Global Safety Assessment of Adverse Events of Special Interest Following 2 Years of Use and 772 Million Administered Doses of mRNA-1273.

Background: Large-scale use of mRNA COVID-19 vaccines during the pandemic was associated with enhanced safety monitoring to ensure accurate and timely review of safety. We reviewed the mRNA-1273 (original strain) safety profile following 2 years of use (>772 million administered doses), primarily focusing on predefined safety topics (ie, adverse events of special interest [AESIs]) proposed in advance of COVID-19 vaccine use. Methods: Cumulative mRNA-1273 safety data were included from spontaneous adverse event (AE) cases reported to Moderna's global safety database between 18 December 2020 and 17 December 2022. Reporting rates of AESIs were calculated per 1 million doses of mRNA-1273 administered. Observed-to-expected (OE) ratios were computed by comparing observed rates of AESIs with the background/expected rate for these events to evaluate potential associations with mRNA-1273. Results: There were 658 759 identified case reports associated with 2 517 669 AEs. Most AEs were nonserious (83.4%; 2 098 954/2 517 669). Overall 0.7% (17 751/2 517 669) were fatal. AESIs represented 13.7% of all AEs (344 921/2 517 669), with reporting rates for most AESIs below the expected background incidence. Exceptions included anaphylaxis (OE ratio 3 days after vaccination, 2.09; 95% CI, 1.93-2.25) and, among individuals aged 12 to 40 years, myocarditis (OE ratio 7 days after any dose, 3.89 [3.50-4.32]; among men after dose 2, 8.57 [6.88-10.68]) and pericarditis (OE ratio 7 days after vaccination, 3.47; 2.89-4.16). Conclusions: This safety analysis of mRNA-1273 identified evidence of increased risk for anaphylaxis, myocarditis, and pericarditis but not for other AESIs identified for enhanced monitoring ahead of COVID-19 vaccine use.

Analysis of Myocarditis Among 252 Million mRNA-1273 Recipients Worldwide.

BACKGROUND: Growing evidence indicates a causal relationship between SARS-CoV-2 infection and myocarditis. Post-authorization safety data have also identified myocarditis as a rare safety event following mRNA COVID-19 vaccination, particularly among adolescent and young-adult males after dose 2. We further evaluated the potential risk by querying the Moderna global safety database for myocarditis/myopericarditis reports among mRNA-1273 recipients worldwide. METHODS: Myocarditis/myopericarditis reports from 18 December 2020 to 15 February 2022 were reviewed and classified. The reported rate after any known mRNA-1273 dose was calculated according to age and sex, then compared with a population-based incidence rate to calculate observed-to-expected rate ratios (RRs). RESULTS: During the study period, 3017 myocarditis/myopericarditis cases among 252 million mRNA-1273 recipients who received at least 1 dose were reported to the Moderna global safety database. The overall reporting rate was 9.23 per 100 000 person-years, which was similar to the expected reference rate (9.0 cases per 100 000 person-years; RR [95% confidence interval (CI)], 1.03 [.97-1.08]). When stratified by sex and age, observed rates were highest for males aged <40 years, particularly those 18-24 years (53.76 per 100 000 person-years), which was higher than expected (RR [95% CI], 3.10 [2.68-3.58]). When considering only cases occurring within 7 days of a known dose, the observed rate was highest for males aged 18-24 years after dose 2 (4.23 per 100 000 doses administered). CONCLUSIONS: Myocarditis/myopericarditis rates were not higher than expected for the overall population of mRNA-1273 recipients but were higher than expected in males aged 18-24 years, with most cases occurring 7 days after dose 2.

A Brighton Collaboration standardized template with key considerations for a benefit/risk assessment for the Moderna COVID-19 Vaccine (mRNA-1273).

The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group has prepared standardized templates to describe the key considerations for the benefit-risk assessment of several vaccine platform technologies, including nucleic acid (RNA and DNA) vaccines. This paper uses the BRAVATO template to review the features of a vaccine employing a proprietary mRNA vaccine platform to develop Moderna COVID-19 Vaccine (mRNA-1273); a highly effective vaccine to prevent coronavirus disease 2019 (Covid-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In response to the pandemic the first in human studies began in March 2020 and the pivotal, placebo-controlled phase 3 efficacy study in over 30,000 adults began in July 2020. Based on demonstration of efficacy and safety at the time of interim analysis in November 2020 and at the time of trial unblinding in March 2021, the mRNA-1273 received Emergency Use Authorization in December 2020 and full FDA approval in January 2022.

Hepatic safety of the antifungal triazole agent posaconazole: characterization of adverse event reports in a manufacturer's safety database.

BACKGROUND: Second generation triazoles including posaconazole are efficacious for prophylaxis and salvage treatment of life-threatening invasive fungal diseases but have been associated with hepatic adverse events (AEs). This report evaluated hepatic AEs in posaconazole-treated patients. RESEARCH DESIGN AND METHODS: Hepatobiliary AEs occurring after posaconazole exposure in the company's global safety database were analyzed to characterize underlying medical conditions and concomitant drug exposure. RESULTS: As of October 2019, 516 cases (168 from clinical trials, 348 from postmarketing use) containing 618 hepatobiliary AEs were reported regardless of causality. Frequently reported terms were hyperbilirubinemia, hepatic failure, and hepatic function abnormal (clinical trial reports) and hepatotoxicity, hepatocellular injury, and hepatic function abnormal (postmarketing reports). Cases reporting concurrent medications associated with drug-induced liver injury (DILI) included 8% with verified severe DILI (vMost-DILI) concern, 24% with verified mild to moderate DILI (vLess-DILI) concern, and 37% received both vMost-DILI and vLess-DILI-concern medications in the DILIrank data set. CONCLUSIONS: Use of concomitant medications with known risks for hepatic injury appears to be an important contributor for the development of hepatotoxicity in patients treated with posaconazole.

Integrative Analysis of Randomized Clinical Trial and Observational Study Data to Inform Post-marketing Safety Decision-Making.

Safety evaluation is a continual and iterative process throughout the drug development life cycle and requires long time horizons and large amounts of data to fully understand the safety profile of a medical product. Although randomized clinical trials (RCT) provide high-quality data for an initial assessment of safety signals, the safety signals may not all have been known at the time of approval because safety data collected from RCT only involve a relatively small number of subjects during a relatively short follow-up period. The increased accumulation of post-marketing real-world data (RWD) presents an opportunity to utilize them for safety decision-making; these include identifying new safety signals, further characterization of safety concerns that are raised in pre-marketing RCT, and further generalization of RCT findings to the broader patient populations not previously studied in RCT. In this paper, we use cardiovascular safety outcome trial for antidiabetic therapies as an illustrative example and discuss how integrative analysis of RCT and observational study data can answer regulatory concerns about cardiovascular risk in a post-marketing setting. A novel statistical analysis strategy is proposed to combine both sources of safety data in a data fusion approach. The proposed approach includes three stages: (1) feasibility analysis that uses an RCT to validate an observational study, applying estimand framework and emulating RCT with RWD; (2) integrative analysis that combines evidence from the RCT and observational study data cooperatively; and (3) sensitivity analysis that examines the consistency of the previous analyses. Two potential utilities of the proposed integrative analysis for the cardiovascular safety outcome trial are discussed.

A Health Literate Patient-focused Approach to the Redesign of the Raltegravir (ISENTRESS) Pediatric Kit and Instructions for Use.

BACKGROUND: Limited data exist regarding how medications for pediatric use can be developed to minimize medication errors. The integrase inhibitor raltegravir was developed for use in neonates (≥2 kg). Anticipating that neonatal administration would be performed primarily by mothers with varying degrees of health literacy, a health literate, patient-focused, iterative process was conducted to update/redesign the raltegravir granules for oral suspension pediatric kit and instructions for use (IFU) for neonatal use to be ready for regulatory submission. METHODS: Prototypes of an updated/redesigned raltegravir IFU were systematically assessed through multi-stage, iterative testing and evaluation involving untrained lay individuals with varying levels of health literacy, healthcare professionals and health literacy experts. RESULTS: This iterative process resulted in numerous refinements to the IFU and kit, including wording, layout, presentation, colored syringes and additional instructional steps. The revised raltegravir pediatric kit and IFU (to include neonatal dosing) were approved by the US Food and Drug Administration in 2017 and the European Union in 2018. No reported medication errors related to IFU utilization had been reported as of March 2021, reflecting >3 years of commercial use worldwide. CONCLUSIONS: This patient-focused process produced health literate instructions for preparing and administering an antiretroviral for neonatal use with complex dosing requirements. Testing demonstrated that lay users with a range of health literacy levels were able to accurately mix, measure and administer the product. This process demonstrates how a neonatal medication can be optimized for use through collaboration between the infectious disease expert community and a manufacturer.

Varicella Virus Vaccine Live: A 22-Year Review of Postmarketing Safety Data.

BACKGROUND: Varicella, a contagious infectious disease caused by varicella zoster virus (VZV), can result in hospitalization and, occasionally, death. Varicella virus vaccine live (VVVL [VARIVAX]) was introduced in the United States in 1995. METHODS: This comprehensive review of the VVVL safety profile is based on 22 years of postmarketing adverse event (AE) data received through spontaneous and noninterventional study reports submitted by health care providers and on a review of the published literature (cumulatively from March 17, 1995, through March 16, 2017, during which period >212 million doses were distributed globally). RESULTS: The VVVL safety profile was consistent with previous publications, with common AEs including varicella, rash, and pyrexia. AE reports have decreased over time, from ~500 per million doses in 1995 to ~40 per million doses in 2016; serious AEs comprise 0.8 reports per million doses. Secondary transmission was rare (8 confirmed cases); polymerase chain reaction analysis indicated that 38 of the 66 reported potential secondary transmission cases of varicella were attributable to wild-type VZV. The prevalence of major birth defects in the Pregnancy Registry was similar to that in the general US population. In total, 86 cases of death were reported after vaccination with VVVL; immunocompromised individuals appeared to be most at risk for a fatal varicella- or herpes zoster-related outcome. CONCLUSIONS: This comprehensive 22-year review confirms the overall safety profile for VVVL, with no new safety concerns identified. Since VVVL's introduction in 1995, notable declines in varicella cases and in varicella-related deaths have occurred compared with the prevaccination period.

Evaluation of Neural Tube Defects (NTDs) After Exposure to Raltegravir During Pregnancy.

OBJECTIVE: To evaluate the risk of neural tube defects (NTDs) after exposure to raltegravir during pregnancy. METHODS: Exposures to raltegravir during pregnancy reported cumulatively through May 31, 2018, to the company safety database were reviewed to identify cases of NTDs. This database includes all reports of pregnancy from Merck-sponsored clinical trials, spontaneous postmarketing reports, and non-interventional data sources, including the Antiretroviral Pregnancy Registry (APR). Reports were classified as prospective (before knowledge of pregnancy outcome) or retrospective (after knowledge of pregnancy outcome). We also reviewed data from 2 ongoing pregnancy cohorts. RESULTS: A total of 2426 pregnancies with reported outcomes were identified among women exposed to raltegravir: 1238 from the Merck database and 1188 from United Kingdom/Ireland and French pregnancy cohorts. Among all 2426 reports, 1991 were prospective. No cases of NTDs were identified among the prospective pregnancy reports, of which 767 were first trimester, including 456 in the periconception period (at or within 28 days after conception). Among the 435 retrospective reports, 3 NTD cases per APR criteria were identified (anencephaly, and 2 meningomyelocele), of which only one (meningomyelocele) was among exposures in the periconception period. Given the inherent limitations and bias of retrospective reports, it is not appropriate to calculate an incidence rate. CONCLUSIONS: Prospectively collected pregnancy outcome data do not suggest an association between raltegravir exposure in the periconception period and NTDs. The current data support the updated DHHS and EACS treatment guidelines for use of raltegravir as a preferred integrase inhibitor in all stages of pregnancy.

Turning up the heat: Effect of new vaccine for children's (VFC) program recommendations for use of temperature monitors upon incorrect product storage adverse event reporting.

BACKGROUND: The Centers for Disease Control and Prevention (CDC) coordinates the Vaccines For Children (VFC) program, which provides free vaccines to qualified children in the US. In 2009, the CDC issued Vaccine Storage Requirements, which were later replaced (2012) with an interim guidance and toolkit for vaccine storage and handling. The guidance called for use of Digital Data Loggers (DDL) to monitor vaccine storage temperatures. We describe a change in frequency of Incorrect Product Storage Reports (IPSRs) following issuance of the 2009 CDC guidance. METHODS: Merck & Co., Inc., Kenilworth, NJ, USA, systematically evaluates vaccine safety concerns for all products. The safety database was queried (01-Jan-2004 through 31-December-2016) to identify all IPSRs associated with 10 vaccines. We compared IPSRs received prior to and following the 2009 CDC guidance, comparing reports received from the US with those received from international sources during the same period. RESULTS: Following the release of the DDL guidance, a progressive increase in IPSRs was identified in the US (1 report received in 2004, 12,993 reports in 2016). In contrast, non-US IPSRs - have not had a similar increase: no reports received in 2004, 216 reports received in 2016. US reports of IPSRs 2004 through 2016 account for 96% of reports worldwide. There were no serious reports found in the database in conjunction with IPSRs, nor were there any additional safety findings in any of the reports with additional events reported. CONCLUSION: VFC DDL guidance was followed by an increase in IPSRs. No similar trend was seen outside the US (where no broad change in DDL guidance occurred). Despite the increase in IPSRs, there have been few associated adverse events (AEs) reported; no new safety concerns were identified. These findings suggest that the increase in IPSRs was associated with the introduction of use of DDLs, and suggests the need for further impact assessment.

Osteoarthritis patients with pain improvement are highly likely to also have improved quality of life and functioning. A post hoc analysis of a clinical trial.

BACKGROUND: This analysis evaluated whether osteoarthritis patients achieving the greatest pain control and lowest pain states also have the greatest improvement in functioning and quality of life. METHODS: Patients (n=419) who failed prior therapies and who were switched to etoricoxib 60mg were categorized as pain responders or non-responders at 4 weeks based on responder definitions established by the Initiative on Methods, Measurement, and Pain (IMMPACT) criteria, including changes from baseline of ≥15%, ≥30%, ≥50%, ≥70% and a final pain status of ≤3/10 (no worse than mild pain). Pain was assessed at baseline and 4 weeks using 4 questions from the Brief Pain Inventory (BPI) (worst pain, least pain, average pain, and pain right now), and also using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale. We examined the relationship between pain responses with changes from baseline in two functional measures (the BPI Pain Interference questions and the WOMAC Function Subscale) as well as changes from baseline in quality of life (assessed on the SF-36 Physical and Mental Component Summaries). We also sought to understand whether these relationships were influenced by the choice of the pain instrument used to assess response. We contrast the mean difference in improvements in the functional and quality of life instruments based on pain responder status (responder versus non-responder) and the associated 95% confidence limits around this difference. RESULTS: Patients with better pain responses were much more likely to have improved functional responses and improved quality of life, with higher mean changes in these outcomes versus pain non-responders, regardless of the choice of IMMPACT pain response definition (e.g., using any of 15%, 30%, 50%, 70% change from baseline) or the final pain state of ≤3/10. There was an evident gradient, where higher levels of pain response were associated with greater mean improvements in function and quality of life. The finding that greater pain responses led to greater functional improvements and quality of life gains was not dependent on the manner in which pain was evaluated. Five different pain instruments (e.g., the 4 questions on pain from the BPI pain questionnaire and the WOMAC pain subscale) consistently demonstrated that pain responders had statistically significantly greater improvements in function and quality of life compared to pain non-responders. This suggests these results are likely to be generalizable to any validated pain measure for osteoarthritis. CONCLUSIONS: Pain is an efficient outcome measure for predicting broader patient response in osteoarthritis. Patients who do not achieve timely, acceptable pain states over 4 weeks were less likely to experience functional or quality of life improvements. IMPLICATIONS: Good pain improvements in osteoarthritis with a valid pain instrument are a proxy for good improvements in both function and quality of life. Therefore proper osteoarthritis pain assessment can lead to efficient evaluations in the clinic.

Burden of childhood rotavirus disease on health systems in the United States.

BACKGROUND: To determine the burden of rotavirus disease before the introduction of rotavirus vaccines. METHODS: From February 2005 to June 2006, prospective rotavirus surveillance was conducted in Cincinnati, Ohio, and Durham, North Carolina. Children < 5 years of age presenting at hospitals and outpatient clinics with acute gastroenteritis (AGE) of < 72 hours duration were enrolled. Stool samples were first tested for rotavirus by EIA and the VP7 type was determined by RT-polymerase chain reaction for rotavirus-positive samples. Medical costs were obtained from billing or accounting data. RESULTS: A total of 1998 children were enrolled, with a mean age of 16.9 months. Among 1601 (80%) patients with a stool specimen, 44% were rotavirus positive. The rotavirus detection rate was 38% for patients admitted to hospital, 60% for patients requiring a short-stay hospital visit (< 24 hour hospitalization), 49% for emergency department visits, and 37% for outpatient visits. During the rotavirus season, rotavirus accounted for 56% of all AGE cases. Only 11% of rotavirus-positive children were assigned the rotavirus-specific ICD-9-CM code and this proportion varied considerably by clinical setting. The VP7 genotypes identified were G1, 79%; G2, 14%; G3, 5%; G9, 1%; and G12, 1%. For children hospitalized with rotavirus, the estimated median direct cost was $4565, the average length of stay was 1.9 days, and parents lost 3.4 days of work. For short-stay, emergency department, and outpatient visits, the estimated median costs were $3160, $867, and $75, respectively. CONCLUSIONS: Before the widespread use of rotavirus vaccines in the United States, rotavirus was prevalent among children treated in hospital-based and outpatient settings and was associated with a substantial proportion of pediatric medical visits for AGE.

International epidemiology of human pre-existing adenovirus (Ad) type-5, type-6, type-26 and type-36 neutralizing antibodies: correlates of high Ad5 titers and implications for potential HIV vaccine trials.

Replication-defective adenoviruses have been utilized as candidate HIV vaccine vectors. Few studies have described the international epidemiology of pre-existing immunity to adenoviruses. We enrolled 1904 participants in a cross-sectional serological survey at seven sites in Africa, Brazil, and Thailand to assess neutralizing antibodies (NA) for adenovirus types Ad5, Ad6, Ad26 and Ad36. Clinical trial samples were used to assess NA titers from the US and Europe. The proportions of participants that were negative were 14.8% (Ad5), 31.5% (Ad6); 41.2% (Ad26) and 53.6% (Ad36). Adenovirus NA titers varied by geographic location and were higher in non-US and non-European settings, especially Thailand. In multivariate logistic regression analysis, geographic setting (non-US and non-European settings) was statistically significantly associated with having higher Ad5 titers; participants from Thailand had the highest odds of having high Ad5 titers (adjusted OR=3.53, 95% CI: 2.24, 5.57). Regardless of location, titers of Ad5NA were the highest and Ad36 NA were the lowest. Coincident Ad5/6 titers were lower than either Ad5 or Ad6 titers alone. Understanding pre-existing immunity to candidate vaccine vectors may contribute to the evaluation of vaccines in international populations.

Effectiveness of a bivalent Haemophilus influenzae type B-hepatitis B vaccine in preventing hepatitis B virus infection among children born to hepatitis B e antigen-positive carrier mothers.

BACKGROUND: This observational study evaluated a modified immunoprophylactic regimen (hepatitis B immune globulin [HBIG]) and a dose of thimerosal-free monovalent hepatitis B (HB) vaccine shortly after birth followed by doses of thimerosal-free bivalent Haemophilus influenzae type b (Hib)-HB vaccine at 2 and 4 months of age, and a booster at 12 months of age) in infants at high risk of hepatitis B virus (HBV) infection (mothers HBeAg+). METHODS: Children >or=6 months of age vaccinated in routine clinical practice were tested twice (>or=6 months apart) for HBV antigens surface antigen (HBsAg) and "e" antigen, and for antibody to HBsAg. Partial nucleotide sequence analysis was performed on HBV DNA isolated from infants identified with a breakthrough chronic HBV infection. A fully sequential statistical design was used to maximize patient safety and study efficiency. RESULTS: Four of 60 children developed chronic HBV infection despite vaccination, but at no point did the cumulative number of cases reach the boundary of statistical significance. Overall, the analysis adjusted for sequential testing yielded an estimated breakthrough rate of 6.7% (90% CI: 2.3%-14.6%). In a subset of uninfected children tested for antibody to HBsAg 1 to 4 months after the second dose of Hib-HB vaccine, 90% (9/10) had >or=10 milli-International Units per milliliter (mIU/mL). The third dose of Hib-HB vaccine induced a secondary increase in the level of antibody; 94.7% (18/19) of a second group developed >or=100 mIU/mL, with a geometric mean concentration of 771 mIU/mL (95% CI: 351.4-1692.1 mIU/mL). CONCLUSION: The tested regimen is comparably effective to historical experience with a standard one employing HBIG plus monovalent thimerosal-containing HB vaccine given at 0, 1, and 6 months of age.

Incidence of and preoperative risk factors for Staphylococcus aureus bacteremia and chest wound infection after cardiac surgery.

OBJECTIVE: Staphylococcus aureus infections after cardiac surgery result in significant morbidity and mortality. Identifying patients at elevated risk for these infections preoperatively could facilitate efforts to reduce infection rates. The objectives of this study were to estimate the incidence of postoperative S. aureus infections in cardiac surgery patients, to identify preoperative risk factors for these infections, and to establish a patient risk profile by means of data available to clinicians prior to surgery. DESIGN: Cohort study. SETTING: Eight medical centers that participate in the Society of Thoracic Surgeons National Cardiac Database. PATIENTS: Patients who were undergoing elective cardiac surgery during the period January 1, 2000 through December 31, 2004. METHODS: Clinical and microbiological data from 16,386 patients were combined. Multivariable stepwise logistic regression analysis was performed to predict S. aureus infection, which was defined by culture results. RESULTS: Of the 16,386 patients, 205 (1.3%) developed S. aureus bloodstream or chest wound infection within 90 days after surgery. On multivariable analysis, bootstrap-validated preoperative risk factors for S. aureus bloodstream or chest wound infection included a body mass index greater than 40 (adjusted odds ratio [aOR], 1.9 [95% confidence interval {CI}, 1.1-3.2]), chronic renal failure (aOR, 1.8 [95% CI, 1.1-2.9]), and chronic lung disease (aOR, 1.4 [95% CI, 1.0-2.0]). Only 8 patients had all 3 risk factors. CONCLUSIONS: Although preoperative risk factors can be easily identified, the majority of patients who developed S. aureus infections after cardiac surgery did not have any risk factors. Preventive measures should not be restricted to a select group of cardiac surgery patients and should rather address the entire patient population.

Detection of HIV vaccine-induced cell-mediated immunity in HIV-seronegative clinical trial participants using an optimized and validated enzyme-linked immunospot assay.

An effective vaccine for HIV is likely to require induction of T-cell-mediated immune responses, and the interferon-gamma (IFNgamma) enzyme-linked immunospot (ELISPOT) assay has become the most commonly used assay for measuring these responses in vaccine trials. We optimized and validated the HIV ELISPOT assay using an empirical method to establish positivity criteria that results in a < or =1% false-positive rate. Using this assay, we detected a broad range of HIV-specific ELISPOT responses to peptide pools of overlapping 20mers, 15mers, or 9mers in study volunteers receiving DNA- or adenovirus vector-based HIV vaccines and in HIV-seropositive donors. We found that 15mers generally had higher response magnitudes than 20mers and lower false-positive rates than 9mers. These studies show that our validated ELISPOT assay using 15mer peptide pools and the positivity criteria of > or =55 spots per 10(6) cells and > or =4-fold over mock (negative control) is a sensitive and specific assay for the detection of HIV vaccine-induced cell-mediated immunity.

Estimating the benefit of an HIV-1 vaccine that reduces viral load set point.

Vaccines designed to induce cell-mediated immune responses against human immunodeficiency virus (HIV)-1 are being developed. Such vaccines are unlikely to provide sterilizing immunity but may be associated with reduced viral set points after infection. We modeled the potential impact of a vaccine that reduces viral set point after infection, using natural history data from 311 HIV-1 seroconverters. Log-normal parametric regression models were used to estimate the log median time to events of interest. Relative times were estimated for those with viral load set points of 30,000 copies/mL (reference group) versus those with lower viral set points. The time to key clinical events in the course of HIV-1 disease progression was significantly extended for those with viral set points 0.5-1.25 log(10) copies/mL lower than the reference group. By quantifying the anticipated clinical benefits associated with a reduction in viral set point, these findings support the use of virologic end points in HIV-1 vaccine trials.

Cross-clade reactivity of HIV-1-specific T-cell responses in HIV-1-infected individuals from Botswana and Cameroon.

An effective HIV type 1 (HIV-1) vaccine will likely require elicitation of broadly reactive cell-mediated immune (CMI) responses against divergent HIV-1 clades. We compared anti-HIV-1 T-cell immune responses among 363 unvaccinated adults infected with diverse HIV-1 clades. Response rates to clade B Gag and/or clade B Nef in Botswana (95%) and Cameroon (98%) were similar when compared with those in countries previously studied, including Brazil (92%), Thailand (96%), South Africa (96%), Malawi (100%), and the United States (100%). Substantial cross-clade cell-mediated immune responses in Botswana and Cameroon confirm previous findings in a larger, more genetically diverse collection of HIV-1 samples.

An evaluation of a patient-reported outcomes found computerized adaptive testing was efficient in assessing osteoarthritis impact.

BACKGROUND AND OBJECTIVES: Evaluate a patient-reported outcomes questionnaire that uses computerized adaptive testing (CAT) to measure the impact of osteoarthritis (OA) on functioning and well-being. MATERIALS AND METHODS: OA patients completed 37 questions about the impact of OA on physical, social and role functioning, emotional well-being, and vitality. Questionnaire responses were calibrated and scored using item response theory, and two scores were estimated: a Total-OA score based on patients' responses to all 37 questions, and a simulated CAT-OA score where the computer selected and scored the five most informative questions for each patient. Agreement between Total-OA and CAT-OA scores was assessed using correlations. Discriminant validity of Total-OA and CAT-OA scores was assessed with analysis of variance. Criterion measures included OA pain and severity, patient global assessment, and missed work days. RESULTS: Simulated CAT-OA and Total-OA scores correlated highly (r = 0.96). Both Total-OA and simulated CAT-OA scores discriminated significantly between patients differing on the criterion measures. F-statistics across criterion measures ranged from 39.0 (P < .001) to 225.1 (P < .001) for the Total-OA score, and from 40.5 (P < .001) to 221.5 (P < .001) for the simulated CAT-OA score. CONCLUSIONS: CAT methods produce valid and precise estimates of the impact of OA on functioning and well-being with significant reduction in response burden.