BACKGROUND: The 2023-2024 influenza season included sustained elevated activity from December 2023-February 2024 and continued activity through May 2024. Influenza A(H1N1), A(H3N2), and B viruses circulated during the season. METHODS: During September 1, 2023-May 31, 2024, a multistate sentinel surveillance network of 24 medical centers in 20 U.S. states enrolled adults aged ≥18 years hospitalized with acute respiratory illness (ARI). Consistent with a test-negative design, cases tested positive for influenza viruses by molecular or antigen test, and controls tested negative for influenza viruses and SARS-CoV-2. Vaccine effectiveness (VE) against influenza-associated hospitalization was calculated as (1 - adjusted odds ratio for vaccination) × 100%. RESULTS: Among 7690 patients, including 1170 influenza cases (33% vaccinated) and 6520 controls, VE was 40% (95% CI: 31%-48%) with varying estimates by age (18-49 years: 53% [34%-67%]; 50-64 years: 47% [31%-60%]; ≥65 years: 31% [16%-43%]). Protection was similar among immunocompetent patients (40% [30%-49%]) and immunocompromised patients (32% [7-50%]). VE was statistically significant against influenza B (67% [35%-84%]) and A(H1N1) (36% [21%-48%]) and crossed the null against A(H3N2) (19% [-8%-39%]). VE was higher for patients 14-60 days from vaccination (54% [40%-65%]) than >120 days (18% [-1%-33%]). CONCLUSIONS: During 2023-2024, influenza vaccination reduced the risk of influenza A(H1N1)- and influenza B-associated hospitalizations among adults; effectiveness was lower in patients vaccinated >120 days prior to illness onset compared with those vaccinated 14-60 days prior.

IMPORTANCE: In 2023, the first respiratory syncytial virus (RSV) vaccines were recommended for US adults 60 years or older, but few data are available about which patients were most likely to receive vaccine to inform future RSV vaccine outreach efforts. OBJECTIVE: To assess patient- and community-level characteristics associated with RSV vaccine receipt and patient knowledge and attitudes related to RSV disease and RSV vaccines. DESIGN, SETTING, AND PARTICIPANTS: During the first season of RSV vaccine use from October 1, 2023, to April 30, 2024, adults 60 years or older hospitalized with RSV-negative acute respiratory illness were enrolled in this cross-sectional study from 26 hospitals in 20 US states. Sociodemographic and clinical data were abstracted from health records, and structured interviews were conducted for knowledge and attitudes about RSV disease and RSV vaccines. EXPOSURES: Age, sex, race and ethnicity, pulmonary disease, immunocompromised status, long-term care facility residence, medical insurance, social vulnerability index (SVI), and educational level. MAIN OUTCOMES AND MEASURES: The exposures were identified a priori as possible factors associated with RSV vaccine receipt and were entered into a modified Poisson regression model accounting for state clustering, to assess for association with RSV vaccine receipt. Knowledge and attitudes were summarized with frequencies and proportions. RESULTS: Among 6746 hospitalized adults 60 years or older, median age was 73 (IQR, 66-80) years and 3451 (51.2%) were female. Among the 6599 patients with self-reported race and ethnicity, 699 (10.6%) were Hispanic, 1288 (19.5%) were non-Hispanic Black, 4299 (65.1%) were non-Hispanic White, and 313 (4.7%) were other race or ethnicity. There were 700 RSV-vaccinated (10.4%) and 6046 unvaccinated (89.6%) adults. Among 3219 unvaccinated adults who responded to RSV knowledge questions, 1519 (47.2%) had not heard of RSV or were unsure; 2525 of 3218 (78.5%) were unsure if they were eligible for RSV vaccine or thought they were not. In adjusted analyses, characteristics associated with RSV vaccination were being 75 years or older (adjusted risk ratio [ARR], 1.23; 95% CI, 1.10-1.38, P < .001), being male (ARR, 1.15; 95% CI, 1.01-1.30; P = .04), and having pulmonary disease (ARR, 1.39; 95% CI, 1.16-1.67; P < .001), immunocompromised status (ARR, 1.30; 95% CI, 1.14-1.48; P < .001), low (ARR, 1.47; 95% CI, 1.18-1.83, P < .001) or moderate (ARR, 1.47; 95% CI, 1.21-1.79; P < .001) SVI, and educational level consisting of 4 or more years of college (ARR, 2.91; 95% CI, 2.14-3.96; P < .001), at least some college or technical training (ARR, 1.85; 95% CI, 1.35-2.53; P < .001), or grade 12 education or General Educational Development (ARR, 1.44; 95% CI, 1.03-2.00; P = .03). RSV vaccination was less likely among residents of long-term care facilities, patients with Medicaid coverage, and uninsured patients. CONCLUSIONS AND RELEVANCE: In this cross-sectional study of hospitalized adults, knowledge of RSV disease and RSV vaccine eligibility was low. Older adults and those with certain medical conditions were more likely to have received vaccine, suggesting appropriate prioritization, but sociodemographic differences in vaccine uptake occurred.

BACKGROUND: Data are limited on whether vaccination reduces post COVID conditions (PCCs) risk after less severe nonhospitalized coronavirus disease 2019 (COVID-19). This study assessed whether COVID-19 vaccination protected against PCCs in persons with mild initial infections during Delta and Omicron variant predominance. METHODS: This study utilized a case-control design, nested within the HEROES-RECOVER cohort. Participants aged ≥18 years with test-confirmed severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2) between 28 June 2021 and 14 September 2022 were surveyed for PCCs, defined by symptoms lasting >4 weeks after initial infection. Cases self-reported PCCs and controls self-reported no PCCs. The exposure was messenger RNA (mRNA) COVID-19 vaccination (2 or 3 monovalent doses). Odds of PCCs among vaccinated and unvaccinated persons were compared with logistic regression. RESULTS: Of 936 participants, 23.6% reported PCCs and 83.2% were vaccinated. Participants who received 3 vaccine doses had lower odds of PCC-related gastrointestinal, neurological, and other symptoms compared to unvaccinated participants (adjusted odds ratio [95% confidence interval]: 0.37 [.16-.85], 0.56 [.32-.97], and 0.48 [.25-.91], respectively). CONCLUSIONS: COVID-19 vaccination protected against development of PCCs among persons with mild infection during both Delta and Omicron variant predominance, supporting vaccination as an important PCCs prevention tool.

Annual influenza vaccination is recommended for all persons aged ≥6 months in the United States. Interim influenza vaccine effectiveness (VE) was calculated among patients with acute respiratory illness-associated outpatient visits and hospitalizations from four VE networks during the 2024-25 influenza season (October 2024-February 2025). Among children and adolescents aged <18 years, VE against any influenza was 32%, 59%, and 60% in the outpatient setting in three networks, and against influenza-associated hospitalization was 63% and 78% in two networks. Among adults aged ≥18 years, VE in the outpatient setting was 36% and 54% in two networks and was 41% and 55% against hospitalization in two networks. Preliminary estimates indicate that receipt of the 2024-2025 influenza vaccine reduced the likelihood of medically attended influenza and influenza-associated hospitalization. CDC recommends annual receipt of an age-appropriate influenza vaccine by all eligible persons aged ≥6 months as long as influenza viruses continue to circulate locally.

IMPORTANCE: An estimated 1% to 3% of children with SARS-CoV-2 infection will develop post-COVID-19 condition (PCC). OBJECTIVE: To evaluate the odds of PCC among children with COVID-19 vaccination prior to SARS-CoV-2 infection compared with odds among unvaccinated children. DESIGN, SETTING, AND PARTICIPANTS: In this case-control study, children were enrolled in a multisite longitudinal pediatric cohort from July 27, 2021, to September 1, 2022, and followed up through May 2023. Analysis used a case (PCC reported)-control (no PCC reported) design and included children aged 5 to 17 years whose first real time-polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infection occurred during the study period, who were COVID-19 vaccine age-eligible at the time of infection, and who completed a PCC survey at least 60 days after infection. From December 1, 2022, to May 31, 2023, children had weekly SARS-CoV-2 testing and were surveyed regarding PCC (≥1 new or ongoing symptom lasting ≥1 month after infection). EXPOSURES: COVID-19 mRNA vaccination status at time of infection was the exposure of interest; participants were categorized as vaccinated (≥2-dose series completed ≥14 days before infection) or unvaccinated. Vaccination status was verified through vaccination cards or vaccine registry and/or medical records when available. MAIN OUTCOME AND MEASURES: Main outcomes were estimates of the odds of PCC symptoms. Multivariate logistic regression was performed to estimate the odds of PCC among vaccinated children compared with odds of PCC among unvaccinated children. RESULTS: A total of 622 participants were included, with 28 (5%) case participants and 594 (95%) control participants. Median (IQR) age was 10.0 (7.0-11.9) years for case participants and 10.3 (7.8-12.7) years for control participants (P = .37). Approximately half of both groups reported female sex (13 case participants [46%] and 287 control participants [48%]). Overall, 57% of case participants (16 children) and 77% of control participants (458 children) were vaccinated (P = .05). After adjusting for demographic characteristics, number of acute COVID-19 symptoms, and baseline health, COVID-19 vaccination was associated with decreased odds of 1 or more PCC symptom (adjusted odds ratio [aOR], 0.43; 95% CI, 0.19-0.98) and 2 or more PCC symptoms (aOR, 0.27; 95% CI, 0.10-0.69). CONCLUSIONS AND RELEVANCE: In this study, mRNA COVID-19 vaccination was associated with reduced odds of PCC in children. The aORs correspond to an estimated 57% and 73% reduced likelihood of 1 or more and 2 or more PCC symptoms, respectively, among vaccinated vs unvaccinated children. These findings suggest benefits of COVID-19 vaccination beyond those associated with protection against acute COVID-19 and may encourage increased pediatric uptake.

Influenza causes 100,000-710,000 hospitalizations annually in the U.S. Patients with liver disease are at higher risk of severe outcomes following influenza infection. This study evaluated influenza vaccine effectiveness (VE) against influenza-associated hospitalization among adults with liver disease. Data from the U.S. Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN), a test-negative case-control study, from 2015 to 2020 were used to estimate VE among adults ≥18 years admitted for acute respiratory illness. VE was calculated as (1-adjusted odds ratio)*100%, comparing the odds of vaccine receipt between laboratory-confirmed influenza cases and test-negative controls using multiple logistic regression with inverse probability of treatment weighting (IPTW). In total, 1,622 (12.8%) of 12,704 adults had ≥1 liver disease(s). Compared with those without liver disease, adults with liver disease were more likely to be admitted to the intensive care unit (15.7% vs 12.8%, p = .001) or to die in hospital (3.0% vs 1.4%, p < .001). The IPTW-adjusted VE against influenza-associated hospitalization was 27% (95% confidence interval [CI], 22-32%) among patients without liver disease, but the VE of 11% (95% CI, -8-26%) was not significant among those with liver disease. Significant effect modification of VE by the presence of liver disease was found (p < .05 for interaction term). While influenza vaccination significantly reduced the risk of influenza-associated hospitalization among adults without liver disease, the protective effect was not significant among those with liver disease. Further studies are warranted to evaluate influenza VE in patients with different types of liver disease and with specific vaccine formulations. | Using a test-negative, case-control study, we observed that influenza vaccination was associated with a significantly lower risk of influenza-associated hospitalization among adults without liver disease, but the protective effect was not significant among those with liver disease. | eng

BACKGROUND: Real-world COVID-19 vaccine effectiveness (VE) studies are investigating exposures of increasing complexity accounting for time since vaccination. These studies require methods that adjust for the confounding that arises when morbidities and demographics are associated with vaccination and the risk of outcome events. Methods based on propensity scores (PS) are well-suited to this when the exposure is dichotomous, but present challenges when the exposure is multinomial. OBJECTIVE: This simulation study aimed to investigate alternative methods to adjust for confounding in VE studies that have a test-negative design. METHODS: Adjustment for a disease risk score (DRS) is compared with multivariable logistic regression. Both stratification on the DRS and direct covariate adjustment of the DRS are examined. Multivariable logistic regression with all the covariates and with a limited subset of key covariates is considered. The performance of VE estimators is evaluated across a multinomial vaccination exposure in simulated datasets. RESULTS: Bias in VE estimates from multivariable models ranged from -5.3% to 6.1% across 4 levels of vaccination. Standard errors of VE estimates were unbiased, and 95% coverage probabilities were attained in most scenarios. The lowest coverage in the multivariable scenarios was 93.7% (95% CI 92.2%-95.2%) and occurred in the multivariable model with key covariates, while the highest coverage in the multivariable scenarios was 95.3% (95% CI 94.0%-96.6%) and occurred in the multivariable model with all covariates. Bias in VE estimates from DRS-adjusted models was low, ranging from -2.2% to 4.2%. However, the DRS-adjusted models underestimated the standard errors of VE estimates, with coverage sometimes below the 95% level. The lowest coverage in the DRS scenarios was 87.8% (95% CI 85.8%-89.8%) and occurred in the direct adjustment for the DRS model. The highest coverage in the DRS scenarios was 94.8% (95% CI 93.4%-96.2%) and occurred in the model that stratified on DRS. Although variation in the performance of VE estimates occurred across modeling strategies, variation in performance was also present across exposure groups. CONCLUSIONS: Overall, models using a DRS to adjust for confounding performed adequately but not as well as the multivariable models that adjusted for covariates individually.

BACKGROUND: The 2023-24 U.S. influenza season was characterized by a predominance of A(H1N1)pdm09 virus circulation with co-circulation of A(H3N2) and B/Victoria viruses. We estimated vaccine effectiveness (VE) in the United States against mild-to-moderate medically attended influenza illness in the 2023-24 season. METHODS: We enrolled outpatients aged ≥8 months with acute respiratory illness in 7 states. Respiratory specimens were tested for influenza type/subtype by reverse-transcriptase polymerase chain reaction (RT-PCR). Influenza VE was estimated with a test-negative design comparing odds of testing positive for influenza among vaccinated versus unvaccinated participants. We estimated VE by virus sub-type/lineage and A(H1N1)pdm09 genetic subclades. RESULTS: Among 6,589 enrolled patients, 1,770 (27%) tested positive for influenza including 796 A(H1N1)pdm09, 563 B/Victoria, and 323 A(H3N2). Vaccine effectiveness against any influenza illness was 41% (95% Confidence Interval [CI]: 32 to 49): 28% (95% CI: 13 to 40) against influenza A(H1N1)pdm09, 68% (95% CI: 59 to 76) against B/Victoria, and 30% (95% CI: 9 to 47) against A(H3N2). Statistically significant protection against any influenza was found for all age groups except adults aged 50-64 years. Lack of protection in this age group was specific to influenza A-associated illness. We observed differences in VE by birth cohort and A(H1N1)pdm09 virus genetic subclade. CONCLUSIONS: Vaccination reduced outpatient medically attended influenza overall by 41% and provided protection overall against circulating influenza A and B viruses. Serologic studies would help inform differences observed by age groups.

The extent to which semi-quantitative antibody levels confer protection against SARS-CoV-2 infection in populations with heterogenous immune histories is unclear. Two nested case-control studies were designed within the multisite HEROES/RECOVER prospective cohort of frontline workers to study the relationship between antibody levels and protection against first-time post-vaccination infection and reinfection with SARS-CoV-2 from December 2021 to January 2023. All participants submitted weekly nasal swabs for rRT-PCR testing and blood samples quarterly and following infection or vaccination. Cases of first-time post-vaccination infection following a third dose of monovalent (origin strain WA-1) mRNA vaccine (n = 613) and reinfection (n = 350) were 1:1 matched to controls based on timing of blood draw and other potential confounders. Conditional logistic regression models were fit to estimate infection risk reductions associated with 3-fold increases in end titers for receptor binding domain (RBD). In first-time post-vaccination and reinfection study samples, most were female (67%, 57%), non-Hispanic (82%, 68%), and without chronic conditions (65%, 65%). The odds of first-time post-vaccination infection were reduced by 21% (aOR = 0.79, 95% CI = [0.66-0.96]) for each 3-fold increase in RBD end titers. The odds of reinfection associated with a 3-fold increase in RBD end titers were reduced by 23% (aOR = 0.77, 95% CI = [0.65-0.92] for unvaccinated individuals and 58% (aOR = 0.42, 95% CI = [0.22-0.84]) for individuals with three mRNA vaccine doses following their first infection. Frontline workers with higher antibody levels following a third dose of mRNA COVID-19 vaccine were at reduced risk of SARS-CoV-2 during Omicron predominance. Among those with previous infections, the point estimates of risk reduction associated with antibody levels was greater for those with three vaccine doses compared to those who were unvaccinated.

To understand how COVID-19 vaccines impact infection risk in children <5 years, we assessed risk of SARS-CoV-2 infection from Sept 2022-April 2023 in three cohort studies. There was no difference in risk by vaccination status. While vaccines reduce severe disease, they may not reduce SARS-CoV-2 infections in young children.

BACKGROUND: Egg-based inactivated quadrivalent seasonal influenza vaccine (eIIV4), cell culture-based inactivated quadrivalent seasonal influenza vaccine (ccIIV4), and recombinant haemagglutinin (HA)-based quadrivalent seasonal influenza vaccine (RIV4) have been licensed for use in the USA. In this study, we used antigen-specific serum proteomics analysis to assess how the molecular composition and qualities of the serological antibody repertoires differ after seasonal influenza immunisation by each of the three vaccines and how different vaccination platforms affect the HA binding affinity and breadth of the serum antibodies that comprise the polyclonal response. METHODS: In this comparative, prospective, observational cohort study, we included female US health-care personnel (mean age 47·6 years [SD 8]) who received a single dose of RIV4, eIIV4, or ccIIV4 during the 2018-19 influenza season at Baylor Scott & White Health (Temple, TX, USA). Eligible individuals were selected based on comparable day 28 serum microneutralisation titres and similar vaccination history. Laboratory investigators were blinded to assignment until testing was completed. The preplanned exploratory endpoints were assessed by deconvoluting the serological repertoire specific to A/Singapore/INFIMH-16-0019/2016 (H3N2) HA before (day 0) and after (day 28) immunisation using bottom-up liquid chromatography-mass spectrometry proteomics (referred to as Ig-Seq) and natively paired variable heavy chain-variable light chain high-throughput B-cell receptor sequencing (referred to as BCR-Seq). Features of the antigen-specific serological repertoire at day 0 and day 28 for the three vaccine groups were compared. Antibodies identified with high confidence in sera were recombinantly expressed and characterised in depth to determine the binding affinity and breadth to time-ordered H3 HA proteins. FINDINGS: During September and October of the 2018-19 influenza season, 15 individuals were recruited and assigned to receive RIV4 (n=5), eIIV4 (n=5), or ccIIV4 (n=5). For all three cohorts, the serum antibody repertoire was dominated by back-boosted antibody lineages (median 98% [95% CI 88-99]) that were present in the serum before vaccination. Although vaccine platform-dependent differences were not evident in the repertoire diversity, somatic hypermutation, or heavy chain complementarity determining region 3 biochemical features, antibodies boosted by RIV4 showed substantially higher binding affinity to the vaccine H3/HA (median half-maximal effective concentration [EC50] to A/Singapore/INFIMH-16-0019/2016 HA: 0·037 μg/mL [95% CI 0·012-0·12] for RIV4; 4·43 μg/mL [0·030-100·0] for eIIV4; and 18·50 μg/mL [0·99-100·0] μg/mL for ccIIV4) and also the HAs from contemporary H3N2 strains than did those elicited by eIIV4 or ccIIV4 (median EC50 to A/Texas/50/2012 HA: 0·037 μg/mL [0·017-0·32] for RIV4; 1·10 μg/mL [0·045-100] for eIIV4; and 12·6 μg/mL [1·8-100] for ccIIV4). Comparison of B-cell receptor sequencing repertoires on day 7 showed that eIIV4 increased the median frequency of canonical egg glycan-targeting B cells (0·20% [95% CI 0·067-0·37] for eIIV4; 0·058% [0·050-0·11] for RIV4; and 0·035% [0-0·062] for ccIIV4), whereas RIV4 vaccination decreased the median frequency of B-cell receptors displaying stereotypical features associated with membrane proximal anchor-targeting antibodies (0·062% [95% CI 0-0·084] for RIV4; 0·12% [0·066-0·16] for eIIV4; and 0·18% [0·016-0·20] for ccIIV4). In exploratory analysis, we characterised the structure of a highly abundant monoclonal antibody that binds to both group 1 and 2 HAs and recognises the HA trimer interface, despite its sequence resembling the stereotypical sequence motif found in membrane-proximal anchor binding antibodies. INTERPRETATION: Although all three licensed seasonal influenza vaccines elicit serological antibody repertoires with indistinguishable features shaped by heavy imprinting, the RIV4 vaccine selectively boosts higher affinity monoclonal antibodies to contemporary strains and elicits greater serum binding potency and breadth, possibly as a consequence of the multivalent structural features of the HA immunogen in this vaccine formulation. Collectively, our findings show advantages of RIV4 vaccines and more generally highlight the benefits of multivalent HA immunogens in promoting higher affinity serum antibody responses. FUNDING: Centers for Disease Control and Prevention, National Institutes of Health, and Bill & Melinda Gates Foundation.

BACKGROUND: clinical guidelines recommend initiation of antiviral therapy as soon as possible for patients hospitalized with confirmed or suspected influenza. METHODS: A multicenter US observational sentinel surveillance network prospectively enrolled adults (aged ≥18 years) hospitalized with laboratory-confirmed influenza at 24 hospitals during October 1, 2022-July 21, 2023. A multivariable proportional odds model was used to compare peak pulmonary disease severity (no oxygen support, standard supplemental oxygen, high-flow oxygen/non-invasive ventilation, invasive mechanical ventilation, or death) after the day of hospital admission among patients starting oseltamivir treatment on the day of admission (early) versus those who did not (late or not treated), adjusting for baseline (admission day) severity, age, sex, site, and vaccination status. Multivariable logistic regression models were used to evaluate the odds of intensive care unit (ICU) admission, acute kidney replacement therapy or vasopressor use, and in-hospital death. RESULTS: A total of 840 influenza-positive patients were analyzed, including 415 (49%) who started oseltamivir treatment on the day of admission, and 425 (51%) who did not. Compared with late or not treated patients, those treated early had lower peak pulmonary disease severity (proportional aOR: 0.60, 95% CI: 0.49-0.72), and lower odds of intensive care unit admission (aOR: 0.24, 95% CI: 0.13-0.47), acute kidney replacement therapy or vasopressor use (aOR: 0.40, 95% CI: 0.22-0.67), and in-hospital death (aOR: 0.36, 95% CI: 0.18-0.72). CONCLUSION: Among adults hospitalized with influenza, treatment with oseltamivir on day of hospital admission was associated reduced risk of disease progression, including pulmonary and extrapulmonary organ failure and death.

BACKGROUND: In test-negative studies of vaccine effectiveness (VE), including patients with co-circulating, vaccine-preventable, respiratory pathogens in the control group for the pathogen of interest can introduce a downward bias on VE estimates. METHODS: A multicenter sentinel surveillance network in the US prospectively enrolled adults hospitalized with acute respiratory illness from September 1, 2022-March 31, 2023. We evaluated bias in estimates of VE against influenza-associated and COVID-19-associated hospitalization based on: inclusion vs exclusion of patients with a co-circulating virus among VE controls; observance of VE against the co-circulating virus (rather than the virus of interest), unadjusted and adjusted for vaccination against the virus of interest; and observance of influenza or COVID-19 against a sham outcome of respiratory syncytial virus (RSV). RESULTS: Overall VE against influenza-associated hospitalizations was 6 percentage points lower when patients with COVID-19 were included in the control group, and overall VE against COVID-19-associated hospitalizations was 2 percentage points lower when patients with influenza were included in the control group. Analyses of VE against the co-circulating virus and against the sham outcome of RSV showed that downward bias was largely attributable the correlation of vaccination status across pathogens, but also potentially attributable to other sources of residual confounding in VE models. CONCLUSION: Excluding cases of confounding respiratory pathogens from the control group in VE analysis for a pathogen of interest can reduce downward bias. This real-world analysis demonstrates that such exclusion is a helpful bias mitigation strategy, especially for measuring influenza VE, which included a high proportion of COVID-19 cases among controls.

BACKGROUND: Assessments of COVID-19 vaccine effectiveness are needed to monitor the protection provided by updated vaccines against severe COVID-19. We evaluated the effectiveness of original monovalent and bivalent (ancestral strain and Omicron BA.4/5) COVID-19 vaccination against COVID-19-associated hospitalization and severe in-hospital outcomes. METHODS: During September 8, 2022 to August 31, 2023, adults aged ≥ 18 years hospitalized with COVID-19-like illness were enrolled at 26 hospitals in 20 US states. Using a test-negative case-control design, we estimated vaccine effectiveness (VE) with multivariable logistic regression adjusted for age, sex, race/ethnicity, admission date, and geographic region. RESULTS: Among 7028 patients, 2924 (41.6%) were COVID-19 case patients, and 4104 (58.4%) were control patients. Compared to unvaccinated patients, absolute VE against COVID-19-associated hospitalization was 6% (-7%-17%) for original monovalent doses only (median time since last dose [IQR] = 421 days [304-571]), 52% (39%-61%) for a bivalent dose received 7-89 days earlier, and 13% (-10%-31%) for a bivalent dose received 90-179 days earlier. Absolute VE against COVID-19-associated invasive mechanical ventilation or death was 51% (34%-63%) for original monovalent doses only, 61% (35%-77%) for a bivalent dose received 7-89 days earlier, and 50% (11%-71%) for a bivalent dose received 90-179 days earlier. CONCLUSION: Bivalent vaccination provided protection against COVID-19-associated hospitalization and severe in-hospital outcomes within 3 months of receipt, followed by a decline in protection to a level similar to that remaining from previous original monovalent vaccination by 3-6 months. These results underscore the benefit of remaining up to date with recommended COVID-19 vaccines.

BACKGROUND: Previous estimates of vaccine effectiveness (VE) against asymptomatic influenza virus infection based on seroconversion have varied widely and may be biased. We estimated 2022-2023 influenza VE against illness and asymptomatic infection in a prospective cohort. METHODS: In the HEROES-RECOVER cohort, adults at increased occupational risk of influenza exposure across 7 US sites provided weekly symptom reports and nasal swabs for reverse transcription-polymerase chain reaction (RT-PCR) influenza testing. Laboratory-confirmed influenza virus infections were classified as symptomatic (≥1 symptom) or asymptomatic during the week of testing. Participants reported demographic information and vaccination through surveys; most sites verified vaccination through medical record and immunization registry review. Person-time was calculated as days from the site-specific influenza season start (September-October 2022) through date of infection, study withdrawal, or season end (May 2023). We compared influenza incidence among vaccinated versus unvaccinated participants overall, by symptom status, and by influenza A subtype, using Cox proportional hazards regression adjusted for site and occupation. We estimated VE as (1 - adjusted hazard ratio) × 100%. RESULTS: In total, 269 of 3785 (7.1%) participants had laboratory-confirmed influenza, including 263 (98%) influenza A virus infections and 201 (75%) symptomatic illnesses. Incidence of laboratory-confirmed influenza illness among vaccinated versus unvaccinated participants was 23.7 and 33.2 episodes per 100 000 person-days, respectively (VE: 38%; 95% CI: 15%-55%). Incidence of asymptomatic influenza virus infection was 8.0 versus 11.6 per 100 000 (VE: 13%; 95% CI: -47%, 49%). CONCLUSIONS: Vaccination reduced incidence of symptomatic but not asymptomatic influenza virus infection, suggesting that influenza vaccination attenuates progression from infection to illness.

Pregnant people face increased risk of severe COVID-19. Current guidelines recommend updated COVID-19 vaccination (2023-2024) for those aged ≥6 months, irrespective of pregnancy status. To refine recommendations for pregnant people, further data are needed. Using a test-negative design, we evaluated COVID-19 vaccine effectiveness against medically attended COVID-19 with COVID-19-like illness among pregnant people aged 18 to 45 years during June 2022 to August 2023. When doses were received during pregnancy, vaccine effectiveness was 52% (95% CI, 29%-67%); when received <6 months prior to pregnancy, 28% (95% CI, 11%-42%); and when received ≥6 months prior to pregnancy, 6% (95% CI, -11% to 21%). Pregnant people should stay up-to-date with recommended COVID-19 vaccination.

Elevated body mass index (BMI) has been linked to severe influenza illness and impaired vaccine immunogenicity, but the relationship between BMI and clinical vaccine effectiveness (VE) is less well described. This secondary analysis of data from a test-negative study of outpatients with acute respiratory illness assessed BMI and VE against medically attended, PCR-confirmed influenza over seven seasons (2011-12 through 2017-18). Vaccination status was determined from electronic medical records (EMR) and self-report; BMI was estimated from EMR-documented height and weight categorized for adults as obesity (≥ 30 kg/m(2)), overweight (25-29 kg/m(2)), or normal and for children based on standardized z-scales. Current season VE by virus type/subtype was estimated separately for adults and children. Pooled VE for all seasons was calculated as 1-adjusted odds ratios from logistic regression with an interaction term for BMI and vaccination. Among 28,089 adults and 12,380 children, BMI category was not significantly associated with VE against outpatient influenza for any type/subtype. Adjusted VE against A/H3N2, A/H1N1pdm09, and B in adults ranged from 16-31, 46-54, and 44-57%, and in children from 29-34, 57-65, and 50-55%, respectively, across the BMI categories. Elevated BMI was not associated with reduced VE against laboratory confirmed, outpatient influenza illness.

Hybrid immunity, as a result of infection and vaccination to SARS-CoV-2, has been well studied in adults but limited evidence is available in children. We evaluated the antibody responses to primary SARS-CoV-2 infection among vaccinated and unvaccinated children aged ≥ 5 years. METHODS: A longitudinal cohort study of children aged ≥ 5 was conducted during August 2021-August 2022, at sites in Arizona, Texas, Utah, and Florida. Children submitted weekly nasal swabs for PCR testing and provided sera 14-59 days after PCR-confirmed SARS-CoV-2 infection. Antibodies were measured by ELISA against the receptor-binding domain (RBD) and S2 domain of ancestral Spike (WA1), in addition to Omicron (BA.2) RBD, following infection in children, with and without prior monovalent ancestral mRNA COVID-19 vaccination. RESULTS: Among the 257 participants aged 5 to 18 years, 166 (65%) had received at least two mRNA COVID-19 vaccine doses ≥ 14 days prior to infection. Of these, 53 occurred during Delta predominance, with 37 (70%) unvaccinated at the time of infection. The remaining 204 infections occurred during Omicron predominance, with 53 (26%) participants unvaccinated. After adjusting for weight, age, symptomatic infection, and gender, significantly higher mean RBD AUC values were observed among the vaccinated group compared to the unvaccinated group for both WA1 and Omicron (p < 0.0001). A smaller percentage of vaccinated children reported fever during illness, with 55 (33%) reporting fever compared to 44 (48%) unvaccinated children reporting fever (p = 0.021). CONCLUSIONS: Children with vaccine-induced immunity at the time of SARS-CoV-2 infection had higher antibody levels during convalescence and experienced less fever compared to unvaccinated children during infection.

BACKGROUND: Assessing variant-specific COVID-19 vaccine effectiveness (VE) and severity can inform public health risk assessments and decisions about vaccine composition. BA.2.86 and its descendants, including JN.1 (referred to collectively as "JN lineages"), emerged in late 2023 and exhibited substantial divergence from co-circulating XBB lineages. METHODS: We analyzed patients hospitalized with COVID-19-like illness at 26 hospitals in 20 U.S. states admitted October 18, 2023-March 9, 2024. Using a test-negative, case-control design, we estimated effectiveness of an updated 2023-2024 (Monovalent XBB.1.5) COVID-19 vaccine dose against sequence-confirmed XBB and JN lineage hospitalization using logistic regression. Odds of severe outcomes, including intensive care unit (ICU) admission and invasive mechanical ventilation (IMV) or death, were compared for JN versus XBB lineage hospitalizations using logistic regression. RESULTS: 585 case-patients with XBB lineages, 397 case-patients with JN lineages, and 4,580 control-patients were included. VE in the first 7-89 days after receipt of an updated dose was 54.2% (95% CI = 36.1%-67.1%) against XBB lineage hospitalization and 32.7% (95% CI = 1.9%-53.8%) against JN lineage hospitalization. Odds of ICU admission (adjusted odds ratio [aOR] 0.80; 95% CI = 0.46-1.38) and IMV or death (aOR 0.69; 95% CI = 0.34-1.40) were not significantly different among JN compared to XBB lineage hospitalizations. CONCLUSIONS: Updated 2023-2024 COVID-19 vaccination provided protection against both XBB and JN lineage hospitalization, but protection against the latter may be attenuated by immune escape. Clinical severity of JN lineage hospitalizations was not higher relative to XBB.

BACKGROUND: The 2022-2023 United States influenza season had unusually early influenza activity with high hospitalization rates. Vaccine-matched A(H3N2) viruses predominated, with lower levels of A(H1N1)pdm09 activity also observed. METHODS: Using the test-negative design, we evaluated influenza vaccine effectiveness (VE) during the 2022-2023 season against influenza A-associated emergency department/urgent care (ED/UC) visits and hospitalizations from October 2022 to March 2023 among adults (aged ≥18 years) with acute respiratory illness (ARI). VE was estimated by comparing odds of seasonal influenza vaccination among case-patients (influenza A test positive by molecular assay) and controls (influenza test negative), applying inverse-propensity-to-be-vaccinated weights. RESULTS: The analysis included 85 389 ED/UC ARI encounters (17.0% influenza A positive; 37.8% vaccinated overall) and 19 751 hospitalizations (9.5% influenza A positive; 52.8% vaccinated overall). VE against influenza A-associated ED/UC encounters was 44% (95% confidence interval [CI], 40%-47%) overall and 45% and 41% among adults aged 18-64 and ≥65 years, respectively. VE against influenza A-associated hospitalizations was 35% (95% CI, 27%-43%) overall and 23% and 41% among adults aged 18-64 and ≥65 years, respectively. CONCLUSIONS: VE was moderate during the 2022-2023 influenza season, a season characterized with increased burden of influenza and co-circulation with other respiratory viruses. Vaccination is likely to substantially reduce morbidity, mortality, and strain on healthcare resources.

We describe humoral immune responses in 105 ambulatory patients with laboratory-confirmed SARS-CoV-2 Omicron variant infection. In dried blood spot (DBS) collected within 5 days of illness onset and during convalescence, we measured binding antibody (bAb) against ancestral spike protein receptor binding domain (RBD) and nucleocapsid (N) protein using a commercial multiplex bead assay. Geometric mean bAb concentrations against RBD increased by a factor of 2.5 from 1258 to 3189 units/mL and by a factor of 47 against N protein from 5.5 to 259 units/mL between acute illness and convalescence; lower concentrations were associated with greater geometric mean ratios. Paired DBS specimens may be used to evaluate humoral response to SARS-CoV-2 infection.

BACKGROUND: The 2022-23 US influenza season peaked early in fall 2022. METHODS: Late-season influenza vaccine effectiveness (VE) against outpatient, laboratory-confirmed influenza was calculated among participants of the US Influenza VE Network using a test-negative design. RESULTS: Of 2561 participants enrolled from December 12, 2022 to April 30, 2023, 91 laboratory-confirmed influenza cases primarily had A(H1N1)pdm09 (6B.1A.5a.2a.1) or A(H3N2) (3C.2a1b.2a.2b). Overall, VE was 30% (95% confidence interval -9%, 54%); low late-season activity precluded estimation for most subgroups. CONCLUSIONS: 2022-23 late-season outpatient influenza VE was not statistically significant. Genomic characterization may improve the identification of influenza viruses that circulate postinfluenza peak.

While the number of immunocompromised (IC) individuals continues to rise, the existing literature on influenza vaccine effectiveness (VE) in IC populations is limited. Understanding the vaccine effectiveness (VE) of the seasonal influenza vaccines in immunocompromised (IC) populations remains paramount. Using 2017–2018 US Flu VE Network data, we examined the VE of the 2017–2018 seasonal influenza vaccine against symptomatic influenza in outpatient settings among IC adults. We used logistic regression and adjusted for enrollment site, race, self-reported general health status, age, and onset date of symptoms. The VE among non-IC was 31% (95% CI: 22, 39) and among IC participants was −4% (95% CI: −66, 35), though the difference was not statistically significant. This study demonstrates the capacity to study a large IC population using an existing influenza VE network and contributes to the literature to support large, multicenter VE studies for IC populations. © 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.

Studies have reported that prior-season influenza vaccination is associated with higher risk of clinical influenza infection among vaccinees. This effect might arise from incomplete consideration of within-season waning and recent infection. Using data from the US Flu Vaccine Effectiveness (VE) Network (2011-2012 to 2018-2019 seasons), we found that repeat vaccinees were vaccinated earlier in a season by one week. After accounting for waning VE, repeat vaccinees were still more likely to test positive for A(H3N2) (OR=1.11, 95%CI:1.02-1.21) but not for influenza B or A(H1N1). We found that clinical infection influenced individuals' decision to vaccinate in the following season while protecting against clinical infection of the same (sub)type. However, adjusting for recent clinical infections did not strongly influence the estimated effect of prior-season vaccination. In contrast, we found that adjusting for subclinical infection could theoretically attenuate this effect. Additional investigation is needed to determine the impact of subclinical infections on VE.

IMPORTANCE: On June 21, 2023, the Centers for Disease Control and Prevention recommended the first respiratory syncytial virus (RSV) vaccines for adults aged 60 years and older using shared clinical decision-making. Understanding the severity of RSV disease in adults can help guide this clinical decision-making. OBJECTIVE: To describe disease severity among adults hospitalized with RSV and compare it with the severity of COVID-19 and influenza disease by vaccination status. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, adults aged 18 years and older admitted to the hospital with acute respiratory illness and laboratory-confirmed RSV, SARS-CoV-2, or influenza infection were prospectively enrolled from 25 hospitals in 20 US states from February 1, 2022, to May 31, 2023. Clinical data during each patient's hospitalization were collected using standardized forms. Data were analyzed from August to October 2023. EXPOSURES: RSV, SARS-CoV-2, or influenza infection. MAIN OUTCOMES AND MEASURES: Using multivariable logistic regression, severity of RSV disease was compared with COVID-19 and influenza severity, by COVID-19 and influenza vaccination status, for a range of clinical outcomes, including the composite of invasive mechanical ventilation (IMV) and in-hospital death. RESULTS: Of 7998 adults (median [IQR] age, 67 [54-78] years; 4047 [50.6%] female) included, 484 (6.1%) were hospitalized with RSV, 6422 (80.3%) were hospitalized with COVID-19, and 1092 (13.7%) were hospitalized with influenza. Among patients with RSV, 58 (12.0%) experienced IMV or death, compared with 201 of 1422 unvaccinated patients with COVID-19 (14.1%) and 458 of 5000 vaccinated patients with COVID-19 (9.2%), as well as 72 of 699 unvaccinated patients with influenza (10.3%) and 20 of 393 vaccinated patients with influenza (5.1%). In adjusted analyses, the odds of IMV or in-hospital death were not significantly different among patients hospitalized with RSV and unvaccinated patients hospitalized with COVID-19 (adjusted odds ratio [aOR], 0.82; 95% CI, 0.59-1.13; P = .22) or influenza (aOR, 1.20; 95% CI, 0.82-1.76; P = .35); however, the odds of IMV or death were significantly higher among patients hospitalized with RSV compared with vaccinated patients hospitalized with COVID-19 (aOR, 1.38; 95% CI, 1.02-1.86; P = .03) or influenza disease (aOR, 2.81; 95% CI, 1.62-4.86; P < .001). CONCLUSIONS AND RELEVANCE: Among adults hospitalized in this US cohort during the 16 months before the first RSV vaccine recommendations, RSV disease was less common but similar in severity compared with COVID-19 or influenza disease among unvaccinated patients and more severe than COVID-19 or influenza disease among vaccinated patients for the most serious outcomes of IMV or death.

BACKGROUND: Although psychiatric disorders have been associated with reduced immune responses to other vaccines, it remains unknown whether they influence COVID-19 vaccine effectiveness (VE). This study evaluated risk of COVID-19 hospitalization and estimated mRNA VE stratified by psychiatric disorder status. METHODS: In a retrospective cohort analysis of the VISION Network in four US states, the rate of laboratory-confirmed COVID-19-associated hospitalization between December 2021 and August 2022 was compared across psychiatric diagnoses and by monovalent mRNA COVID-19 vaccination status using Cox proportional hazards regression. RESULTS: Among 2,436,999 adults, 22.1% had ≥1 psychiatric disorder. The incidence of COVID-19-associated hospitalization was higher among patients with any versus no psychiatric disorder (394 vs. 156 per 100,000 person-years, p < 0.001). Any psychiatric disorder (adjusted hazard ratio [aHR], 1.27; 95% CI, 1.18-1.37) and mood (aHR, 1.25; 95% CI, 1.15-1.36), anxiety (aHR, 1.33, 95% CI, 1.22-1.45), and psychotic (aHR, 1.41; 95% CI, 1.14-1.74) disorders were each significant independent predictors of hospitalization. Among patients with any psychiatric disorder, aHRs for the association between vaccination and hospitalization were 0.35 (95% CI, 0.25-0.49) after a recent second dose, 0.08 (95% CI, 0.06-0.11) after a recent third dose, and 0.33 (95% CI, 0.17-0.66) after a recent fourth dose, compared to unvaccinated patients. Corresponding VE estimates were 65%, 92%, and 67%, respectively, and were similar among patients with no psychiatric disorder (68%, 92%, and 79%). CONCLUSION: Psychiatric disorders were associated with increased risk of COVID-19-associated hospitalization. However, mRNA vaccination provided similar protection regardless of psychiatric disorder status, highlighting its benefit for individuals with psychiatric disorders.

BACKGROUND: Symptoms of COVID-19 including fatigue and dyspnea, may persist for weeks to months after SARS-CoV-2 infection. This study compared self-reported disability among SARS-CoV-2-positive and negative persons with mild to moderate COVID-19-like illness who presented for outpatient care before widespread COVID-19 vaccination. METHODS: Unvaccinated adults with COVID-19-like illness enrolled within 10 days of illness onset at three US Flu Vaccine Effectiveness Network sites were tested for SARS-CoV-2 by molecular assay. Enrollees completed an enrollment questionnaire and two follow-up surveys (7-24 days and 2-7 months after illness onset) online or by phone to assess illness characteristics and health status. The second follow-up survey included questions measuring global health, physical function, fatigue, and dyspnea. Scores in the four domains were compared by participants' SARS-CoV-2 test results in univariate analysis and multivariable Gamma regression. RESULTS: During September 22, 2020 - February 13, 2021, 2712 eligible adults were enrolled, 1541 completed the first follow-up survey, and 650 completed the second follow-up survey. SARS-CoV-2-positive participants were more likely to report fever at acute illness but were otherwise comparable to SARS-CoV-2-negative participants. At first follow-up, SARS-CoV-2-positive participants were less likely to have reported fully or mostly recovered from their illness compared to SARS-CoV-2-negative participants. At second follow-up, no differences by SARS-CoV-2 test results were detected in the four domains in the multivariable model. CONCLUSION: Self-reported disability was similar among outpatient SARS-CoV-2-positive and -negative adults 2-7 months after illness onset.

BACKGROUND: There are limited data on whether hybrid immunity differs by count and order of immunity-conferring events (SARS-CoV-2 infection or COVID-19 vaccination). From a cohort of health care personnel, first responders, and other frontline workers in six US states, we examined heterogeneity of the effect of hybrid immunity on SARS-CoV-2 antibody levels. METHODS: Exposures included event-count (sum of infections and vaccine doses) and event-order, categorized into seven permutations of vaccination and/or infection. Outcome was level of serum binding antibodies against receptor binding domain (RBD) of the ancestral SARS-CoV-2 spike protein (total RBD-binding Ig), measured by enzyme-linked immunosorbent assay. Mean antibody levels were examined up to 365 days after each of the 1st-7th events. RESULTS: Analysis included 5,793 participants measured from August 7, 2020 to April 15, 2023. Hybrid immunity from infection before one or two vaccine doses elicited modestly superior antibody responses after the 2nd and 3rd events (compared to infections or vaccine-doses alone). This superiority was not evident after the 4th and 5th events (additional doses). Among adults infected before vaccination, adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated-only) were 1.23 (1.14-1.33), 1.09 (1.03-1.14), 0.87 (0.81-0.94), and 0.99 (0.85-1.15) after the 2nd-5th events, respectively. Post-vaccination infections elicited superior responses: adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated-only) were: 0.93 (0.75-1.17), 1.11 (1.06-1.16), 1.17 (1.11-1.24), and 1.20 (1.07-1.34) after the 2nd-5th events, respectively. CONCLUSIONS AND RELEVANCE: Findings reflecting heterogeneity in antibody levels by permutations of infection and vaccination history could inform COVID-19 vaccination policy.

In September 2023, CDC's Advisory Committee on Immunization Practices recommended updated 2023-2024 (monovalent XBB.1.5) COVID-19 vaccination for all persons aged ≥6 months to prevent COVID-19, including severe disease. However, few estimates of updated vaccine effectiveness (VE) against medically attended illness are available. This analysis evaluated VE of an updated COVID-19 vaccine dose against COVID-19-associated emergency department (ED) or urgent care (UC) encounters and hospitalization among immunocompetent adults aged ≥18 years during September 2023-January 2024 using a test-negative, case-control design with data from two CDC VE networks. VE against COVID-19-associated ED/UC encounters was 51% (95% CI = 47%-54%) during the first 7-59 days after an updated dose and 39% (95% CI = 33%-45%) during the 60-119 days after an updated dose. VE estimates against COVID-19-associated hospitalization from two CDC VE networks were 52% (95% CI = 47%-57%) and 43% (95% CI = 27%-56%), with a median interval from updated dose of 42 and 47 days, respectively. Updated COVID-19 vaccine provided increased protection against COVID-19-associated ED/UC encounters and hospitalization among immunocompetent adults. These results support CDC recommendations for updated 2023-2024 COVID-19 vaccination. All persons aged ≥6 months should receive updated 2023-2024 COVID-19 vaccine.

In the United States, annual influenza vaccination is recommended for all persons aged ≥6 months. Using data from four vaccine effectiveness (VE) networks during the 2023-24 influenza season, interim influenza VE was estimated among patients aged ≥6 months with acute respiratory illness-associated medical encounters using a test-negative case-control study design. Among children and adolescents aged 6 months-17 years, VE against influenza-associated outpatient visits ranged from 59% to 67% and against influenza-associated hospitalization ranged from 52% to 61%. Among adults aged ≥18 years, VE against influenza-associated outpatient visits ranged from 33% to 49% and against hospitalization from 41% to 44%. VE against influenza A ranged from 46% to 59% for children and adolescents and from 27% to 46% for adults across settings. VE against influenza B ranged from 64% to 89% for pediatric patients in outpatient settings and from 60% to 78% for all adults across settings. These findings demonstrate that the 2023-24 seasonal influenza vaccine is effective at reducing the risk for medically attended influenza virus infection. CDC recommends that all persons aged ≥6 months who have not yet been vaccinated this season get vaccinated while influenza circulates locally.