Durability of protection from original monovalent and bivalent COVID-19 vaccines against COVID-19-associated hospitalization and severe in-hospital outcomes among adults in the United States -- September 2022-August 2023 (preprint)

ObjectiveTo evaluate the durability of protection provided by original monovalent and bivalent COVID-19 vaccination against COVID-19-associated hospitalization and severe in-hospital outcomes. DesignMulticenter case-control design with prospective enrollment Setting26 hospitals in 20 US states ParticipantsAdults aged [≥]18 years admitted to hospital with COVID-19-like illness from 8 September 2022 to 31 August 2023 Main outcome measuresThe main outcomes were absolute and relative vaccine effectiveness of original monovalent and bivalent COVID-19 vaccines against COVID-19-associated hospitalization and severe in-hospital outcomes, including advanced respiratory support (defined as receipt of high-flow nasal cannula, non-invasive ventilation, or invasive mechanical ventilation [IMV]) and IMV or death. Vaccine effectiveness was estimated using multivariable logistic regression, in which the odds of vaccination (versus being unvaccinated or receiving original monovalent vaccination only) were compared between COVID-19 case patients and control-patients. Bivalent vaccine effectiveness analyses were stratified by time since dose receipt. ResultsAmong 7028 adults without immunocompromising conditions, 2924 (41.6%) were COVID-19 case patients and 4104 (58.4%) were control patients. Compared to unvaccinated patients, absolute vaccine effectiveness against COVID-19-associated hospitalization was 6% (-7% to 17%) for original monovalent doses only (median time since last dose [IQR] = 421 days [304-571]), 52% (39% to 61%) for a bivalent dose received 7-89 days earlier, and 13% (-10% to 31%) for a bivalent dose received 90-179 days earlier. Absolute vaccine effectiveness against COVID-19-associated advanced respiratory support was 31% (15% to 45%) for original monovalent doses only, 66% (47% to 78%) for a bivalent dose received 7-89 days earlier, and 33% (-1% to 55%) for a bivalent dose received 90-179 days earlier. Absolute vaccine effectiveness against COVID-19-associated IMV or death was 51% (34% to 63%) for original monovalent doses only, 61% (35% to 77%) for a bivalent dose received 7-89 days earlier, and 50% (11% to 71%) for a bivalent dose received 90-179 days earlier. ConclusionWhen compared to original monovalent vaccination only, bivalent COVID-19 vaccination provided additional protection against COVID-19-associated hospitalization and certain severe in-hospital outcomes within 3 months of dose receipt. By 3-6 months, protection from a bivalent dose declined to a level similar to that remaining from original monovalent vaccination only. Although no protection remained from original monovalent vaccination against COVID-19-associated hospitalization, it provided durable protection against severe in-hospital outcomes >1 year after receipt of the last dose, particularly against IMV or death. SUMMARY BOX What is already known on this topic- On September 1, 2022, bivalent mRNA COVID-19 vaccination was recommended for US adults who had completed at least an original monovalent COVID-19 primary series. - Early estimates of bivalent vaccine effectiveness are available for the period soon after dose receipt; however fewer data exist on their durability of protection and effectiveness against severe outcomes. What this study adds- When compared to original monovalent vaccination only, bivalent mRNA COVID-19 vaccination provided additional protection against COVID-19-associated hospitalization and certain severe in-hospital outcomes within 3 months of dose receipt. By 3-6 months, protection from a bivalent dose declined to a level similar to that remaining from original monovalent vaccination only. - Although no protection remained from original monovalent vaccination against COVID-19-associated hospitalization, it provided durable protection against severe in-hospital outcomes >1 year after receipt of the last dose, particularly against invasive mechanical ventilation or death.

Antibody response to symptomatic infection with SARS-CoV-2 Omicron variant viruses, December 2021 to June 2022 (preprint)

To describe humoral immune responses to symptomatic SARS-CoV-2 infection, we assessed immunoglobulin G binding antibody levels using a commercial multiplex bead assay against SARS-CoV-2 ancestral spike protein receptor binding domain (RBD) and nucleocapsid protein (N). We measured binding antibody units per mL (BAU/mL) during acute illness within 5 days of illness onset and during convalescence in 105 ambulatory patients with laboratory-confirmed SARS-CoV-2 infection with Omicron variant viruses. Comparing acute- to convalescent phase antibody concentrations, geometric mean anti-N antibody concentrations increased 47-fold from 5.5 to 259 BAU/mL. Anti-RBD antibody concentrations increased 2.5-fold from 1258 to 3189 BAU/mL.

Anti-SARS-CoV-2 Antibody Levels Associated with COVID-19 Protection in Outpatients Tested for SARS-CoV-2, US Flu VE Network, October 2021 to June 2022 (preprint)

BackgroundWe assessed the association between antibody concentration [≤]5 days of symptom onset and COVID-19 illness among patients enrolled in a test-negative study MethodsFrom October 2021[boxh]June 2022, study sites in seven states enrolled and tested respiratory specimens from patients of all ages presenting with acute respiratory illness for SARS-CoV-2 infection using rRT-PCR. In blood specimens, we measured concentration of anti- SARS-CoV-2 antibodies against the ancestral strain spike protein receptor binding domain (RBD) and nucleocapsid (N) antigens in standardized binding antibody units (BAU/mL). Percent reduction in odds of symptomatic COVID-19 by anti-RBD antibody was estimated using logistic regression modeled as (1-adjusted odds ratio of COVID-19)x100, adjusting for COVID-19 vaccination status, age, site, and high-risk exposure. ResultsA total of 662 (33%) of 2,018 symptomatic patients tested positive for acute SARS- CoV-2 infection. During the Omicron-predominant period, geometric mean anti-RBD binding antibody concentrations measured 823 BAU/mL (95%CI:690[boxh]981) among COVID-19 case- patients versus 1,189 BAU/mL (95%CI:1,050[boxh]1,347) among SARS-CoV-2 test-negative patients. In the adjusted logistic regression, increasing levels of anti-RBD antibodies were associated with reduced odds of COVID-19 for both Delta and Omicron infections. ConclusionHigher anti-RBD antibodies in patients were associated with protection against symptomatic COVID-19 during emergence of SARS-CoV-2 Delta and Omicron variants.

SARS-CoV-2 shedding and evolution in immunocompromised hosts during the Omicron period: a multicenter prospective analysis (preprint)

Background: Prolonged SARS-CoV-2 infections in immunocompromised hosts may predict or source the emergence of highly mutated variants. The types of immunosuppression placing patients at highest risk for prolonged infection and associated intrahost viral evolution remain unclear. Methods: Adults aged >18 years were enrolled at 5 hospitals and followed from 4/11/2022-2/1/2023. Eligible patients were SARS-CoV-2 positive in the previous 14 days and had a moderate or severely immunocompromising condition or treatment. Nasal specimens were tested by rRT-PCR every 2-4 weeks until negative in consecutive specimens. Positive specimens underwent viral culture and whole genome sequencing. A Cox proportional hazards model was used to assess factors associated with duration of infection. Results: We enrolled 150 patients with: B cell malignancy or anti-B cell therapy (n=18), solid organ or hematopoietic stem cell transplant (SOT/HSCT) (n=59), AIDS (n=5), non-B cell malignancy (n=23), and autoimmune/autoinflammatory conditions (n=45). Thirty-eight (25%) were rRT-PCR positive and 12 (8%) were culture-positive [≥]21 days after initial SARS-CoV-2 detection or illness onset. Patients with B cell dysfunction had longer duration of rRT-PCR positivity compared to those with autoimmune/autoinflammatory conditions (aHR 0.32, 95% CI 0.15-0.64). Consensus (>50% frequency) spike mutations were identified in 5 individuals who were rRT-PCR positive >56 days; 61% were in the receptor-binding domain (RBD). Mutations shared by multiple individuals were rare (<5%) in global circulation.

Work Attendance during Acute Respiratory Illness Before and During the COVID-19 Pandemic, United States, 2018-2022 (preprint)

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and influenza viruses can be transmitted by infected persons who are pre-symptomatic or symptomatic. To assess impact of the COVID-19 pandemic on work attendance during illness, we analyzed prospectively collected data from persons with acute respiratory illness (ARI) enrolled in a multi-state study during 2018-2022. Persons with prior experience working from home were significantly less likely than those without this experience to work onsite on the day before illness and during the first 3 days of illness; the effect was more pronounced for the COVID-19 pandemic period than the pre-pandemic influenza seasons. Persons with influenza or COVID-19 were significantly less likely to work onsite than persons with other ARIs. Among persons for whom positive COVID-19 test results were available by the second or third day of illness, few worked onsite. Work-from-home policies may reduce the likelihood of workplace exposures to respiratory viruses.

Vaccine Effectiveness of Primary Series and Booster Doses against Omicron Variant COVID-19-Associated Hospitalization in the United States (preprint)

Objectives: To compare the effectiveness of a primary COVID-19 vaccine series plus a booster dose with a primary series alone for the prevention of Omicron variant COVID-19 hospitalization. Design: Multicenter observational case-control study using the test-negative design to evaluate vaccine effectiveness (VE). Setting: Twenty-one hospitals in the United States (US). Participants: 3,181 adults hospitalized with an acute respiratory illness between December 26, 2021 and April 30, 2022, a period of SARS-CoV-2 Omicron variant (BA.1, BA.2) predominance. Participants included 1,572 (49%) case-patients with laboratory confirmed COVID-19 and 1,609 (51%) control patients who tested negative for SARS-CoV-2. Median age was 64 years, 48% were female, and 21% were immunocompromised; 798 (25%) were vaccinated with a primary series plus booster, 1,326 (42%) were vaccinated with a primary series alone, and 1,057 (33%) were unvaccinated. Main Outcome Measures: VE against COVID-19 hospitalization was calculated for a primary series plus a booster and a primary series alone by comparing the odds of being vaccinated with each of these regimens versus being unvaccinated among cases versus controls. VE analyses were stratified by immune status (immunocompetent; immunocompromised) because the recommended vaccine schedules are different for these groups. The primary analysis evaluated all COVID-19 vaccine types combined and secondary analyses evaluated specific vaccine products. Results: Among immunocompetent patients, VE against Omicron COVID-19 hospitalization for a primary series plus one booster of any vaccine product dose was 77% (95% CI: 71-82%), and for a primary series alone was 44% (95% CI: 31-54%) (p<0.001). VE was higher for a boosted regimen than a primary series alone for both mRNA vaccines used in the US (BNT162b2: primary series plus booster VE 80% (95% CI: 73-85%), primary series alone VE 46% (95% CI: 30-58%) [p<0.001]; mRNA-1273: primary series plus booster VE 77% (95% CI: 67-83%), primary series alone VE 47% (95% CI: 30-60%) [p<0.001]). Among immunocompromised patients, VE for a primary series of any vaccine product against Omicron COVID-19 hospitalization was 60% (95% CI: 41-73%). Insufficient sample size has accumulated to calculate effectiveness of boosted regimens for immunocompromised patients. Conclusions: Among immunocompetent people, a booster dose of COVID-19 vaccine provided additional benefit beyond a primary vaccine series alone for preventing COVID-19 hospitalization due to the Omicron variant.

Effectiveness of 2 and 3 mRNA COVID-19 Vaccines Doses against Omicron and Delta-Related Outpatient Illness among Adults, October 2021 - February 2022 (preprint)

Background: We estimated SARS-CoV-2 Delta and Omicron-specific effectiveness of 2 and 3 mRNA COVID-19 vaccine doses in adults against symptomatic illness in US outpatient settings. Methods: Between October 1, 2021, and February 12, 2022, research staff consented and enrolled eligible participants who had fever, cough, or loss of taste or smell and sought outpatient medical care or clinical SARS-CoV-2 testing within 10 days of illness onset. Using the test-negative design, we compared the odds of receiving 2 or 3 mRNA COVID-19 vaccine doses among SARS-CoV-2 cases versus controls using logistic regression. Regression models were adjusted for study site, age, onset week, and prior SARS-CoV-2 infection. Vaccine effectiveness (VE) was calculated as (1-adjusted odds ratio) x 100%. Results: Among 3847 participants included for analysis, 574 (32%) of 1775 tested positive for SARS-CoV-2 during the Delta predominant period and 1006 (56%) of 1794 participants tested positive during the Omicron predominant period. When Delta predominated, VE against symptomatic illness in outpatient settings was 63% (95% CI: 51% to 72%) among mRNA 2-dose recipients and 96% (95% CI: 93% to 98%) for 3-dose recipients. When Omicron predominated, VE was 21% (95% CI: -6% to 41%) among 2-dose recipients and 62% (95% CI: 48% to 72%) among 3-dose recipients. Conclusions: In this adult population, 3 mRNA COVID-19 vaccine doses provided substantial protection against symptomatic illness in outpatient settings when the Omicron variant became the predominant cause of COVID-19 in the U.S. These findings support the recommendation for a 3rd mRNA COVID-19 vaccine dose.

Clinical Severity and mRNA Vaccine Effectiveness for Omicron, Delta, and Alpha SARS-CoV-2 Variants in the United States: A Prospective Observational Study (preprint)

Objectives: To characterize the clinical severity of COVID-19 caused by Omicron, Delta, and Alpha SARS-CoV-2 variants among hospitalized adults and to compare the effectiveness of mRNA COVID-19 vaccines to prevent hospitalizations caused by each variant. Design: A case-control study of 11,690 hospitalized adults. Setting: Twenty-one hospitals across the United States. Participants: This study included 5728 cases hospitalized with COVID-19 and 5962 controls hospitalized without COVID-19. Cases were classified into SARS-CoV-2 variant groups based on viral whole genome sequencing, and if sequencing did not reveal a lineage, by the predominant circulating variant at the time of hospital admission: Alpha (March 11 to July 3, 2021), Delta (July 4 to December 25, 2021), and Omicron (December 26, 2021 to January 14, 2022). Main Outcome Measures: Vaccine effectiveness was calculated using a test-negative design for COVID-19 mRNA vaccines to prevent COVID-19 hospitalizations by each variant (Alpha, Delta, Omicron). Among hospitalized patients with COVID-19, disease severity on the WHO Clinical Progression Ordinal Scale was compared among variants using proportional odds regression. Results: Vaccine effectiveness of the mRNA vaccines to prevent COVID-19-associated hospitalizations included: 85% (95% CI: 82 to 88%) for 2 vaccine doses against Alpha; 85% (95% CI: 83 to 87%) for 2 doses against Delta; 94% (95% CI: 92 to 95%) for 3 doses against Delta; 65% (95% CI: 51 to 75%) for 2 doses against Omicron; and 86% (95% CI: 77 to 91%) for 3 doses against Omicron. Among hospitalized unvaccinated COVID-19 patients, severity on the WHO Clinical Progression Scale was higher for Delta than Alpha (adjusted proportional odds ratio [aPOR] 1.28, 95% CI: 1.11 to 1.46), and lower for Omicron than Delta (aPOR 0.61, 95% CI: 0.49 to 0.77). Compared to unvaccinated cases, severity was lower for vaccinated cases for each variant, including Alpha (aPOR 0.33, 95% CI: 0.23 to 0.49), Delta (aPOR 0.44, 95% CI: 0.37 to 0.51), and Omicron (aPOR 0.61, 95% CI: 0.44 to 0.85). Conclusions: mRNA vaccines were highly effective in preventing COVID-19-associated hospitalizations from Alpha, Delta, and Omicron variants, but three vaccine doses were required to achieve protection against Omicron similar to the protection that two doses provided against Delta and Alpha. Among adults hospitalized with COVID-19, Omicron caused less severe disease than Delta, but still resulted in substantial morbidity and mortality. Vaccinated patients hospitalized with COVID-19 had significantly lower disease severity than unvaccinated patients for all the variants.

Surveillance and correlation of SARS-CoV-2 viral RNA, antigen, virus isolation, and self-reported symptoms in a longitudinal study with daily sampling (preprint)

The novel coronavirus pandemic incited unprecedented demand for assays that detect viral nucleic acids, viral proteins, and corresponding antibodies. The 320 molecular diagnostics in receipt of FDA emergency use authorization mainly focus on viral detection; however, no currently approved test can be used to infer infectiousness, i.e., the presence of replicable virus. As the number of tests conducted increased, persistent SARS-CoV-2 RNA positivity by RT-PCR in some individuals led to concerns over quarantine guidelines. To this end, we attempted to design an assay that reduces the frequency of positive test results from individuals who do not shed culturable virus. We describe multiplex quantitative RT-PCR (qRT-PCR) assays that detect genomic RNA (gRNA) and subgenomic RNA (sgRNA) species of SARS-CoV-2, including spike (S), nucleocapsid (N), membrane (M), envelope (E), and ORF8. The absolute copy number of each RNA target was determined in longitudinal specimens from a household transmission study. Calculated viral RNA levels over the 14-day follow up period were compared with antigen testing and self-reported symptoms to characterize the clinical and molecular dynamics of infection and infer predictive values of these qRT-PCR assays relative to culture isolation. When detection of sgS RNA was added to the CDC 2019-Novel Coronavirus Real-Time RT-PCR Diagnostic Panel, we found a qRT-PCR positive result was 98% predictive of a positive culture (negative predictive value was 94%). Our findings suggest sgRNA presence correlates with active infection, may help identify individuals shedding culturable virus, and that similar multiplex assays can be adapted to current and future variants.

Household Transmission and Clinical Features of SARS-CoV-2 Infections by Age in 2 US Communities (preprint)

OBJECTIVESExamine age differences in SARS-CoV-2 transmission risk from primary cases and infection risk among household contacts, and symptoms among those with SARS-CoV-2 infection. METHODSPeople with SARS-CoV-2 infection in Nashville, Tennessee and central and western Wisconsin and their household contacts were followed daily for 14 days to ascertain symptoms and secondary transmission events. Households were enrolled between April 2020 and April 2021. Secondary infection risks (SIR) by age of the primary case and contacts were estimated using generalized estimating equations. RESULTSThe 226 primary cases were followed by 198 (49%) secondary SARS-CoV-2 infections among 404 household contacts. Age group-specific SIR among contacts ranged from 36% to 53%, with no differences by age. SIR was lower from primary cases aged 12-17 years than from primary cases 18-49 years (risk ratio [RR] 0.42; 95% confidence interval [CI] 0.19-0.91). SIR was 55% and 45%, respectively, among primary case-contact pairs in the same versus different age group (RR 1.47; 95% CI 0.98-2.22). SIR was highest among primary case-contacts pairs aged [≥]65 years (76%) and 5-11 years (69%). Among secondary SARS-CoV-2 infections, 19% were asymptomatic; there was no difference in the frequency of asymptomatic infections by age group. CONCLUSIONSBoth children and adults can transmit and are susceptible to SARS-CoV-2 infection. SIR did not vary by age, but further research is needed to understand age-related differences in probability of transmission from primary cases by age.

Effectiveness of SARS-CoV-2 mRNA Vaccines for Preventing Covid-19 Hospitalizations in the United States (preprint)

Background: As SARS-CoV-2 vaccination coverage increases in the United States (US), there is a need to understand the real-world effectiveness against severe Covid-19 and among people at increased risk for poor outcomes. Methods: In a multicenter case-control analysis of US adults hospitalized March 11 through May 5, 2021, we evaluated vaccine effectiveness to prevent Covid-19 hospitalizations by comparing odds of prior vaccination with an mRNA vaccine (Pfizer-BioNTech or Moderna) between cases hospitalized with Covid-19 and hospital-based controls who tested negative for SARS-CoV-2. Results: Among 1210 participants, median age was 58 years, 22.8% were Black, 13.8% were Hispanic, and 20.6% had immunosuppression. SARS-CoV-2 lineage B.1.1.7 was most common variant (59.7% of sequenced viruses). Full vaccination (receipt of two vaccine doses at least 14 days before illness onset) had been received by 45/590 (7.6%) cases and 215/620 (34.7%) controls. Overall vaccine effectiveness was 86.9% (95% CI: 80.4 to 91.2%). Vaccine effectiveness was similar for Pfizer-BioNTech and Moderna vaccines, and highest in adults aged 18-49 years (97.3%; 95% CI: 78.9 to 99.7%). Among 45 patients with vaccine-breakthrough Covid hospitalizations, 44 (97.8%) were at least 50 years old and 20 (44.4%) had immunosuppression. Vaccine effectiveness was lower among patients with immunosuppression (59.2%; 95% CI: 11.9 to 81.1%) than without immunosuppression (91.3%; 95% CI: 85.5 to 94.7%). Conclusion: During March through May 2021, SARS-CoV-2 mRNA vaccines were highly effective for preventing Covid-19 hospitalizations among US adults. SARS-CoV-2 vaccination was beneficial for patients with immunosuppression, but effectiveness was lower in the immunosuppressed population.