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Clinical severity of COVID-19 caused by SARS-CoV-2 variants and the effectiveness of mRNA vaccines against them

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A recent study posted to the medRxiv* preprint server examined the clinical severity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Alpha, Delta, and Omicron variants of concern (VOCs) and compared vaccine effectiveness against each VOC. 

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Study: Clinical Severity and mRNA Vaccine Effectiveness for Omicron, Delta, and Alpha SARS-CoV-2 Variants in the United States: A Prospective Observational Study. Image Credit: joshimerbin/Shutterstock

The various VOCs of SARS-CoV-2 have been reported to differ in transmissibility, clinical severity, and risk of hospitalizations among patients of different age groups. Understanding the impact of the newly emerging VOCs on the epidemiology of coronavirus disease 2019 (COVID-19) infections and assessing the efficacy of COVID-19 vaccines is essential to formulate effective measures against the pandemic. 

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About the study

The present prospective observational study compared the clinical severity of SARS-CoV-2 Alpha, Delta, and Omicron VOCs in COVID-19-related hospitalizations in the US and assessed the protection provided by COVID-19 messenger ribonucleic acid (mRNA) vaccines against the VOCs.  

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The study included hospitalized COVID-19 cases who were adults aged 18 years and older who showed one or more clinical symptoms of COVID-19 infection and a positive SARS-CoV-2 antigen or molecular test, detected within ten days of onset of symptoms. The study included three groups of COVID-19 patients classified based on their causal SARS-CoV-2 VOC and two control groups consisting of test-negative and syndrome-negative individuals.

Data of the eligible individuals, including demographics, vaccination status, medical conditions, and comorbidities, were collected along with information such as vaccination dates and the type of vaccine administered. Based on the number of COVID-19 mRNA vaccine doses received by the patient, the study cohorts were classified into zero doses (unvaccinated); one dose administered 14 or more days before symptom onset (partially vaccinated); two doses given 14 or more days before symptom onset (fully vaccinated); or three doses administered seven or more days before symptom onset (boosted).

A primary analysis of vaccine effectiveness was conducted after the administration of two or three vaccine doses in the individuals. The secondary analysis assessed vaccine effectiveness for partial vaccination. Upper respiratory specimens sampled from the participants were tested for the presence of SARS-CoV-2 using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and also underwent viral genome sequencing.

Three parameters were used to compare the Alpha, Delta, and Omicron VOCs – efficacy of the COVID-19 mRNA vaccines against hospitalizations caused by each VOC, the severity of disease for each VOC in hospitalized patients who were either vaccinated and vaccinated, the impact of the vaccine in the prevention of disease progression to the patients requiring invasive mechanical ventilation or death.    


The study results showed that a total of 11,690 patients were eligible for the analysis, of which 5,728 were COVID-19 patients, and 5,962 were controls. Of the 45% cases with complete SARS-CoV-2 sequencing data, 57% had the Alpha VOC, 97% had the Delta VOC while 77% had the Omicron VOC.

Vaccine effectiveness against COVID-19-related hospitalization was tested on 5,582 patients and 5,962 controls. Vaccine effectiveness after administration of two doses of mRNA vaccines was 85% during the period of Alpha VOC dominance, 85% during Delta VOC dominance, and 65% when the Omicron VOC was dominant. Vaccine effectiveness after administration of three mRNA vaccine doses was 86% during the period of Omicron dominance while Delta and Alpha too showed a similar level of effectiveness.

The vaccine effectiveness during the Delta period was 88% when the second vaccine dose was received 14 to 150 days before symptom onset compared to 81% when the vaccine was administered before 150 days from onset of symptoms. In the case of patients who received three vaccine doses in the Delta period, the vaccine efficacy was 94%, with 97% and 87% efficacies observed in immunocompetent and immunocompromised patients, respectively.   

Among vaccinated and unvaccinated patients, an overall total of 11% of patients hospitalized due to COVID-19 died after 28 days of hospital admission, including 8% deaths due to Alpha VOC infection, 12% due to Delta, and 7% as a result of Omicron infection. For unvaccinated cases, the severity of disease was the highest for Delta infections with an adjusted proportional odds ratio (aPOR) of 1.28 and lowest for Omicron infections with aPOR of 0.79 while in-hospital deaths were observed in 8%, 12%, and 9% of the Alpha, Delta, and Omicron VOC patients, respectively. Among the vaccinated patients, aPOR of 0.33, 0.44, and 0.61 were noted in Alpha, Delta, and Omicron VOC cases, respectively.


The study findings showed that mRNA vaccines were highly efficacious in protecting against COVID-19-related hospitalizations caused due to SARS-CoV-2 Alpha, Delta, and Omicron VOCs. Notably, two mRNA vaccine doses provided the same level of protection against COVID-19-related hospitalizations for Omicron VOC cases, as did three vaccine doses for Delta and Alpha VOCs. The lower disease severity observed in vaccinated cases as compared to unvaccinated cases proved the preventative ability of vaccines against the clinical severity of COVID-19. 

*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.

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