Natural History of Coronavirus Disease 2019: Risk Factors for Hospitalizations and Deaths Among >26 Million US Medicare Beneficiaries.

BACKGROUND: The current study was performed to evaluate risk factors for severe coronavirus disease 2019 (COVID-19) outcomes among Medicare beneficiaries during the pandemic's early phase. METHODS: In a retrospective cohort study covering Medicare fee-for-service beneficiaries, we separated out elderly residents in nursing homes (NHs) and those with end-stage renal disease (ESRD) from the primary study population of individuals age ≥65 years. Outcomes included COVID-19 hospital encounters and COVID-19-associated deaths. We estimated adjusted odds ratios (ORs) using logistic regression. RESULTS: We analyzed 25 333 329 elderly non-NH beneficiaries without ESRD, 653 966 elderly NH residents, and 292 302 patients with ESRD. COVID-related death rates (per 10 000) were much higher among elderly NH residents (275.7) and patients with ESRD (60.8) than in the primary study population (5.0). Regression-adjusted clinical predictors of death among the primary population included immunocompromised status (OR, 1.43), frailty index conditions such as cognitive impairment (3.16), and other comorbid conditions, including congestive heart failure (1.30). Demographic-related risk factors included male sex (OR, 1.77), older age (3.09 for 80- vs 65-year-olds), Medicaid dual-eligibility status (2.17), and racial/ethnic minority. Compared with whites, ORs were higher for blacks (2.47), Hispanics (3.11), and Native Americans (5.82). Results for COVID-19 hospital encounters were consistent. CONCLUSIONS: Frailty, comorbid conditions, and race/ethnicity were strong risk factors for COVID-19 hospitalization and death among the US elderly.

Comparative Effectiveness of Influenza Vaccines Among US Medicare Beneficiaries Ages 65 Years and Older During the 2019-2020 Season.

BACKGROUND: Approximately 50 000 influenza-associated deaths occur annually in the United States, overwhelmingly among individuals aged ≥65 years. Although vaccination is the primary prevention tool, investigations have shown low vaccine effectiveness (VE) in recent years, particularly among the elderly. We analyzed the relative VE (RVE) of all influenza vaccines among Medicare beneficiaries aged ≥65 years to prevent influenza hospital encounters during the 2019-2020 season. METHODS: Retrospective cohort study using Poisson regression and inverse probability of treatment weighting (IPTW). Exposures included egg-based high-dose trivalent (HD-IIV3), egg-based adjuvanted trivalent (aIIV3), egg-based standard dose (SD) quadrivalent (IIV4), cell-based SD quadrivalent (cIIV4), and recombinant quadrivalent (RIV4) influenza vaccines. RESULTS: We studied 12.7 million vaccinated beneficiaries. Following IPTW, cohorts were well balanced for all covariates and health-seeking behavior indicators. In the adjusted analysis, RIV4 (RVE, 13.3%; 95% CI, 7.4-18.9%), aIIV3 (RVE, 8.2%; 95% CI, 4.2-12.0%), and HD-IIV3 (RVE, 6.8%; 95% CI, 3.3-10.1%) were significantly more effective in preventing hospital encounters than the reference egg-based SD IIV4, while cIIV4 was not significantly more effective than IIV4 (RVE, 2.8%; 95% CI, -2.8%, 8.2%). Our results were consistent across all analyses. CONCLUSIONS: In this influenza B-Victoria and A(H1N1)-dominated season, RIV4 was moderately more effective than other vaccines, while HD-IIV3 and aIIV3 were more effective than the IIV4 vaccines, highlighting the contributions of antigen amount and adjuvant use to VE. Egg adaptation likely did not substantially affect our RVE evaluation. Our findings, specific to the 2019-2020 season, should be evaluated in other studies using virological case confirmation.

Relative Effectiveness of Influenza Vaccines Among the United States Elderly, 2018-2019.

BACKGROUND: Studies among individuals ages ≥65 years have found a moderately higher relative vaccine effectiveness (RVE) for the high-dose (HD) influenza vaccine compared with standard-dose (SD) products for most seasons. Studies during the A(H3N2)-dominated 2017-2018 season showed slightly higher RVE for the cell-cultured vaccine compared with SD egg-based vaccines. We investigated the RVE of influenza vaccines among Medicare beneficiaries ages ≥65 years during the 2018-2019 season. METHODS: This is a retrospective cohort study using inverse probability of treatment weighting and Poisson regression to evaluate RVE in preventing influenza hospital encounters. RESULTS: Among 12 777 214 beneficiaries, the egg-based adjuvanted (RVE, 7.7%; 95% confidence interval [CI], 3.9%-11.4%) and HD (RVE, 4.9%; 95% CI, 1.7%-8.1%) vaccines were marginally more effective than the egg-based quadrivalent vaccines. The cell-cultured quadrivalent vaccine was not significantly more effective than the egg-based quadrivalent vaccine (RVE, 2.5%; 95% CI, -2.4% to 7.3%). CONCLUSIONS: We did not find major effectiveness differences between licensed vaccines used among the elderly during the 2018-2019 season. Consistent with prior research, we found that the egg-based adjuvanted and HD vaccines were slightly more effective than the egg-based quadrivalent vaccines.

Zostavax vaccine effectiveness among US elderly using real-world evidence: Addressing unmeasured confounders by using multiple imputation after linking beneficiary surveys with Medicare claims.

PURPOSE: Medicare claims can provide real-world evidence (RWE) to support the Food and Drug Administration's ability to conduct postapproval studies to validate products' safety and effectiveness. However, Medicare claims do not contain comprehensive information on some important sources of bias. Thus, we piloted an approach using the Medicare Current Beneficiary Survey (MCBS), a nationally representative survey of the Medicare population, to (a) assess cohort balance with respect to unmeasured confounders in a herpes zoster vaccine (HZV) effectiveness claims-based study and (b) augment Medicare claims with MCBS data to include unmeasured covariates. METHODS: We reanalyzed data from our published HZV effectiveness Medicare analysis, using linkages to MCBS to obtain information on impaired mobility, education, and health-seeking behavior. We assessed survey variable balance between the matched cohorts and selected imbalanced variables for model adjustment, applying multiple imputation by chained equations (MICE) to impute these potential unmeasured confounders. RESULTS: The original HZV effectiveness study cohorts appeared well balanced with respect to variables we selected from the MCBS. Our imputed results showed slight shifts in HZV effectiveness point estimates with wider confidence intervals, but indicated no statistically significant differences from the original study estimates. CONCLUSIONS: Our innovative use of linked survey data to assess cohort balance and our imputation approach to augment Medicare claims with MCBS data to include unmeasured covariates provide potential solutions for addressing bias related to unmeasured confounding in large database studies, thus adding new tools for RWE studies.

Use of controlled human infection models (CHIMs) to support vaccine development: US regulatory considerations.

In 2016, the United States (U.S.) Food and Drug Administration (FDA) licensed Vaxchora® for active immunization against disease caused by Vibrio cholerae serogroup 01 in adults. Vaxchora was the first US-licensed vaccine for which the primary evidence supporting effectiveness was derived from human challenge studies. Following this precedent, FDA has received numerous inquiries from manufacturers, academic researchers, funders and other stakeholders regarding how controlled human infection models (CHIMs) can be used to support the development of safe and effective vaccines to address public health needs. The aims of this article are to discuss: (1) Chemistry, Manufacturing and Controls (CMC) for challenge inocula, (2) conduct of controlled human infection studies under US IND and (3) use of CHIMs to support vaccine development. General concepts and regulatory considerations for the safe conduct of CHIMs and use of CHIMs to evaluate vaccine effectiveness are discussed.

Relative Effectiveness of Cell-Cultured and Egg-Based Influenza Vaccines Among Elderly Persons in the United States, 2017-2018.

BACKGROUND: The low influenza vaccine effectiveness (VE) observed during the A(H3N2)-dominated 2017-2018 season may be due to vaccine virus adaptation to growth in eggs. We compared the effectiveness of cell-cultured and egg-based vaccines among Medicare beneficiaries. METHODS: Retrospective cohort study on Medicare beneficiaries aged ≥65 years who received an influenza vaccine (cell-cultured, egg-based quadrivalent; egg-based high-dose, adjuvanted, or standard-dose trivalent) during the 2017-2018 season. We used Poisson regression to evaluate relative VE (RVE) in preventing influenza-related hospital encounters. RESULTS: Of >13 million beneficiaries, RVE for cell-cultured vaccines relative to egg-based quadrivalent vaccines was 10% (95% confidence interval [CI], 7%-13%). In a midseason interim analysis, this estimate was 16.5% (95% CI, 10.3%-22.2%). In a 5-way comparison, cell-cultured (RVE, 11%; 95% CI, 8%-14%) and egg-based high-dose (RVE, 9%; 95% CI, 7%-11%) vaccines were more effective than egg-based quadrivalent vaccines. CONCLUSIONS: The modest VE difference between cell-cultured and egg-based vaccines only partially explains the low overall VE reported by the Centers for Disease Control and Prevention, suggesting that egg adaptation was not the main contributor to the low VE found among individuals aged ≥65 years. The midseason interim analysis we performed demonstrates that our methods can be used to evaluate VE actively during the influenza season.

Understanding FDA-Approved Labeling and CDC Recommendations for Use of Vaccines.

Adherence to recommendations for the use of licensed vaccines ensures maximum individual and societal benefits from the national immunization program. The US Food and Drug Administration (FDA) licenses a vaccine once it determines that data submitted by the manufacturer reveal that the vaccine is safe and effective for its intended use. For each US-licensed vaccine, the FDA-approved prescribing information contains detailed information for health care providers to ensure safe and effective use. Centers for Disease Control and Prevention recommendations for the use of a licensed vaccine often are based on additional considerations, such as disease epidemiology, public acceptance, vaccine supply, and cost. Our objective in this article is to explain the reasons for the differences between FDA-approved prescribing information and Centers for Disease Control and Prevention recommendations for vaccine use.

Statin Use and Risks of Influenza-Related Outcomes Among Older Adults Receiving Standard-Dose or High-Dose Influenza Vaccines Through Medicare During 2010-2015.

Background: Statins are used to reduce cardiovascular disease risk. Recent studies suggest that statin use may be associated with an increased influenza risk among influenza vaccinees. We used Medicare data to evaluate associations between statins and risks of influenza-related encounters among vaccinees. Methods: In this retrospective cohort study, we identified Medicare beneficiaries aged > 65 years who received high-dose (HD) or standard-dose (SD) influenza vaccines at pharmacies from 2010-2011 through 2014-2015. Statin users were matched to nonusers by vaccine type, demographics, prior medical encounters, and comorbidities. We used multivariable Poisson models to estimate associations between statin use around the time of vaccination and risk of influenza-related encounters. Study outcomes included influenza-related office visits with a rapid test followed by dispensing of oseltamivir and influenza-related hospitalizations (including emergency room visits) during high influenza circulation periods. Results: The study included 1403651 statin users matched to nonusers. Cohorts were well balanced, with standardized mean differences ≤0.03 for all measured covariates. For statin users compared to nonusers, the adjusted relative risk was 1.086 (95% confidence interval [CI], 1.025-1.150) for influenza-related visits and 1.096 (95% CI, 1.013-1.185) for influenza-related hospitalizations. The risk difference ranged from ‒0.02 to 0.23 for influenza-related visits and from ‒0.04 to 0.13 for hospitalizations, depending on season severity. Results were similar for HD and SD vaccinees and for nonsynthetic and synthetic statin users. Conclusions: Among 2.8 million Medicare beneficiaries, these results suggest that statin use around the time of vaccination does not substantially affect the risk of influenza-related medical encounters among older adults.

Effectiveness and Duration of Protection Provided by the Live-attenuated Herpes Zoster Vaccine in the Medicare Population Ages 65 Years and Older.

Background: Tens of millions of seniors are at risk of herpes zoster (HZ) and its complications. Live attenuated herpes zoster vaccine (HZV) reduces that risk, although questions regarding effectiveness and durability of protection in routine clinical practice remain. We used Medicare data to investigate HZV effectiveness (VE) and its durability. Methods: This retrospective cohort study included beneficiaries ages ≥65 years during January 2007 through July 2014. Multiple adjustments to account for potential bias were made. HZV-vaccinated beneficiaries were matched to unvaccinated beneficiaries (primary analysis) and to HZV-unvaccinated beneficiaries who had received pneumococcal vaccination (secondary analysis). HZ outcomes in community and hospital settings were analyzed, including ophthalmic zoster (OZ) and postherpetic neuralgia (PHN). Results: Among eligible beneficiaries (average age 77 years), the primary analysis found VE for community HZ of 33% (95% CI: 32%-35%) and 19% (95% CI: 17%-22%), for the first 3, and subsequent 4+ years postvaccination, respectively. In the secondary analysis, VE was, respectively, 37% (95% CI: 36%-39%) and 22% (95% CI: 20%-25%). In the primary analysis, VE for PHN was 57% (95% CI: 52%-61%) and 45% (95% CI: 36%-53%) in the first 3 and subsequent 4+ years, respectively; VE for hospitalized HZ was, respectively, 74% (95% CI: 67%-79%) and 55% (95% CI: 39%-67%). Differences in VE by age group were not significant. Conclusions: In both the primary and secondary analyses, HZV provided protection against HZ across all ages, but effectiveness declined over time. VE was higher and better preserved over time for PHN and HZ-associated hospitalizations than for community HZ.

Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis.

BACKGROUND: A high-dose trivalent inactivated influenza vaccine was licensed in 2009 by the US Food and Drug Administration (FDA) on the basis of serological criteria. We sought to establish whether high-dose inactivated influenza vaccine was more effective for prevention of influenza-related visits and hospital admissions in US Medicare beneficiaries than was standard-dose inactivated influenza vaccine. METHODS: In this retrospective cohort study, we identified Medicare beneficiaries aged 65 years and older who received high-dose or standard-dose inactivated influenza vaccines from community pharmacies that offered both vaccines during the 2012-13 influenza season. Outcomes were defined with billing codes on Medicare claims. The primary outcome was probable influenza infection, defined by receipt of a rapid influenza test followed by dispensing of the neuraminidase inhibitor oseltamivir. The secondary outcome was a hospital or emergency department visit, listing a Medicare billing code for influenza. We estimated relative vaccine effectiveness by comparing outcome rates in Medicare beneficiaries during periods of high influenza circulation. Univariate and multivariate Poisson regression models were used for analyses. FINDINGS: Between Aug 1, 2012 and Jan 31, 2013, we studied 929,730 recipients of high-dose vaccine and 1,615,545 recipients of standard-dose vaccine. Participants enrolled in each cohort were well balanced with respect to age and presence of underlying medical disorders. The high-dose vaccine (1·30 outcomes per 10,000 person-weeks) was 22% (95% CI 15-29) more effective than the standard-dose vaccine (1·01 outcomes per 10,000 person-weeks) for prevention of probable influenza infections (rapid influenza test followed by oseltamivir treatment) and 22% (95% CI 16-27%) more effective for prevention of influenza hospital admissions (0·86 outcomes per 10,000 person-weeks in the high-dose cohort vs 1·10 outcomes per 10,000 person-weeks in the standard-dose cohort). INTERPRETATION: Our retrospective cohort study in US Medicare beneficiaries shows that, in people 65 years of age and older, high-dose inactivated influenza vaccine was significantly more effective than standard-dose vaccine in prevention of influenza-related medical encounters. Additionally, the large population in our study enabled us to show, for the first time, a significant reduction in influenza-related hospital admissions in high-dose compared to standard-dose vaccine recipients, an outcome not shown in randomised studies. These results provide important new information to be considered by policy makers recommending influenza vaccinations for elderly people. FUNDING: FDA and the office of the Assistant Secretary of Planning and Evaluation.

Inclusion chemistry of a thiazyl radical in zeolite-Y.

High loading of the radical PhCNSSN˙ (1) into faujasite has been achieved via gas phase diffusion. Whilst the large 12 Å pores can accommodate the enthalpically preferred dimer, the smaller pores dictate inclusion as a paramagnetic monomer. Powder X-ray diffraction studies reveal the host framework is unchanged whilst TGA reveal that the void space has high radical loadings. SQUID magnetometry coupled with EPR spectroscopy indicate that the majority of radicals adopt diamagnetic π*-π* dimers consistent with predominant location of 1 as dimers within the large cavities.

Adverse events reported following live, cold-adapted, intranasal influenza vaccine.

CONTEXT: In June 2003, the US Food and Drug Administration licensed a trivalent live, attenuated influenza vaccine (LAIV-T) for intranasal administration to healthy persons 5 to 49 years of age. Although prelicensure testing involved 20 228 vaccinees, clinical trials were not of sufficient size to detect rare adverse events reliably. OBJECTIVE: To identify adverse events reported following LAIV-T administration after licensure. DESIGN, SETTING, AND PARTICIPANTS: All adverse events reported to the US Vaccine Adverse Event Reporting System (VAERS) during the 2003-2004 and the 2004-2005 influenza seasons. MAIN OUTCOME MEASURES: Numbers and proportions of reported adverse events and reporting rates of adverse events per 100,000 vaccinees. RESULTS: Approximately 2,500,000 persons received LAIV-T during the first 2 postlicensure seasons. As of August 16, 2005, VAERS received 460 adverse event reports for vaccinations received from August 2003 through July 2005. No fatalities were reported. There were 7 reports of possible anaphylaxis, 2 reports of Guillain-Barré syndrome, 1 report of Bell palsy, and 8 reports of asthma exacerbation among individuals with a prior asthma history. Events in individuals for whom the vaccine was not indicated accounted for 73 reports (16%). CONCLUSIONS: Reports to VAERS in the first 2 seasons of LAIV-T use did not identify any unexpected serious risks with this vaccine when used according to approved indications. Like many vaccines and other medical products, LAIV-T may rarely cause anaphylaxis. Secondary transmission of the vaccine virus merits further investigation. Reports of asthma exacerbations in vaccinees with prior asthma history highlight the risks of vaccine use inconsistent with approved labeling.