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BackgroundTest-negative design (TND) studies have produced validated estimates of vaccine effectiveness (VE) for influenza vaccine studies. However, syndrome-negative controls have been proposed for differentiating bias and true estimates in VE evaluations for COVID-19. To understand the use of alternative control groups, we compared characteristics and VE estimates of syndrome-negative and test-negative VE controls.MethodsAdults hospitalized at 21 medical centers in 18 states March 11-August 31, 2021 were eligible for analysis. Case patients had symptomatic acute respiratory infection (ARI) and tested positive for SARS-CoV-2. Control groups were test-negative patients with ARI but negative SARS-CoV-2 testing, and syndrome-negative controls were without ARI and negative SARS-CoV-2 testing. Chi square and Wilcoxon rank sum tests were used to detect differences in baseline characteristics. VE against COVID-19 hospitalization was calculated using logistic regression comparing adjusted odds of prior mRNA vaccination between cases hospitalized with COVID-19 and each control group.Results5811 adults (2726 cases, 1696 test-negative controls, and 1389 syndrome-negative controls) were included. Control groups differed across characteristics including age, race/ethnicity, employment, previous hospitalizations, medical conditions, and immunosuppression. However, control-group-specific VE estimates were very similar. Among immunocompetent patients aged 18-64years, VE was 93% (95% CI: 90-94) using syndrome-negative controls and 91% (95% CI: 88-93) using test-negative controls.ConclusionsDespite demographic and clinical differences between control groups, the use of either control group produced similar VE estimates across age groups and immunosuppression status. These findings support the use of test-negative controls and increase confidence in COVID-19 VE estimates produced by test-negative design studies.

The SARS-CoV-2 Omicron variant (B.1.1.529 or BA.1) became predominant in the United States by late December 2021 (1). BA.1 has since been replaced by emerging lineages BA.2 (including BA.2.12.1) in March 2022, followed by BA.4 and BA.5, which have accounted for a majority of SARS-CoV-2 infections since late June 2022 (1). Data on the effectiveness of monovalent mRNA COVID-19 vaccines against BA.4/BA.5-associated hospitalizations are limited, and their interpretation is complicated by waning of vaccine-induced immunity (2-5). Further, infections with earlier Omicron lineages, including BA.1 and BA.2, reduce vaccine effectiveness (VE) estimates because certain persons in the referent unvaccinated group have protection from infection-induced immunity. The IVY Network

Accurate estimates of the total burden of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to inform policy, planning, and response. We sought to quantify SARS-CoV-2 cases, hospitalizations, and deaths by age in Michigan. Coronavirus disease 2019 cases reported to the Michigan Disease Surveillance System were multiplied by age and time-specific adjustment factors to correct for under-detection. Adjustment factors were estimated in a model fit to incidence data and seroprevalence estimates. Age-specific incidence of SARS-CoV-2 hospitalization, death, vaccination, and variant proportions were estimated from publicly available data. We estimated substantial under-detection of infection that varied by age and time. Accounting for under-detection, we estimate the cumulative incidence of infection in Michigan reached 75% by mid-November 2021, and over 87% of Michigan residents were estimated to have had ≥1 vaccination dose and/or previous infection. Comparing pandemic waves, the relative burden among children increased over time. In general, the proportion of cases who were hospitalized or who died decreased over time. Our results highlight the ongoing risk of periods of high SARS-CoV-2 incidence despite widespread prior infection and vaccination. This underscores the need for long-term planning for surveillance, vaccination, and other mitigation measures amidst continued response to the acute pandemic.

During the COVID-19 pandemic, self-reported COVID-19 vaccination might facilitate rapid evaluations of vaccine effectiveness (VE) when source documentation (e.g., immunization information systems [IIS]) is not readily available. We evaluated the concordance of COVID-19 vaccination status ascertained by self-report versus source documentation and its impact on VE estimates.Hospitalized adults (≥18 years) admitted to 18 U.S. medical centers March-June 2021 were enrolled, including COVID-19 cases and SARS-CoV-2 negative controls. Patients were interviewed about COVID-19 vaccination. Abstractors simultaneously searched IIS, medical records, and other sources for vaccination information. To compare vaccination status by self-report and documentation, we estimated percent agreement and unweighted kappa with 95% confidence intervals (CIs). We then calculated VE in preventing COVID-19 hospitalization of full vaccination (2 doses of mRNA product ≥14 days prior to illness onset) independently using data from self-report or source documentation.Of 2520 patients, 594 (24%) did not have self-reported vaccination information to assign vaccination group; these patients tended to be more severely ill. Among 1924 patients with both self-report and source documentation information, 95.0% (95% CI: 93.9-95.9%) agreement was observed, with a kappa of 0.9127 (95% CI: 0.9109-0.9145). VE was 86% (95% CI: 81-90%) by self-report data only and 85% (95% CI: 81-89%) by source documentation data only.Approximately one-quarter of hospitalized patients could not provide self-report COVID-19 vaccination status. Among patients with self-report information, there was high concordance with source documented status. Self-report may be a reasonable source of COVID-19 vaccination information for timely VE assessment for public health action.

Influenza vaccines can mitigate illness severity, including reduced risk of ICU admission and death, in people with breakthrough infection. Less is known about vaccine attenuation of mild/moderate influenza illness. We compared subjective severity scores in vaccinated and unvaccinated persons with medically attended illness and laboratory-confirmed influenza. Participants were prospectively recruited when presenting for care at five US sites over nine seasons. Participants aged ≥ 16 years completed the EQ-5D-5L visual analog scale (VAS) at enrollment. After controlling for potential confounders in a multivariable model, including age and general health status, VAS scores were significantly higher among 2,830 vaccinated participants compared with 3,459 unvaccinated participants, indicating vaccinated participants felt better at the time of presentation for care. No differences in VAS scores were observed by the type of vaccine received among persons aged ≥ 65 years. Our findings suggest vaccine-associated attenuation of milder influenza illness is possible.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses continue to co-circulate, representing 2 major public health threats from respiratory infections with similar clinical presentations. SARS-CoV-2 and influenza vaccines can also now be co-administered. However, data on antibody responses to SARS-CoV-2 and influenza coinfection and vaccine co-administration remain limited. Methods We developed a 41-plex antibody immunity assay that can simultaneously characterize antibody landscapes to SARS-CoV-2/influenza/common human coronaviruses. We analyzed sera from 840 individuals (11–93 years), including sera from reverse transcription–polymerase chain reaction (RT-PCR)–confirmed SARS-CoV-2–positive (n = 218) and –negative (n = 120) cases, paired sera from SARS-CoV-2 vaccination (n = 29) and infection (n = 11), and paired sera from influenza vaccination (n = 56) and RT-PCR–confirmed influenza infection (n = 158) cases. Last, we analyzed sera collected from 377 individuals who exhibited acute respiratory illness (ARI) in 2020. Results This 41-plex assay has high sensitivity and specificity in detecting SARS-CoV-2 infections. It differentiated SARS-CoV-2 vaccination (antibody responses only to spike protein) from infection (antibody responses to both spike and nucleoprotein). No cross-reactive antibodies were induced to SARS-CoV-2 from influenza vaccination and infection, and vice versa, suggesting no interaction between SARS-CoV-2 and influenza antibody responses. However, cross-reactive antibodies were detected between spike proteins of SARS-CoV-2 and common human coronaviruses that were removed by serum adsorption. Among 377 individuals who exhibited ARI in 2020, 129 were influenza positive; none had serological evidence of SARS-CoV-2/influenza coinfections. Conclusions Multiplex detection of antibody landscapes can provide in-depth analysis of the antibody protective immunity to SARS-CoV-2 in the context of other respiratory viruses, including influenza.

Background . Adults in the United States (US) began receiving the adenovirus vector coronavirus disease 2019 (COVID-19) vaccine, Ad26.COV2.S (Johnson & Johnson [Janssen]), in February 2021. We evaluated Ad26.COV2.S vaccine effectiveness (VE) against COVID-19 hospitalization and high disease severity during the first 10 months of its use. Methods . In a multicenter case-control analysis of US adults (≥18 years) hospitalized 11 March to 15 December 2021, we estimated VE against susceptibility to COVID-19 hospitalization (VEs), comparing odds of prior vaccination with a single dose Ad26.COV2.S vaccine between hospitalized cases with COVID-19 and controls without COVID-19. Among hospitalized patients with COVID-19, we estimated VE against disease progression (VEp) to death or invasive mechanical ventilation (IMV), comparing odds of prior vaccination between patients with and without progression. Results . After excluding patients receiving mRNA vaccines, among 3979 COVID-19 case-patients (5% vaccinated with Ad26.COV2.S) and 2229 controls (13% vaccinated with Ad26.COV2.S), VEs of Ad26.COV2.S against COVID-19 hospitalization was 70% (95% confidence interval [CI]: 63–75%) overall, including 55% (29–72%) among immunocompromised patients, and 72% (64–77%) among immunocompetent patients, for whom VEs was similar at 14–90 days (73% [59–82%]), 91–180 days (71% [60–80%]), and 181–274 days (70% [54–81%]) postvaccination. Among hospitalized COVID-19 case-patients, VEp was 46% (18–65%) among immunocompetent patients. Conclusions . The Ad26.COV2.S COVID-19 vaccine reduced the risk of COVID-19 hospitalization by 72% among immunocompetent adults without waning through 6 months postvaccination. After hospitalization for COVID-19, vaccinated immunocompetent patients were less likely to require IMV or die compared to unvaccinated immunocompetent patients.

BackgroundSerological responses from influenza vaccination or infection are typically measured by Hemagglutinin Inhibition (HAI) or Microneutralization (MN). Both methods are limited in feasibility, standardization, and generalizability. We describe a luciferase MN (LMN) assay that combines the advantages of the conventional MN assay with the ease of the HAI assayMethodsSera were obtained from the HIVE study. Plasmid transfection was used to generate recombinant influenza viruses expressing the hemagglutinin and neuraminidase of test strains, all other viral proteins from A/WSN33, and a NanoLuc reporter. Serum neutralization of luciferase-expressing targets was quantified as a reduction in Relative Light Unit (RLU) emission from infected cells. Neutralization titers were measured for cell- and egg-adapted versions of A/H3N2/Hong Kong/4801/2014 and A/H3N2/Singapore/INFIMH-16-0019/2016 and compared to HAI titers against egg-grown antigens.Results333 sera were collected from 259 participants between May 2016 and July 2018. Sampled participants ranged from 7 to 68 years of age and >80% were vaccinated against influenza. HAI and LMN titers were correlated for A/H3N2/Hong Kong/4801/2014 (ρ=0.45, p≤0.01) and A/H3N2/Singapore/INFIMH-16-0019/2016 (ρ=0.75, p≤0.01). LMN titers were lower for cell strains compared to egg strains (A/H3N2/Hong Kong/4801/2014 mean log2fold change = −2.66, p≤0.01 and A/H3N2/Singapore/INFIMH-16-0019/2016 mean log2fold change= −3.15, p≤0.01).ConclusionsThe LMN assay was feasible using limited sample volumes and was able to differentiate small antigenic differences, specifically between egg-adapted and cell-derived strains. The correspondence of these results with the commonly-used HAI confirms the potential utility of this assay for high-throughput studies of correlates of protection and vaccine response.

Background and Objectives Infants and children are at increased risk of severe influenza virus infection and its complications. Influenza vaccine effectiveness (VE) varies by age, influenza season, and influenza virus type/subtype. This study’s objective was to examine the effectiveness of inactivated influenza vaccine against outpatient influenza illness in the pediatric population over 9 influenza seasons after the 2009 A(H1N1) pandemic. Methods During the 2011–2012 through the 2019–2020 influenza seasons at outpatient clinics at 5 sites of the US Influenza Vaccine Effectiveness Network, children aged 6 months to 17 years with an acute respiratory illness were tested for influenza using real-time, reverse-transcriptase polymerase chain reaction. Vaccine effectiveness was estimated using a test-negative design. Results Among 24 148 enrolled children, 28% overall tested positive for influenza, 3017 tested positive for influenza A(H3N2), 1459 for influenza A(H1N1)pdm09, and 2178 for influenza B. Among all enrollees, 39% overall were vaccinated, with 29% of influenza cases and 43% of influenza-negative controls vaccinated. Across all influenza seasons, the pooled VE for any influenza was 46% (95% confidence interval, 43–50). Overall and by type/subtype, VE against influenza illness was highest among children in the 6- to 59-month age group compared with older pediatric age groups. VE was lowest for influenza A(H3N2) virus infection. Conclusions Analysis of multiple seasons suggested substantial benefit against outpatient illness. Investigation of host-specific or virus-related mechanisms that may result in differences by age and virus type/subtype may help further efforts to promote increased vaccination coverage and other influenza-related preventative measures.

Over 645 million people worldwide have been infected with SARS-CoV-2, the virus that causes COVID-19. Critical knowledge gaps regarding the characteristics, duration, and impact of symptoms due to “long COVID”. This study evaluated the persistence of symptoms at one year following hospitalization with COVID-19, comparing responses on standardized measurement tools to population norms. Adults hospitalized with COVID-19 March-October 2020 during the initial emergence period in Southeast Michigan were eligible. A detailed survey was conducted via telephone 9-15 months after hospital discharge. Questions assessed fatigue, dyspnea, and physical functioning related to their COVID-19 illness. The median World Health Organization Disability Assessment Schedule (WHODAS) polytomous score placed 50% (n=20/40) of participants in the 90 percentile of disability based on population norms. The mean SF-36 physical functioning score was almost nine points below population norms (mean=70.6, standard deviation=27.4). Additionally, 47.5% of individuals (n=19) were severely emotionally affected by their health condition. Over half of participants surveyed were still impacted a year after initial infection, experiencing limited functional ability, fatigue, and emotional difficulties. Given the impact of these symptoms on day-to-day quality of life, further studies are needed to develop strategies for treatment and management of post-COVID conditions.

Individuals in contact with persons with COVID-19 are at high risk of developing COVID-19; protection offered by COVID-19 vaccines in the context of known exposure is poorly understood.Symptomatic outpatients aged ≥12 years reporting acute onset of COVID-19-like illness and tested for SARS-CoV-2 between February 1 and September 30, 2021 were enrolled. Participants were stratified by self-report of having known contact with a COVID-19 case in the 14 days prior to illness onset. Vaccine effectiveness was evaluated using the test-negative study design and multivariable logistic regression.Among 2229 participants, 283/451 (63%) of those reporting contact and 331/1778 (19%) without known contact tested SARS-CoV-2-positive. Adjusted vaccine effectiveness was 71% (95% confidence interval [CI], 49%-83%) among fully vaccinated participants reporting a known contact versus 80% (95% CI, 72%-86%) among those with no known contact (p-value for interaction = 0.2).This study contributes to growing evidence of the benefits of vaccinations in preventing COVID-19 and support vaccination recommendations and the importance of efforts to increase vaccination coverage.

Background Current understanding of severe respiratory syncytial virus (RSV) infections in adults is limited by clinical underrecognition. We compared the prevalence, clinical characteristics, and outcomes of RSV infections vs influenza in adults hospitalized with acute respiratory illnesses (ARIs) in a prospective national surveillance network. Methods Hospitalized adults who met a standardized ARI case definition were prospectively enrolled across 3 respiratory seasons from hospitals participating across all sites of the US Hospitalized Adult Influenza Vaccine Effectiveness Network (2016–2019). All participants were tested for RSV and influenza using real-time reverse-transcription polymerase chain reaction assay. Multivariable logistic regression was used to test associations between laboratory-confirmed infection and characteristics and clinical outcomes. Results Among 10 311 hospitalized adults, 6% tested positive for RSV (n = 622), 18.8% for influenza (n = 1940), and 75.1% negative for RSV and influenza (n = 7749). Congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD) was more frequent with RSV than influenza (CHF: 37.3% vs 28.8%, P < .0001; COPD: 47.6% vs 35.8%, P < .0001). Patients with RSV more frequently had longer admissions (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.06–1.80) for stays >1 week) and mechanical ventilation (OR, 1.45; 95% CI, 1.09–1.93) compared with influenza but not compared with the influenza-negative group (OR, 1.03; 95% CI, .82–1.28 and OR, 1.17; 95% CI, .91–1.49, respectively). Conclusions The prevalence of RSV across 3 seasons was considerable. Our findings suggest that those with RSV have worse outcomes compared with influenza and frequently have cardiopulmonary conditions. This study informs future vaccination strategies and underscores a need for RSV surveillance among adults with severe ARI.

BackgroundThe annual reappearance of respiratory viruses has been recognized for decades. The onset of the COVID-19 pandemic altered typical respiratory virus transmission patterns. COVID-19 mitigation measures taken during the pandemic were targeted at SARS-CoV-2 respiratory transmission and thus broadly impacted the burden of acute respiratory illnesses (ARIs), in general.MethodsWe used the longitudinal Household Influenza Vaccine Evaluation (HIVE) cohort of households in southeast Michigan to characterize mitigation strategy adherence, respiratory illness burden, and the circulation of 15 respiratory viruses during the COVID-19 pandemic determined by RT-PCR of respiratory specimens collected at illness onset. Study participants were surveyed twice during the study period (March 1, 2020, to June 30, 2021), and serologic specimens were collected for antibody measurement by electrochemiluminescence immunoassay. Incidence rates of ARI reports and virus detections were calculated and compared using incidence rate ratios for the study period and a pre-pandemic period of similar length.ResultsOverall, 437 participants reported a total of 772 ARIs and 329 specimens (42.6%) had respiratory viruses detected. Rhinoviruses were the most frequently detected organism, but seasonal coronaviruses—excluding SARS-CoV-2—were also common. Illness reports and percent positivity were lowest from May to August 2020, when mitigation measures were most stringent. Study participants were more adherent to mitigation measures in the first survey compared with the second survey. Supplemental serology surveillance identified 5.3% seropositivity for SARS-CoV-2 in summer 2020; 3.0% between fall 2020 and winter 2021; and 11.3% in spring 2021. Compared to a pre-pandemic period of similar length, the incidence rate of total reported ARIs for the study period was 50% lower (95% CI: 0.5, 0.6; pConclusionsThe burden of ARI in the HIVE cohort during the COVID-19 pandemic fluctuated, with declines occurring concurrently with the widespread use of public health measures. It is notable, however, that rhinovirus and seasonal coronaviruses continued to circulate even as influenza and SARS-CoV-2 circulation was low.

BackgroundRSV is a frequent cause of respiratory illness less often diagnosed outside hospital settings; thus, overall prevalence of RSV-associated illness is under-recognized. Information about presence of RSV among those with chronic conditions is especially needed with recent advances in vaccine development.MethodsParticipants prospectively enrolled in an ambulatory surveillance study of respiratory illness (MFIVE) were tested by RT-PCR for RSV and influenza. Participant and illness characteristics were collected by in-person survey and EMR review. Chronic conditions were characterized by the Multimorbidity-weighted index (MWI). Viral factors, including subtype and viral load, were compared between RSV-A and RSV-B. Multivariate logistic regression models were used to compare participant and illness characteristics between those with RSV and those with influenza. Comparisons were also made across RSV subtypes.ResultsAmong 4,442 individuals enrolled in MFIVE from fall 2017 to spring 2020, 9.9% (n=441) had RSV detected. RSV+ participants with increased viral load had increased odds of illness lasting ≥ 7 days [ORadj=2.39 (95% CI: 1.03-5.51) p-value=0.04]. Adults with RSV had higher median MWI scores compared to influenza and RSV/influenza-negative (1.62, 0.40, 0.64, respectively).ConclusionsOur findings support the need for ongoing RSV surveillance, particularly in older adults and those with multimorbidity. Our findings support a recognition of multimorbidity as a significant contributor to RSV-associated MAARI among outpatient adults, with particularly notable impacts among adults under 65.

BackgroundRespiratory syncytial virus (RSV) is under-recognized in hospitalized adults. We evaluated severity of acute respiratory illness (ARI) including intensive care unit (ICU) admission and mechanical ventilation in a national surveillance network.MethodsHospitalized adults who met a standardized ARI case definition were prospectively enrolled across three respiratory seasons from hospitals participating across all sites of the U.S. Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN, 2016-2019). Multivariable logistic regression was used to test associations between lab-confirmed infection and characteristics and clinical outcomes.ResultsAmong 10,311 hospitalized adults, 6% tested positive for RSV (n=622), 18.8% positive for influenza (n=1,940), and 75.1% negative for RSV and influenza (n=7,749). The proportion of adults with Congestive Heart Failure (CHF) or Chronic Obstructive Pulmonary Disease (COPD) was higher among adults with RSV than influenza (CHF: 37.3% vs. 28.8%, pConclusionsOur findings suggest patients with RSV might incur worse outcomes than influenza in hospitalized adults, who are likely to have pre-existing cardiopulmonary conditions.

Three COVID-19 vaccines are authorized or approved for use among adults in the United States (1,2). Two 2-dose mRNA vaccines, mRNA-1273 from Moderna and BNT162b2 from Pfizer-BioNTech, received Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) in December 2020 for persons aged ≥18 years and aged ≥16 years, respectively. A 1-dose viral vector vaccine (Ad26.COV2 from Janssen [Johnson & Johnson]) received EUA in February 2021 for persons aged ≥18 years (3). The Pfizer-BioNTech vaccine received FDA approval for persons aged ≥16 years on August 23, 2021 (4). Current guidelines from FDA and CDC recommend vaccination of eligible persons with one of these three products, without preference for any specific vaccine (4,5). To assess vaccine effectiveness (VE) of these three products in preventing COVID-19 hospitalization, CDC and collaborators conducted a case-control analysis among 3,689 adults aged ≥18 years who were hospitalized at 21 U.S. hospitals across 18 states during March 11-August 15, 2021. An additional analysis compared serum antibody levels (anti-spike immunoglobulin G [IgG] and anti-receptor binding domain [RBD] IgG) to SARS-CoV-2, the virus that causes COVID-19, among 100 healthy volunteers enrolled at three hospitals 2-6 weeks after full vaccination with the Moderna, Pfizer-BioNTech, or Janssen COVID-19 vaccine. Patients with immunocompromising conditions were excluded. VE against COVID-19 hospitalizations was higher for the Moderna vaccine (93%; 95% confidence interval [CI] = 91%-95%) than for the Pfizer-BioNTech vaccine (88%; 95% CI = 85%-91%) (p = 0.011); VE for both mRNA vaccines was higher than that for the Janssen vaccine (71%; 95% CI = 56%-81%) (all p

Transmission bottlenecks limit the spread of novel mutations and reduce the efficiency of natural selection along a transmission chain. Many viruses exhibit tight bottlenecks, and studies of early SARS-CoV-2 lineages identified a bottleneck of 1-3 infectious virions. While increased force of infection, host receptor binding, or immune evasion may influence bottleneck size, the relationship between transmissibility and the transmission bottleneck is unclear. Here, we compare the transmission bottleneck of non-variant-of-concern (non-VOC) SARS-CoV-2 lineages to those of the Alpha, Delta, and Omicron variants. We sequenced viruses from 168 individuals in 65 multiply infected households in duplicate to high depth of coverage. In 110 specimens collected close to the time of transmission, within-host diversity was extremely low. At a 2% frequency threshold, 51% had no intrahost single nucleotide variants (iSNV), and 42% had 1-2 iSNV. In 64 possible transmission pairs with detectable iSNV, we identified a bottleneck of 1 infectious virion (95% CI 1-1) for Alpha, Delta, and Omicron lineages and 2 (95% CI 2-2) in non-VOC lineages. The latter was driven by a single iSNV shared in one non-VOC household. The tight transmission bottleneck in SARS-CoV-2 is due to low genetic diversity at the time of transmission, a relationship that may be more pronounced in rapidly transmissible variants. The tight bottlenecks identified here will limit the development of highly mutated VOC in typical transmission chains, adding to the evidence that selection over prolonged infections in immunocompromised patients may drive their evolution.

Background In the United States, influenza activity during the 2021–2022 season was modest and sufficient enough to estimate influenza vaccine effectiveness (VE) for the first time since the beginning of the coronavirus disease 2019 pandemic. We estimated influenza VE against laboratory-confirmed outpatient acute illness caused by predominant A(H3N2) viruses. Methods Between October 2021 and April 2022, research staff across 7 sites enrolled patients aged ≥6 months seeking outpatient care for acute respiratory illness with cough. Using a test-negative design, we assessed VE against influenza A(H3N2). Due to strong correlation between influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, participants who tested positive for SARS-CoV-2 were excluded from VE estimations. Estimates were adjusted for site, age, month of illness, race/ethnicity, and general health status. Results Among 6260 participants, 468 (7%) tested positive for influenza only, including 440 (94%) for A(H3N2). All 206 sequenced A(H3N2) viruses were characterized as belonging to genetic group 3C.2a1b subclade 2a.2, which has antigenic differences from the 2021–2022 season A(H3N2) vaccine component that belongs to clade 3C.2a1b subclade 2a.1. After excluding 1948 SARS-CoV-2–positive patients, 4312 patients were included in analyses of influenza VE; 2463 (57%) were vaccinated against influenza. Effectiveness against A(H3N2) for all ages was 36% (95% confidence interval, 20%–49%) overall. Conclusions Influenza vaccination in 2021–2022 provided protection against influenza A(H3N2)-related outpatient visits among young persons.

Epidemics of seasonal influenza vary in intensity annually, and influenza vaccine effectiveness (VE) fluctuates based in part on antigenic match to circulating viruses. We estimated the incidence of influenza and influenza cases averted by vaccination in four ambulatory care sites in the United States, during seasons when overall influenza VE ranged from 29% to 40%.We conducted active surveillance for influenza at ambulatory care settings at four sites within the United States Influenza Vaccine Effectiveness Network. We extrapolated the total number of influenza cases in the source populations served by these organizations based on incidence of medically attended acute respiratory illness in the source population and influenza test results in those actively tested for influenza. We estimated the number of medically attended influenza cases averted based on incidence, vaccine coverage, and VE.From 2016/17 through 2018/19, incidence of ambulatory visits for laboratory-confirmed influenza ranged from 31 to 51 per 1,000 population. Incidence was highest in children aged 9-17 years (range, 56 to 81 per 1,000) and lowest in adults aged 18-49 years (range, 23-32 per 1,000). Medically attended cases averted by vaccination ranged from a high of 46.6 (95 % CI, 12.1- 91.9) per 1,000 vaccinees in children aged 6 months to 8 years, to a low of 6.9 (95 % CI, -5.1- 27.3) per 1,000 vaccinees in adults aged ≥ 65 years.Even in seasons with low vaccine effectiveness for a particular virus subtype, influenza vaccines can still lead to clinically meaningful reductions in ambulatory care visits for influenza.

BackgroundEvidence for vaccine effectiveness (VE) against influenza-associated pneumonia has varied by season, location, and strain. We estimate VE against hospitalization for radiographically identified influenza-associated pneumonia during 2015–2016 to 2017–2018 seasons in the US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN).MethodsAmong adults aged ≥18 years admitted to 10 US hospitals for acute respiratory illness (ARI), clinician-investigators used keywords from reports of chest imaging performed during 3 days around hospital admission to assign a diagnosis of “definite/probable pneumonia.” We used a test-negative design to estimate VE against hospitalization for radiographically identified laboratory-confirmed influenza-associated pneumonia, comparing reverse transcriptase–polymerase chain reaction–confirmed influenza cases with test-negative subjects. Influenza vaccination status was documented in immunization records or self-reported, including date and location. Multivariable logistic regression models were used to adjust for age, site, season, calendar-time, and other factors.ResultsOf 4843 adults hospitalized with ARI included in the primary analysis, 266 (5.5%) had “definite/probable pneumonia” and confirmed influenza. Adjusted VE against hospitalization for any radiographically confirmed influenza-associated pneumonia was 38% (95% confidence interval [CI], 17–53%); by type/subtype, it was 74% (95% CI, 52–87%) influenza A (H1N1)pdm09, 25% (95% CI, −15% to 50%) A (H3N2), and 23% (95% CI, −32% to 54%) influenza B. Adjusted VE against intensive care for any influenza was 57% (95% CI, 19–77%).ConclusionsInfluenza vaccination was modestly effective among adults in preventing hospitalizations and the need for intensive care associated with influenza pneumonia. VE was significantly higher against A (H1N1)pdm09 and was low against A (H3N2) and B.

Intraseason timing of influenza infection among persons of different ages could reflect relative contributions to propagation of seasonal epidemics and has not been examined among ambulatory patients. Using data from the US Influenza Vaccine Effectiveness Network, we calculated risk ratios derived from comparing weekly numbers of influenza cases prepeak with those postpeak during the 2010–2011 through 2018–2019 influenza seasons. We sought to determine age-specific differences during the ascent versus descent of an influenza season by influenza virus type and subtype. We estimated 95% credible intervals around the risk ratios using Bayesian joint posterior sampling of weekly cases. Our population consisted of ambulatory patients with laboratory-confirmed influenza who enrolled in an influenza vaccine effectiveness study at 5 US sites during 9 influenza seasons after the 2009 influenza A virus subtype H1N1 (H1N1) pandemic. We observed that young children aged

IntroductionMore than 65% of children aged ≤5 years in the United States require out-of-home child care. Child care attendance has been associated with an elevated risk of respiratory illness and acute gastroenteritis (AGE). While child care–associated respiratory disease cases are more numerous, AGE is associated with more severe symptoms and more than double the number of absences from child care. In addition, viral pathogens such as norovirus, rotavirus, and adenovirus are highly infectious and may be spread to parents and other household members. As a result, child care–associated viral AGE may incur substantial economic costs due to healthcare service usage and lost productivity.MethodsWe used surveillance data from a network of child care centers in Washtenaw County, Michigan, as well as a household transmission model to estimate the annual cost of child care–associated viral AGE in the state of Michigan.ResultsWe estimated that child care–associated viral AGE in Michigan costs between $15 million and $31 million annually, primarily due to lost productivity.ConclusionsThe economic burden of child care–associated infections is considerable. Effective targeted interventions are needed to mitigate this impact.

Introduction Mid-season influenza vaccine effectiveness (VE) estimates are a useful tool to help guide annual influenza vaccine strain selection, vaccine policy, and public health messaging. We propose using a sample size-driven approach with data-driven inputs for publication of mid-season influenza VE. Methods We used pooled inputs for VE by (sub)type and average vaccine coverage by age groups using data from eight seasons of the US Influenza VE Network to calculate sample sizes needed to estimate mid-season VE. Results We estimate that 135 influenza-positive cases would be needed to detect an overall VE of 40% with 55% vaccine coverage among test-negative controls. Larger sample sizes would be required to produce reliable estimates specifically against influenza A/H3N2 and for older age groups. Conclusion Using an existing network, most of the recent influenza seasons in the US would facilitate valid mid-season VE estimates using the proposed sample sizes for broad age groupings.

Background Novel coronavirus disease 2019 (COVID-19) is frequently compared with influenza. The Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) conducts studies on the etiology and characteristics of U.S. hospitalized adults with influenza. It began enrolling patients with COVID-19 hospitalizations in March 2020. Patients with influenza were compared with those with COVID-19 in the first months of the U.S. epidemic. Methods Adults aged ≥ 18 years admitted to hospitals in 4 sites with acute respiratory illness were tested by real-time reverse transcription polymerase chain reaction for influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing COVID-19. Demographic and illness characteristics were collected for influenza illnesses during 3 seasons 2016–2019. Similar data were collected on COVID-19 cases admitted before June 19, 2020. Results Age groups hospitalized with COVID-19 (n = 914) were similar to those admitted with influenza (n = 1937); 80% of patients with influenza and 75% of patients with COVID-19 were aged ≥50 years. Deaths from COVID-19 that occurred in younger patients were less often related to underlying conditions. White non-Hispanic persons were overrepresented in influenza (64%) compared with COVID-19 hospitalizations (37%). Greater severity and complications occurred with COVID-19 including more ICU admissions (AOR = 15.3 [95% CI: 11.6, 20.3]), ventilator use (AOR = 15.6 [95% CI: 10.7, 22.8]), 7 additional days of hospital stay in those discharged alive, and death during hospitalization (AOR = 19.8 [95% CI: 12.0, 32.7]). Conclusions While COVID-19 can cause a respiratory illness like influenza, it is associated with significantly greater severity of illness, longer hospital stays, and higher in-hospital deaths., COVID-19 is commonly compared with a “flu-like” illness; however, even during a high-burden influenza season, COVID-19 causes greater severity and complications in hospitalizations with increased ICU admissions, need for mechanical ventilation, and death.

Background The evidence that influenza vaccination programs regularly provide protection to unvaccinated individuals (ie, indirect effects) of a community is lacking. We sought to determine the direct, indirect, and total effects of influenza vaccine in the Household Influenza Vaccine Evaluation (HIVE) cohort. Methods Using longitudinal data from the HIVE cohort from 2010–11 through 2017–18, we estimated direct, indirect, and total influenza vaccine effectiveness (VE) and the incidence rate ratio of influenza virus infection using adjusted mixed-effect Poisson regression models. Total effectiveness was determined through comparison of vaccinated members of full or partially vaccinated households to unvaccinated individuals in completely unvaccinated households. Results The pooled, direct VE against any influenza was 30.2% (14.0–43.4). Direct VE was higher for influenza A/H1N1 43.9% (3.9 to 63.5) and B 46.7% (17.2 to 57.5) than A/H3N2 31.7% (10.5 to 47.8) and was higher for young children 42.4% (10.1 to 63.0) than adults 18.6% (−6.3 to 37.7). Influenza incidence was highest in completely unvaccinated households (10.6 per 100 person-seasons) and lower at all other levels of household vaccination coverage. We found little evidence of indirect VE after adjusting for potential confounders. Total VE was 56.4% (30.1–72.9) in low coverage, 43.2% (19.5–59.9) in moderate coverage, and 33.0% (12.1 to 49.0) in fully vaccinated households. Conclusions Influenza vaccines may have a benefit above and beyond the direct effect but that effect in this study was small. Although there may be exceptions, the goal of global vaccine recommendations should remain focused on provision of documented, direct protection to those vaccinated., We estimate direct, indirect, and total influenza vaccine effectiveness in a household cohort study over 8 seasons. In this population we found consistent, moderate direct protection of mild influenza illness by vaccination but we found little evidence of indirect protection.

To compare the effectiveness of a primary covid-19 vaccine series plus booster doses with a primary series alone for the prevention of hospital admission with omicron related covid-19 in the United States.Multicenter observational case-control study with a test negative design.Hospitals in 18 US states.4760 adults admitted to one of 21 hospitals with acute respiratory symptoms between 26 December 2021 and 30 June 2022, a period when the omicron variant was dominant. Participants included 2385 (50.1%) patients with laboratory confirmed covid-19 (cases) and 2375 (49.9%) patients who tested negative for SARS-CoV-2 (controls).The main outcome was vaccine effectiveness against hospital admission with covid-19 for a primary series plus booster doses and a primary series alone by comparing the odds of being vaccinated with each of these regimens versus being unvaccinated among cases versus controls. Vaccine effectiveness analyses were stratified by immunosuppression status (immunocompetent, immunocompromised). The primary analysis evaluated all covid-19 vaccine types combined, and secondary analyses evaluated specific vaccine products.Overall, median age of participants was 64 years (interquartile range 52-75 years), 994 (20.8%) were immunocompromised, 85 (1.8%) were vaccinated with a primary series plus two boosters, 1367 (28.7%) with a primary series plus one booster, and 1875 (39.3%) with a primary series alone, and 1433 (30.1%) were unvaccinated. Among immunocompetent participants, vaccine effectiveness for prevention of hospital admission with omicron related covid-19 for a primary series plus two boosters was 63% (95% confidence interval 37% to 78%), a primary series plus one booster was 65% (58% to 71%), and for a primary series alone was 37% (25% to 47%) (P0.001 for the pooled boosted regimens compared with a primary series alone). Vaccine effectiveness was higher for a boosted regimen than for a primary series alone for both mRNA vaccines (BNT162b2 (Pfizer-BioNTech): 73% (44% to 87%) for primary series plus two boosters, 64% (55% to 72%) for primary series plus one booster, and 36% (21% to 48%) for primary series alone (P0.001); mRNA-1273 (Moderna): 68% (17% to 88%) for primary series plus two boosters, 65% (55% to 73%) for primary series plus one booster, and 41% (25% to 54%) for primary series alone (P=0.001)). Among immunocompromised patients, vaccine effectiveness for a primary series plus one booster was 69% (31% to 86%) and for a primary series alone was 49% (30% to 63%) (P=0.04).During the first six months of 2022 in the US, booster doses of a covid-19 vaccine provided additional benefit beyond a primary vaccine series alone for preventing hospital admissions with omicron related covid-19.This article is a living test negative design study that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

An H1N1 influenza virus caused a pandemic in 2009 and descendants of this virus continue to circulate seasonally in humans. Upon infection with the 2009 H1N1 pandemic strain (pH1N1), many humans produced antibodies against epitopes in the hemagglutinin (HA) stalk. HA stalk-focused antibody responses were common among pH1N1-infected individuals because HA stalk epitopes were conserved between the pH1N1 strain and previously circulating H1N1 strains. Here, we completed a series of experiments to determine if the pH1N1 HA stalk has acquired substitutions since 2009 that prevent the binding of human antibodies. We identified several amino acid substitutions that have accrued in the pH1N1 HA stalk from 2009-2019. We completed enzyme-linked immunosorbent assays, absorption-based binding assays, and surface plasmon resonance experiments to determine if these substitutions affect antibody binding. Using sera collected from 230 humans (aged 21-80 years), we found that pH1N1 HA stalk substitutions that have emerged since 2009 do not affect antibody binding. Our data suggest that the HA stalk domain of pH1N1 viruses remained antigenically stable after circulating in humans for a decade.ImportanceIn 2009, a new pandemic H1N1 (pH1N1) virus began circulating in humans. Many individuals mounted hemagglutinin (HA) stalk-focused antibody responses upon infection with the 2009 pH1N1, since the HA stalk of this virus was relatively conserved with other seasonal H1N1 strains. Here, we completed a series of studies to determine if the 2009 pH1N1 strain has undergone antigenic drift in the HA stalk domain over the past decade. We found that serum antibodies from 230 humans could not antigenically distinguish the 2009 and 2019 HA stalk. These data suggest that the HA stalk of pH1N1 has remained antigenically stable, despite the presence of high levels of HA stalk antibodies within the human population.

Author(s): Galindo, Demi; Martin, Emily; Franzen, Douglas | Abstract: Introduction: Although rare, iatrogenic cases of pneumopericardium have been documented following laparoscopic surgery and mechanical ventilation. Electrocardiogram (ECG) changes, including ST-segment depressions and T-wave inversions, have been documented in cases of pneumopericardium, and can mimic more concerning causes of chest pain including myocardial ischemia or pulmonary embolism.Case Report: This unique case describes a patient who presented with chest pain and ST-segment changes on ECG hours after a laparoscopic inguinal hernia repair and who was found to have pneumopericardium.Conclusion: While iatrogenic pneumopericardium is often self-limiting and rarely requires intervention, it is critical to differentiate pneumopericardium from other etiologies of chest pain, including myocardial ischemia and pulmonary embolism, to prevent unnecessary intervention.

Background We investigated frequency of reinfection with seasonal human coronaviruses (HCoVs) and serum antibody response following infection over 8 years in the Household Influenza Vaccine Evaluation (HIVE) cohort. Methods Households were followed annually for identification of acute respiratory illness with reverse-transcription polymerase chain reaction–confirmed HCoV infection. Serum collected before and at 2 time points postinfection were tested using a multiplex binding assay to quantify antibody to seasonal, severe acute respiratory syndrome coronavirus (SARS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins and SARS-CoV-2 spike subdomains and N protein. Results Of 3418 participants, 40% were followed for ≥3 years. A total of 1004 HCoV infections were documented; 303 (30%) were reinfections of any HCoV type. The number of HCoV infections ranged from 1 to 13 per individual. The mean time to reinfection with the same type was estimated at 983 days for 229E, 578 days for HKU1, 615 days for OC43, and 711 days for NL63. Binding antibody levels to seasonal HCoVs were high, with little increase postinfection, and were maintained over time. Homologous, preinfection antibody levels did not significantly correlate with odds of infection, and there was little cross-response to SARS-CoV-2 proteins. Conclusions Reinfection with seasonal HCoVs is frequent. Binding anti-spike protein antibodies do not correlate with protection from seasonal HCoV infection.

Objective:In the era of widespread resistance, there are 2 time points at which most empiric prescription errors occur among hospitalized adults: (1) upon admission (UA) when treating patients at risk of multidrug-resistant organisms (MDROs) and (2) during hospitalization, when treating patients at risk of extensively drug-resistant organisms (XDROs). These errors adversely influence patient outcomes and the hospital’s ecology.Design and setting:Retrospective cohort study, Shamir Medical Center, Israel, 2016.Patients:Adult patients (aged >18 years) hospitalized with sepsis.Methods:Logistic regressions were used to develop predictive models for (1) MDRO UA and (2) nosocomial XDRO. Their performances on the derivation data sets, and on 7 other validation data sets, were assessed using the area under the receiver operating characteristic curve (ROC AUC).Results:In total, 4,114 patients were included: 2,472 patients with sepsis UA and 1,642 with nosocomial sepsis. The MDRO UA score included 10 parameters, and with a cutoff of ≥22 points, it had an ROC AUC of 0.85. The nosocomial XDRO score included 7 parameters, and with a cutoff of ≥36 points, it had an ROC AUC of 0.87. The range of ROC AUCs for the validation data sets was 0.7–0.88 for the MDRO UA score and was 0.66–0.75 for nosocomial XDRO score. We created a free web calculator (https://assafharofe.azurewebsites.net).Conclusions:A simple electronic calculator could aid with empiric prescription during an encounter with a septic patient. Future implementation studies are needed to evaluate its utility in improving patient outcomes and in reducing overall resistances.

We observed decreased effectiveness of influenza vaccine with increasing time since vaccination for prevention of influenza A(H3N2), influenza A(H1N1)pdm09, and influenza B/Yamagata–associated hospitalizations among adults. Maximum vaccine effectiveness (VE) was observed shortly after vaccination, followed by an absolute decline in VE of about 8%–9% per month postvaccination.