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The SARS-CoV-2 BA.2.86 lineage, and its sublineage JN.1 in particular, achieved widespread transmission in the US during winter 2023–24. However, this surge in infections was not accompanied by COVID-19 hospitalizations and mortality commensurate with prior waves. To understand shifts in COVID-19 epidemiology associated with JN.1 emergence, we compared characteristics and clinical outcomes of time-matched cases infected with BA.2.86 lineages (predominantly representing JN.1) versus co-circulating XBB-derived lineages in December, 2023 and January, 2024. Cases infected with BA.2.86 lineages received greater numbers of COVID-19 vaccine doses, including XBB.1.5-targeted boosters, in comparison to cases infected with XBB-derived lineages. Additionally, cases infected with BA.2.86 lineages experienced greater numbers of documented prior SARS-CoV-2 infections. Cases infected with BA.2.86 lineages also experienced lower risk of progression to severe clinical outcomes requiring emergency department consultations or hospital admission. Sensitivity analyses suggested under-ascertainment of prior infections could not explain this apparent attenuation of severity. Our findings implicate escape from immunity acquired from prior vaccination or infection in the emergence of the JN.1 lineage and suggest infections with this lineage are less likely to experience clinically-severe disease. Monitoring of immune escape and clinical severity in emerging SARS-CoV-2 variants remains a priority to inform responses. The SARS-CoV-2 JN.1 lineage spread rapidly in winter 2023-24 with high estimated levels of transmission but limited increase in severe disease burden. Here, the authors use electronic health record data from the United States to investigate the immune history and clinical outcomes of patients infected with this strain.

Test-negative designs (TNDs) are used to assess vaccine effectiveness (VE). Protection from infection-induced immunity may confound the association between case and vaccination status, but collecting reliable infection history can be challenging. If vaccinated individuals have less infection-induced protection than unvaccinated individuals, failure to account for infection history could underestimate VE, though the bias is not well understood. We simulated individual-level SARS-CoV-2 infection and COVID-19 vaccination histories and a TND. VE against symptomatic infection and VE against severe disease estimates unadjusted for infection history underestimated VE compared to estimates adjusted for infection history, and unadjusted estimates were more likely to be below 0%, which could lead to an incorrect interpretation that COVID-19 vaccines are harmful. TNDs assessing VE immediately following vaccine rollout introduced the largest bias and potential for negative VE against symptomatic infection. Despite the potential for bias, VE estimates from TNDs without prior infection information are useful because underestimation is rarely more than 8 percentage points. The test-negative study design has been widely used to evaluate COVID-19 vaccine effectiveness, but the accuracy of estimates is likely to be impacted by prior infection and vaccination history. Here, the authors perform a simulation study to quantify how these impacts may bias vaccine effectiveness estimates.

CDC recommends that all persons aged ≥12 years receive a booster dose of COVID-19 mRNA vaccine ≥5 months after completion of a primary mRNA vaccination series and that immunocompromised persons receive a third primary dose.* Waning of vaccine protection after 2 doses of mRNA vaccine has been observed during the period of the SARS-CoV-2 B.1.617.2 (Delta) variant predominance (1-5), but little is known about durability of protection after 3 doses during periods of Delta or SARS-CoV-2 B.1.1.529 (Omicron) variant predominance. A test-negative case-control study design using data from eight VISION Network sites examined vaccine effectiveness (VE) against COVID-19 emergency department/urgent care (ED/UC) visits and hospitalizations among U.S. adults aged ≥18 years at various time points after receipt of a second or third vaccine dose during two periods: Delta variant predominance and Omicron variant predominance (i.e., periods when each variant accounted for ≥50% of sequenced isolates). Persons categorized as having received 3 doses included those who received a third dose in a primary series or a booster dose after a 2 dose primary series (including the reduced-dosage Moderna booster). The VISION Network analyzed 241,204 ED/UC encounters** and 93,408 hospitalizations across 10 states during August 26, 2021-January 22, 2022. VE after receipt of both 2 and 3 doses was lower during the Omicron-predominant than during the Delta-predominant period at all time points evaluated. During both periods, VE after receipt of a third dose was higher than that after a second dose; however, VE waned with increasing time since vaccination. During the Omicron period, VE against ED/UC visits was 87% during the first 2 months after a third dose and decreased to 66% among those vaccinated 4-5 months earlier; VE against hospitalizations was 91% during the first 2 months following a third dose and decreased to 78% ≥4 months after a third dose. For both Delta- and Omicron-predominant periods, VE was generally higher for protection against hospitalizations than against ED/UC visits. All eligible persons should remain up to date with recommended COVID-19 vaccinations to best protect against COVID-19-associated hospitalizations and ED/UC visits.

Observed peaks of acute flaccid myelitis (AFM) cases have occurred biennially since 2014 in the United States. We aimed to determine if AFM etiology differed between peak and nonpeak years, considering that clinical features of AFM differ by virus etiology. We compared clinical and laboratory characteristics of AFM cases that occurred during peak (2016 and 2018, n = 366) and nonpeak (2015 and 2017, n = 50) years. AFM patients in peak years were younger (5.2 years) than those in nonpeak years (8.3 years). A higher percentage of patients in peak years than nonpeak years had pleocytosis (86% vs. 60%), upper extremity involvement (33% vs. 16%), and an illness preceding limb weakness (90% vs. 62%) and were positive for enterovirus or rhinovirus RNA (38% vs. 16%). Enterovirus D68 infection was associated with AFM only in peak years. Our findings suggest AFM etiology differs between peak and nonpeak years.

Nursing home and long-term care facility residents live in congregate settings and are often elderly and frail, putting them at high risk for infection with SARS-CoV-2, the virus that causes COVID-19, and severe COVID-19-associated outcomes; therefore, this population was prioritized for early vaccination in the United States (1). Following rapid distribution and administration of the mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna) under an Emergency Use Authorization by the Food and Drug Administration (2), observational studies among nursing home residents demonstrated vaccine effectiveness (VE) ranging from 53% to 92% against SARS-CoV-2 infection (3-6). However, concerns about the potential for waning vaccine-induced immunity and the recent emergence of the highly transmissible SARS-CoV-2 B.1.617.2 (Delta) variant highlight the need to continue to monitor VE (7). Weekly data reported by the Centers for Medicaid & Medicare (CMS)-certified skilled nursing facilities or nursing homes to CDC's National Healthcare Safety Network (NHSN) were analyzed to evaluate effectiveness of full vaccination (2 doses received ≥14 days earlier) with any of the two currently authorized mRNA COVID-19 vaccines during the period soon after vaccine introduction and before the Delta variant was circulating (pre-Delta [March 1-May 9, 2021]), and when the Delta variant predominated (Delta [June 21-August 1, 2021]). Using 17,407 weekly reports from 3,862 facilities from the pre-Delta period, adjusted effectiveness against infection for any mRNA vaccine was 74.7% (95% confidence interval [CI] = 70.0%-78.8%). Analysis using 33,160 weekly reports from 11,581 facilities during an intermediate period (May 10-June 20) found that the adjusted effectiveness was 67.5% (95% CI = 60.1%-73.5%). Analysis using 85,593 weekly reports from 14,917 facilities during the Delta period found that the adjusted effectiveness was 53.1% (95% CI = 49.1%-56.7%). Effectiveness estimates were similar for Pfizer-BioNTech and Moderna vaccines. These findings indicate that mRNA vaccines provide protection against SARS-CoV-2 infection among nursing home residents; however, VE was lower after the Delta variant became the predominant circulating strain in the United States. This analysis assessed VE against any infection, without being able to distinguish between asymptomatic and symptomatic presentations. Additional evaluations are needed to understand protection against severe disease in nursing home residents over time. Because nursing home residents might remain at some risk for SARS-CoV-2 infection despite vaccination, multiple COVID-19 prevention strategies, including infection control, testing, and vaccination of nursing home staff members, residents, and visitors, are critical. An additional dose of COVID-19 vaccine might be considered for nursing home and long-term care facility residents to optimize a protective immune response.

Estimates of COVID-19 mRNA vaccine effectiveness (VE) have declined in recent months (1,2) because of waning vaccine induced immunity over time,* possible increased immune evasion by SARS-CoV-2 variants (3), or a combination of these and other factors. CDC recommends that all persons aged ≥12 years receive a third dose (booster) of an mRNA vaccine ≥5 months after receipt of the second mRNA vaccine dose and that immunocompromised individuals receive a third primary dose. A third dose of BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine increases neutralizing antibody levels (4), and three recent studies from Israel have shown improved effectiveness of a third dose in preventing COVID-19 associated with infections with the SARS-CoV-2 B.1.617.2 (Delta) variant (5-7). Yet, data are limited on the real-world effectiveness of third doses of COVID-19 mRNA vaccine in the United States, especially since the SARS-CoV-2 B.1.1.529 (Omicron) variant became predominant in mid-December 2021. The VISION Network examined VE by analyzing 222,772 encounters from 383 emergency departments (EDs) and urgent care (UC) clinics and 87,904 hospitalizations from 259 hospitals among adults aged ≥18 years across 10 states from August 26, 2021 to January 5, 2022. Analyses were stratified by the period before and after the Omicron variant became the predominant strain (>50% of sequenced viruses) at each study site. During the period of Delta predominance across study sites in the United States (August-mid-December 2021), VE against laboratory-confirmed COVID-19-associated ED and UC encounters was 86% 14-179 days after dose 2, 76% ≥180 days after dose 2, and 94% ≥14 days after dose 3. Estimates of VE for the same intervals after vaccination during Omicron variant predominance were 52%, 38%, and 82%, respectively. During the period of Delta variant predominance, VE against laboratory-confirmed COVID-19-associated hospitalizations was 90% 14-179 days after dose 2, 81% ≥180 days after dose 2, and 94% ≥14 days after dose 3. During Omicron variant predominance, VE estimates for the same intervals after vaccination were 81%, 57%, and 90%, respectively. The highest estimates of VE against COVID-19-associated ED and UC encounters or hospitalizations during both Delta- and Omicron-predominant periods were among adults who received a third dose of mRNA vaccine. All unvaccinated persons should get vaccinated as soon as possible. All adults who have received mRNA vaccines during their primary COVID-19 vaccination series should receive a third dose when eligible, and eligible persons should stay up to date with COVID-19 vaccinations.

On September 1, 2022, bivalent COVID-19 mRNA vaccines, composed of components from the SARS-CoV-2 ancestral and Omicron BA.4/BA.5 strains, were recommended by the Advisory Committee on Immunization Practices (ACIP) to address reduced effectiveness of COVID-19 monovalent vaccines during SARS-CoV-2 Omicron variant predominance (1). Initial recommendations included persons aged ≥12 years (Pfizer-BioNTech) and ≥18 years (Moderna) who had completed at least a primary series of any Food and Drug Administration-authorized or -approved monovalent vaccine ≥2 months earlier (1). On October 12, 2022, the recommendation was expanded to include children aged 5-11 years. At the time of recommendation, immunogenicity data were available from clinical trials of bivalent vaccines composed of ancestral and Omicron BA.1 strains; however, no clinical efficacy data were available. In this study, effectiveness of the bivalent (Omicron BA.4/BA.5-containing) booster formulation against symptomatic SARS-CoV-2 infection was examined using data from the Increasing Community Access to Testing (ICATT) national SARS-CoV-2 testing program.* During September 14-November 11, 2022, a total of 360,626 nucleic acid amplification tests (NAATs) performed at 9,995 retail pharmacies for adults aged ≥18 years, who reported symptoms consistent with COVID-19 at the time of testing and no immunocompromising conditions, were included in the analysis. Relative vaccine effectiveness (rVE) of a bivalent booster dose compared with that of ≥2 monovalent vaccine doses among persons for whom 2-3 months and ≥8 months had elapsed since last monovalent dose was 30% and 56% among persons aged 18-49 years, 31% and 48% among persons aged 50-64 years, and 28% and 43% among persons aged ≥65 years, respectively. Bivalent mRNA booster doses provide additional protection against symptomatic SARS-CoV-2 in immunocompetent persons who previously received monovalent vaccine only, with relative benefits increasing with time since receipt of the most recent monovalent vaccine dose. Staying up to date with COVID-19 vaccination, including getting a bivalent booster dose when eligible, is critical to maximizing protection against COVID-19 (1).

On September 12, 2023, CDC's Advisory Committee on Immunization Practices recommended updated 2023-2024 (updated) COVID-19 vaccination with a monovalent XBB.1.5-derived vaccine for all persons aged ≥6 months to prevent COVID-19, including severe disease. During fall 2023, XBB lineages co-circulated with JN.1, an Omicron BA.2.86 lineage that emerged in September 2023. These variants have amino acid substitutions that might increase escape from neutralizing antibodies. XBB lineages predominated through December 2023, when JN.1 became predominant in the United States. Reduction or failure of spike gene (S-gene) amplification (i.e., S-gene target failure [SGTF]) in real-time reverse transcription-polymerase chain reaction testing is a time-dependent, proxy indicator of JN.1 infection. Data from the Increasing Community Access to Testing SARS-CoV-2 pharmacy testing program were analyzed to estimate updated COVID-19 vaccine effectiveness (VE) (i.e., receipt versus no receipt of updated vaccination) against symptomatic SARS-CoV-2 infection, including by SGTF result. Among 9,222 total eligible tests, overall VE among adults aged ≥18 years was 54% (95% CI = 46%-60%) at a median of 52 days after vaccination. Among 2,199 tests performed at a laboratory with SGTF testing, VE 60-119 days after vaccination was 49% (95% CI = 19%-68%) among tests exhibiting SGTF and 60% (95% CI = 35%-75%) among tests without SGTF. Updated COVID-19 vaccines provide protection against symptomatic infection, including against currently circulating lineages. CDC will continue monitoring VE, including for expected waning and against severe disease. All persons aged ≥6 months should receive an updated COVID-19 vaccine dose.

Importance Recent SARS-CoV-2 Omicron variant sublineages, including BA.4 and BA.5, may be associated with greater immune evasion and less protection against COVID-19 after vaccination. Objectives To evaluate the estimated vaccine effectiveness (VE) of 2, 3, or 4 doses of COVID-19 mRNA vaccination among immunocompetent adults during a period of BA.4 or BA.5 predominant circulation; and to evaluate the relative severity of COVID-19 in hospitalized patients across Omicron BA.1, BA.2 or BA.2.12.1, and BA.4 or BA.5 sublineage periods. Design, Setting, and Participants This test-negative case-control study was conducted in 10 states with data from emergency department (ED) and urgent care (UC) encounters and hospitalizations from December 16, 2021, to August 20, 2022. Participants included adults with COVID-19–like illness and molecular testing for SARS-CoV-2. Data were analyzed from August 2 to September 21, 2022. Exposures mRNA COVID-19 vaccination. Main Outcomes and Measures The outcomes of interest were COVID-19 ED or UC encounters, hospitalizations, and admission to the intensive care unit (ICU) or in-hospital death. VE associated with protection against medically attended COVID-19 was estimated, stratified by care setting and vaccine doses (2, 3, or 4 doses vs 0 doses as the reference group). Among hospitalized patients with COVID-19, demographic and clinical characteristics and in-hospital outcomes were compared across sublineage periods. Results During the BA.4 and BA.5 predominant period, there were 82 229 eligible ED and UC encounters among patients with COVID-19–like illness (median [IQR] age, 51 [33-70] years; 49 682 [60.4%] female patients), and 19 114 patients (23.2%) had test results positive for SARS-CoV-2; among 21 007 hospitalized patients (median [IQR] age, 71 [58-81] years; 11 209 [53.4%] female patients), 3583 (17.1 %) had test results positive for SARS-CoV-2. Estimated VE against hospitalization was 25% (95% CI, 17%-32%) for receipt of 2 vaccine doses at 150 days or more after receipt, 68% (95% CI, 50%-80%) for a third dose 7 to 119 days after receipt, and 36% (95% CI, 29%-42%) for a third dose 120 days or more (median [IQR], 235 [204-262] days) after receipt. Among patients aged 65 years or older who had received a fourth vaccine dose, VE was 66% (95% CI, 53%-75%) at 7 to 59 days after vaccination and 57% (95% CI, 44%-66%) at 60 days or more (median [IQR], 88 [75-105] days) after vaccination. Among hospitalized patients with COVID-19, ICU admission or in-hospital death occurred in 21.4% of patients during the BA.1 period vs 14.7% during the BA.4 and BA.5 period (standardized mean difference: 0.17). Conclusions and Relevance In this case-control study of COVID-19 vaccines and illness, VE associated with protection against medically attended COVID-19 illness was lower with increasing time since last dose; estimated VE was higher after receipt of 1 or 2 booster doses compared with a primary series alone.

Background In the United States, national ecological studies suggest a positive impact of COVID-19 vaccination coverage on outcomes in adults. However, the national impact of the vaccination program on COVID-19 in children remains unknown. To determine the association of COVID-19 vaccination with U.S. case incidence, emergency department visits, and hospital admissions for pediatric populations during the Delta and Omicron periods. Methods We conducted an ecological analysis among children aged 5–17 and compared incidence rate ratios (RRs) of COVID-19 cases, emergency department visits, and hospital admissions by pediatric vaccine coverage, with jurisdictions in the highest vaccine coverage quartile as the reference. Results RRs comparing states with lowest pediatric vaccination coverage to the highest pediatric vaccination coverage were 2.00 and 0.64 for cases, 2.96 and 1.11 for emergency department visits, and 2.76 and 1.01 for hospital admissions among all children during the Delta and Omicron periods, respectively. During the 3-week peak period of the Omicron wave, only children aged 12–15 and 16–17 years in the states with the lowest versus highest coverage, had a significantly higher rate of emergency department visits (RR = 1.39 and RR = 1.34, respectively). Conclusions COVID-19 vaccines were associated with lower case incidence, emergency department visits and hospital admissions among children during the Delta period but the association was weaker during the Omicron period. Pediatric COVID-19 vaccination should be promoted as part of a program to decrease COVID-19 impact among children; however, vaccine effectiveness may be limited when available vaccines do not match circulating viral variants.