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