Safety and immunogenicity of intramuscular, single-dose V590 (rVSV-SARS-CoV-2 Vaccine) in healthy adults: Results from a phase 1 randomised, double-blind, placebo-controlled, dose-ranging trial.

BACKGROUND: Vaccines against COVID-19 are needed to overcome challenges associated with mitigating the global pandemic. We report the safety and immunogenicity of V590, a live recombinant vesicular stomatitis virus-based COVID-19 vaccine candidate. METHODS: In this placebo-controlled, double-blind, three-part phase 1 study, healthy adults were randomised to receive a single intramuscular dose of vaccine or placebo. In Part 1, younger (18-54 years) and, in Part 2, older (≥55 years) adults seronegative for SARS-CoV-2 nucleocapsid received one of four V590 dose levels (5.00 × 105; 2.40 × 106; 1.15 × 107; or 5.55 × 107 plaque-forming units [pfu]) or placebo. In Part 3, a single V590 dose level (5.55 × 107 pfu) or placebo was administered to younger SARS-CoV-2 seropositive adults. Primary endpoints included adverse events (AEs) and for Parts 1 and 2 anti-SARS-CoV-2 serum neutralising antibody responses measured by 50% plaque reduction neutralisation (PRNT50) assay at Day 28. Registration NCT04569786 [P001-02]. FINDINGS: 232 participants were randomised and 219 completed the study. In seronegative participants, anti-SARS-CoV-2 spike-specific antibody responses to V590 were low and comparable to placebo across the lower dose levels. At the highest dose level (5.55 × 107 pfu), anti-SARS-CoV-2 spike-specific PRNT50 was 2.3-fold higher than placebo. The most frequently reported AEs were injection-site pain (38.4%), headache (15.1%) and fatigue (13.4%). INTERPRETATION: V590 was generally well-tolerated. However, Day 28 anti-SARS-Cov-2 spike-specific antibody responses in seronegative participants following a single intramuscular administration of V590 were not sufficient to warrant continued development. FUNDING: The study was funded by Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Forward and reverse translational approaches to predict efficacy of neutralizing respiratory syncytial virus (RSV) antibody prophylaxis.

BACKGROUND: Neutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.e., seasonal variation) are necessary. METHODS: Five decades of clinical trial literature were leveraged to build a model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinical endpoints. The MBMA was validated by backward translation to animal challenge experiments and forward translation to predict results of a recent RSV mAb trial. MBMA predictions were evaluated against a human trial of 70 participants who received either placebo or one of four dose-levels of MK-1654 and were challenged with RSV [NCT04086472]. The MBMA was used to perform clinical trial simulations and predict efficacy of MK-1654 in the infant target population. FINDINGS: The MBMA established a quantitative relationship between RSV SNA and clinical endpoints. This relationship was quantitatively consistent with animal model challenge experiments and results of a recently published clinical trial. Additionally, SNA elicited by increasing doses of MK-1654 in humans reduced RSV symptomatic infection rates with a quantitative relationship that approximated the MBMA. The MBMA indicated a high probability that a single dose of ≥ 75 mg of MK-1654 will result in prophylactic efficacy (> 75% for 5 months) in infants. INTERPRETATION: An MBMA approach can predict efficacy of neutralizing antibodies against RSV and potentially other respiratory pathogens.

"In-House" Data on the Outside-A Mobile Health Approach.

Mobile health (mHealth) technologies have the potential to capture dense patient data on the background of real-life behavior. Merck & Co., Inc. (Kenilworth, NJ), in collaboration with Koneksa Health, conducted a phase I clinical trial to validate cardiovascular mHealth technologies for concordance with traditional approaches and to establish sensitivity to detect effects of pharmacological intervention. This two-part study enrolled 18 healthy male subjects. Part I, a 5-day study, compared mHealth measures of heart rate (HR) and blood pressure (BP) to those from traditional methods. Hypotheses of similarity, in the clinic and at home, were tested individually for HR, systolic BP, and diastolic BP, at a 2-sided 0.05 alpha level, with a prespecified criterion for similarity being the percentage differences between the 2 measurements within 15%. Part II, a 7-day, 3-period randomized balanced crossover study, evaluated the mHealth technology's ability to detect effects of bisoprolol and salbutamol. Hypotheses that the changes from baseline in HR were greater in the bisoprolol (reduction in HR) and salbutamol (increase in HR) groups compared with no treatment were tested, at a 1-sided 0.05 alpha level. Linear mixed-effects models, Pearson's correlation coefficients, summary statistics, and exploratory plots were applied to analyze the data. The mHealth measures of HR and BP were demonstrated to be similar to those from traditional methods, and sensitive to changes in cardiovascular parameters induced by bisoprolol and salbutamol.

Parents of Children With Cancer: At-Risk or Resilient?

OBJECTIVE: To examine adjustment in parents of children with cancer using a design that minimizes focusing effects and allows for direct comparison with parents of healthy children. METHOD: Parents of 305 children with cancer and a demographically similar sample of 231 parents of healthy children were evaluated using diagnostic interviews for posttraumatic stress disorder (PTSD), and questionnaire measures of posttraumatic stress symptoms (PTSS) and psychological growth (PG), as well as measures of global psychological functioning. RESULTS: Rates of current and lifetime PTSD in parents of children with cancer were low, and did not differ from comparison parents. Likewise, levels of PTSS were not significantly different from comparison parents, but differed as a function of time since diagnosis, with parents of children who were ≥ 5 years from diagnosis reporting significantly lower PTSS than comparison parents. PG was higher in parents of children with cancer than in comparison parents regardless of time since diagnosis. CONCLUSION: Parents of children with cancer demonstrate resilience to this challenge.

Reduction of Secondhand Smoke Exposure in the Cars of Children With Cancer.

This study examined whether an intervention designed to reduce secondhand smoke exposure (SHSe) among children being treated for cancer had effects in the specific setting of a motor vehicle. The parents or guardians (n = 71) of children being treated for cancer were randomized to either a behavioral secondhand smoke (SHS) reduction program or a standard care control group. Parental reports of SHSe were collected over the course of 12 months. Younger children were exposed at baseline more than their older counterparts. The greatest initial declines in car exposure were observed among children ≤5 years old in the intervention group compared with same-aged peers in the control group. After the 3-month time point, the control group showed greater reductions in car exposure in comparison with the intervention group. Interventions that teach parents strategies to manage their smoking while driving in their personal vehicles may produce even greater reductions in child exposure and should be developed. Based on the age-specific results reported here, future studies should account for effects of child age and use setting-specific measures of SHS.

Full and home smoking ban adoption after a randomized controlled trial targeting secondhand smoke exposure reduction.

INTRODUCTION: The current study examined home and full (i.e., home plus car) smoking ban adoption as secondary outcomes to a randomized controlled trial targeting reduced secondhand smoke exposure (SHSe) for children under treatment for cancer. METHODS: Families with at least 1 adult smoker who reported SHSe for their children (n = 119) were randomized to control or intervention conditions and followed for 1 year with 5 assessments. Both groups were advised of the negative health outcomes associated with SHSe; the intervention group provided more in-depth counseling from baseline to 3 months. Parents reported on household and car smoking behavior, demographic, psychosocial, and medical/treatment-related information. RESULTS: Regardless of group assignment, there was an increase in home (odds ration [OR] = 1.16, p = .074) and full (OR = 1.37, p = .001) smoking ban adoption across time. Families in the intervention group were more likely to adopt a full ban by 3 months, but this difference was nonsignificant by 12 months. Married parents (OR = 2.33, p = .006) and those with higher self-efficacy for controlling children's SHSe (OR = 1.11, p = .023) were more likely to have a home smoking ban; parents who reported smoking fewer cigarettes were more likely to adopt a home (OR = 1.62, p < .0001) or full (OR = 7.32, p = .038) ban. CONCLUSIONS: Smoking bans are in-line with Healthy People 2020's tobacco objectives and may be more feasible for parents with medically compromised children for immediate SHSe reduction. Furthermore, interventions targeting full smoking bans may be a more effective for comprehensive elimination of SHSe.

Cognitive outcome after pediatric stem-cell transplantation: impact of age and total-body irradiation.

PURPOSE: To examine the influence of age and conditioning with total-body irradiation (TBI) on the trajectory of cognitive functioning after treatment with pediatric hematopoietic stem-cell transplantation (SCT). PATIENTS AND METHODS: Pediatric patients who were scheduled to undergo a SCT were eligible for the study, with 315 patients completing a baseline assessment. Of these, 183 patients (58.1%) were alive at 1 year after SCT and completed additional assessments at 1, 3, and 5 years after SCT. Half of the long-term sample (52.1%) received TBI during conditioning. Cognitive functioning was assessed via age-appropriate standardized measures. RESULTS: At baseline, there were no differences in intelligence quotient (IQ) based on age. At 5 years after SCT, the youngest patients (< 3 years old at baseline) who received TBI demonstrated a significantly lower IQ than those who did not receive TBI (P = .05). Longitudinal analyses (piecewise linear mixed-effects models with a knot at 1 year after SCT) revealed a significant impact of age and TBI over time. The youngest patients evidenced declines in cognitive functioning during the first year; however, patients who did not receive TBI largely recovered their functioning in subsequent years. In contrast, young patients who received TBI failed to recover the losses experienced during the first year after SCT, demonstrating stability in their functioning, but at a lower level. CONCLUSION: Our findings clarify the relationship between TBI and age on cognitive outcomes in pediatric SCT survivors. Young patients who receive TBI may benefit from early intervention efforts to minimize cognitive losses during the first year after SCT and to maximize potential recovery.

Working memory abilities among children treated for medulloblastoma: parent report and child performance.

OBJECTIVE: We investigated the 5-year postsurgical developmental trajectory of working memory (WM) in children with medulloblastoma using parent and performance-based measures. METHOD: This study included 167 patients treated for medulloblastoma. Serial assessments of WM occurred at predetermined time points for 5 years. RESULTS: There was a subtle, statistically significant increase in parental concern about WM, coupled with a statistically significant decrease in age-standardized scores on performance-based measures. However, whole-group mean scores on both parent and performance-based measures remained in the age-expected range. Posterior fossa syndrome was consistently associated with poorer WM. Younger age at treatment and higher treatment intensity were associated with greater negative change in WM performance only. CONCLUSIONS: Most children treated for medulloblastoma display WM within the age-appropriate range according to parent report and performance. However, the subtle negative changes over time and identified subgroups at increased risk highlight the need for ongoing monitoring of this population.

Posttraumatic stress and psychological growth in children with cancer: has the traumatic impact of cancer been overestimated?

PURPOSE: To examine posttraumatic stress disorder and posttraumatic stress symptoms (PTSD/PTSS) in children with cancer using methods that minimize focusing effects and allow for direct comparison to peers without a history of cancer. PATIENTS AND METHODS: Children with cancer (n = 255) stratified by time since diagnosis, and demographically matched peers (n = 101) were assessed for PTSD using structured diagnostic interviews by both child and parent reports, and survey measures of PTSS and psychological benefit/growth by child report. RESULTS: Cancer was identified as a traumatic event by 52.6% of children with cancer, declining to 23.8% in those ≥ 5 years from diagnosis. By diagnostic interview, 0.4% of children with cancer met criteria for current PTSD, and 2.8% met lifetime criteria by self-report. By parent report, 1.6% of children with cancer met current criteria and 5.9% met lifetime criteria for PTSD. These rates did not differ from controls (all Ps >.1). PTSS levels were descriptively lower in children with cancer but did not differ from controls when all were referring to their most traumatic event (P = .067). However, when referring specifically to cancer-related events, PTSS in the cancer group were significantly lower than in controls (P = .002). In contrast, perceived growth was significantly higher in the cancer group when referring to cancer (P < .001). CONCLUSION: These findings suggest no evidence of increased PTSD or PTSS in youths with cancer. Although childhood cancer remains a significant and challenging event, these findings highlight the capacity of children to adjust, and even thrive, in the face of such challenge.

Adjustment in parents of children undergoing stem cell transplantation.

Pediatric stem cell transplantation (SCT) is a demanding procedure for children and parents. Interventions to promote positive adjustment of parents in this setting are needed. A total of 171 patient-parent dyads from 4 sites received 1 of 3 interventions to reduce SCT-related distress: a child intervention with massage and humor therapy, an identical child intervention plus a parent intervention with massage and relaxation/imagery, or standard care. Parents completed weekly self-report measures of distress and positive affect during the acute phase of treatment (weeks -1 through +6); and measures of depression, posttraumatic stress (PTSD), and benefit finding at baseline and week +24. No significant differences across treatment arms were observed on repeated measures of parental distress. There was a marginally significant effect of the child intervention on parental positive affect. Over time, parental distress decreased significantly and positive affect increased significantly in all groups. Similarly, there were no significant intervention effects on the global adjustment outcomes of depression, PTSD, and benefit finding. However, reports of depression and PTSD decreased significantly and reports of benefit finding increased significantly from baseline to week +24 for all groups. Across all study arms, parent adjustment improved over time, suggesting that parents demonstrate a transient period of moderately elevated distress at the time of their child's admission for transplantation, followed by rapid improved to normative levels of adjustment. Similar to results previously reported for their children, these parents appear resilient to the challenges of transplantation.

Intervention to reduce secondhand smoke exposure among children with cancer: a controlled trial.

OBJECTIVE: This randomized controlled trial tested the efficacy of parent-based behavioral counseling for reducing secondhand smoke exposure (SHSe) among children with cancer. It also examined predictors of smoking and SHSe outcomes. METHODS: Participants were 135 parents or guardians of nonsmoking children with cancer, <18 years, at least 30 days postdiagnosis, and living with at least one adult smoker. Parents were randomized to either a standard care control group or an intervention consisting of six counseling sessions delivered over 3 months. Parent-reported smoking and child SHSe levels were obtained at baseline, 3, 6, 9, and 12 months. Children provided urine samples for cotinine analyses. RESULTS: Reductions in parent-reported smoking and exposure were observed in both the intervention and control conditions. There was a significantly greater reduction in parent-reported smoking and child SHSe at 3 months for the intervention group compared with the control group. Child SHSe was significantly lower at 12 months relative to baseline in both groups. Children's cotinine levels did not show significant change over time in either group. Exposure outcomes were influenced by the number of smokers at home, smoking status of the parent participating in the trial, and the child's environment (home versus hospital) the day before the assessment. CONCLUSIONS: Children's SHSe can be reduced by advising parents to protect their child from SHSe, combined with routine reporting of their child's exposure and cotinine testing, when delivered in the context of the pediatric cancer setting. More intensive interventions may be required to achieve greater reductions in SHSe.

Resilience in children undergoing stem cell transplantation: results of a complementary intervention trial.

BACKGROUND: Children undergoing stem cell transplantation (SCT) are thought to be at risk for increased distress, adjustment difficulties, and impaired health-related quality of life (HRQL). We report results of a multisite trial designed to improve psychological adjustment and HRQL in children undergoing SCT. METHODS: A total of 171 patients and parents from 4 sites were randomized to receive a child-targeted intervention; a child and parent intervention; or standard care. The child intervention included massage and humor therapy; the parent intervention included massage and relaxation/imagery. Outcomes included symptoms of depression and posttraumatic stress, HRQL, and benefit finding. Assessments were conducted by patient and parent report at admission and SCT week+24. RESULTS: Across the sample, significant improvements were seen on all outcomes from admission to week+24. Surprisingly, patients who had SCT reported low levels of adjustment difficulties at admission, and improved to normative or better than average levels of adjustment and HRQL at week+24. Benefit finding was high at admission and increased at week+24; however, there were no statistically significant differences between intervention arms for any of the measures. CONCLUSIONS: Although the results do not support the benefits of these complementary interventions in pediatric SCT, this may be explained by the remarkably positive overall adjustment seen in this sample. Improvements in supportive care, and a tendency for patients to find benefit in the SCT experience, serve to promote positive outcomes in children undergoing this procedure, who appear particularly resilient to the challenge.

Changing work, changing health: can real work-time flexibility promote health behaviors and well-being?

This article investigates a change in the structuring of work time, using a natural experiment to test whether participation in a corporate initiative (Results Only Work Environment; ROWE) predicts corresponding changes in health-related outcomes. Drawing on job strain and stress process models, we theorize greater schedule control and reduced work-family conflict as key mechanisms linking this initiative with health outcomes. Longitudinal survey data from 659 employees at a corporate headquarters shows that ROWE predicts changes in health-related behaviors, including almost an extra hour of sleep on work nights. Increasing employees' schedule control and reducing their work-family conflict are key mechanisms linking the ROWE innovation with changes in employees' health behaviors; they also predict changes in well-being measures, providing indirect links between ROWE and well-being. This study demonstrates that organizational changes in the structuring of time can promote employee wellness, particularly in terms of prevention behaviors.

Work, family and life-course fit: Does control over work time matter?

This study moves from "work-family" to a multi-dimensional "life-course fit" construct (employees' cognitive assessments of resources, resource deficits, and resource demands), using a combined work-family, demands-control and ecology of the life course framing. It examined (1) impacts of job and home ecological systems on fit dimensions, and (2) whether control over work time predicted and mediated life-course fit outcomes. Using cluster analysis of survey data on a sample of 917 white-collar employees from Best Buy headquarters, we identified four job ecologies (corresponding to the job demands-job control model) and five home ecologies (theorizing an analogous home demands-home control model). Job and home ecologies predicted fit dimensions in an additive, not interactive, fashion. Employees' work-time control predicted every life-course fit dimension and partially mediated effects of job ecologies, organizational tenure, and job category.