SARS-CoV-2 breakthrough infections elicit potent, broad, and durable neutralizing antibody responses.

Although infections among vaccinated individuals lead to milder COVID-19 symptoms relative to those in unvaccinated subjects, the specificity and durability of antibody responses elicited by breakthrough cases remain unknown. Here, we demonstrate that breakthrough infections induce serum-binding and -neutralizing antibody responses that are markedly more potent, durable, and resilient to spike mutations observed in variants than those in subjects who received only 2 doses of vaccine. However, we show that breakthrough cases, subjects who were vaccinated after infection, and individuals vaccinated three times have serum-neutralizing activity of comparable magnitude and breadth, indicating that an increased number of exposures to SARS-CoV-2 antigen(s) enhance the quality of antibody responses. Neutralization of SARS-CoV was moderate, however, underscoring the importance of developing vaccines eliciting broad sarbecovirus immunity for pandemic preparedness.

Protective prototype-Beta and Delta-Omicron chimeric RBD-dimer vaccines against SARS-CoV-2.

Breakthrough infections by SARS-CoV-2 variants become the global challenge for pandemic control. Previously, we developed the protein subunit vaccine ZF2001 based on the dimeric receptor-binding domain (RBD) of prototype SARS-CoV-2. Here, we developed a chimeric RBD-dimer vaccine approach to adapt SARS-CoV-2 variants. A prototype-Beta chimeric RBD-dimer was first designed to adapt the resistant Beta variant. Compared with its homotypic forms, the chimeric vaccine elicited broader sera neutralization of variants and conferred better protection in mice. The protection of the chimeric vaccine was further verified in macaques. This approach was generalized to develop Delta-Omicron chimeric RBD-dimer to adapt the currently prevalent variants. Again, the chimeric vaccine elicited broader sera neutralization of SARS-CoV-2 variants and conferred better protection against challenge by either Delta or Omicron SARS-CoV-2 in mice. The chimeric approach is applicable for rapid updating of immunogens, and our data supported the use of variant-adapted multivalent vaccine against circulating and emerging variants.

Neutralizing immunity in vaccine breakthrough infections from the SARS-CoV-2 Omicron and Delta variants.

Virus-like particle (VLP) and live virus assays were used to investigate neutralizing immunity against Delta and Omicron SARS-CoV-2 variants in 259 samples from 128 vaccinated individuals. Following Delta breakthrough infection, titers against WT rose 57-fold and 3.1-fold compared with uninfected boosted and unboosted individuals, respectively, versus only a 5.8-fold increase and 3.1-fold decrease for Omicron breakthrough infection. Among immunocompetent, unboosted patients, Delta breakthrough infections induced 10.8-fold higher titers against WT compared with Omicron (p = 0.037). Decreased antibody responses in Omicron breakthrough infections relative to Delta were potentially related to a higher proportion of asymptomatic or mild breakthrough infections (55.0% versus 28.6%, respectively), which exhibited 12.3-fold lower titers against WT compared with moderate to severe infections (p = 0.020). Following either Delta or Omicron breakthrough infection, limited variant-specific cross-neutralizing immunity was observed. These results suggest that Omicron breakthrough infections are less immunogenic than Delta, thus providing reduced protection against reinfection or infection from future variants.

Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination.

During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination.

Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone progressive change, with variants conferring advantage rapidly becoming dominant lineages, e.g., B.1.617. With apparent increased transmissibility, variant B.1.617.2 has contributed to the current wave of infection ravaging the Indian subcontinent and has been designated a variant of concern in the United Kingdom. Here we study the ability of monoclonal antibodies and convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2, complement this with structural analyses of Fab/receptor binding domain (RBD) complexes, and map the antigenic space of current variants. Neutralization of both viruses is reduced compared with ancestral Wuhan-related strains, but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2, suggesting that individuals infected previously by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insights for immunization policy with future variant vaccines in non-immune populations.

Experimental SARS-CoV-2 Infection of Elk and Mule Deer.

To assess the susceptibility of elk (Cervus canadensis) and mule deer (Odocoileus hemionus) to SARS-CoV-2, we performed experimental infections in both species. Elk did not shed infectious virus but mounted low-level serologic responses. Mule deer shed and transmitted virus and mounted pronounced serologic responses and thus could play a role in SARS-CoV-2 epidemiology.

Clinical Features and Outcomes of Hospitalized Adult Patients With Breakthrough COVID-19 Infections: A Propensity-Score-Matched Observational Study.

In this study, we aimed to evaluate the impact of vaccination on intensive care unit (ICU) admission and in-hospital mortality among breakthrough coronavirus disease 2019 (COVID-19) infections. A total of 3,351 adult patients hospitalized with COVID-19 in the Memorial Healthcare System (Hollywood, Florida) between June 1 and September 20, 2021, were included; 284 (8.5%) were fully vaccinated. A propensity-score-matched analysis was conducted to compare fully vaccinated patients with unvaccinated controls. Propensity scores were calculated on the basis of variables associated with vaccination status. A 1:1 matching ratio was applied using logistic regression models, ensuring balanced characteristics between the two groups. The matched samples were then subjected to multivariate analysis. Among breakthrough infections, vaccinated patients demonstrated lower incidences of ICU admission (10.3% vs. 16.4%; P = 0.042) and death (12.2% vs. 18.7%; P = 0.041) than the matched controls. Risk-adjusted multivariate analysis demonstrated a significant inverse association between vaccination and ICU admission (odds ratio = 0.52, 95% confidence interval: 0.31, 0.89; P = 0.019) as well as in-hospital mortality (odds ratio = 0.57, 95% confidence interval: 0.34, 0.94; P = 0.027). Vaccinated individuals experiencing breakthrough infections had significantly lower risks of ICU admission and in-hospital mortality. These findings highlight the benefits of COVID-19 vaccines in reducing severe outcomes among patients with breakthrough infections.

Computationally prioritized drugs inhibit SARS-CoV-2 infection and syncytia formation.

The pharmacological arsenal against the COVID-19 pandemic is largely based on generic anti-inflammatory strategies or poorly scalable solutions. Moreover, as the ongoing vaccination campaign is rolling slower than wished, affordable and effective therapeutics are needed. To this end, there is increasing attention toward computational methods for drug repositioning and de novo drug design. Here, multiple data-driven computational approaches are systematically integrated to perform a virtual screening and prioritize candidate drugs for the treatment of COVID-19. From the list of prioritized drugs, a subset of representative candidates to test in human cells is selected. Two compounds, 7-hydroxystaurosporine and bafetinib, show synergistic antiviral effects in vitro and strongly inhibit viral-induced syncytia formation. Moreover, since existing drug repositioning methods provide limited usable information for de novo drug design, the relevant chemical substructures of the identified drugs are extracted to provide a chemical vocabulary that may help to design new effective drugs.

A mouse xenograft long-term replication yields a SARS-CoV-2 Delta mutant with increased lethality.

We recently established a long-term SARS-CoV-2 infection model using lung-cancer xenograft mice and identified mutations that arose in the SARS-CoV-2 genome during long-term propagation. Here, we applied our model to the SARS-CoV-2 Delta variant, which has increased transmissibility and immune escape compared with ancestral SARS-CoV-2. We observed limited mutations in SARS-CoV-2 Delta during long-term propagation, including two predominant mutations: R682W in the spike protein and L330W in the nucleocapsid protein. We analyzed two representative isolates, Delta-10 and Delta-12, with both predominant mutations and some additional mutations. Delta-10 and Delta-12 showed lower replication capacity compared with SARS-CoV-2 Delta in cultured cells; however, Delta-12 was more lethal in K18-hACE2 mice compared with SARS-CoV-2 Delta and Delta-10. Mice infected with Delta-12 had higher viral titers, more severe histopathology in the lungs, higher chemokine expression, increased astrocyte and microglia activation, and extensive neutrophil infiltration in the brain. Brain tissue hemorrhage and mild vacuolation were also observed, suggesting that the high lethality of Delta-12 was associated with lung and brain pathology. Our long-term infection model can provide mutant viruses derived from SARS-CoV-2 Delta and knowledge about the possible contributions of emergent mutations to the properties of new variants.

Sequence analysis of the Spike, RNA-dependent RNA polymerase, and protease genes reveals a distinct evolutionary pattern of SARS-CoV-2 variants circulating in Yogyakarta and Central Java provinces, Indonesia.

During the Covid-19 pandemic, the resurgence of SARS-CoV-2 was due to the development of novel variants of concern (VOC). Thus, genomic surveillance is essential to monitor continuing evolution of SARS-CoV-2 and to track the emergence of novel variants. In this study, we performed phylogenetic, mutation, and selection pressure analyses of the Spike, nsp12, nsp3, and nsp5 genes of SARS-CoV-2 isolates circulating in Yogyakarta and Central Java provinces, Indonesia from May 2021 to February 2022. Various bioinformatics tools were employed to investigate the evolutionary dynamics of distinct SARS-CoV-2 isolates. During the study period, 213 and 139 isolates of Omicron and Delta variants were identified, respectively. Particularly in the Spike gene, mutations were significantly more abundant in Omicron than in Delta variants. Consistently, in all of four genes studied, the substitution rates of Omicron were higher than that of Delta variants, especially in the Spike and nsp12 genes. In addition, selective pressure analysis revealed several sites that were positively selected in particular genes, implying that these sites were functionally essential for virus evolution. In conclusion, our study demonstrated a distinct evolutionary pattern of SARS-CoV-2 variants circulating in Yogyakarta and Central Java provinces, Indonesia.

Transmission chains of the first local outbreak cause by Delta VariantB.1.617.2 COVID-19 in Guangzhou, Southern China.

BACKGROUND: The first local outbreak of Delta Variant B.1.617.2 COVID-19 of China occurred in Guangzhou city, south China, in May 2021. This study analyzed the transmission chains and local cluster characteristics of this outbreak, intended to provide information support for the development and adjustment of local prevention and control strategies. METHODS: The transmission chains and local cluster characteristics of 161 local cases in the outbreak were described and analyzed. Incubation period, serial interval and generation time were calculated using the exact time of exposure and symptom onset date of the cases. The daily number of reported cases and the estimated generation time were used to estimate the effective reproduction number (Rt). RESULTS: We identified 7 superspreading events who had more than 5 next generation cases and their infected cases infected 70.81%(114/161) of all the cases transmission. Dining and family exposure were the main transmission routes in the outbreak, with 29.19% exposed through dining and 32.30% exposed through family places. Through further analysis of the outbreak, the estimated mean incubation period was 4.22 (95%CI: 3.66-4.94) days, the estimated mean generation time was 2.60 (95%CI: 1.96-3.11) days, and the estimated Rt was 3.29 (95%CI: 2.25-5.07). CONCLUSIONS: Classification and dynamically adjusted prevention and control measures had been carried out according to analysis of transmission chains and epidemical risk levels, including promoting nucleic acid screening at different regions and different risk levels, dividing closed-off area, controlled area according to the risk of infection, raising the requirements of leaving Guangzhou. By the above control measures, Guangzhou effectively control the outbreak within 28 days without implementing a large-scale lockdown policy.

Genetics, structure, transmission, epidemiology, immune response, and vaccine efficacies of the SARS-CoV-2 Delta variant: A comprehensive review.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant (B.1.617.2) was the predominant variant behind the surges of COVID-19 in the United States, Europe, and India in the second half of 2021. The information available regarding the defining mutations and their effects on the structure, transmission, and vaccine efficacy of SARS-CoV-2 is constantly evolving. With waning vaccine immunity and relaxation of social distancing policies across the globe driving the increased spread of the Delta variant, there is a great need for a resource aggregating the most recent information for clinicians and researchers concerning the Delta variant. Accordingly, this narrative review comprehensively reviews the genetics, structure, epidemiology, clinical course, and vaccine efficacy of the Delta variant. Comparison with the omicron variant is also discussed. The Delta variant is defined by 15 mutations in the Spike protein, most of which increase affinity for the ACE-2 receptor or enhance immune escape. The Delta variant causes similar symptoms to prototypical COVID-19, but it is more likely to be severe, with a greater inflammatory phenotype and viral load. The reproduction number is estimated to be approximately twice the prototypical strains present during the early pandemic, and numerous breakthrough infections have been reported. Despite studies demonstrating breakthrough infection and reduced antibody neutralisation, full vaccination effectively reduces the likelihood of severe illness and hospitalisation.

Vertical transmission of SARS-CoV-2 delta-variant in a preterm infant.

BACKGROUND: As SARS-CoV-2 continues to be relevant and cause illnesses, the effect of emerging virus variants on perinatal health remains to be elucidated. It was demonstrated that vertical transmission of SARS-CoV-2 is a relatively rare event in the original SARS-CoV-2 strain. However, very few reports describe vertical transmission related to the delta-variant. CASE PRESENTATION: We report a case of a preterm male neonate born to a mother with positive SARS-CoV-2 and mild respiratory complications. The neonate was born by cesarean section due to fetal distress. The rupture of the amniotic membrane was at delivery. The neonate had expected prematurity-related complications. His nasopharyngeal swabs for RT-PCR were positive from birth till three weeks of age. RT-ddPCR of the Placenta showed a high load of the SARS-CoV-2 virus with subgenomic viral RNA. RNAscope technique demonstrated both the positive strand of the S gene and the orf1ab negative strand. Detection of subgenomic RNA and the orf1ab negative strand indicats active viral replication in the placenta. CONCLUSIONS: Our report demonstrates active viral replication of the SARS-CoV-2 delta-variant in the placenta associated with vertical transmission in a preterm infant.

Characteristics, outcome, duration of hospitalization, and cycle threshold of patients with COVID-19 referred to four hospitals in Babol City: a multicenter retrospective observational study on the fourth, fifth, and sixth waves.

BACKGROUND: The aim of the present study was to compare the epidemiological patterns of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infections, hospitalizations, deaths, and duration of hospitalization during the fourth, fifth and sixth epidemic waves of coronavirus disease 2019 (COVID-19) in Iran. METHODS: A multicenter retrospective observational study was conducted on hospitalized patients in four hospitals in the Babol district of northern Iran. The study periods were during the fourth, fifth, and sixth waves of the epidemic in Iran, (March 2021 to March 2022). A total of 13,312 patients with suspected COVID-19 were included. Patient demographics, medical history, length of hospital stay, and clinical outcomes were obtained from the hospital information system. Data on the cycle threshold (Ct) and SARS-CoV2 variant were collected for SARS-CoV2-positive cases. RESULTS: The highest number of hospitalized patients was reported during the fifth (Delta) wave (5231; 39.3%), while the lowest number of hospitalized patients was reported during the sixth (Omicron) wave (2143; 16.1%). In total, 6459 (48.5%) out of 13,312 hospitalized patients with suspected COVID-19 had a positive rRT-PCR result. The fifth (Delta) wave had the highest number of SARS-CoV2 rRT-PCR-positive hospitalized patients (3573, 55.3%), while the sixth (Omicron) wave had the lowest number (835, 12.9%). Moreover, 238 (3.7%) patients with laboratory-confirmed COVID-19 died. The hospital mortality rate was 6.8% in the fourth (Alpha) wave, which reduced to 2.7 and 3.5% in the fifth (Delta) and sixth (Omicron) waves, respectively (p < 0.001). CONCLUSIONS: This is the most comprehensive study evaluating the epidemiologic characteristics of laboratory-confirmed SARS-CoV2 cases in Iran during the Alpha, Delta, and Omicron waves. The highest number of SARS-CoV2-positive hospitalized patients was in the fifth wave of COVID-19 (dominance of the Delta variant), while the sixth wave (dominance of the Omicron variant) had the lowest number. Comorbidities were similar, and cardiovascular disease, diabetes, kidney disease, and hypertension were the main risk factors in all waves.

COVID-19: Recent Insight in Genomic Feature, Pathogenesis, Immunological Biomarkers, Treatment Options and Clinical Updates on SARS-CoV-2.

SARS-CoV-2 is a highly contagious and transmissible viral infection that first emerged in 2019 and since then has sparked an epidemic of severe respiratory problems identified as "coronavirus disease 2019" (COVID-19) that causes a hazard to human life and safety. The virus developed mainly from bats. The current epidemic has presented a significant warning to life across the world by showing mutation. There are different tests available for testing Coronavirus, and RT-PCR is the best, giving more accurate results, but it is also time-consuming. There are different options available for treating n-CoV-19, which include medications such as Remdesivir, corticosteroids, plasma therapy, Dexamethasone therapy, etc. The development of vaccines such as BNT126b2, ChAdOX1, mRNA-1273 and BBIBP-CorV has provided great relief in dealing with the virus as they decreased the mortality rate. BNT126b2 and ChAdOX1 are two n-CoV vaccines found to be most effective in controlling the spread of infection. In the future, nanotechnology-based vaccines and immune engineering techniques can be helpful for further research on Coronavirus and treatment of this deadly virus. The existing knowledge about the existence of SARS-CoV-2, along with its variants, is summarized in this review. This review, based on recently published findings, presents the core genetics of COVID-19, including heritable characteristics, pathogenesis, immunological biomarkers, treatment options and clinical updates on the virus, along with patents.

Immune Dysregulation in SARS-CoV-2 patients coinfected with Mycobacterium tuberculosis (Mtb) or HIV in China.

BACKGROUND: SARS-CoV-2 infections usually cause immune dysregulation in the human body. Studies of immunological changes resulting from coinfections with Mycobacterium tuberculosis (Mtb) or HIV are limited. METHODS: We conducted a retrospective study focusing on patients with COVID-19. A total of 550 patients infected with SARS-CoV-2 were enrolled in our study and categorized into four groups based on the presence of coinfections; 166 Delta-infected patients, among whom 103 patients had no coinfections, 52 who were coinfected with Mtb, 11 who were coinfected with HIV, and 384 Omicron-infected patients. By collecting data on epidemiologic information, laboratory findings, treatments, and clinical outcomes, we analyzed and compared clinical and immunological characteristics. RESULTS: Compared with those in the Delta group, the median white blood cell, CD4 + T-cell and B-cell counts were lower in the Mtb group and the HIV group. Except for those in the Omicron group, more than half of the patients in the three groups had abnormal chest CT findings. Among the three groups, there were no significant differences in any of the cytokines. Compared with those in the Delta group, the disease duration and LOS were longer in the Mtb group and the HIV group. For unvaccinated Delta-infected patients, in the Mtb and HIV groups, the number of B cells and CD4 + T cells was lower than that in the Delta group, with no significant difference in the LOS or disease duration. In the Mtb group, three (6%) patients presented with a disease duration greater than four months and had decreased lymphocyte and IL17A counts, possibly due to double infections in the lungs caused by SARS-CoV-2 and M. tuberculosis. CONCLUSIONS: We found that SARS-CoV-2 patients coinfected with Mtb or HIV exhibited a longer disease duration and longer LOS, with a decrease in B cells and CD4 + T cells, suggesting that these cells are related to immune function. Changes in cytokine levels suggest that coinfection with Mtb or HIV does not result in dysregulation of the immune response. Importantly, we discovered a chronic course of coinfection involving more than four months of Mtb and SARS-CoV-2 infection.

Differences in New Variant of Concern Replication at Physiological Temperatures In Vitro.

Using multiple cell types and isolates of Delta and Omicron variants of SARS-CoV-2, we report differences in virus production, replication, and infectivity in vitro. Ancestral and Delta SARS-CoV-2 variant exhibit reduced virus production and replication at 34°C compared to 37°C while Omicron replication is balanced between temperatures.

Comparison of the Risk of Hospitalization and Severe Disease Among Co-circulating Severe Acute Respiratory Syndrome Coronavirus 2 Variants.

BACKGROUND: We compare the risk of coronavirus disease 2019 (COVID-19) outcomes among co-circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants between January 2021 and May 2022 in Navarra, Spain. METHODS: We compared the frequency of hospitalization and severe disease (intensive care unit admission or death) due to COVID-19 among the co-circulating variants. Variants analyzed were nonvariants of concern (non-VOCs), Alpha, Delta, Omicron BA.1, and Omicron BA.2. Logistic regression models were used to estimate adjusted odds ratio (aOR). RESULTS: The Alpha variant had a higher risk of hospitalization (aOR, 1.86 [95 confidence interval {CI}, 1.282.71]) and severe disease (aOR, 2.40 [95 CI, 1.314.40]) than non-VOCs. The Delta variant did not show a significantly different risk of hospitalization (aOR, 0.73 [95 CI, .401.30]) and severe disease (aOR, 3.04 [95 CI, .5716.22]) compared to the Alpha variant. The Omicron BA.1 significantly reduced both risks relative to the Delta variant (aORs, 0.28 [95 CI, .16.47] and 0.23 [95 CI, .12.46], respectively). The Omicron BA.2 reduced the risk of hospitalization compared to BA.1 (aOR, 0.52 [95 CI, .29.95]). CONCLUSIONS: The Alpha and Delta variants showed an increased risk of hospitalization and severe disease, which decreased considerably with the Omicron BA.1 and BA.2. Surveillance of variants can lead to important differences in severity.

SARS-CoV-2 neutralizing antibody epitopes are overlapping and highly mutated which raises the chances of escape variants and requires development of broadly reactive vaccines.

The rapid adaptation of SARS-CoV-2 within the host species and the increased viral transmission triggered the evolution of different SARS-CoV-2 variants. Though numerous monoclonal antibodies (mAbs) have been identified as prophylactic therapy for SARS-CoV-2, the ongoing surge in the number of SARS-CoV-2 infections shows the importance of understanding the mutations in the spike and developing novel vaccine strategies to target all variants. Here, we report the map of experimentally validated 74 SARS-CoV-2 neutralizing mAb binding epitopes of all variants. The majority (87.84%) of the potent neutralizing epitopes are localized to the receptor-binding domain (RBD) and overlap with each other, whereas limited (12.16%) epitopes are found in the N-terminal domain (NTD). Notably, 69 out of 74 mAb targets have at least one mutation at the epitope sites. The potent epitopes found in the RBD show higher mutations (4-10aa) compared to lower or modest neutralizing antibodies, suggesting that these epitopes might co-evolve with the immune pressure. The current study shows the importance of determining the critical mutations at the antibody recognition epitopes, leading to the development of broadly reactive immunogens targeting multiple SARS-CoV-2 variants. Further, vaccines inducing both humoral and cell-mediated immune responses might prevent the escape of SARS-CoV-2 variants from neutralizing antibodies.

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Variants on Inpatient Clinical Outcome.

BACKGROUND: Prior observation has shown differences in COVID-19 hospitalization risk between SARS-CoV-2 variants, but limited information describes hospitalization outcomes. METHODS: Inpatients with COVID-19 at 5 hospitals in the eastern United States were included if they had hypoxia, tachypnea, tachycardia, or fever, and SARS-CoV-2 variant data, determined from whole-genome sequencing or local surveillance inference. Analyses were stratified by history of SARS-CoV-2 vaccination or infection. The average effect of SARS-CoV-2 variant on 28-day risk of severe disease, defined by advanced respiratory support needs, or death was evaluated using models weighted on propensity scores derived from baseline clinical features. RESULTS: Severe disease or death within 28 days occurred for 977 (29%) of 3369 unvaccinated patients and 269 (22%) of 1230 patients with history of vaccination or prior SARS-CoV-2 infection. Among unvaccinated patients, the relative risk of severe disease or death for Delta variant compared with ancestral lineages was 1.30 (95% confidence interval [CI]: 1.11-1.49). Compared with Delta, the risk for Omicron patients was .72 (95% CI: .59-.88) and compared with ancestral lineages was .94 (.78-1.1). Among Omicron and Delta infections, patients with history of vaccination or prior SARS-CoV-2 infection had half the risk of severe disease or death (adjusted hazard ratio: .40; 95% CI: .30-.54), but no significant outcome difference by variant. CONCLUSIONS: Although risk of severe disease or death for unvaccinated inpatients with Omicron was lower than with Delta, it was similar to ancestral lineages. Severe outcomes were less common in vaccinated inpatients, with no difference between Delta and Omicron infections.