Prior infection and vaccination protects against severe outcomes from SARS-CoV-2 Omicron infection

A new study published in The Journal of Infectious Diseases reports that both previous infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and booster vaccination protect against intensive care unit (ICU) admission and mortality following infection with the SARS-CoV-2 Omicron variant. However, the extent of this protection is reduced against the Omicron variant compared to the Delta variant.

Study: Impact of vaccination, prior infection and therapy on Omicron Infection and mortality. Image Credit: Chaikom /


As of December 1, 2022, almost three years after the first coronavirus disease 2019 (COVID-19) case was reported in Wuhan, China, over 648 million people have been infected with SARS-CoV-2 around the world, 6.6 million of whom have died.

Viral genomes undergo adaptive changes that modify their pathogenic potential. As with other ribonucleic acid (RNA) viruses, SARS-CoV-2 is susceptible to genetic evolution when adapting to new human hosts.

This has resulted in the emergence of different viral variants with properties distinct from the original SARS-CoV-2 strain. To date, five major SARS-CoV-2 variants of concern (VOCs) have been identified, which include the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) variants.

South Africa was the first country to identify the Omicron variant in late November 2021. Since then, this VOC has spread rampantly throughout the world and has remained the dominant circulating strain.

The Omicron VOC can evade immunity conferred by COVID-19 vaccines and infection with the other SARS-CoV-2 variants. However, there is a lack of evidence specifying the degree to which waning immunity from COVID-19 vaccines or prior SARS-COV-2 infection against predilects severe Omicron infection-related outcomes. Furthermore, few studies have discussed the effectiveness of monoclonal antibody therapy administered after Omicron infection against severe outcomes in real-world settings.

Considering these concerns, researchers in the U.S. conducted an extensive study examining the link between COVID-19 immunization and prior SARS-CoV-2 infection. In addition, the risk of severe disease caused by the Delta and Omicron VOCs was also compared regarding vaccination, previous infection, and monoclonal antibody statuses. 

Delta variants were used in this study as controls to determine whether immunization, prior infection and therapy protect against infection from the Omicron VOC and its severe outcomes, as well as the lethality of Omicron infections.

About the study

In the current study, 295,691 individuals were tested for SARS-CoV-2 at the Cleveland Clinic between October 1, 2022, and January 31, 2022. A case-control study design was used to independently assess the association between vaccination and prior infection with SARS-CoV-2 infection for Delta- and Omicron-predominant phases. 

Six vaccination status categories were identified, which included 14-179 days after the third dose of the messenger RNA (mRNA) vaccine (BNT162b2 or mRNA-1273), over 180 days after the third dose of the mRNA vaccine, 14-179 days after the second dose of the mRNA vaccine; 180 days after the second dose of the mRNA vaccine; any other COVID-19 vaccination; and unvaccinated. 

SARS-CoV-2 monoclonal antibodies were administered to individuals aged 18 years and older who developed symptoms within seven days of testing positive for COVID-19. During the Delta-and Omicron-dominant periods, the Kaplan-Meier curve was used to assess and compare the likelihood of survival for patients who tested positive for COVID-19.

The researchers used logistic and Cox regression analyses to assess whether vaccination, prior infection and/or monoclonal antibody therapy correlate with the risks of prolonged hospitalization and death in ICUs.

Prior infection conferred limited protection against the Omicron variant

Over time, there was a significant decrease in the effectiveness of both the two- and three-dose vaccination series. Both vaccine regimens were significantly less effective against Omicron than the Delta VOC.

Infection with the Delta VOC was associated with a third vaccination dose taken closer than 180 days ago, relative to the unvaccinated. Comparatively, infection with the Omicron variant was associated with taking the second vaccination dose greater than 180 days before testing positive for COVID-19.

According to the estimated odds ratios of infection with the Delta and Omicron variants, prior SARS-CoV-2 infection offered less protection against the Omicron VOC than the Delta VOC.

Delta variant causes more severe disease than Omicron

During the Omicron-predominant period, Kaplan-Meier estimates of survival probabilities were significantly higher than those during the Delta-predominant period. The 28-day mortality rates were 1% and 1.80%, respectively, and the hazard ratio for death due to Omicron versus Delta infection was 0.60.

Furthermore, the survival curves between the two time periods were significantly closer, and the hazard ratio decreased from 0.63 to 0.83. This demonstrates that the Omicron VOC precipitates less severe outcomes than the Delta VOC.

Vaccination and prior infection reduce the risk of ICU hospitalization and death due to Omicron infection

During the Omicron-predominant period, the effectiveness of two mRNA vaccine doses in preventing death decreased over time. However, receiving the two- or three-dose vaccination series over the previous six-month duration significantly reduced the risk of death from Omicron infection. 

The 95% confidence intervals for the hazard ratios of death from Delta and Omicron variants were 0.43 and 0.28, respectively, when vaccination was provided within 180 days of being infected. Delta and Omicron infections in individuals with a history of COVID-19 were predicted to have a death risk ratio of 0.22 and 0.47, respectively. 

For Delta and Omicron VOCs, the relative risk associated with prior infection was 0.04 and 0.27, respectively. Relative to the mortality rate, the association with hospitalization was weaker, while that with ICU admissions was comparable.


Vaccination and previous infection appear less protective against infection with the Omicron variant than the Delta variant. Nevertheless, these factors reduce the likelihood of ICU hospitalizations and death due to Omicron infection.

A significant increase in the efficacy of two mRNA vaccine doses against infection, ICU admission, and death was notable after receipt of a third booster vaccine dose; however, the efficacy of these vaccine doses significantly declined over time. Furthermore, monoclonal antibody therapy administered after Omicron infection significantly reduced the likelihood of ICU admissions and mortality. 

The relatively low mortality posed by Omicron compared to the Delta VOC can be attributed to both the reduced lethality of the Omicron variant and the improved immunity acquired amongst populations who received booster vaccinations and experienced prior infection with SARS-CoV-2.

According to the study findings, a second vaccine dose administered more than 180 days prior to being infected provides minimal protection against the Omicron variant. This is likely because the Omicron spike (S) protein can evade neutralizing antibodies generated by two mRNA vaccine doses. Similarly, prior SARS-CoV-2 infection confers less protection against the Omicron variant compared to the Delta variant.

Journal reference:
  • Wang, X., Zein, J., Ji, X., et al. (2022). Impact of vaccination, prior infection and therapy on Omicron Infection and mortality. The Journal of Infectious Diseases. doi:10.1093/infdis/jiac460
Nidhi Saha

Written by

Nidhi Saha

I am a medical content writer and editor. My interests lie in public health awareness and medical communication. I have worked as a clinical dentist and as a consultant research writer in an Indian medical publishing house. It is my constant endeavor is to update knowledge on newer treatment modalities relating to various medical fields. I have also aided in proofreading and publication of manuscripts in accredited medical journals. I like to sketch, read and listen to music in my leisure time.


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