Clinical Infectious Diseases

ObjectiveTo compare the frequency of replication-competent virologic rebound with and without nirmatrelvir-ritonavir treatment for acute COVID-19. Secondary aims were to estimate the validity of symptoms to detect rebound and the incidence of emergent nirmatrelvir-resistance mutations after rebound. DesignObservational cohort study. SettingMulticenter healthcare system in Boston, Massachusetts. ParticipantsWe enrolled ambulatory adults with a positive COVID-19 test and/or a prescription for nirmatrelvir-ritonavir. ExposuresReceipt of 5 days of nirmatrelvir-ritonavir treatment versus no COVID-19 therapy. Main Outcome and MeasuresThe primary outcome was COVID-19 virologic rebound, defined as either (1) a positive SARS-CoV-2 viral culture following a prior negative culture or (2) two consecutive viral loads [&ge;]4.0 log10 copies/milliliter after a prior reduction in viral load to <4.0 log10 copies/milliliter. ResultsCompared with untreated individuals (n=55), those taking nirmatrelvir-ritonavir (n=72) were older, received more COVID-19 vaccinations, and were more commonly immunosuppressed. Fifteen individuals (20.8%) taking nirmatrelvir-ritonavir experienced virologic rebound versus one (1.8%) of the untreated (absolute difference 19.0% [95%CI 9.0-29.0%], P=0.001). In multivariable models, only N-R was associated with VR (AOR 10.02, 95%CI 1.13-88.74). VR occurred more commonly among those with earlier nirmatrelvirritonavir initiation (29.0%, 16.7% and 0% when initiated days 0, 1, and [&ge;]2 after diagnosis, respectively, P=0.089). Among participants on N-R, those experiencing rebound had prolonged shedding of replication-competent virus compared to those that did not rebound (median: 14 vs 3 days). Only 8/16 with virologic rebound reported worsening symptoms (50%, 95%CI 25%-75%); 2 were completely asymptomatic. We detected no post-rebound nirmatrelvir-resistance mutations in the NSP5 protease gene. Conclusions and RelevanceVirologic rebound occurred in approximately one in five people taking nirmatrelvir-ritonavir and often occurred without worsening symptoms. Because it is associated with replication-competent viral shedding, close monitoring and potential isolation of those who rebound should be considered.

BackgroundIn the United States, oral nirmatrelvir-ritonavir (Paxlovid) is authorized for use among patients aged [&ge;]12 years with mild-to-moderate SARS-CoV-2 infection who are at risk for progression to severe COVID-19, including hospitalization. However, effectiveness under current real-world prescribing practices in outpatient settings is unclear. MethodsWe undertook a matched observational cohort study of non-hospitalized cases with SARS-CoV-2 infection to compare outcomes among those who received or did not receive nirmatrelvir-ritonavir within the Kaiser Permanente Southern California healthcare system. Cases were matched on testing date, age, sex, clinical status (including care received, presence or absence of acute COVID-19 symptoms at testing, and time from symptom onset to testing), history of vaccination, Charlson comorbidity index, prior-year healthcare utilization, and body mass index. Primary analyses evaluated effectiveness of nirmatrelvir-ritonavir in preventing hospital admission or death within 30 days after a positive test. Secondary analyses evaluated effectiveness against intensive care unit admission, mechanical ventilation, or death within 60 days after a positive test. We measured treatment effectiveness as (1-adjusted hazards ratio [aHR])x100%, estimating the aHR via Cox proportional hazards models. ResultsAnalyses included 7,274 nirmatrelvir-ritonavir recipients and 126,152 non-recipients with positive results from SARS-CoV-2 tests undertaken in outpatient settings between 8 April and 7 October, 2022. Overall, 114,208 (85.6%) and 81,739 (61.3%) of 133,426 participants had received [&ge;]2 and [&ge;]3 COVID-19 vaccine doses, respectively. A total of 111,489 (83.6% of 133,426) cases were symptomatic at the point of testing, with 5,472 (75.2% of 7,274) treatment recipients and 84,657 (67.1% of 126,152) non-recipients testing within 0-5 days after symptom onset. Effectiveness in preventing hospital admission or death within 30 days after a positive test was 79.6% (95% confidence interval: 33.9% to 93.8%) for cases dispensed nirmatrelvir-ritonavir within 0-5 days after symptom onset; within the subgroup of cases tested 0-5 days after symptom onset and dispensed treatment on the day of their test, effectiveness was 89.6% (50.2% to 97.8%). Effectiveness declined to 43.8% (-33.3% to 81.7%) for treatment course dispensed [&ge;]6 days after symptom onset or to cases who were not experiencing acute clinical symptoms. Overall, for cases dispensed treatment at any time within their clinical course, effectiveness was 53.6% (6.6% to 77.0%). Effectiveness in preventing the secondary endpoint of intensive care unit admission, mechanical ventilation, or death within 60 days after a positive test was 89.2% (-25.0% to 99.3%) for cases dispensed treatment 0-5 days after symptom onset and 84.1% (18.8% to 96.9%) for cases dispensed treatment at any time. Subgroup analyses identified similar effectiveness estimates among cases who had received [&ge;]2 or [&ge;]3 COVID-19 vaccine doses. ImplicationsIn a setting with high levels of COVID-19 vaccine and booster uptake, receipt of nirmatrelvir-ritonavir 0-5 days after symptom onset was associated with substantial reductions in risk of hospital admission or death within 30 days after a positive outpatient SARS-CoV-2 test. FundingUS Centers for Disease Control and Prevention, US National Institutes of Health

BackgroundThe Toto Bora trial tested whether a course of azithromycin reduced rates of re-hospitalization or death in the 6 months following hospitalization among Kenyan children. We hypothesized that azithromycin would reduce enteric bacteria and increase carriage of macrolide resistance in the subsequent 3 months. MethodsKenyan children (1-59 months) hospitalized and subsequently discharged for non-traumatic conditions provided fecal samples before and 3 months after randomization to a 5-day course of azithromycin or placebo. Quantitative PCR identified enteropathogens and AMR-conferring genes in fecal samples. Generalized estimating equations assessed the impact of the randomization arm on pathogen and resistance gene detection, accounting for baseline presence and site. ResultsAmong 1,393 baseline stools, 12.4% had at least one bacterial enteropathogen, 94.7% had at least one macrolide-resistance gene, and 92.6% had at least one beta-lactamase-resistance gene identified. At month 3, children randomized to azithromycin had a 6.1% higher likelihood of carrying a macrolide resistance gene compared to placebo (adjusted prevalence ratio [aPR], 1.06; 95% CI, 1.04-1.08; P<0.001). Specifically, azithromycin randomization was associated with a higher relative prevalence of erm(B) (aPR, 1.09 [95% CI, 1.04-1.15]; P=0.001), erm(C) (aPR, 1.23 [95% CI, 1.14-1.31]; P<0.001), msr(A) (aPR, 1.14 [95% CI, 1.04-1.25]; P=0.007), and msr(D) (aPR, 1.07 [95% CI, 1.03-1.11]; P=0.001). There was no difference in overall bacterial pathogen prevalence (18.9% vs 17.3%) between randomization arms, but a slightly lower proportion of children had Shigella after randomization in the azithromycin arm (3% vs. 5%, aPR, 0.79 [95% CI, 0.62, 1.01]; P=0.063). InterpretationAzithromycin at hospital discharge was associated with higher carriage of macrolide-resistance-conferring genes in the post-discharge period compared with placebo, without significant declines in enteric pathogen carriage other than modest changes to Shigella. The potential benefits and risks of empiric azithromycin need to be considered, as children are increasingly exposed to this broad-spectrum antibiotic.

BackgroundThe epidemiology of adult pneumococcal carriage remains poorly understood. We assessed risk factors for pneumococcal carriage among adults in socioeconomically-disadvantaged farmworker communities with prevalent overcrowding. MethodsFrom July-November 2020, we administered surveys and collected saliva from working-age adults within clinical and community settings throughout Monterey County, California. We detected pneumococci via qPCR assays targeting lytA and piaB genes. We evaluated predictors of pneumococcal carriage detection via conditional logistic regression. ResultsAmong 1,283 participants, 117 (9.1%) had any detectable pneumococcal carriage and 53 (4.1%) carried pneumococci at a higher density threshold (lytA and piaB cT<35). Pneumococcal carriage was more common among individuals of lower socioeconomic status, as signified by indigenous background (odds ratio [OR]=3.94 [95% confidence interval: 2.36-6.60]), engagement in fieldwork (OR=2.01 [1.12-3.63]), and lacking high school-level education (OR=0.48 [0.26-0.90]). Within the household, carriers were more likely than non-carriers to be exposed to children aged <5 years (OR=1.45 [0.95-2.20]), and to be exposed to crowding (OR=1.48 [0.96-2.30] and 2.84 [1.20-6.73], respectively, for participants living in households with >2-4 and >4 persons per bedroom vs. [&le;]2 persons per bedroom). Household crowding was independently associated with increased risk of carriage among participants not exposed to children aged <5 years (OR=2.05 [1.18-3.59] for participants living in households with >2 vs. [&le;]2 persons per bedroom). Exposure to children aged <5 years and exposure to household crowding were each associated with increased pneumococcal density among carriers (piaB cT difference of 2.04 [0.36-3.73] and 2.44 [0.80-4.11], respectively). ConclusionsWhile exposure to young children was an important risk factor for pneumococcal carriage, the association of crowding with increased risk of carriage in households without young children suggests transmission among adults may also occur in crowded congregate settings.

A previous controlled human influenza transmission trial produced minimal transmission using nasal inoculation of an egg adapted virus. Therefore, we implemented a new trial with naturally infected Donors. We recruited healthy Recipients for four, two-week hotel quarantine cohorts and naturally infected, qRT-PCR confirmed Donors for two cohorts. Five Donors (mean age: 21; 80% female; two H1N1, three H3N2, one for cohort 24b and 4 for 24c, Jan-Feb 2024) exposed Recipients (mean age: 36; 55% female, eight in cohort 24b and 3 in 24c) in a hotel room with limited ventilation but a high air recirculation rate. We collected exhaled breath, ambient and personal bioaerosols, fomite swabs, and sera, and analyzed samples using dPCR and fluorescent focus assays, hemagglutination inhibition (HAI) assay, and enzyme-linked immunosorbent assay (ELISA). Compared with previously studied community-acquired influenza cases, we detected viral RNA (44%) and culturable virus (6%) less frequently and measured fewer viral RNA copies (79 - 8.9x103 copies/30-min) in Donors exhaled fine aerosols. One of 23 surface swab samples was culture positive. At admission, 8 of 11 Recipients had HAI titers [&le;]10 but 9 of 11 had stronger binding antibody responses than Donors against vaccine strains corresponding to Donor viruses. No Recipient developed influenza-like illness, PCR-positive respiratory samples, or serological evidence of infection. Potential explanations and insights regarding lack of transmission include importance of cough and seasonal variation in viral aerosol shedding by Donors, of potential cross-reactive immunity in middle-aged Recipients with decades of exposure, and of exposure to concentrated exhaled breath plumes limited by rapid air mixing from environmental controls that distributed aerosols evenly. Future trials over multiple seasons, Donors that cough, younger recipients, and environments that preserve normal exhaled breath plumes will be required to observe transmission from naturally infected Donors under controlled conditions and generate new insights into influenza transmission dynamics. Author SummaryHuman-to-human influenza virus transmission under controlled conditions could provide insights leading to better control of epidemics and pandemics. However, a previous study using laboratory adapted viruses produced minimal transmission. Therefore, we aimed to study transmission from people naturally infected with circulating viruses. We recruited four cohorts of healthy volunteer Recipients to stay in a quarantine hotel for two weeks. We could not recruit Donors for the first two cohorts. In the last two cohorts, one Donor exposed eight Recipients in the first and four Donors exposed three Recipients in the second. The Donors coughed infrequently and shed less virus into the air than we had observed during previous influenza seasons. No Recipients became infected. Possible explanations include that people infected during mild influenza seasons or who cough very little may be minimally contagious. Our middle-aged Recipient cohorts were older than Donors and possibly less susceptible to infection because of additional years of vaccination and infection. Finally, environmental controls in the hotel distributed aerosols evenly but reduced short-range exposure to concentrated clouds of exhaled breath that may play an important role in transmission. New designs will need to address these issues.

BackgroundGeneration time, representing the interval between infection events in primary and secondary cases, is important for understanding disease transmission dynamics including predicting the effective reproduction number (Rt), which informs public health decisions. While previous estimates of SARS-CoV-2 generation times have been reported for early Omicron variants, there is a lack of data for subsequent sub-variants, such as XBB. MethodsWe estimated SARS-CoV-2 generation times using data from the Respiratory Virus Transmission Network - Sentinel (RVTN-S) household transmission study conducted across seven U.S. sites from December 2021 to May 2023. The study spanned three Omicron sub-periods dominated by the sub-variants BA.1/2, BA.4/5, and XBB. We employed a Susceptible-Exposed-Infectious-Recovered (SEIR) model with a Bayesian data augmentation method that imputes unobserved infection times of cases to estimate the generation time. FindingsThe estimated mean generation time for the overall Omicron period was 3.5 days (95% credible interval, CrI: 3.3-3.7). During the sub-periods, the estimated mean generation times were 3.8 days (95% CrI: 3.4-4.2) for BA.1/2, 3.5 days (95% CrI: 3.3-3.8) for BA.4/5, and 3.5 days (95% CrI: 3.1-3.9) for XBB. InterpretationOur study provides estimates of generation times for the Omicron variant, including the sub-variants BA.1/2, BA.4/5, and XBB. These up-to-date estimates specifically address the gap in knowledge regarding these sub-variants and are consistent with earlier studies. They enhance our understanding of SARS-CoV-2 transmission dynamics by aiding in the prediction of Rt, offering insights for improving COVID-19 modeling and public health strategies. FundingCenters for Disease Control and Prevention, and National Center for Advancing Translational Sciences.

BackgroundWe aimed to estimate the burden of antibiotic-nonsusceptible non-bacteremic pneumonia and sinusitis due to Streptococcus pneumoniae (pneumococcus) in US adults ([&ge;]18 years). MethodsWe estimated antibiotic-nonsusceptible pneumococcal sinusitis and non-bacteremic pneumonia incidence as products of non-bacteremic pneumococcal pneumonia and sinusitis incidence rates, serotype distribution, and serotype-specific antimicrobial nonsusceptibility prevalences by antibiotic class and guideline-recommended agents from 2016-2019. We derived pneumonia and sinusitis incidence rates from national healthcare utilization surveys and administrative datasets; pneumococcal-attributable attributable percents and serotype distributions from published data; and serotype-specific nonsusceptibility estimates from Active Bacterial Core surveillance data. We evaluated nonsusceptibility for all serotypes and those targeted by 15-, 20- and 21-valent pneumococcal conjugate vaccines (PCV15/20/21). ResultsAn estimated 16.4% (95% confidence interval 12.8-21.4%) of non-bacteremic pneumococcal pneumonia and 19.0% (14.8-24.9%) of sinusitis cases were nonsusceptible to [&ge;]3 antibiotic classes, translating to 243,521 (179,673-333,675) and 1,844,726 (1,070,763-2,904,089) outpatient visits for pneumonia and sinusitis, respectively, and 10,155 (7,542-13,803) pneumonia hospitalizations annually. An estimated 31.2% (26.6-36.3%) of non-bacteremic pneumococcal pneumonia and 10.5% (9.4-12.0%) of pneumococcal sinusitis cases were nonsusceptible to [&ge;]1 outpatient first-line antibiotic agent. Cases attributable to serotypes targeted by PCV15, PCV20, and PCV21 that were nonsusceptible to [&ge;]3 antibiotic classes accounted for 7.4% (4.7-11.1%), 8.5% (5.8-12.1%), and 12.6% (9.2-17.5%) of all non-bacteremic pneumococcal pneumonia cases, and 8.4% (5.3-12.5%), 9.4% (6.2-13.4), and 14.4% (10.4-20.0%) of all pneumococcal sinusitis cases. ConclusionsWe demonstrated high proportions of antibiotic nonsusceptibility in non-bacteremic pneumococcal pneumonia and sinusitis in US adults. PCVs and antibiotic stewardship may mitigate antibiotic nonsusceptibility in pneumococcal disease.

We estimated the proportion of hospitalizations that could have been averted had all eligible high-risk adults with SARS-CoV-2 infection in a clinical cohort been treated with an oral SARS-CoV-2 antiviral agent early in infection. Among 3,037 patients with risk factors for progressing to severe COVID-19, 946 (31.1%) received an oral antiviral prescription (834 nirmatrelvir and 112 molnupiravir). Only 3.0% of treated patients vs 9.1% of untreated patients were hospitalized (adjusted risk ratio [RR]=0.27; 95% confidence interval [CI]: 0.18-0.41). If all patients had been treated, an estimated 63.3% (95% CI: 50.4-75.1) of hospitalizations within 30 days could have been prevented. This finding is attributed to large gaps in treatment and a strong protective association of antiviral treatment with subsequent hospitalization.

BackgroundPre-exposure prophylaxis for COVID-19 with tixagevimab/cilgavimab (T/C) received Emergency Use Authorization (EUA) based off of results from a clinical trial conducted prior to the Omicron variant. Its clinical effectiveness has not been well described in the Omicron era. We examined the incidence of symptomatic illness and hospitalizations among T/C recipients when Omicron accounted for virtually all cases. MethodsWe used the electronic medical record to identify patients who received T/C at our institution. Among these patients, we assessed for cases of symptomatic COVID-19 and associated hospitalizations before and after receiving T/C. We used chi square tests and Fishers exact p-values to examine differences between characteristics of those who got COVID before and after T/C prophylaxis. ResultsOf 1295 T/C recipients, 121 (9.3%) developed symptomatic COVID-19 before receiving T/C, and 102 (7.9%) developed symptomatic disease after receiving it. Among those with infection prior to T/C, 36/121 (29.8%) were hospitalized, including 8 (6.6%) admitted to the ICU. Among those with COVID-19 after receiving T/C, 6/102 (5.9%) were hospitalized but none required ICU admission. No COVID-related deaths occurred in either group. The majority of COVID-19 cases among those infected prior to T/C treatment occurred during Omicron BA.1 surge, while the majority of cases among post-T/C recipients occurred when BA.5 was predominant. Patients infected with COVID-19 prior to receiving T/C had received fewer vaccine doses and were less likely to receive COVID-19 therapeutics compared to those with COVID-19 after having received T/C. ConclusionWe identified COVID-19 infections after T/C prophylaxis. Among persons eligible for T/C, COVID-19 illnesses occurring after T/C were less likely to require hospitalization compared to those with COVID-19 prior to T/C. In the presence of changing vaccine coverage, multiple therapies, and changing variants, the effectiveness of T/C in the Omicron era remains difficult to assess.

ImportanceStreptococcus pneumoniae is a known etiology of acute respiratory infections (ARIs), which account for large proportions of outpatient visits and antibiotic use in children. In 2023, 15- and 20-valent pneumococcal conjugate vaccines (PCV15, PCV20) were recommended for routine use in infants. However, the burden of outpatient healthcare utilization among U.S. children attributable to the additional, non-PCV13 serotypes in PCV15/20 is unknown. ObjectiveTo estimate the incidence of outpatient visits and antibiotic prescriptions in U.S. children for acute otitis media, pneumonia, and sinusitis associated with PCV15- and PCV20-additional serotypes (non-PCV13 serotypes) to quantify potential impacts of PCV15/20 on outpatient visits and antibiotic prescriptions for these conditions. DesignMulti-component study including descriptive analyses of cross-sectional and cohort data on outpatient visits and antibiotic prescriptions from 2016-2019 and meta-analyses of pneumococcal serotype distribution in non-invasive respiratory infections. SettingOutpatient visits and antibiotic prescriptions among U.S. children. ParticipantsPediatric visits and antibiotic prescriptions among children captured in the National Ambulatory Medical Care Survey (NAMCS), the National Hospital Ambulatory Medicare Care Survey (NHAMCS), and Merative MarketScan, collectively representing healthcare delivery across all outpatient settings. Incidence denominators estimated using census (NAMCS/NHAMCS) and enrollment (MarketScan) data. Main outcome(s) and measure(s)Pediatric outpatient visit and antibiotic prescription incidence for acute otitis media, pneumonia, and sinusitis associated with PCV15/20-additional serotypes. ResultsWe estimated that per 1000 children annually, PCV15-additional serotypes accounted for 2.7 (95% confidence interval 1.8-3.9) visits and 2.4 (1.6-3.4) antibiotic prescriptions. PCV20-additional serotypes resulted in 15.0 (11.2-20.4) visits and 13.2 (9.9-18.0) antibiotic prescriptions annually per 1,000 children. Projected to national counts, PCV15/20-additional serotypes account for 173,000 (118,000-252,000) and 968,000 (722,000-1,318,000) antibiotic prescriptions among U.S. children each year, translating to 0.4% (0.2-0.6%) and 2.1% (1.5-3.0%) of all outpatient antibiotic use among children. Conclusions and relevancePCV15/20-additional serotypes account for a large burden of pediatric outpatient healthcare utilization. Compared with PCV15-additional serotypes, PCV20-additional serotypes account for >5 times the burden of visits and antibiotic prescriptions. These higher-valency PCVs, especially PCV20, may contribute to preventing ARIs and antibiotic use in children. Key pointsQuestion: What is the incidence of pediatric outpatient visits and antibiotic prescriptions for acute respiratory tract infections associated with the additional (non-13-valent pneumococcal conjugate vaccine) serotypes in 15- and 20-valent pneumococcal conjugate vaccines (PCV15, PCV20)? Findings: PCV15- and PCV20-additional serotypes account for an estimated 197,000 and 1,098,000 visits and 173,000 and 968,000 antibiotic prescriptions, respectively, for acute respiratory infections among U.S. children annually. Visit and antibiotic prescription burdens were concentrated among children aged <5 years. Meaning: Respiratory infections caused by serotypes in PCV15/20, especially PCV20, may be important contributors to outpatient visits and antibiotic use in children.

Omicron sub-lineages such as BA2.12.1 and BA5 have breached prior infection-induced immunity and vaccine-induced immunity. This capacity of Omicron to reinfect patients calls for a characterization of vaccination, infection, and reinfection patterns. We analyzed de-identified longitudinal electronic health records for 389,746 individuals (88,679 fully-vaccinated, 184,205 boosted, 73,184 with prior infection) across multiple US states. Compared to individuals with only full vaccination, the rates of SARS-CoV-2 infections in the Omicron era were reduced for individuals with additional prior infection (1.4 to 1.8-fold reduced, depending on vaccine status) or booster vaccination (1.3 to 2.0-fold reduced). Although prior infection was associated with lower incidence of SARS-CoV-2 infection, we found that the relative risk (RR) of infections for individuals with prior infection has increased during Omicron. During October, 2021, RR was 0.11 [0.10-0.13, 95% CI] while during May, 2022, it increased to 0.57 [0.46-0.68, 95% CI], suggesting an increase in reinfections with Omicron. Furthermore, we found that time since prior infection is associated with risk of reinfection, providing evidence of waning immunity. Prior infections before June, 2021, were associated with marginal reduction in risk of infection (eg., RR = 0.80 [0.68-0.90] for prior infection during January, 2021), while recent prior infections were associated with significant reduction in risk (eg., RR = 0.24 [0.20-0.29, 95% CI] for prior infection during November, 2021). Despite an observed increase in reinfections and vaccine breakthrough infections, our findings emphasize the protective effect of natural and vaccine immunity, with prior infection providing [~]6 months of protection from reinfection.

Identification of host genetic factors that predispose individuals to severe COVID-19 is important, not only for understanding the disease and guiding the development of treatments, but also for risk prediction when combined to form a polygenic risk score (PRS). Using population controls, Pairo-Castineira et al. identified 12 SNPs (a panel of 8 SNPs and a panel of 6 SNPs, with two SNPs in both panels) associated with severe COVID-19. Using controls with asymptomatic or mild COVID-19, we were able to replicate the association with severe COVID-19 for only three of their SNPs and found marginal evidence for an association for one other. When combined as an 8-SNP PRS and a 6-SNP PRS, we found no evidence of association with severe COVID-19. The difference in our results and the results of Pairo-Castineira et al. might be the choice of controls: population controls vs controls with asymptomatic or mild COVID-19.

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

II.ImportanceThe U.S. arrival of the Omicron variant led to a rapid increase in SARS-CoV-2 infections. While numerous studies report characteristics of Omicron infections among vaccinated individuals and/or persons with a prior history of infection, comprehensive data describing infections among immunologically naive adults is lacking. ObjectiveTo examine COVID-19 acute and post-acute clinical outcomes among a well-characterized cohort of unvaccinated and previously uninfected adults who contracted SARS-CoV-2 during the Omicron (BA.1/BA.2) surge, and to compare outcomes with infections that occurred during the Delta wave. DesignA prospective cohort undergoing high-resolution symptom and virologic monitoring between June 2021 and September 2022 SettingMultisite recruitment of community-dwelling adults in 8 U.S. states ParticipantsHealthy, unvaccinated adults between 30 to 64 years of age without an immunological history of SARS-CoV-2 who were at high-risk of infection were recruited. Participants were followed for up to 48 weeks, submitting regular COVID-19 symptom surveys and nasal swabs for SARS-CoV-2 PCR testing. Exposure(s)Omicron (BA.1/BA.2 lineages) versus Delta SARS-CoV-2 infection, defined as a positive PCR that occurred during a period when the variant represented [&ge;]50% of circulating SARS-CoV-2 variants in the participants geographic region. Main Outcome(s) and Measure(s)The main outcomes examined were the prevalence and severity of acute ([&le;]28 days post-onset) and post-acute ([&ge;]5 weeks post-onset) symptoms. ResultsAmong 274 immunologically naive participants, 166 (61%) contracted SARS-CoV-2. Of these, 137 (83%) and 29 (17%) infections occurred during the Omicron- and Delta-predominant periods, respectively. Asymptomatic infections occurred among 6.7% (95% CI: 3.1%, 12.3%) of Omicron cases and 0.0% (95% CI: 0.0%, 11.9%) of Delta cases. Healthcare utilization among Omicron cases was 79% (95% CI: 43%, 92%, P =0.001) lower relative to Delta cases. Relative to Delta, Omicron infections also experienced a 56% (95% CI: 26%, 74%, P =0.004) and 79% (95% CI: 54%, 91%, P <0.001) reduction in the risk and rate of post-acute symptoms, respectively. Conclusions and RelevanceThese findings suggest that among previously immunologically naive adults, few Omicron (BA.1/BA.2) and Delta infections are asymptomatic, and relative to Delta, Omicron infections were less likely to seek healthcare and experience post-acute symptoms. KEY POINTSO_ST_ABSQuestionC_ST_ABSWhat are acute and post-acute outcomes among previously uninfected and unvaccinated adults who contracted Omicron (BA.1/BA.2), and how do these compare with Delta infections? FindingsIn this prospective cohort of 274 immunologically naive adults, 166 (61%) contracted SARS-CoV-2, with 9 (5.5%) asymptomatic infections. Compared with Delta, Omicron infections experienced a 79% relative reduction in healthcare utilization, and 56% and 79% relative reductions in the risk and rate of post-acute symptoms ([&ge;]5-weeks), respectively. MeaningThese findings suggest among immunologically naive adults, few infections are asymptomatic, and relative to Delta, Omicron infections have lower likelihoods of severe illness and post-acute symptoms.

IMPORTANCENirsevimab, a long-acting monoclonal antibody, has demonstrated efficacy against RSV-related lower respiratory tract infections (LRTIs) in clinical trials. Post-licensure monitoring is essential to confirm these benefits in real-world settings. OBJECTIVETo evaluate the real-world effectiveness of nirsevimab against medically attended RSV infections in infants and to assess how effectiveness varies by disease severity, dosage, and time since immunization. DESIGN, SETTING, AND PARTICIPANTSThis test-negative case-control study used inpatient, outpatient, and emergency room data from the Yale New Haven Health System. Nirsevimab-eligible infants who were tested for RSV using polymerase chain reaction between October 1, 2023 and May 9, 2024 were included. Cases were infants with confirmed RSV infections; controls were those who tested negative. EXPOSURENirsevimab immunization, verified through state immunization registries. MAIN OUTCOMES AND MEASURESEffectiveness was estimated using multivariable logistic regression, adjusting for age, calendar month, and individual risk factors. Separate models examined effectiveness by clinical setting, disease severity, dose, and time since immunization. Broader outcomes, including all-cause LRTI and LRTI-related hospitalization, were also analyzed, with stratification by early and late respiratory seasons. RESULTSThe analytic sample included 3,090 infants (median age 6.7 months, IQR 3.6-9.7), with 680 (22.0%) RSV-positive and 2,410 (78.0%) RSV-negative. 21 (3.1%) RSV-positive and 309 (12.8%) RSV-negative infants received nirsevimab. Effectiveness against RSV infection was 68.4% (95% CI, 50.3%-80.8%). Effectiveness was 61.6% (95% CI, 35.6%-78.6%) for outpatient visits and 80.5% (95% CI, 52.0%-93.5%) for hospitalizations. The highest effectiveness, 84.6% (95% CI, 58.7%-95.6%), was observed against severe RSV outcomes requiring ICU admission or high-flow oxygen. Although effectiveness against RSV infections declined over time, it remained significant at 55% (95% credible interval, 16%-75%) at 14 weeks post-immunization. Protective effectiveness was also observed against all-cause LRTI and LRTI-related hospitalizations during peak RSV season (49.4% [95% CI, 10.7%-72.9%] and 79.1% [95% CI, 27.6%-94.9%], respectively). However, from February to May, when RSV positivity was low, effectiveness against these broader outcomes was negligible. CONCLUSIONS AND RELEVANCENirsevimab provided substantial protection against RSV-related outcomes for at least three months. These findings support the continued use of nirsevimab and provide evidence that may help build public confidence in the immunization program. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the effectiveness of nirsevimab against medically attended respiratory syncytial virus (RSV) infections in infants? Findings680 RSV test-positive cases and 2,410 RSV test-negative controls were included in this test-negative case-control study. Nirsevimabs effectiveness was 69% against RSV infections, 81% against RSV-associated hospitalization, and 85% against severe RSV disease. Effectiveness against RSV infection declined from 79% at 2 weeks post-immunization to 55% at 14 weeks post-immunization. MeaningNirsevimab provides strong protection against a wide range of RSV outcomes, but its effectiveness diminishes over time. These data can be utilized to optimize nirsevimabs implementation and sustain its uptake.

BackgroundCurrent active case-finding (ACF) efforts for tuberculosis (TB) are limited by the costs, operational barriers, and sensitivity of available tools to confirm a TB diagnosis. However, it is not well understood which of these limitations has the greatest epidemiological relevance and might therefore warrant prioritization in test development. MethodsWe developed a state-transition model of a one-time, community-based ACF intervention, with a fixed budget of one million United States dollars for screening and confirmatory testing. Assuming an adult population with four time the national prevalence of Uganda, we compared the impact of this intervention on TB diagnoses, mortality, and transmission when using a currently available confirmatory test (mirroring sputum-based Xpert Ultra) versus an improved confirmatory test. We considered the following test improvements: (1) increased sensitivity (from 69% to 80%), (2) non-sputum specimen type (increasing specimen availability from 93% to 100%), (3) immediate turn-around of test results (increasing delivery of positive results from 91% to 100%), (4) reduced costs (from $20 to $9 per confirmatory test). For those individuals not included in ACF efforts, TB outcomes under routine care were informed by recent natural history models. ResultsIn a simulated target population of 400,000 adults, 6,421 (1.6%; 95% uncertainty range [UR] 5,316-7,531) had TB disease, and 873 (612-1,182) were projected to die of TB in the absence of ACF. Assuming current tests, ACF efforts could reach 83,808 (59,388-118,601; 21% of the target population) people under the allotted budget, connecting 651 (429-983) individuals with TB to treatment and averting 76 (39-132) deaths. Of all hypothetical confirmatory test improvements modeled, higher diagnostic sensitivity most increased the number of people with TB who received treatment as a result of ACF (by 14% [4-26%]). However, considering mortality or transmission as a metric, the largest reductions resulted from tests that provided immediate turn-around of results (by 11% [5-18%]). ConclusionMaking confirmatory tests for community-based TB screening more accessible and rapid may lead to greater population health benefits than further increasing sensitivity. Nonetheless, achieving large (>20%) increases in the health impact of ACF will require improvements to components of ACF other than the confirmatory diagnostic test.

In this South African phase 1/2b study, we demonstrated vaccine efficacy (VE) of two doses of AZD1222 for asymptomatic and symptomatic SARS-CoV-2 infection: 90.6% against wild-type and 77.1% against the Delta variant [&ge;]9 months after vaccination. VE against infection with the Beta variant, which preceded circulation of Delta, was 6.7%. Clinical trial identifierCT.gov NCT04444674

Since the emergence of SARS-CoV-2, vaccines have been heralded as the best way to curtail the pandemic. Clinical trials have shown SARS-CoV-2 vaccines to be highly efficacious against both disease and infection. However, those currently in use were primarily tested against early lineages. Data on vaccine effectiveness (VE) against variants of concern (VOC), including the Delta variant (B.1.617.2), remain limited. To examine the effectiveness of vaccination in Utah we compared the proportion of cases reporting vaccination to that expected at different VEs, then estimated the combined daily vaccine effectiveness using a field evaluation approach. Delta has rapidly outcompeted all other variants and, as of June 20th, represents 70% of all SARS-CoV-2 viruses sequenced in Utah. If we attribute the entire change in VE to the Delta variant, the estimated vaccine effectiveness against Delta would be 82% (95% CI: 78%, 85%). We show a modest reduction in vaccine effectiveness against COVID-19 in Utah corresponding to the expansion of the Delta lineage in the state. This reduction in the effectiveness of available vaccines correlated with the arrival of novel VOCs, rather than waning immunity, is highly concerning.

BackgroundMeta-analysis and single site studies have established that children are less infectious within a household when positive for ancestral SARS-CoV-2. In addition, children appear less susceptible to infection when exposed to ancestral SARS-CoV-2 within a household. The emergence of SARS-CoV-2 variants of concern (VOC) has been associated with an increased number of pediatric infections worldwide. However, the role of children in the household transmission of VOCs, relative to the ancestral virus, remains unclear. MethodsHere, we perform a meta-analysis of the role of children in the household transmission of both ancestral SARS-CoV-2 and SARS-CoV-2 VOCs. Results: Unlike the ancestral virus, children infected with VOCs spread SARS-CoV-2 to an equivalent number of household contacts as infected adults. Similarly, unlike the ancestral virus, children within a household were equally as likely as adults to acquire SARS-CoV-2 from an infected family member. Interestingly, this same observation was noted when unvaccinated children exposed to VOCs were compared to unvaccinated adults exposed to VOCs. ConclusionsTogether, these data suggest that the emergence of VOCs were associated with a fundamental shift in the epidemiology of SARS-CoV-2. This is unlikely to solely be the result of age-dependent differences in vaccination during the VOCs period and instead may reflect virus evolution over the course of the pandemic. summaryThe role of children in the household transmission of VOCs, relative to the ancestral virus, remains unclear. Using a meta-analysis we show that the emergence of VOCs were associated with a fundamental shift in the epidemiology of SARS-CoV-2

Between November 2024 and April 2025, the Canadian Sentinel Practitioner Surveillance Network assessed KP.2 vaccine effectiveness against outpatient COVID-19 by test-negative design. Vaccination protected best during the first two months, reducing risk by two-thirds among vaccinated versus unvaccinated individuals, declining by 3-4 months, and reducing the risk overall by half.