Modeling US blood donor deferrals under a policy of individual risk assessment for HIV risk sexual behavior.

BACKGROUND: In May 2023, the Food and Drug Administration (FDA) released final guidance for blood donor eligibility that recommended the elimination of 3-month deferral for men who have sex with men (MSM) and the related deferral for women who have sex with MSM. In its place, FDA introduced an individual risk assessment policy of asking all presenting blood donors, regardless of sex or gender, if they have had a new partner or more than one sexual partner in the last 3 months and deferring those who also report anal sex (penile-anal intercourse) during this period. We modeled the possible impact of this policy on the US blood donor base. STUDY DESIGN AND METHODS: We developed a computational model to estimate the percentage of blood donors who would be deferred under a policy of individual HIV risk assessment. The model incorporated demographic information about donors and national survey data on HIV risk behaviors and included age and sex distributions and dependencies. RESULTS: Our model estimates that approximately 1.2% of US blood donors would be deferred under the individual HIV risk assessment paradigm. DISCUSSION: The model predicts a relatively minor effect of replacing the time-based deferral for MSM with individual risk-based deferral for sexual behavior. As US blood centers implement this new policy, the effect may be mitigated by donor gains, which warrant further study. The new policy is unlikely to adversely affect the availability of blood and blood components.

Effectiveness of BNT162b2 COVID-19 primary series vaccination in children aged 5-17 years in the United States: a cohort study.

BACKGROUND: COVID-19 vaccines are authorized for use in children in the United States; real-world assessment of vaccine effectiveness in children is needed. This study's objective was to estimate the effectiveness of receiving a complete primary series of monovalent BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine in US children. METHODS: This cohort study identified children aged 5-17 years vaccinated with BNT162b2 matched with unvaccinated children. Participants and BNT162b2 vaccinations were identified in Optum and CVS Health insurance administrative claims databases linked with Immunization Information System (IIS) COVID-19 vaccination records from 16 US jurisdictions between December 11, 2020, and May 31, 2022 (end date varied by database and IIS). Vaccinated children were followed from their first BNT162b2 dose and matched to unvaccinated children on calendar date, US county of residence, and demographic and clinical factors. Censoring occurred if vaccinated children failed to receive a timely dose 2 or if unvaccinated children received any dose. Two COVID-19 outcome definitions were evaluated: COVID-19 diagnosis in any medical setting and COVID-19 diagnosis in hospitals/emergency departments (EDs). Propensity score-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards models, and vaccine effectiveness (VE) was estimated as 1 minus HR. VE was estimated overall, within age subgroups, and within variant-specific eras. Sensitivity, negative control, and quantitative bias analyses evaluated various potential biases. RESULTS: There were 453,655 eligible vaccinated children one-to-one matched to unvaccinated comparators (mean age 12 years; 50% female). COVID-19 hospitalizations/ED visits were rare in children, regardless of vaccination status (Optum, 41.2 per 10,000 person-years; CVS Health, 44.1 per 10,000 person-years). Overall, vaccination was associated with reduced incidence of any medically diagnosed COVID-19 (meta-analyzed VE = 38% [95% CI, 36-40%]) and hospital/ED-diagnosed COVID-19 (meta-analyzed VE = 61% [95% CI, 56-65%]). VE estimates were lowest among children 5-11 years and during the Omicron-variant era. CONCLUSIONS: Receipt of a complete BNT162b2 vaccine primary series was associated with overall reduced medically diagnosed COVID-19 and hospital/ED-diagnosed COVID-19 in children; observed VE estimates differed by age group and variant era. REGISTRATION: The study protocol was publicly posted on the BEST Initiative website ( https://bestinitiative.org/wp-content/uploads/2022/03/C19-VX-Effectiveness-Protocol_2022_508.pdf ).

Stroke Risk After COVID-19 Bivalent Vaccination Among US Older Adults.

Importance: In January 2023, the US Centers for Disease Control and Prevention and the US Food and Drug Administration noted a safety concern for ischemic stroke among adults aged 65 years or older who received the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine. Objective: To evaluate stroke risk after administration of (1) either brand of the COVID-19 bivalent vaccine, (2) either brand of the COVID-19 bivalent plus a high-dose or adjuvanted influenza vaccine on the same day (concomitant administration), and (3) a high-dose or adjuvanted influenza vaccine. Design, Setting, and Participants: Self-controlled case series including 11 001 Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine (among 5 397 278 vaccinated individuals). The study period was August 31, 2022, through February 4, 2023. Exposures: Receipt of (1) either brand of the COVID-19 bivalent vaccine (primary) or (2) a high-dose or adjuvanted influenza vaccine (secondary). Main Outcomes and Measures: Stroke risk (nonhemorrhagic stroke, transient ischemic attack, combined outcome of nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke) during the 1- to 21-day or 22- to 42-day risk window after vaccination vs the 43- to 90-day control window. Results: There were 5 397 278 Medicare beneficiaries who received either brand of the COVID-19 bivalent vaccine (median age, 74 years [IQR, 70-80 years]; 56% were women). Among the 11 001 beneficiaries who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there were no statistically significant associations between either brand of the COVID-19 bivalent vaccine and the outcomes of nonhemorrhagic stroke, transient ischemic attack, nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke during the 1- to 21-day or 22- to 42-day risk window vs the 43- to 90-day control window (incidence rate ratio [IRR] range, 0.72-1.12). Among the 4596 beneficiaries who experienced stroke after concomitant administration of either brand of the COVID-19 bivalent vaccine plus a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window for the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine (IRR, 1.20 [95% CI, 1.01-1.42]; risk difference/100 000 doses, 3.13 [95% CI, 0.05-6.22]) and a statistically significant association between vaccination and transient ischemic attack during the 1- to 21-day risk window for the Moderna mRNA-1273.222 COVID-19 bivalent vaccine (IRR, 1.35 [95% CI, 1.06-1.74]; risk difference/100 000 doses, 3.33 [95% CI, 0.46-6.20]). Among the 21 345 beneficiaries who experienced stroke after administration of a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window (IRR, 1.09 [95% CI, 1.02-1.17]; risk difference/100 000 doses, 1.65 [95% CI, 0.43-2.87]). Conclusions and Relevance: Among Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there was no evidence of a significantly elevated risk for stroke during the days immediately after vaccination.

HIV risk behavior profiles among men who have sex with men interested in donating blood: Findings from the Assessing Donor Variability and New Concepts in Eligibility study.

BACKGROUND: Individual risk assessment allows donors to be evaluated based on their own behaviors. Study objectives were to assess human immunodeficiency virus (HIV) risk behaviors in men who have sex with men (MSM) and estimate the proportion of the study population who would not be deferred for higher risk HIV sexual behaviors. STUDY DESIGN AND METHODS: Cross-sectional survey and biomarker assessment were conducted in eight U.S. cities. Participants were sexually active MSM interested in blood donation aged 18-39 years, assigned male sex at birth. Participants completed surveys during two study visits to define eligibility, and self-reported sexual and HIV prevention behaviors. Blood was drawn at study visit 1 and tested for HIV and the presence of tenofovir, one of the drugs in oral HIV pre-exposure prophylaxis (PrEP). Associations were assessed between HIV infection status or HIV PrEP use and behaviors, including sex partners, new partners, and anal sex. RESULTS: A total of 1566 MSM completed the visit 1 questionnaire and blood draw and 1197 completed the visit 2 questionnaire. Among 1562 persons without HIV, 789 (50.4%) were not taking PrEP. Of those not taking PrEP, 66.2% reported one sexual partner or no anal sex and 69% reported no new sexual partners or no anal sex with a new partner in the past 3 months. CONCLUSION: The study found that questions were able to identify sexually active, HIV-negative MSM who report lower risk sexual behaviors. About a quarter of enrolled study participants would be potentially eligible blood donors using individual risk assessment questions.

Risk Factors for COVID-19 Deaths Among Elderly Nursing Home Medicare Beneficiaries in the Prevaccine Period.

BACKGROUND: We evaluated prevaccine pandemic period COVID-19 death risk factors among nursing home (NH) residents. METHODS: In a retrospective cohort study covering Medicare fee-for-service beneficiaries aged ≥65 years residing in US NHs, we estimated adjusted hazard ratios (HRs) using multivariate Cox proportional hazards regressions. RESULTS: Among 608251 elderly NH residents, 57398 (9.4%) died of COVID-19-related illness 1 April to 22 December 2020; 46.9% (26893) of these deaths occurred without prior COVID-19 hospitalizations. We observed a consistently increasing age trend for COVID-19 deaths. Racial/ethnic minorities shared similarly high risk of NH COVID-19 deaths with whites. NH facility characteristics for-profit ownership and low health inspection ratings were associated with higher death risk. Resident characteristics (male [HR, 1.69], end-stage renal disease [HR, 1.42], cognitive impairment [HR, 1.34], and immunocompromised status [HR, 1.20]) were death risk factors. Other individual-level characteristics were less predictive of death than in community-dwelling population. CONCLUSIONS: Low NH health inspection ratings and private ownership contributed to COVID-19 death risks. Nearly half of NH COVID-19 deaths occurred without prior COVID-19 hospitalization and older residents were less likely to get hospitalized with COVID-19. No substantial differences were observed by race/ethnicity and socioeconomic status for NH COVID-19 deaths.

Guillain-Barré Syndrome After High-Dose Influenza Vaccine Administration in the United States, 2018-2019 Season.

BACKGROUND: The Vaccine Safety Datalink (VSD) identified a statistical signal for an increased risk of Guillain-Barré syndrome (GBS) in days 1-42 after 2018-2019 high-dose influenza vaccine (IIV3-HD) administration. We evaluated the signal using Medicare. METHODS: We conducted early- and end-of-season claims-based self-controlled risk interval analyses among Medicare beneficiaries ages ≥65 years, using days 8-21 and 1-42 postvaccination as risk windows and days 43-84 as control window. The VSD conducted chart-confirmed analyses. RESULTS: Among 7 453 690 IIV3-HD vaccinations, we did not detect a statistically significant increased GBS risk for either the 8- to 21-day (odds ratio [OR], 1.85; 95% confidence interval [CI], 0.99-3.44) or 1- to 42-day (OR, 1.31; 95% CI, 0.78-2.18) risk windows. The findings from the end-of-season analyses were fully consistent with the early-season analyses for both the 8- to 21-day (OR, 1.64; 95% CI, 0.92-2.91) and 1- to 42-day (OR, 1.12; 95% CI, 0.70-1.79) risk windows. The VSD's chart-confirmed analysis, involving 646 996 IIV3-HD vaccinations, with 1 case each in the risk and control windows, yielded a relative risk of 1.00 (95% CI, 0.06-15.99). CONCLUSIONS: The Medicare analyses did not exclude an association between IIV3-HD and GBS, but it determined that, if such a risk existed, it was similar in magnitude to prior seasons. Chart-confirmed VSD results did not confirm an increased risk of GBS.

Risk of Covid-19-Related Hospitalization and More Severe Outcomes in Medicare Beneficiaries Treated with Renin-Angiotensin-Aldosterone System Inhibitors for Hypertension.

BACKGROUND: There are theoretical concerns that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could increase the risk of severe Covid-19. OBJECTIVE: To determine if ACEIs and ARBs are associated with an increased risk of Covid-19 hospitalization overall, or hospitalization involving intensive care unit (ICU) admission, invasive mechanical ventilation, or death. DESIGN: Observational case-control study. PARTICIPANTS: Medicare beneficiaries aged ≥ 66 years with hypertension, treated with ACEIs, ARBs, calcium channel blockers (CCBs), or thiazide diuretics. MAIN MEASURES: Adjusted odds ratios (OR) and 95% confidence intervals (CI) for the outcomes of Covid-19 hospitalization, or hospitalization involving ICU admission, invasive mechanical ventilation, or death. RESULTS: A total of 35,300 cases of hospitalized Covid-19 were matched to 228,228 controls on calendar date and neighborhood of residence. The median age of cases was 79 years, 57.4% were female, and the median duration of hospitalization was 8 days (interquartile range 5-12). ACEIs and ARBs were associated with a slight reduction in Covid-19 hospitalization risk compared with treatment with other first-line antihypertensives (OR for ACEIs 0.95, 95% CI 0.92-0.98; OR for ARBs 0.94, 95% CI 0.90-0.97). Similar results were obtained for hospitalizations involving ICU admission, invasive mechanical ventilation, or death. There were no meaningful differences in risk for ACEIs compared with ARBs. In an analysis restricted to monotherapy with a first-line agent, CCBs were associated with a small increased risk of Covid-19 hospitalization compared with ACEIs (OR 1.09, 95% CI 1.04-1.14), ARBs (OR 1.10, 95% CI 1.05-1.15), or thiazide diuretics (OR 1.11, 95% CI 1.03-1.19). CONCLUSIONS: ACEIs and ARBs were not associated with an increased risk of Covid-19 hospitalization or with hospitalization involving ICU admission, invasive mechanical ventilation, or death. The finding of a small increased risk of Covid-19 hospitalization with CCBs was unexpected and could be due to residual confounding.

Assessment of risk of variant creutzfeldt-Jakob disease (vCJD) from use of bovine heparin.

PURPOSE: In the late1990s, reacting to the outbreak of bovine spongiform encephalopathy (BSE) in the United Kingdom that caused a new variant of Creutzfeldt-Jakob disease (vCJD) in humans, manufacturers withdrew bovine heparin from the market in the United States. There have been growing concerns about the adequate supply and safety of porcine heparin. Since the BSE epidemic has been declining markedly, the US Food and Drug Administration reevaluates the vCJD risk via use of bovine heparin. METHODS: We developed a computational model to estimate the vCJD risk to patients receiving bovine heparin injections. The model incorporated information including BSE prevalence, infectivity levels in the intestines, manufacturing batch size, yield of heparin, reduction in infectivity by manufacturing process, and the dose-response relationship. RESULTS: The model estimates a median risk of vCJD infection from a single intravenous dose (10 000 USP units) of heparin made from US-sourced bovine intestines to be 6.9 × 10-9 (2.5-97.fifth percentile: 1.5 × 10-9 -4.3 × 10-8 ), a risk of 1 in 145 million, and 4.6 × 10-8 (2.5-97.fifth percentile: 1.1 × 10-8 -2.6 × 10-7 ), a risk of 1 in 22 million for Canada-sourced products. The model estimates a median risk of 1.4 × 10-7 (2.5-97.fifth percentile: 2.9 × 10-8 -9.3 × 10-7 ) and 9.6 × 10-7 (2.5-97.fifth percentile: 2.1 × 10-7 -5.6 × 10-6 ) for a typical treatment for venous thromboembolism (infusion of 2-4 doses daily per week) using US-sourced and Canada-sourced bovine heparin, respectively. CONCLUSIONS: The model estimates the vCJD risk from use of heparin when appropriately manufactured from US or Canadian cattle is likely small. The model and conclusions should not be applied to other medicinal products manufactured using bovine-derived materials.

Effect of Age on Relative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines Among US Medicare Beneficiaries Aged ≥65 Years.

BACKGROUND: Studies have found that the high-dose influenza vaccine has a higher relative vaccine effectiveness (RVE) versus standard-dose vaccines in some seasons. We evaluated the effect of age on the RVE of high-dose versus standard-dose influenza vaccines among Medicare beneficiaries. METHODS: A 6-season retrospective cohort study from 2012 to 2018 among Medicare beneficiaries aged ≥65 years was performed. Poisson regression was used to evaluate the effect of age on the RVE of high-dose versus standard-dose influenza vaccines in preventing influenza-related hospitalizations. RESULTS: The study included >19 million vaccinated beneficiaries in a community pharmacy setting. The Poisson models indicated a slightly increasing trend in RVE with age in all seasons. The high-dose vaccine was more effective than standard-dose vaccines in preventing influenza-related hospital encounters (ie, influenza-related inpatient stays and emergency department visits) in the 2012-2013 (RVE, 23.1%; 95% confidence interval [CI], 17.6%-28.3%), 2013-2014 (RVE, 15.3%; 95% CI, 7.8%-22.3%), 2014-2015 (RVE, 8.9%; 95% CI, 5.6%-12.1%), and 2016-2017 (RVE, 12.6%; 95% CI, 6.3%-18.4%) seasons and was at least as effective in all other seasons. We also found that the high-dose vaccine was consistently more effective than standard-dose vaccines across all seasons for people aged ≥85 years. Similar trends were observed for influenza-related inpatient stays. CONCLUSIONS: The RVE of high-dose versus standard-dose influenza vaccines increases with age.

Predictive model for Zika virus RNA minipool nucleic acid testing in outbreak scenarios.

BACKGROUND: Zika virus (ZIKV), a mosquito-borne flavivirus, causes asymptomatic infections in blood donors and can be transmitted by transfusion. During the 2016 US outbreak, universal individual-donation nucleic acid testing (ID-NAT) was used to screen the blood supply for ZIKV. Testing pooled samples from multiple donations with minipool (MP)-NAT is less sensitive than ID-NAT, which raised questions about its utility in ZIKV outbreaks. STUDY DESIGN AND METHODS: A mathematical model and computer simulation determined the risk of missing ID-NAT-reactive and immunoglobulin (Ig) M-negative donations in a ZIKV outbreak if MP-NAT is used initially instead of ID-NAT. The model calculated the time required for ZIKV RNA to replicate to a concentration detectable by testing donations individually or in pools of 6 (MP6) or 16 (MP16). A computer simulation then randomly selected infection times to determine the probability of detection by the candidate tests. RESULTS: The probability of detecting the first ID-NAT-reactive unit in an outbreak is 92% (2.5th-97.5th percentile, 79%-99%) by MP6 and 85% (2.5th-97.5th percentile, 67%-99%) by MP16. When one donation is detected by MP-NAT, the model predicts that the chance of having missed one or more ID-NAT-reactive donations is 8% to 15%. The probability of missing a unit by MP-NAT is constant over the course of the outbreak (8% by MP6, 15% by MP16). CONCLUSION: The model predicts that the probability that a candidate MP-NAT will detect the first ID-NAT-reactive unit in a ZIKV outbreak is 85% to 92% and remains constant over time.

A simulation study of the statistical power and signaling characteristics of an early season sequential test for influenza vaccine safety.

PURPOSE: The US Food and Drug Administration monitors the risk of Guillain-Barré syndrome (GBS) following influenza vaccination using several data sources including Medicare. In the 2017 to 2018 season, we transitioned our near real-time surveillance in Medicare to more effectively detect large GBS risk increases early in the season while avoiding false positives. METHODS: We conducted a simulation study examining the ability of the updating sequential probability ratio test (USPRT) to detect substantially elevated GBS risk in the 8- to 21-day postvaccination versus 5× to 30× the historical rate. We varied the first testing week (weeks 5-8) and the null rate (1×-3×) and evaluated power. We estimated signal probability and the risk ratio (RR) after signaling when high-risk seasons were rare. RESULTS: Applying fixed alternatives, we found >80% power to detect a risk 30× the historical rate in week 5 for the 1× null and in week 6 for the 1.5× to 3× nulls. Nearly all testing schedules had >80% power for a 5× risk by week 11. To test the robustness of USPRT, we further simulated seasons where 1% were true high-risk seasons. Using a 1× null led to 10% of seasons signaling by week 11 (median RR approximately 1.4), which decreased to approximately 1% with the ≥2.5× null (median RR approximately 16.0). CONCLUSIONS: On the basis of the results from this simulation and subsequent consultations with experts and stakeholders, we specified USPRT to test continuously from weeks 7 to 11 using the null hypothesis that the observed GBS rate was 2.5× the historical rate. This helped improve the ability of USPRT to provide early detection of GBS risk following influenza vaccination as part of a multilayered system of surveillance.

Comparative pharmacokinetic and biodistribution study of two distinct squalene-containing oil-in-water emulsion adjuvants in H5N1 influenza vaccines.

BACKGROUND: In recent years, there has been great interest from academia, industry and government scientists for an increased understanding of the mode of action of vaccine adjuvants to characterize the safety and efficacy of vaccines. In this context, pharmacokinetic (PK) and biodistribution studies are useful for quantifying the concentration of vaccine adjuvants in mechanistically or toxicologically relevant target tissues. METHODS: In this study, we conducted a comparative analysis of the PK and biodistribution profile of radiolabeled squalene for up to 336 h (14 days) after intramuscular injection of mice with adjuvanted H5N1 influenza vaccines. The evaluated adjuvants included an experimental-grade squalene-in-water (SQ/W) emulsion (AddaVax®) and an adjuvant system (AS03®) that contained squalene and α-tocopherol in the oil phase of the emulsion. RESULTS: The half-life of the initial exponential decay from quadriceps muscle was 1.5 h for AS03 versus 12.9 h for AddaVax. At early time points (1-6 h), there was about a 10-fold higher concentration of labeled squalene in draining lymph nodes following AS03 injection compared to AddaVax. The area-under-concentration curve up to 336 h (AUC0-336hr) and peak concentration of squalene in spleen (immune organ) was about 1.7-fold higher following injection of AS03 than AddaVax. The peak systemic tissue concentration of squalene from the two adjuvants, with or without antigen, remained below 1% of injected dose for toxicologically relevant target tissues, such as spinal cord, brain, and kidney. The pharmacokinetics of AS03 was unaffected by the presence of H5N1 antigen. CONCLUSIONS: This study demonstrates a rapid decline of AS03 from the quadriceps muscles of mice as compared to conventional SQ/W emulsion adjuvant, with an increased transfer to mechanistically relevant tissues such as local lymph nodes. Systemic tissue exposure to potential toxicological target tissues was very low.

Occurrence of hemolytic reactions on the same day as immune globulin product administrations during 2008 to 2014.

BACKGROUND: Hemolytic reactions (HRs) are rare serious adverse events after immune globulin (IG) use. Our large claims-based study evaluated occurrence of same-day hemolysis after administration of different IG products and potential risk factors, during the 2008 to 2014 study period. STUDY DESIGN AND METHODS: We conducted a retrospective cohort study using a large commercial administrative database. The study included individuals exposed to IG products as identified by procedure codes. HRs were ascertained using ICD-9-CM diagnosis codes. Unadjusted same-day hemolysis rates (per 1000 persons) were estimated overall, by age, sex, and IG products. Multivariable regression analyses were used to evaluate potential risk factors. RESULTS: Of 20,440 persons exposed, 211 (10.3 per 1000) had same-day HRs. The median numbers of doses for IG users with versus without same-day hemolysis were one and six, respectively. The unadjusted product-specific HR rates ranged from 1.92 for subcutaneous product Hizentra to 17.99 for intravenous Octagam. The multivariable regression analyses showed significantly increased same-day HR risk in males and in IG users with histories of hemolysis, pneumonia, and hereditary hemolytic anemias. Compared to Gammagard Liquid, significantly elevated overall hemolysis risk was identified with Octagam (odds ratio, 2.36; 95% confidence interval, 1.04-5.35), using Firth's method to account for small sample size bias. CONCLUSION: The study showed variation in the same-day IG-related hemolysis by age, sex, and IG products administered. The results suggest importance of underlying health conditions, especially prior hemolysis, and first IG product dose. Differences in HR occurrence may also be explained by product manufacturing processes, indications, routes, and rates of administration, which warrant further investigation.

Detection of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus in postmortem blood specimens using infectious disease assays licensed for cadaveric donor screening.

BACKGROUND: Evaluation of assay performance on postmortem blood specimens (obtained after cessation of the heartbeat) presents unique scientific and regulatory challenges. In the United States, assay performance is evaluated in part by spiking postmortem specimens. METHODS: Fifty-four specimens obtained from decedents known to be infected with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV), including some coinfections, were tested for each virus using Food and Drug Administration (FDA)-licensed donor screening tests for nucleic acid, antibody, and antigen. RESULTS: For each disease, >95% of subjects who were reported to have an infection at the time of death had a positive test result on at least one of the donor screening assays for that infection. CONCLUSION: Licensed donor screening tests were positive on postmortem specimens obtained within 24 hours of death from individuals dying with HIV, HCV, and/or HBV, and were able to detect presence of the virus. The use of multiple tests (including antibody and direct viral detection methods) is necessary to adequately evaluate donors.

Comparative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines Among US Medicare Beneficiaries in Preventing Postinfluenza Deaths During 2012-2013 and 2013-2014.

Background: Recipients of high-dose vs standard-dose influenza vaccines have fewer influenza illnesses. We evaluated the comparative effectiveness of high-dose vaccine in preventing postinfluenza deaths during 2012-2013 and 2013-2014, when influenza viruses and vaccines were similar. Methods: We identified Medicare beneficiaries aged ≥65 years who received high-dose or standard-dose vaccines in community-located pharmacies offering both vaccines. The primary outcome was death in the 30 days following an inpatient or emergency department encounter listing an influenza International of Classification of Diseases, Ninth Revision, Clinical Modification code. Effectiveness was estimated by using multivariate Poisson regression models; effectiveness was allowed to vary by season. Results: We studied 1039645 recipients of high-dose and 1683264 recipients of standard-dose vaccines during 2012-2013, and 1508176 high-dose and 1877327 standard-dose recipients during 2013-2014. Vaccinees were well-balanced for medical conditions and indicators of frail health. Rates of postinfluenza death were 0.028 and 0.038/10000 person-weeks in high-dose and standard-dose recipients, respectively. Comparative effectiveness was 24.0% (95% confidence interval [CI], .6%-42%); there was evidence of variation by season (P = .12). In 2012-2013, high-dose was 36.4% (95% CI, 9.0%-56%) more effective in reducing mortality; in 2013-2014, it was 2.5% (95% CI, -47% to 35%). Conclusions: High-dose vaccine was significantly more effective in preventing postinfluenza deaths in 2012-2013, when A(H3N2) circulation was common, but not in 2013-2014.

Geographic exposure risk of variant Creutzfeldt-Jakob disease in US blood donors: a risk-ranking model to evaluate alternative donor-deferral policies.

BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) has been transmitted by blood transfusion (TTvCJD). The US Food and Drug Administration (FDA) recommends deferring blood donors who resided in or traveled to 30 European countries where they may have been exposed to bovine spongiform encephalopathy (BSE) through beef consumption. Those recommendations warrant re-evaluation, because new cases of BSE and vCJD have markedly abated. STUDY DESIGN AND METHODS: The FDA developed a risk-ranking model to calculate the geographic vCJD risk using country-specific case rates and person-years of exposure of US blood donors. We used the reported country vCJD case rates, when available, or imputed vCJD case rates from reported BSE and UK beef exports during the risk period. We estimated the risk reduction and donor loss should the deferral be restricted to a few high-risk countries. We also estimated additional risk reduction by leukocyte reduction (LR) of red blood cells (RBCs). RESULTS: The United Kingdom, Ireland, and France had the greatest vCJD risk, contributing approximately 95% of the total risk. The model estimated that deferring US donors who spent extended periods of time in these three countries, combined with currently voluntary LR (95% of RBC units), would reduce the vCJD risk by 89.3%, a reduction similar to that achieved under the current policy (89.8%). Limiting deferrals to exposure in these three countries would potentially allow donations from an additional 100,000 donors who are currently deferred. CONCLUSION: Our analysis suggests that a deferral option focusing on the three highest risk countries would achieve a level of blood safety similar to that achieved by the current policy.

Occurrence of acute renal failure on the same day as immune globulin product administrations during 2008 to 2014.

BACKGROUND: Acute renal failure (ARF) is a rare serious adverse event after immune globulin (IG) use. Our large claims-based study evaluated occurrence of same-day ARF after administration of different IGs and ascertained potential risk factors, during the 2008 to 2014 study period. STUDY DESIGN AND METHODS: A retrospective cohort study was conducted using a large commercial administrative database. The cohort included individuals exposed to IG products as identified by procedure codes. ARF was ascertained using ICD-9-CM diagnoses. Unadjusted same-day ARF rates (per 1000 persons exposed) were estimated overall and by age, sex, and IG products. Regression analyses were conducted to control for confounding and assess potential risk factors. RESULTS: Of 20,440 persons exposed, 163 (7.97 per 1000) had a recorded same-day ARF. The unadjusted nonzero same-day ARF rates (per 1000) ranged from 1.92 (95% confidence interval [CI], 0.05-10.69) for Hizentra to 16.97 (95% CI, 11.36-24.37) for Privigen and differed by sex. In multivariate analyses, compared to Gammagard Liquid, no significantly elevated ARF risks were identified with any IGs. A significantly lower odds ratio was identified with Gamunex, 0.53 (95% CI, 0.30-0.93). Age 45 and over, prior renal impairment, hypertension, and other factors were associated with increased risk of same-day ARF. CONCLUSION: The study showed variation in the risk of IG-related ARF by age, sex, and IG products. The study results suggest the importance of recipient factors, such as older age and underlying health conditions. Variations in ARF occurrence may also be explained by product dosage, administration route and rate, and manufacturing processes, which warrant further evaluation.

Quantitative Bias Analysis in Regulatory Settings.

Nonrandomized studies are essential in the postmarket activities of the US Food and Drug Administration, which, however, must often act on the basis of imperfect data. Systematic errors can lead to inaccurate inferences, so it is critical to develop analytic methods that quantify uncertainty and bias and ensure that these methods are implemented when needed. "Quantitative bias analysis" is an overarching term for methods that estimate quantitatively the direction, magnitude, and uncertainty associated with systematic errors influencing measures of associations. The Food and Drug Administration sponsored a collaborative project to develop tools to better quantify the uncertainties associated with postmarket surveillance studies used in regulatory decision making. We have described the rationale, progress, and future directions of this project.

Pharmacokinetics and biodistribution of squalene-containing emulsion adjuvant following intramuscular injection of H5N1 influenza vaccine in mice.

Squalene is a component of oil-in-water emulsion adjuvants developed for potential use in some influenza vaccines. The biodistribution of the squalene-containing emulsion adjuvant (AddaVax™) alone and as part of complete H5N1 vaccine was quantified in mechanistically and toxicologically relevant target tissues up to 336 h (14 days) following injection into quadriceps muscle. At 1 h, about 55% of the intramuscularly injected dose of squalene was detected in the local quadriceps muscles and this decreased to 26% at 48 h. Twenty-four hours after the injection, approximately 5%, 1%, and 0.6% of the injected dose was detected in inguinal fat, draining lymph nodes, and sciatic nerve, respectively. The peak concentration for kidney, brain, spinal cord, bone marrow, and spleen was each less than 1% of the injected dose, and H5N1 antigen did not significantly alter the biodistribution of squalene to these tissues. The area-under-blood-concentration curve (AUC) and peak blood concentration (Cmax) of squalene were slightly higher (20-25%) in the presence of H5N1 antigen. A population pharmacokinetic model-based statistical analysis identified body weight and H5N1 antigen as covariates influencing the clearance of squalene. The results contribute to the body of knowledge informing benefit-risk analyses of squalene-containing emulsion vaccine adjuvants.