Longitudinal analyses reveal immunological misfiring in severe COVID-19.

Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19)1-4. However, the longitudinal immunological correlates of disease outcome remain unclear. Here we serially analysed immune responses in 113 patients with moderate or severe COVID-19. Immune profiling revealed an overall increase in innate cell lineages, with a concomitant reduction in T cell number. An early elevation in cytokine levels was associated with worse disease outcomes. Following an early increase in cytokines, patients with moderate COVID-19 displayed a progressive reduction in type 1 (antiviral) and type 3 (antifungal) responses. By contrast, patients with severe COVID-19 maintained these elevated responses throughout the course of the disease. Moreover, severe COVID-19 was accompanied by an increase in multiple type 2 (anti-helminths) effectors, including interleukin-5 (IL-5), IL-13, immunoglobulin E and eosinophils. Unsupervised clustering analysis identified four immune signatures, representing growth factors (A), type-2/3 cytokines (B), mixed type-1/2/3 cytokines (C), and chemokines (D) that correlated with three distinct disease trajectories. The immune profiles of patients who recovered from moderate COVID-19 were enriched in tissue reparative growth factor signature A, whereas the profiles of those with who developed severe disease had elevated levels of all four signatures. Thus, we have identified a maladapted immune response profile associated with severe COVID-19 and poor clinical outcome, as well as early immune signatures that correlate with divergent disease trajectories.

Incorporating Efficacy Data from Initial Trials Into Subsequent Evaluations: Application to Vaccines Against Respiratory Syncytial Virus.

BACKGROUND: When a randomized controlled trial fails to demonstrate statistically significant efficacy against the primary endpoint, a potentially costly new trial would need to be conducted to receive licensure. Incorporating data from previous trials might allow for more efficient follow-up trials to demonstrate efficacy, speeding the availability of effective vaccines. METHODS: Based on the outcomes from a failed trial of a maternal vaccine against respiratory syncytial virus (RSV), we simulated data for a new Bayesian group-sequential trial. We analyzed the data either ignoring data from the previous trial (i.e., weakly informative prior distributions) or using prior distributions incorporating the historical data into the analysis. We evaluated scenarios where efficacy in the new trial was the same, greater than, or less than that in the original trial. For each scenario, we evaluated the statistical power and type I error rate for estimating the vaccine effect following interim analyses. RESULTS: When we used a stringent threshold to control the type I error rate, analyses incorporating historical data had a small advantage over trials that did not. If control of type I error is less important (e.g., in a postlicensure evaluation), the incorporation of historical data can provide a substantial boost in efficiency. CONCLUSIONS: Due to the need to control the type I error rate in trials used to license a vaccine, incorporating historical data provides little additional benefit in terms of stopping the trial early. However, these statistical approaches could be promising in evaluations that use real-world evidence following licensure.

Measuring waning protection from seasonal influenza vaccination during nine influenza seasons, Ontario, Canada, 2010/11 to 2018/19.

BackgroundWaning immunity from seasonal influenza vaccination can cause suboptimal protection during peak influenza activity. However, vaccine effectiveness studies assessing waning immunity using vaccinated and unvaccinated individuals are subject to biases.AimWe examined the association between time since vaccination and laboratory-confirmed influenza to assess the change in influenza vaccine protection over time.MethodsUsing linked laboratory and health administrative databases in Ontario, Canada, we identified community-dwelling individuals aged ≥ 6 months who received an influenza vaccine before being tested for influenza by RT-PCR during the 2010/11 to 2018/19 influenza seasons. We estimated the adjusted odds ratio (aOR) for laboratory-confirmed influenza by time since vaccination (categorised into intervals) and for every 28 days.ResultsThere were 53,065 individuals who were vaccinated before testing for influenza, with 10,264 (19%) influenza-positive cases. The odds of influenza increased from 1.05 (95% CI: 0.91-1.22) at 42-69 days after vaccination and peaked at 1.27 (95% CI: 1.04-1.55) at 126-153 days when compared with the reference interval (14-41 days). This corresponded to 1.09-times increased odds of influenza every 28 days (aOR = 1.09; 95% CI: 1.04-1.15). Individuals aged 18-64 years showed the greatest decline in protection against influenza A(H1N1) (aORper 28 days = 1.26; 95% CI: 0.97-1.64), whereas for individuals aged ≥ 65 years, it was against influenza A(H3N2) (aORper 28 days = 1.20; 95% CI: 1.08-1.33). We did not observe evidence of waning vaccine protection for individuals aged < 18 years.ConclusionsInfluenza vaccine protection wanes during an influenza season. Understanding the optimal timing of vaccination could ensure robust protection during seasonal influenza activity.

Your Outpatient has Coronavirus Disease 2019: What Are the Treatment Options in the Current Severe Acute Respiratory Syndrome Coronavirus 2 Variant Climate?

Mutations accumulated by novel Severe Acute Respiratory Syndrome Coronavirus 2 Omicron sublineages contribute to evasion of previously effective monoclonal antibodies for treatment or prevention of Coronavirus Disease 2019 (COVID-19). Other authorized or approved antiviral drugs such as nirmatrelvir/ritonavir, remdesivir, and molnupiravir are, however, predicted to maintain activity against these sublineages and are key tools to reduce severe COVID-19 outcomes in vulnerable populations. A stepwise approach may be taken to target the appropriate antiviral drug to the appropriate patient, beginning with identifying whether a patient is at high risk for hospitalization or other complications of COVID-19. Among higher risk individuals, patient profile (including factors such as age, organ function, and comedications) and antiviral drug access inform suitable antiviral drug selection. When applied in targeted fashion, these therapies serve as a complement to vital ongoing nonpharmaceutical interventions and vaccination strategies that reduce morbidity and maximize protection against COVID-19.

Individual and social determinants of SARS-CoV-2 testing and positivity in Ontario, Canada: a population-wide study.

BACKGROUND: Optimizing the public health response to reduce the burden of COVID-19 necessitates characterizing population-level heterogeneity of risks for the disease. However, heterogeneity in SARS-CoV-2 testing may introduce biased estimates depending on analytic design. We aimed to explore the potential for collider bias in a large study of disease determinants, and evaluate individual, environmental and social determinants associated with SARS-CoV-2 testing and diagnosis among residents of Ontario, Canada. METHODS: We explored the potential for collider bias and characterized individual, environmental and social determinants of being tested and testing positive for SARS-CoV-2 infection using cross-sectional analyses among 14.7 million community-dwelling people in Ontario, Canada. Among those with a diagnosis, we used separate analytic designs to compare predictors of people testing positive versus negative; symptomatic people testing positive versus testing negative; and people testing positive versus people not testing positive (i.e., testing negative or not being tested). Our analyses included tests conducted between Mar. 1 and June 20, 2020. RESULTS: Of 14 695 579 people, we found that 758 691 were tested for SARS-CoV-2, of whom 25 030 (3.3%) had a positive test result. The further the odds of testing from the null, the more variability we generally observed in the odds of diagnosis across analytic design, particularly among individual factors. We found that there was less variability in testing by social determinants across analytic designs. Residing in areas with the highest household density (adjusted odds ratio [OR] 1.86, 95% confidence interval [CI] 1.75-1.98), highest proportion of essential workers (adjusted OR 1.58, 95% CI 1.48-1.69), lowest educational attainment (adjusted OR 1.33, 95% CI 1.26-1.41) and highest proportion of recent immigrants (adjusted OR 1.10, 95% CI 1.05-1.15) were consistently related to increased odds of SARS-CoV-2 diagnosis regardless of analytic design. INTERPRETATION: Where testing is limited, our results suggest that risk factors may be better estimated using population comparators rather than test-negative comparators. Optimizing COVID-19 responses necessitates investment in and sufficient coverage of structural interventions tailored to heterogeneity in social determinants of risk, including household crowding, occupation and structural racism.

Young Adult Human Papillomavirus and Influenza Vaccine Coverage: A Comparison Across College Enrollment Status.

To determine human papillomavirus and influenza vaccine coverage among young adults in the US and assess differences in vaccine uptake by college enrollment status, we conducted an online survey of young adults aged 18-26 (n = 417) using Survey Monkey, with recruitment occurring through Amazon's Mechanical Turk (MTurk) platform. We collected data on self-reported preventive health behaviors, including vaccine receipt, current college enrollment status, and other demographics. Overall, 49% of participants reported receiving at least one dose of human papillomavirus vaccine and 57% reported receiving at least one influenza vaccine over the past three years. Vaccine coverage estimates did not differ between college-enrolled and non-enrolled respondents. Low vaccine coverage rates demonstrate the need to improve vaccine strategies for young adults. The strongest predictor of vaccine receipt was having received a provider recommendation. There does not appear to be healthcare utilization differences related to ability to access care through student health or community-based settings. Additional research is needed to develop interventions to improve vaccination coverage among young adults, both currently enrolled and not enrolled in college.

Pilot screening study of targeted genetic polymorphisms for association with seasonal influenza hospital admission.

Host response to influenza is highly variable, suggesting a potential role of host genetic variation. To investigate the host genetics of severe influenza in a targeted fashion, 32 single nucleotide polymorphisms (SNPs) within viral immune response genes were evaluated for association with seasonal influenza hospitalization in an adult study population with European ancestry. SNP allele and genotype frequencies were compared between hospitalized influenza patients (cases) and population controls in a case-control study that included a discovery group (26 cases and 993 controls) and two independent, validation groups (1 with 84 cases and 4076 controls; the other with 128 cases and 9187 controls). Cases and controls had similar allele frequencies for variant rs12252 in interferon-inducible transmembrane protein 3 (IFITM3) (P > 0.05), and the study did not replicate the previously reported association of rs12252 with hospitalized influenza. In the discovery group, the preliminary finding of an association with a nonsense polymorphism (rs8072510) within the schlafen family member 13 (SFLN13) gene (P = 0.0099) was not confirmed in either validation group. Neither rs12252 nor rs8072510 showed an association according to the presence of clinical risk factors for influenza complications (P > 0.05), suggesting that these factors did not modify associations between the SNPs and hospitalized influenza. No other SNPs showed a statistically significant association with hospitalized influenza. Further research is needed to identify genetic factors involved in host response to seasonal influenza infection and to assess whether rs12252, a low-frequency variant in Europeans, contributes to influenza severity in populations with European ancestry.

Seasonal Influenza Vaccination of Children Induces Humoral and Cell-Mediated Immunity Beyond the Current Season: Cross-reactivity With Past and Future Strains.

BACKGROUND: Influenza viruses gradually accumulate point mutations, reducing the effectiveness of prior immune protection. METHODS: Children aged 9-14 years received 2010-2011 trivalent inactivated influenza vaccine (TIV). Vaccination history, hemagglutination-inhibition (HI) titers, and cell-mediated immune responses were assessed to investigate the cross-reactivity with past and future influenza virus strains. RESULTS: 2010-2011 TIV induced significant T-cell responses and HI titers of ≥160, with a fold-rise of ≥4 and titers of ≥100 maintained for >7 months in the majority of children. Pre-existing memory B cells in these children differentiated quickly to antibody-secreting cells to the new vaccine antigens. Children vaccinated in the previous year maintained high HI titers well into 2010, demonstrating elevated HI titers against A/Perth/16/2009, the future (in 2010-2011) H3N2 component. Prior vaccination enhanced CD8+ T-cell responses to A/Perth/16/2009. Children vaccinated with the prior 2009-2010 seasonal vaccine also demonstrated higher preexisting levels of interferon γ-secreting CD4+CD69+ T cells to 2009 pandemic influenza A(H1N1). Children previously vaccinated with 2009-2010 seasonal influenza vaccine also showed greater expansion of tumor necrosis factor α-secreting CD8+CD69+ T cells to 2009 pandemic influenza A(H1N1) upon vaccination in the 2010-2011 season than those who were not previously vaccinated. CONCLUSIONS: Seasonal influenza viruses continuously drift, which allows them to circumvent protective immunity, but conserved epitopes provide immunological cross-reactivity in children through either vaccination directly or through prime/boost in the prior influenza season.

Factors associated with real-time RT-PCR cycle threshold values among medically attended influenza episodes.

We evaluated the cycle threshold (CT) values of 1,160 influenza A positive and 806 influenza B positive specimens from two seasons of the US Flu VE Network to identify factors associated with CT values. Low CT values (high genomic load) were associated with shorter intervals between illness onset and specimen collection, young age (ages 3-8 years old), and self-rated illness severity for both influenza A and B. Low CT values were also associated with reported fever/feverishness and age ≥65 years for influenza A.

Déterminants individuels et sociaux du test de dépistage du SRAS-CoV-2 et de l'obtention d'un résultat positif en Ontario, au Canada: une étude populationnelle.

CONTEXTE: Optimiser la réponse de la santé publique pour diminuer le fardeau de la COVID-19 nécessite la caractérisation de l'hétérogénéité du risque posé par la maladie à l'échelle de la population. Cependant, l'hétérogénéité du dépistage du SRAS-CoV-2 peut fausser les estimations selon le modèle d'étude analytique utilisé. Notre objectif était d'explorer les biais collisionneurs dans le cadre d'une vaste étude portant sur les déterminants de la maladie et d'évaluer les déterminants individuels, environnementaux et sociaux du dépistage et du diagnostic du SRAS-CoV-2 parmi les résidents de l'Ontario, au Canada. MÉTHODES: Nous avons exploré la présence potentielle de biais collisionneurs et caractérisé les déterminants individuels, environnementaux et sociaux de l'obtention d'un test de dépistage et d'un résultat positif à la présence de l'infection au SRAS-CoV-2 à l'aide d'analyses transversales parmi les 14,7 millions de personnes vivant dans la collectivité en Ontario, au Canada. Parmi les personnes ayant obtenu un diagnostic, nous avons utilisé des études analytiques distinctes afin de comparer les prédicteurs pour les personnes d'obtenir un résultat de test de dépistage positif plutôt que négatif, pour les personnes symptomatiques d'obtenir un résultat de test de dépistage positif plutôt que négatif et pour les personnes d'obtenir un résultat de test de dépistage positif plutôt que de ne pas obtenir un résultat positif (c.-à-d., obtenir un résultat de test de dépistage négatif ou ne pas obtenir de test de dépistage). Nos analyses comprennent des tests de dépistage réalisés entre le 1er mars et le 20 juin 2020. RÉSULTATS: Sur 14 695 579 personnes, nous avons constaté que 758 691 d'entre elles ont passé un test de dépistage du SRAS-CoV-2, parmi lesquelles 25 030 (3,3 %) ont obtenu un résultat positif. Plus la probabilité d'obtenir un test de dépistage s'éloignait de zéro, plus la variabilité généralement observée dans la probabilité d'un diagnostic était grande parmi les modèles d'études analytiques, particulièrement en ce qui a trait aux facteurs individuels. Nous avons constaté que la variabilité dans l'obtention d'un test de dépistage était moins importante en fonction des déterminants sociaux dans l'ensemble des études analytiques. Les facteurs tels que le fait d'habiter dans une région ayant une plus haute densité des ménages (rapport de cotes corrigé 1,86; intervalle de confiance [IC] à 95 % 1,75­1,98), une plus grande proportion de travailleurs essentiels (rapport de cotes corrigé 1,58; IC à 95 % 1,48­1,69), une population atteignant un plus faible niveau de scolarité (rapport de cotes corrigé 1,33; IC à 95 % 1,26­1,41) et une plus grande proportion d'immigrants récents (rapport de cotes corrigé 1,10; IC à 95 % 1,05­1,15), étaient systématiquement corrélés à une probabilité plus importante d'obtenir un diagnostic de SRAS-CoV-2, peu importe le modèle d'étude analytique employé. INTERPRÉTATION: Lorsque la capacité de dépister est limitée, nos résultats suggèrent que les facteurs de risque peuvent être estimés plus adéquatement en utilisant des comparateurs populationnels plutôt que des comparateurs de résultat négatif au test de dépistage. Optimiser la lutte contre la COVID-19 nécessite des investissements dans des interventions structurelles déployées de façon suffisante et adaptées à l'hétérogénéité des déterminants sociaux du risque, dont le surpeuplement des ménages, l'occupation professionnelle et le racisme structurel.

Influenza vaccine effectiveness in the United States during 2012-2013: variable protection by age and virus type.

BACKGROUND: During the 2012-2013 influenza season, there was cocirculation of influenza A(H3N2) and 2 influenza B lineage viruses in the United States. METHODS: Patients with acute cough illness for ≤7 days were prospectively enrolled and had swab samples obtained at outpatient clinics in 5 states. Influenza vaccination dates were confirmed by medical records. The vaccine effectiveness (VE) was estimated as [100% × (1 - adjusted odds ratio)] for vaccination in cases versus test-negative controls. RESULTS: Influenza was detected in 2307 of 6452 patients (36%); 1292 (56%) had influenza A(H3N2), 582 (25%) had influenza B/Yamagata, and 303 (13%) had influenza B/Victoria. VE was 49% (95% confidence interval [CI], 43%-55%) overall, 39% (95% CI, 29%-47%) against influenza A(H3N2), 66% (95% CI, 58%-73%) against influenza B/Yamagata (vaccine lineage), and 51% (95% CI, 36%-63%) against influenza B/Victoria. VE against influenza A(H3N2) was highest among persons aged 50-64 years (52%; 95% CI, 33%-65%) and persons aged 6 months-8 years (51%; 95% CI, 32%-64%) and lowest among persons aged ≥65 years (11%; 95% CI, -41% to 43%). In younger age groups, there was evidence of residual protection from receipt of the 2011-2012 vaccine 1 year earlier. CONCLUSIONS: The 2012-2013 vaccines were moderately effective in most age groups. Cross-lineage protection and residual effects from prior vaccination were observed and warrant further investigation.

Comparison of Interviewer-Administered and Automated Self-Administered 24-Hour Dietary Recalls in 3 Diverse Integrated Health Systems.

Twenty-four-hour dietary recalls provide high-quality intake data but have been prohibitively expensive for large epidemiologic studies. This study's goal was to assess whether the web-based Automated Self-Administered 24-Hour Recall (ASA24) performs similarly enough to the standard interviewer-administered, Automated Multiple-Pass Method (AMPM) 24-hour dietary recall to be considered a viable alternative. In 2010-2011, 1,081 adults from 3 integrated health systems in Detroit, Michigan; Marshfield, Wisconsin; and Kaiser-Permanente Northern California participated in a field trial. A quota design ensured a diverse sample by sex, age, and race/ethnicity. Each participant was asked to complete 2 recalls and was randomly assigned to 1 of 4 protocols differing by type of recall and administration order. For energy, the mean intakes were 2,425 versus 2,374 kcal for men and 1,876 versus 1,906 kcal for women by AMPM and ASA24, respectively. Of 20 nutrients/food groups analyzed and controlling for false discovery rate, 87% were judged equivalent at the 20% bound. ASA24 was preferred over AMPM by 70% of the respondents. Attrition was lower in the ASA24/AMPM study group than in the AMPM/ASA24 group, and it was lower in the ASA24/ASA24 group than in the AMPM/AMPM group. ASA24 offers the potential to collect high-quality dietary intake information at low cost with less attrition.

Factors associated with maintenance of antibody responses to influenza vaccine in older, community-dwelling adults.

BACKGROUND: Little is known about factors associated with maintenance of hemagglutinin inhibition (HAI) antibodies after influenza vaccination in older adults. METHODS: Adults ≥50 years of age were vaccinated prior to the 2009-10 influenza season. Serum was drawn pre-vaccination (S1), 21-28 days post-vaccination (S2), and after the influenza season (S3) for HAI assays. Seroconversion was defined as ≥ 4-fold increase S1 to S2 (or if S1 < 10, by an S2 ≥ 40) and seroprotection was defined as S2 ≥ 40. Maintenance of antibody response was measured in participants with an S2 ≥ 40, and defined as an S3 ≥ 40. RESULTS: We enrolled 510 participants during Fall 2009 at Vanderbilt University Medical Center and Marshfield Clinic Research Foundation. Participants' mean age was 64 years with 62% female and 96% white. Seroconversion and seroprotection rates were lowest for influenza A H1N1 (12% and 26%, respectively), highest for influenza A H3N2 (45% and 82%), and intermediate for influenza B (28% and 72%). Of the participants with an S2 ≥ 40, 36% (46/126), 71% (289/407), and 74% (263/354) maintained an S3 ≥ 40 for H1N1, H3N2, and B influenza vaccine strains, respectively. S1 HAI titer was strongly associated with both post-vaccination seroprotection and maintaining seroprotection at S3 for all three influenza antigens. Age, sex, body mass index, self-reported stress, and vaccination site were not consistently associated with vaccine response or maintenance of response. CONCLUSIONS: Pre-vaccination antibody titer was the only study variable consistently and positively associated with both serologic response to vaccination and maintenance of response. Antibody responses were lowest for the H1N1 vaccine strain. CLINICALTRIALS: gov Identifier: NCT02401893.

Medically attended respiratory syncytial virus infections in adults aged ≥ 50 years: clinical characteristics and outcomes.

BACKGROUND: Few studies have examined respiratory syncytial virus (RSV) infections in adults. We assessed the characteristics and outcomes of RSV relative to other viral infections. METHODS: Patients ≥ 50 years old with acute respiratory illness were recruited for studies of influenza vaccine effectiveness from 2004 through 2010. Nasopharyngeal swabs from enrollees were analyzed for the presence of RSV and other respiratory viruses by multiplex reverse transcription polymerase chain reaction. Clinical data were obtained from interview and medical records. RESULTS: A total of 2225 samples were tested across all seasons. The mean age was 64.2 (SD, 10.7) years; the mean interval from illness onset to sample collection was 4 (SD, 2.2) days. One or more viruses were detected in 1202 (54%) participants. In a multivariable logistic regression model, RSV was associated with ages 65-79 years (vs 50-64 years), symptoms of cough, nasal congestion and wheezing, and longer interval from illness onset to clinical encounter. RSV was not associated with the presence of chronic obstructive pulmonary disease or congestive heart failure in univariate analyses. Hospital admission within 30 days after illness onset was less common among patients with RSV compared to those with influenza (unadjusted odds ratio = 0.54 [95% confidence interval, .29-1.01], P = .06). CONCLUSIONS: RSV is a common cause of acute respiratory illness in adults aged ≥ 50 years; the risk of infection increases with age. Delays in healthcare seeking and reduced risk of hospital admission in patients with RSV suggest a milder course of illness relative to influenza.

Impact of repeated vaccination on vaccine effectiveness against influenza A(H3N2) and B during 8 seasons.

BACKGROUND: Recent studies suggest that influenza vaccination in the previous season may influence the effectiveness of current-season vaccination, but this has not been assessed in a single population over multiple years. METHODS: Patients presenting with acute respiratory illness were prospectively enrolled during the 2004-2005 through 2012-2013 influenza seasons. Respiratory swabs were tested for influenza and vaccination dates obtained from a validated registry. Vaccination status was determined for the current, previous, and prior 5 seasons. Vaccine effectiveness (VE) was calculated for participants aged ≥9 years using logistic regression models with an interaction term for vaccination history. RESULTS: There were 7315 enrollments during 8 seasons; 1056 (14%) and 650 (9%) were positive for influenza A(H3N2) and B, respectively. Vaccination during current only, previous only, or both seasons yielded similar protection against H3N2 (adjusted VE range, 31%-36%) and B (52%-66%). In the analysis using 5 years of historical vaccination data, current season VE against H3N2 was significantly higher among vaccinated individuals with no prior vaccination history (65%; 95% confidence interval [CI], 36%-80%) compared with vaccinated individuals with a frequent vaccination history (24%; 95% CI, 3%-41%; P = .01). VE against B was 75% (95% CI, 50%-87%) and 48% (95% CI, 29%-62%), respectively (P = .05). Similar findings were observed when analysis was restricted to adults 18-49 years. CONCLUSIONS: Current- and previous-season vaccination generated similar levels of protection, and vaccine-induced protection was greatest for individuals not vaccinated during the prior 5 years. Additional studies are needed to understand the long-term effects of annual vaccination.

A cross-sectional analysis of symptom severity in adults with influenza and other acute respiratory illness in the outpatient setting.

BACKGROUND: Acute respiratory infections (ARIs) are common in outpatient practice, and the severity of symptoms contributes to the overall burden of illness. We examined the association between a subjective symptom severity score, demographic and clinical characteristics, and presence of laboratory-confirmed influenza among central Wisconsin adults who sought care for ARI during four influenza seasons. We hypothesized that adults with laboratory-confirmed influenza would rate their symptoms as more severe relative to adults without influenza, and vaccinated adults with influenza would rate symptoms as less severe than those who were not vaccinated. METHODS: Patients with acute respiratory illness, including feverishness or cough symptoms ≤ 7 days duration, were prospectively enrolled and tested for influenza by reverse transcription polymerase chain reaction (RT-PCR) during influenza seasons 2007-08 through 2010-11. Perceived severity was self-rated during the enrollment interview for eight symptoms, on a scale of 0 (absent) to 3 (severe). Scores for each symptom were summed to generate a combined severity score ranging from 1 to 24 for each individual. The association between influenza test result and severity score was examined using linear regression. RESULTS: There were 2,374 individuals included in the analysis, including 324 with RT-PCR confirmed influenza. The mean symptom severity score was 12.3 (±4.1) points, and the most common symptoms were cough (92%), fatigue (91%), and nasal congestion (84%). In the final adjusted model, influenza infection was the strongest independent predictor of higher severity score, with a mean increase of 1.7 points compared to those who were influenza negative (p < 0.001). Among adults with influenza, the association between influenza vaccination and symptom severity was modified by age (p < 0.001). In adults ≥ 65 years old with RT-PCR confirmed influenza, symptom severity was 31% lower in those who were vaccinated as compared to those who were not vaccinated. CONCLUSIONS: Influenza is associated with more severe symptoms of acute respiratory illness. The association between influenza vaccination and reduced symptom severity in older adults should be confirmed and explored further in other populations and seasons.

The safety of seasonal influenza vaccination among adults prescribed immune checkpoint inhibitors: A self-controlled case series study using administrative data.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy for patients undergoing cancer treatment carries a risk of severe immune-related adverse events (IRAEs). Questions remain about whether seasonal influenza vaccination might increase the risk of developing IRAEs among these patients given that vaccines are immunomodulatory. Previous vaccine safety studies on patients with cancer prescribed ICI therapy have demonstrated conflicting results. METHODS: Using health administrative data from Ontario, Canada among adults diagnosed with cancer who had been prescribed ICI therapy and who had received an influenza vaccine from 2012 to 2019, we conducted a self-controlled case series study. The pre-vaccination control period started 42-days post-ICI initiation until 14-days prior to vaccination, the risk period was 1-42 days post-vaccination, and the post-vaccination control period was after the risk period until ICI discontinuation or a maximum period of two years. Emergency department (ED) visit(s) and/or hospitalization for any cause after ICI initiation was used to identify severe IRAEs. We fitted a fixed-effects Poisson regression model accounting for seasonality and calendar time to estimate relative incidence of IRAEs between risk and control periods. RESULTS: We identified 1133 records of cancer patients who received influenza vaccination while prescribed ICI therapy. Most were aged ≥ 66 years (73 %), were male (63 %), had lung cancer (54 %), and had received ICI therapy with a programmed cell death protein 1(PD-1) inhibitor (91 %). A quarter (26 %) experienced an ED visit and/or hospitalization during the observation period. Rates of ED visits and/or hospitalizations in the risk vs. control periods were similar, with an incidence rate ratio of 1.04 (95 % CI: 0.75-1.45). Subgroup and sensitivity analyses yielded similar results. CONCLUSION: Seasonal influenza vaccination was not associated with an increased incidence of ED visit or hospitalization among adults with cancer treated with ICI therapy and our results support further evidence of vaccine safety.

COVID-19 Vaccination Coverage and Factors Associated With Vaccine Uptake Among People With HIV.

Importance: People with HIV (PWH) may be at increased risk for severe outcomes with COVID-19 illness compared with people without HIV. Little is known about COVID-19 vaccination coverage and factors associated with primary series completion among PWH. Objectives: To evaluate COVID-19 vaccination coverage among PWH and examine sociodemographic, clinical, and community-level factors associated with completion of the primary series and an additional primary dose. Design, Setting, and Participants: This retrospective cohort study used electronic health record data to assess COVID-19 vaccination information from December 14, 2020, through April 30, 2022, from 8 health care organizations of the Vaccine Safety Datalink project in the US. Participants were adults diagnosed with HIV on or before December 14, 2020, enrolled in a participating site. Main Outcomes and Measures: The percentage of PWH with at least 1 dose of COVID-19 vaccine and PWH who completed the COVID-19 vaccine primary series by December 31, 2021, and an additional primary dose by April 30, 2022. Rate ratios (RR) and 95% CIs were estimated using Poisson regression models for factors associated with completing the COVID-19 vaccine primary series and receiving an additional primary dose. Results: Among 22 058 adult PWH (mean [SD] age, 52.1 [13.3] years; 88.8% male), 90.5% completed the primary series by December 31, 2021. Among 18 374 eligible PWH who completed the primary series by August 12, 2021, 15 982 (87.0%) received an additional primary dose, and 4318 (23.5%) received a booster dose by April 30, 2022. Receipt of influenza vaccines in the last 2 years was associated with completion of the primary series (RR, 1.17; 95% CI, 1.15-1.20) and an additional primary dose (RR, 1.61; 95% CI, 1.54-1.69). PWH with uncontrolled viremia (HIV viral load ≥200 copies/mL) (eg, RR, 0.90 [95% CI, 0.85-0.95] for viral load 200-10 000 copies/mL vs undetected or <200 copies/mL for completing the primary series) and Medicaid insurance (eg, RR, 0.89 [95% CI, 0.87-0.90] for completing the primary series) were less likely to be fully vaccinated. By contrast, greater outpatient utilization (eg, RR, 1.07 [95% CI, 1.05-1.09] for ≥7 vs 0 visits for primary series completion) and residence in counties with higher COVID-19 vaccine coverage (eg, RR, 1.06 [95% CI, 1.03-1.08] for fourth vs first quartiles for primary series completion) were associated with primary series and additional dose completion (RRs ranging from 1.01 to 1.21). Conclusions and Relevance: Findings from this cohort study suggest that, while COVID-19 vaccination coverage was high among PWH, outreach efforts should focus on those who did not complete vaccine series and those who have uncontrolled viremia.