Safety and Immunogenicity of the mRNA-1273 COVID-19 Vaccine in Solid Organ Transplant Recipients.

BACKGROUND: Immunosuppressed individuals, including solid organ transplant recipients (SOTRs), are at high risk for severe COVID-19. METHODS: This open-label, phase 3b trial evaluated mRNA-1273 in 137 adult kidney and 77 liver SOTRs and 20 immunocompetent participants. In Part A, SOTRs received three 100-µg doses of mRNA-1273; immunocompetent participants received 2 doses. In Part B, an additional 100-µg dose was offered ≥4 months post-primary series. Here, we report interim trial results. RESULTS: mRNA-1273 was well-tolerated in SOTRs. Four serious adverse events were considered vaccine-related by the investigator in 3 SOTRs with pre-existing comorbidities. No vaccine-related biopsy-proven organ rejection events or deaths were reported. mRNA-1273 elicited modest neutralizing antibody (nAb) responses after dose 2 and improved responses after dose 3 in SOTRs. Post-dose 3 responses among liver SOTRs were comparable to post-dose 2 responses in immunocompetent participants. Post-additional dose responses were increased in SOTRs regardless of the primary series vaccination. In liver SOTRs, post-additional dose responses were ∼3-fold higher versus post-dose 2 but were lower than immunocompetent participant responses. Most kidney SOTRs received multiple immunosuppressants and had reduced antibody responses versus liver SOTRs. CONCLUSIONS: mRNA-1273 (100 µg) was well-tolerated and dose 3 and the additional dose improved antibody responses among SOTRs.

Associations of Immunogenicity and Reactogenicity After Severe Acute Respiratory Syndrome Coronavirus 2 mRNA-1273 Vaccine in the COVE and TeenCOVE Trials.

BACKGROUND: The reactogenicity and immunogenicity of coronavirus disease 2019 (COVID-19) vaccines are well studied. Little is known regarding the relationship between immunogenicity and reactogenicity of COVID-19 vaccines. METHODS: This study assessed the association between immunogenicity and reactogenicity after 2 mRNA-1273 (100 µg) injections in 1671 total adolescent and adult participants (≥12 years) from the primary immunogenicity sets of the blinded periods of the Coronavirus Efficacy (COVE) and TeenCOVE trials. Associations between immunogenicity through day 57 and solicited adverse reactions (ARs) after the first and second injections of mRNA-1273 were evaluated among participants with and without solicited ARs using linear mixed-effects models. RESULTS: mRNA-1273 reactogenicity in this combined analysis set was similar to that reported for these trials. The vaccine elicited high neutralizing antibody (nAb) geometric mean titers (GMTs) in evaluable participants. GMTs at day 57 were significantly higher in participants who experienced solicited systemic ARs after the second injection (1227.2 [1164.4-1293.5]) than those who did not (980.1 [886.8-1083.2], P = .001) and were associated with fever, chills, headache, fatigue, myalgia, and arthralgia. Significant associations with local ARs were not found. CONCLUSIONS: These data show an association of systemic ARs with increased nAb titers following a second mRNA-1273 injection. While these data indicate systemic ARs are associated with increased antibody titers, high nAb titers were observed in participants after both injections, consistent with the immunogenicity and efficacy in these trials. These results add to the body of evidence regarding the relationship of immunogenicity and reactogenicity and can contribute toward the design of future mRNA vaccines.

Classical and Bayesian random-effects meta-analysis models with sample quality weights in gene expression studies.

BACKGROUND: Random-effects (RE) models are commonly applied to account for heterogeneity in effect sizes in gene expression meta-analysis. The degree of heterogeneity may differ due to inconsistencies in sample quality. High heterogeneity can arise in meta-analyses containing poor quality samples. We applied sample-quality weights to adjust the study heterogeneity in the DerSimonian and Laird (DSL) and two-step DSL (DSLR2) RE models and the Bayesian random-effects (BRE) models with unweighted and weighted data, Gibbs and Metropolis-Hasting (MH) sampling algorithms, weighted common effect, and weighted between-study variance. We evaluated the performance of the models through simulations and illustrated application of the methods using Alzheimer's gene expression datasets. RESULTS: Sample quality adjusting within study variance (wP6) models provided an appropriate reduction of differentially expressed (DE) genes compared to other weighted functions in classical RE models. The BRE model with a uniform(0,1) prior was appropriate for detecting DE genes as compared to the models with other prior distributions. The precision of DE gene detection in the heterogeneous data was increased with the DSLR2wP6 weighted model compared to the DSLwP6 weighted model. Among the BRE weighted models, the wP6weighted- and unweighted-data models and both Gibbs- and MH-based models performed similarly. The wP6 weighted common-effect model performed similarly to the unweighted model in the homogeneous data, but performed worse in the heterogeneous data. The wP6weighted data were appropriate for detecting DE genes with high precision, while the wP6weighted between-study variance models were appropriate for detecting DE genes with high overall accuracy. Without the weight, when the number of genes in microarray increased, the DSLR2 performed stably, while the overall accuracy of the BRE model was reduced. When applying the weighted models in the Alzheimer's gene expression data, the number of DE genes decreased in all metadata sets with the DSLR2wP6weighted and the wP6weighted between study variance models. Four hundred and forty-six DE genes identified by the wP6weighted between study variance model could be potentially down-regulated genes that may contribute to good classification of Alzheimer's samples. CONCLUSIONS: The application of sample quality weights can increase precision and accuracy of the classical RE and BRE models; however, the performance of the models varied depending on data features, levels of sample quality, and adjustment of parameter estimates.

Interim analysis of a phase 1 randomized clinical trial on the safety and immunogenicity of the mRNA-1283 SARS-CoV-2 vaccine in adults.

This interim analysis of an ongoing phase 1 randomized clinical trial evaluated the safety, reactogenicity, and immunogenicity of mRNA-1283, a next-generation SARS-CoV-2 messenger RNA (mRNA)-based vaccine encoding two segments of the spike protein (i.e. receptor binding and N-terminal domains). Healthy adults aged 18-55 years (n = 104) were randomized (1:1:1:1:1) to receive two doses of mRNA-1283 (10, 30, or 100 µg) or mRNA-1273 (100 µg) administered 28 days apart, or a single dose of mRNA-1283 (100 µg). Safety was assessed and immunogenicity was measured by serum neutralizing antibody (nAb) or binding antibody (bAb) responses. At the interim analysis, no safety concerns were identified and no serious adverse events, adverse events of special interest, or deaths were reported. Solicited systemic adverse reactions were more frequent with higher dose levels of mRNA-1283 than with mRNA-1273. At day 57, all dose levels of the 2-dose mRNA-1283 regimen (including the lowest dose level [10 µg]) induced robust nAb and bAb responses that were comparable to those of mRNA-1273 (100 µg). mRNA-1283 was generally safe in adults, with all dose levels of the 2-dose regimen (10, 30, and 100 µg) eliciting similar immunogenicity as the 2-dose mRNA-1273 regimen (100 µg).Clinical Trials Registration: Clinicaltrials.gov, NCT04813796.

Associations of antiretroviral therapy and comorbidities with neurocognitive outcomes in HIV-1-infected patients.

OBJECTIVE: The aim of this study was to evaluate associations of antiretroviral therapy (ART) and comorbidities with neurocognitive impairments (NCIs) in ART-naive HIV-1-infected patients in clinical practice. DESIGN: A retrospective study was conducted in ART-naive patients with HIV-1 diagnosis between January 2009 and December 2013 in the United States. METHODS: The primary outcome was any NCI that included HIV-associated neurocognitive disorders (HAND), Alzheimer's disease, Parkinson's disease, multiple sclerosis, and other dementias. RESULTS: A total of 47 862 patients met eligibility criteria (30 828 antiretroviral-treated and 17 034 antiretroviral-untreated). The median age was 45 years [interquartile range (IQR) 35--52] with 31% of patients aged at least 50 years. Seventy-five percent were men. Overall, ART was associated with reduced risks of any NCI (hazard ratio 0.41, 95% CI: 0.37--0.45), HAND (hazard ratio 0.57, 95% CI: 0.48--0.69), Alzheimer's disease (hazard ratio 0.36, 95% CI: 0.24--0.54), Parkinson's disease (hazard ratio 0.36, 95% CI: 0.25--0.51), multiple sclerosis (hazard ratio 0.26, 95% CI: 0.18--0.37), and other dementias (hazard ratio 0.50, 95% CI: 0.45--0.55). Meanwhile, the risk of any NCI was significantly increased in patients with various comorbidities including cardiac arrhythmia, paralysis, other neurological disorders, complicated diabetes, hypothyroidism, renal failure, lymphoma, rheumatoid arthritis, weight loss, and depression as compared with patients without those comorbidities. CONCLUSION: ART may reduce the risk of NCIs in HIV-infected patients in general. Further research to investigate NCIs on specific antiretroviral regimens and comorbidities may provide insights regarding the long-term clinical care of these patients.

Relationships Among Fatigue, Anxiety, Depression, and Pain and Health-Promoting Lifestyle Behaviors in Women With Early-Stage Breast Cancer.

BACKGROUND: With a nearly 89% 5-year survival rate for women with early-stage breast cancer, symptoms are a priority. Healthy lifestyle behaviors may be temporally associated with symptoms; however, evidence is lacking. OBJECTIVE: This research examined temporal relationships among healthy lifestyle behaviors and symptoms in women diagnosed with breast cancer receiving chemotherapy. METHODS: This research was part of a study (R01NR012667) approved by the institutional review board. Women (n = 76) providing written informed consent participated in this longitudinal study examining health-promoting lifestyle behaviors and symptoms (fatigue, anxiety, depression, and pain). Participants completed well-validated self-report questionnaires primarily at a clinic visit. Statistical methods included descriptive statistics, linear mixed-effects models, and pairwise comparisons using SAS 9.4; α was set at .05. RESULTS: Lowest healthy lifestyle behavior scores for physical activity and highest scores for spiritual growth were reported. Significant changes in physical activity and stress management were noted. Fatigued patients had lower physical activity and nutrition scores than did patients without fatigue. Patients with anxiety had lower spiritual growth and interpersonal relation scores than did patients without anxiety. Relationships demonstrated temporal differences. CONCLUSIONS: Breast cancer survivors did not routinely engage in healthy lifestyle behaviors. Significant temporal changes in healthy lifestyle behaviors and symptoms and significant associations among healthy lifestyle behaviors, symptoms, and demographic and clinical factors were noted in this study. IMPLICATIONS FOR PRACTICE: Knowing the temporal relationships among these variables provides insight that could be useful for nurses so they can encourage healthy lifestyle behaviors to mitigate symptoms throughout the cancer trajectory.

Analysis of Delays in Breast Cancer Treatment and Late-Stage Diagnosis in Kazakhstan

Objective: Although Kazakhstan has made significant investments to improve health and life expectancy of its population, high cancer rates persist, with breast cancer being the most prevalent type. Factors contributing to delays in treatment and late staging for breast cancer patients were assessed. Methods: A retrospective follow-up study with registry data identified 4,248 breast cancer patients in sixteen regions of Kazakhstan in 2014. We used logistic regressions to estimate (i) associations of treatment delays with patient demographics and cancer center regions; and (ii) associations of late-stage (III and IV) cancer diagnosis with patient demographics and cancer center regions, with and without controlling for treatment delays. Results: Breast cancer patients treated in regions located further away from Almaty City had higher risks of treatment delays. However, the risks of late-stage cancer diagnosis were greater for patients treated in Almaty City and those with treatment delays. Conclusion: The main driver of delayed treatment is cancer center region. Residents of Almaty City, a major urban area of Kazakhstan, may have a better access to a tertiary cancer center, resulting in less treatment delays. Referrals of sicker patients from neighboring regions to Almaty City for cancer treatment is likely to increase risks of late-stage diagnosis. New or upgraded cancer centers may reduce treatment delays, but their case-mix is likely to increase.