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.

Risk of myocarditis and pericarditis after the COVID-19 mRNA vaccination in the USA: a cohort study in claims databases.

BACKGROUND: Several passive surveillance systems reported increased risks of myocarditis or pericarditis, or both, after COVID-19 mRNA vaccination, especially in young men. We used active surveillance from large health-care databases to quantify and enable the direct comparison of the risk of myocarditis or pericarditis, or both, after mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) vaccinations. METHODS: We conducted a retrospective cohort study, examining the primary outcome of myocarditis or pericarditis, or both, identified using the International Classification of Diseases diagnosis codes, occurring 1-7 days post-vaccination, evaluated in COVID-19 mRNA vaccinees aged 18-64 years using health plan claims databases in the USA. Observed (O) incidence rates were compared with expected (E) incidence rates estimated from historical cohorts by each database. We used multivariate Poisson regression to estimate the adjusted incidence rates, specific to each brand of vaccine, and incidence rate ratios (IRRs) comparing mRNA-1273 and BNT162b2. We used meta-analyses to pool the adjusted incidence rates and IRRs across databases. FINDINGS: A total of 411 myocarditis or pericarditis, or both, events were observed among 15 148 369 people aged 18-64 years who received 16 912 716 doses of BNT162b2 and 10 631 554 doses of mRNA-1273. Among men aged 18-25 years, the pooled incidence rate was highest after the second dose, at 1·71 (95% CI 1·31 to 2·23) per 100 000 person-days for BNT162b2 and 2·17 (1·55 to 3·04) per 100 000 person-days for mRNA-1273. The pooled IRR in the head-to-head comparison of the two mRNA vaccines was 1·43 (95% CI 0·88 to 2·34), with an excess risk of 27·80 per million doses (-21·88 to 77·48) in mRNA-1273 recipients compared with BNT162b2. INTERPRETATION: An increased risk of myocarditis or pericarditis was observed after COVID-19 mRNA vaccination and was highest in men aged 18-25 years after a second dose of the vaccine. However, the incidence was rare. These results do not indicate a statistically significant risk difference between mRNA-1273 and BNT162b2, but it should not be ruled out that a difference might exist. Our study results, along with the benefit-risk profile, continue to support vaccination using either of the two mRNA vaccines. FUNDING: US Food and Drug Administration.

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.

Comparison of adverse pregnancy and birth outcomes using archival medical records before and during the first wave of the COVID-19 pandemic in Kinshasa, Democratic Republic of Congo: a facility-based, retrospective cohort study.

BACKGROUND: Little research has been conducted on the impact of the coronavirus disease 2019 (COVID-19) pandemic on either birth outcomes or the ability of archival medical records to accurately capture these outcomes. Our study objective is thus to compare the prevalence of preterm birth, stillbirth, low birth weight (LBW), small for gestational age (SGA), congenital microcephaly, and neonatal bloodstream infection (NBSI) before and during the first wave of the COVID-19 pandemic in Kinshasa, Democratic Republic of Congo (DRC). METHODS: We conducted a facility-based retrospective cohort study in which identified cases of birth outcomes were tabulated at initial screening and subcategorized according to level of diagnostic certainty using Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) definitions. Documentation of any birth complications, delivery type, and maternal vaccination history were also evaluated. The prevalence of each birth outcome was compared in the pre-COVID-19 (i.e., July 2019 to February 2020) and intra-COVID-19 (i.e., March to August 2020) periods via two-sample z-test for equality of proportions. RESULTS: In total, 14,300 birth records were abstracted. Adverse birth outcomes were identified among 22.0% and 14.3% of pregnancies in the pre-COVID-19 and intra-COVID-19 periods, respectively. For stillbirth, LBW, SGA, microcephaly, and NBSI, prevalence estimates were similar across study periods. However, the prevalence of preterm birth in the intra-COVID-19 period was significantly lower than that reported during the pre-COVID-19 period (8.6% vs. 11.5%, p < 0.0001). Furthermore, the level of diagnostic certainty declined slightly across all outcomes investigated from the pre-COVID-19 to the intra-COVID-19 period. Nonetheless, diagnostic certainty was especially low for certain outcomes (i.e., stillbirth and NBSI) regardless of period; still, other outcomes, such as preterm birth and LBW, had moderate to high levels of diagnostic certainty. Results were mostly consistent when the analysis was focused on the facilities designated for COVID-19 care. CONCLUSION: This study succeeded in providing prevalence estimates for key adverse birth outcomes using GAIA criteria during the COVID-19 pandemic in Kinshasa, DRC. Furthermore, our study adds crucial real-world data to the literature surrounding the impact of the COVID-19 pandemic on maternal and neonatal services and outcomes in Africa.

HIV incidence in US first-time blood donors and transfusion risk with a 12-month deferral for men who have sex with men.

In 2015, the US Food and Drug Administration published revised guidance that recommended a change in blood donor deferral of men who have sex with men (MSM) from an indefinite to a 12-month deferral since the donor last had sex with a man. We assessed whether HIV incidence in first-time blood donors or associated transfusion risk increased. Donations in 4 major blood collection organizations were monitored for 15 months before and 2 years after implementation of the 12-month MSM deferral policy. HIV-positive donations were classified as recently acquired or long-term using a recent infection testing algorithm and incidence in both periods estimated. Residual transfusion transmission risk was estimated by multiplying incidence by the length of the infectious window period. The latter was estimated using a model based on infectious dose and the sensitivity of nucleic acid testing. Factors associated with incident infection in each period were assessed using Poisson regression. Overall HIV incidence in first-time donors before implementation of the 12-month MSM deferral was estimated at 2.62 cases per 100 000 person-years (105 PY) (95% credible interval [CI], 1.53-3.93 cases/105 PY), and after implementation at 2.85 cases/105 PY (95% CI, 1.96-3.93 cases/105 PY), with no statistically significant change. In male first-time donors, the incidence difference was 0.93 cases/105 PY (95% CI, -1.74-3.58 cases/105 PY). The residual risk of HIV transfusion transmission through components sourced from first-time donors was estimated at 0.32 transmissions per million (106) packed red blood cell transfusions (95% CI, 0.29-0.65 transmissions/106 transfusions) before and 0.35 transmissions/106 transfusions (95% CI, 0.31-0.65 transmissions/106 transfusions) after implementation. The difference was not statistically significant. Factors associated with incident infection were the same in each period. We observed no increase in HIV incidence or HIV transfusion transmission risk after implementation of a 12-month MSM deferral policy.

HIV antiretroviral therapy and prevention use in US blood donors: a new blood safety concern.

Antiretroviral therapy (ART) to treat and pre-exposure prophylaxis (PrEP) to prevent HIV infection are effective tools to help end the HIV epidemic. However, their use could affect HIV transfusion-transmission risk. Three different ART/PrEP prevalence analyses in blood donors were conducted. First, blood samples from HIV-positive and a comparison group of infection-nonreactive donors were tested under blind using liquid chromatography-tandem mass spectrometry for ART. Second, blood donor samples from infection-nonreactive, 18- to 45-year-old, male, first-time blood donors in 6 US locations were tested for emtricitabine and tenofovir. Third, in men who have sex with men (MSM) participating in the 2017 Centers for Disease Control and Prevention National HIV Behavioral Surveillance (NHBS) from 5 US cities, self-reported PrEP use proximate to donation was assessed. In blind testing, no ART was detected in 300 infection-nonreactive donor samples, but in 299 HIV confirmed-infected donor samples, 46 (15.4%; 95% confidence interval [CI], 11.5% to 20.0%) had evidence of ART. Of the 1494 samples tested from first-time male donors, 9 (0.6%; 95% CI, 0.03% to 1.1%) had tenofovir and emtricitabine. In the NHBS MSM survey, 27 of 591 respondents (4.8%; 95% CI, 3.2% to 6.9%) reported donating blood in 2016 or 2017 and PrEP use within the same time frame as blood donation. Persons who are HIV positive and taking ART and persons taking PrEP to prevent HIV infection are donating blood. Both situations could lead to increased risk of HIV transfusion transmission if blood screening assays are unable to detect HIV in donations from infected donors.

Early administration of COVID-19 convalescent plasma with high titer antibody content by live viral neutralization assay is associated with modest clinical efficacy.

The efficacy of COVID-19 convalescent plasma (CCP) as a treatment for hospitalized patients with COVID-19 remains somewhat controversial; however, many studies have not evaluated CCP documented to have high neutralizing antibody titer by a highly accurate assay. To evaluate the correlation of the administration of CCP with titer determined by a live viral neutralization assay with 7- and 28-day death rates during hospitalization, a total of 23 118 patients receiving a single unit of CCP were stratified into two groups: those receiving high titer CCP (>250 50% inhibitory dilution, ID50; n = 13 636) or low titer CCP (≤250 ID50; n = 9482). Multivariable Cox regression was performed to assess risk factors. Non-intubated patients who were transfused with high titer CCP showed 1.1% and 1.7% absolute reductions in overall 7- and 28-day death rates, respectively, compared to those non-intubated patients receiving low titer CCP. No benefit of CCP was observed in intubated patients. The relative benefit of high titer CCP was confirmed in multivariable Cox regression. Administration of CCP with high titer antibody content determined by live viral neutralization assay to non-intubated patients is associated with modest clinical efficacy. Although shown to be only of modest clinical benefit, CCP may play a role in the future should viral variants develop that are not neutralized by other available therapeutics.

HIV, HCV, and HBV incidence and residual risk in US blood donors before and after implementation of the 12-month deferral policy for men who have sex with men.

BACKGROUND: In December 2015, the men who have sex with men (MSM) deferral was reduced to 12 months in the United States. We compared human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) incidence and residual risk before and after this policy change using data from >50% of the US blood supply. STUDY DESIGN AND METHODS: Three estimation intervals from the Transfusion-Transmissible Infections Monitoring System were compared: 15-months pre- and two consecutive, nonoverlapping 15-month post-MSM deferral implementation. Repeat, first-time, and weighted all-donor incidences were estimated. Residual risk was calculated for all incidence estimates using the incidence/window-period method. RESULTS: HIV repeat donor incidence was 1.57 per 100 000 person-years (phtpy) in the second 15-month post change and not significantly different from pre-MSM incidence of 2.19 phtpy. Similar values were seen for HCV (1.49 phtpy vs 1.46 phtpy) and HBV (1.14 phtpy vs 0.97 phtpy). In some cases, higher estimated incidence, but without significant change from pre-MSM to the second post change period occurred for males and first-time donors (eg, first-time donors, second post change period: 6.12 phtpy HIV, 6.41 phtpy HCV and 5.34 phtpy HBV). Estimated per donation residual risk was 1:1.6 million for HIV, 1:2.0 million for HCV and 1:1.0 million for HBV based on weighted incidence for all donors. CONCLUSIONS: Repeat, first-time, and overall donor incidence did not vary significantly comparing pre-MSM to either of the post-MSM estimation intervals. Residual risk estimates vary by study, but all yield residual risks in the United States of ≤1 per million, and thus far have not shown increasing risk with the 12-month MSM policy change.

Use of a rapid electronic survey methodology to estimate blood donors' potential exposure to emerging infectious diseases: Application of a statistically representative sampling methodology to assess risk in US blood centers.

Risk assessments of transfusion-transmitted emerging infectious diseases (EIDs) are complicated by the fact that blood donors' demographics and behaviors can be different from the general population. Therefore, when assessing potential blood donor exposure to EIDs, the use of general population characteristics, such as U.S. travel statistics, may invoke uncertainties that result in inaccurate estimates of blood donor exposure. This may, in turn, lead to the creation of donor deferral policies that do not match actual risk. STUDY DESIGN AND METHODS: This article reports on the development of a system to rapidly assess EID risks for a nationally representative portion of the U.S. blood donor population. To assess the effectiveness of this system, a test survey was developed and deployed to a statistically representative sample frame of blood donors from five blood collecting organizations. Donors were directed to an online survey to ascertain their recent travel and potential exposure to Middle East respiratory syndrome coronavirus (MERS-CoV). RESULTS: A total of 7128 responses were received from 54 256 invitations. The age-adjusted estimated total number of blood donors potentially exposed to MERS-CoV was approximately 15 640 blood donors compared to a lower U.S. general population-based estimate of 9610 blood donors. CONCLUSION: The structured donor demographic sample-based data provided an assessment of blood donors' potential exposure to an emerging pathogen that was 63% larger than the U.S. population-based estimate. This illustrates the need for tailored blood donor-based EID risk assessments that provide more specific demographic risk intelligence and can inform appropriate regulatory decision making.

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.

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.

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.

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.

Development of dose-response models of Creutzfeldt-Jakob disease infection in nonhuman primates for assessing the risk of transfusion-transmitted variant Creutzfeldt-Jakob disease.

UNLABELLED: Estimates for the risk of transmitting variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion have relied largely on data from rodent experiments, but the relationship between dose (amount of infected blood) and response (vCJD infection) has never been well quantified. The goal of this study was to develop a dose-response model based on nonhuman primate data to better estimate the likelihood of transfusion-transmitted vCJD (TTvCJD) in humans. Our model used dose-response data from nonhuman primates inoculated intracerebrally (i.c.) with brain tissues of patients with sporadic and familial CJD. We analyzed the data statistically by using a beta-Poisson dose-response model. We further adjusted model parameters to account for the differences in infectivity between blood and brain tissue and in transmission efficiency between intravenous (i.v.) and i.c. routes to estimate dose-dependent TTvCJD infection. The model estimates a mean infection rate of 76% among recipients who receive one unit of whole blood collected from an infected donor near the end of the incubation period. The nonhuman primate model provides estimates that are more consistent with those derived from a risk analysis of transfused nonleukoreduced red blood cells in the United Kingdom than prior estimates based on rodent models. IMPORTANCE: TTvCJD was recently identified as one of three emerging infectious diseases posing the greatest immediate threat to the safety of the blood supply. Cases of TTvCJD were reported in recipients of nonleukoreduced red blood cells and coagulation factor VIII manufactured from blood of United Kingdom donors. As the quantity of abnormal prions (the causative agent of TTvCJD) varies significantly in different blood components and products, it is necessary to quantify the dose-response relationship for a wide range of doses for the vCJD agent in transfused blood and plasma derivatives. In this paper, we suggest the first mechanistic dose-response model for TTvCJD infection based on data from experiments with nonhuman primates. This new model may improve estimates of the possible risk to humans.

Posttransfusion purpura occurrence and potential risk factors among the inpatient US elderly, as recorded in large Medicare databases during 2011 through 2012.

BACKGROUND: Posttransfusion purpura (PTP) is a serious transfusion complication resulting in sudden thrombocytopenia with bleeding. The study's objective was to assess PTP occurrence and potential risk factors among the inpatient US elderly, ages 65 and older, during 2011 through 2012. STUDY DESIGN AND METHODS: This retrospective claims-based study utilized large Medicare databases for calendar years 2011 and 2012. Transfusions of blood and blood components were identified by recorded ICD-9-CM procedure codes and revenue center codes, and PTP was ascertained via ICD-9-CM diagnosis code. Our study evaluated PTP rates (per 100,000 inpatient transfusion stays) among elderly Medicare beneficiaries, overall and by age, sex, race, number of units, and blood components transfused. Multivariate regression analyses were used to assess potential risk factors. RESULTS: Among 4,336,338 inpatient transfusion stays for elderly beneficiaries during the study period, 78 had a PTP diagnosis code recorded, an overall rate of 1.8 per 100,000 stays. PTP occurrence varied by the blood components, units transfused, and other characteristics. Significantly higher odds of PTP were found for platelet (PLT)-containing transfusions, with greater number of units transfused, as well as for elderly with histories of cardiac arrhythmias (odds ratio [OR], 2.65; 95% confidence interval [CI], 1.43-4.93), coagulopathy (OR, 1.79; 95% CI, 1.01-3.21), leukemia (OR, 2.37; 95% CI, 1.07-5.26), transplant (OR, 2.68; 95% CI, 1.41-5.09), and other conditions. CONCLUSION: Our population-based study suggests a substantially higher PTP risk with PLT-containing transfusions. The study also suggests increased PTP risk with greater number of units transfused as well as the importance of underlying health conditions and prior recipient alloimmunization for PTP occurrence among the elderly.