Study finds Omicron infection effectively induces immunity against itself and enhances protection against other variants in vaccinated individuals

In a recent study posted to the medRxiv* preprint server, researchers investigated the effectiveness of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron-variant induced immunity, whether it is cross-protective against other variants, and if earlier infection with the SARS-CoV-2 Delta variant offers protection against Omicron.

Study: Limited cross-variant immunity after infection with the SARS-CoV-2 Omicron variant without vaccination. Image Credit: PHOTOCREO Michal Bednarek/Shutterstock

The Delta and Omicron variants are the most significant SARS-CoV-2 variant of concerns. While Delta infection can lead to serious lung disease, Omicron infection has been found to cause less severe symptoms, especially in the upper respiratory tract.

About the study

The researchers studied SARS-CoV-2 WA1, Delta, and Omicron infections in mice. The three viral isolates were intranasally introduced into transgenic mice overexpressing human angiotensin-converting enzyme-2 (ACE2) (K18-hACE2), and their body temperature and weight were evaluated for seven days as indications of disease progression.

The team measured infectious particle generation and viral RNA expression in the respiratory tracts and lungs of infected mice to determine viral replication dynamics. Infected mouse lungs were then examined for mRNA expression of inflammatory and innate immune markers. As severe coronavirus disease 2019 (COVID-19) is linked to cytokine storms and T cell exhaustion, the researchers analyzed if the strong proinflammatory response is also linked to T cell exhaustion in late infection.

Sera from infected mice were collected and examined for their neutralization efficiency against SARS-CoV-2 strains WA1, Alpha, Beta, Delta, and Omicron to determine humoral immune responses generated by infection with the three distinct strains. They also calculated the individual sera's 50% neutralization titers (NT50) against the various virus strains. Following that, they investigated the level of viral neutralizing immunity in convalescent sera from Delta-infected people.


The researchers noted that Delta- and WA1-infected mice developed gradual hypothermia and significant weight loss during the one-week trial. In contrast, Omicron-infected mice displayed only minor signs, such as a mild increase in body temperature and minimal weight loss. The WA1- and B.1.617.2-infected mice were hunched or lethargic five days after infection, but the B.1.1.529-infected mice were entirely normal. During this period, all Omicron-infected mice survived, while 100% of WA1-infected mice and 60% of Delta-infected mice reached the humane endpoint.

High viral titers were seen in the airways and lungs of WA1- and Delta-infected mice at all time points, although Omicron replication was much lower in these organs. At four and seven days after infection, brain tissue, a target for viral replication in K18-hACE2 animals, showed decreased Omicron replication. Compared to WA1 and Delta infections, Omicron produced fewer infectious particles in human airway organoids and the human alveolar A549 epithelial cell line overexpressing ACE2. In the respiratory tract samples, Omicron infectious titers declined less over time than in the lungs, indicating a more sustained reproduction of Omicron in this compartment.

While infection with WA1 and Delta quickly generated severe COVID-19 proinflammatory markers such as CXCL10 and CCL219, induction by Omicron was dramatically inhibited early on. Although the induction of interleukin 1 did not differ substantially among the three virus strains, it did show a trend toward reduced expression two days after infection in Omicron-infected mice.

Given the Omicron strain's significantly decreased viral replication, no significant alterations in the induction of interferon (IFN) or key downstream induced genes such as interferon-stimulated gene 15 (ISG15) and 2'-5'-oligoadenylate synthetase 1 (OAS1) were identified. These findings demonstrate decreased expression of several proinflammatory genes in the lungs of Omicron-infected mice but stimulation of innate antiviral immunity, which could explain the mice's modest illness phenotype.

Infected mice's CD4+ and CD8+ T cells segregate from their mock-infected counterparts, showing that WA1 infection causes significant phenotypic alterations in pulmonary T cells. The significant expression of the exhaustion markers programmed cell death 1 (PD1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4) on T cells from infected mice was noticeable. Still, these markers were scarcely expressed on T cells from mock-infected mice. These findings imply that WA1 infection in K18-hACE2 mice causes a strong proinflammatory cytokine response and exhausted pulmonary T cells.

Sera from mice infected with Delta had the largest cross-variant neutralization, effectively neutralizing all strains except Beta. While Omicron-infected sera efficiently neutralized Omicron, it only had a minimal cross-neutralization effect on other strains. Sera from WA1-infected mice protected against WA1, Alpha, and Delta, but not against Beta and Omicron. Sera from vaccinated people with confirmed Omicron breakthrough infection, in particular, exhibited the highest level of protection against all strains, including Omicron.


Based on the study findings, while the Omicron variant is immunogenic, infection with this variant in uninfected and unvaccinated individuals may not elicit effective cross-neutralizing antibodies against other variants. However, Omicron infection promotes immunity against itself in vaccinated individuals and improves protection against other variants. This suggests that Omicron- and Delta-based immunogens should be included in future multivalent vaccination regimens to provide widespread protection against all variants.

In vaccinated individuals, however, Omicron infection effectively induces immunity against itself and enhances protection against other variants."

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Suryawanshi, R. et al. (2022) "Limited cross-variant immunity after infection with the SARS-CoV-2 Omicron variant without vaccination". medRxivdoi: 10.1101/2022.01.13.22269243.

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: ACE2, Angiotensin, Antibodies, Brain, CD4, Cell, Cell Death, Cell Line, Coronavirus, Coronavirus Disease COVID-19, covid-19, CXCL10, Cytokine, Enzyme, Exhaustion, Gene, Genes, Hypothermia, immunity, Interferon, Interleukin, Lung Disease, Lungs, Lymphocyte, Omicron, Organoids, Phenotype, Programmed Cell Death, Protein, Reproduction, Respiratory, RNA, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Transgenic, Virus, Weight Loss

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Saurabh Chaturvedi

Saurabh Chaturvedi is a freelance writer from Jaipur, India. He is a gold medalist in Masters in Pharmaceutical Chemistry and has extensive experience in medical writing. He is passionate about reading and enjoys watching sci-fi movies.

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