Equivalence of freeze-dried and liquid-frozen formulations of MVA-BN as smallpox and mpox vaccine.

Modified Vaccinia Ankara Bavarian Nordic (MVA-BN) as a smallpox and mpox vaccine has been approved in its liquid-frozen (LF) formulation in the US, Canada, and EU. A freeze-dried (FD) formulation may offer additional benefits, such as a longer shelf life and reduced dependence on cold chain storage and transport. In a phase 2 clinical trial, 651 vaccinia-naïve participants were vaccinated with two doses of MVA-BN LF or FD, 4 weeks apart. The objectives were to compare MVA-BN FD with LF in terms of vaccine-induced immune responses, safety, and reactogenicity. Non-inferiority of the immune response was assessed by the 95% CI of the geometric mean ratios. Both formulations induced robust vaccinia-specific humoral and cellular immune responses. At peak humoral responses (Week 6), geometric means of total antibody titers were 1096 (95% CI 1013, 1186) from the FD group and 877 (95% CI 804, 956) from the LF group, achieving the primary endpoint of non-inferiority of MVA-BN FD compared to MVA-BN LF. At peak cellular responses (Week 2), geometric means of T cell spot forming units were 449 (95% CI 341, 590) from the FD group and 316 (95% CI 234, 427) from the LF group. Both formulations of MVA-BN were well tolerated, with similar unsolicited AEs and solicited systemic reactions in both groups but slightly more local reactions in the FD group. No vaccine-related serious adverse events (SAEs) or vaccine-related AE of special interest were reported. The FD formulation of MVA-BN was shown to be equivalent to MVA-BN LF.

Broad Antibody and Cellular Immune Response From a Phase 2 Clinical Trial With a Novel Multivalent Poxvirus-Based Respiratory Syncytial Virus Vaccine.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in young children and the elderly. Protective immunity is not generated after repeated infections, but vaccination may hopefully prove effective. METHODS: This phase 2 clinical study investigated a multivalent RSV vaccine (MVA-BN-RSV) designed to induce broad antibody and cellular immune responses by encoding RSV surface proteins F, G (for both A and B subtypes), and internal antigens (M2, N). This study evaluated the immune response in adults aged ≥55 years to identify the optimal MVA-BN-RSV dose and vaccination schedule. RESULTS: A single dose increased the levels of neutralizing (plaque reduction neutralization test to RSV A and B) and total (IgG and IgA ELISA) antibodies (1.6 to 3.4-fold increase from baseline) and induced a broad Th1-biased cellular immune response (interferon-γ ELISPOT) to all 5 vaccine inserts (5.4 to 9.7-fold increases). Antibody responses remained above baseline for 6 months. A 12-month booster dose elicited a booster effect in antibody and T-cell responses (up to 2.8-fold from preboost levels). No drug-related serious adverse events were reported. CONCLUSIONS: MVA-BN-RSV induces a broad immune response that persists at least 6 months and can be boosted at 12 months, without significant safety findings. CLINICAL TRIALS REGISTRATION: NCT02873286.

Safety and immunogenicity of novel modified vaccinia Ankara-vectored RSV vaccine: A randomized phase I clinical trial.

Respiratory disease caused by RSV infection is recognized as a severe public health issue in infants, young children and elderly with no specific treatment option. Vaccination may be the most effective strategy to combat this highly infectious virus although no vaccine has been approved. The novel vaccine candidate MVA-BN-RSV encodes RSV surface proteins F and G (subtypes A, B) as well as internal proteins N and M2 in the MVA-BN viral vector backbone to provide broad protection against RSV. This was a first in human study to investigate safety, reactogenicity and immunogenicity of MVA-BN-RSV. Sixty-three participants were allocated to 3 groups: adult (18-49 years) low (1 × 107 TCID50) or high (1 × 108 TCID50) dose and older adult (50-65 years) high dose. Participants in each group were randomized in a 6:1 ratio to receive 2 doses of MVA-BN-RSV or placebo 4 weeks apart and were monitored for 30 weeks. All participants completed the study, receiving both doses. No serious AEs or AEs of special interest were reported. The most common AEs were injection site pain (56% in the combined high dose groups, 17% in the low dose group). MVA-BN-RSV induced robust T cell responses covering all 5 inserts with fold increases ranging from 1.8 to 3.8. Higher and broader responses were observed in the high dose groups (83% responders to at least 3 peptide pools in the combined high dose groups compared to 63% in the low dose group). Moderate but consistent humoral responses were observed against A and B RSV subtypes (up to approximately 2-fold increases in the high dose groups). No differences were observed between the adult and the older adult groups in safety, reactogenicity or immunogenicity. The study demonstrated that the well tolerated MVA-BN-RSV vaccine candidate induces broad cellular and humoral immune responses, warranting further development.

Author Correction: Effects of larvae density and food concentration on Crown-of-Thorns seastar (Acanthaster cf. solaris) development in an automated flow-through system.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Effects of larvae density and food concentration on Crown-of-Thorns seastar (Acanthaster cf. solaris) development in an automated flow-through system.

Coral-eating Crown-of-Thorns Sea stars (Acanthaster spp.) are major contributors to coral reef loss in the Indo-Pacific region. A release from food limitation of their planktotrophic larvae through enhanced pelagic productivity is one of the main hypothesis explaining population outbreaks ('nutrient limitation hypothesis'). To improve the understanding of these outbreaks we developed an automated flow- through larvae rearing system that maintained food (microalgae) at set levels over the course of four 15d experiments. This resulted in stable food concentrations in experimental tanks. Increased algae concentrations had a significant positive effect on larval development and size at 10 and 15 days post fertilization (dpf). Larvae densities had no effect at 10 dpf. At 15 dpf greater larvae densities were associated with declines in larvae size. Larval development was slowed under higher larvae densities. Thus, the effects of algae concentration and larvae density were additive at 15 dpf, with larvae under low densities at a given algae concentration being further developed than those under higher densities. The development of a flow-through system gives greater insight into the effect of algae and larvae concentrations on Acanthaster development, and the system can be applied to further test the nutrient-limitation hypothesis for present and future outbreaks.

Climate change as an unexpected co-factor promoting coral eating seastar (Acanthaster planci) outbreaks.

Coral reefs face a crisis due to local and global anthropogenic stressors. A large proportion of the ~50% coral loss on the Great Barrier Reef has been attributed to outbreaks of the crown-of-thorns-seastar (COTS). A widely assumed cause of primary COTS outbreaks is increased larval survivorship due to higher food availability, linked with anthropogenic runoff . Our experiment using a range of algal food concentrations at three temperatures representing present day average and predicted future increases, demonstrated a strong influence of food concentration on development is modulated by temperature. A 2°C increase in temperature led to a 4.2-4.9 times (at Day 10) or 1.2-1.8 times (Day 17) increase in late development larvae. A model indicated that food was the main driver, but that temperature was an important modulator of development. For instance, at 5000 cells ml(-1) food, a 2°C increase may shorten developmental time by 30% and may increase the probability of survival by 240%. The main contribution of temperature is to 'push' well-fed larvae faster to settlement. We conclude that warmer sea temperature is an important co-factor promoting COTS outbreaks.

Sample size determination in shared frailty models for multivariate time-to-event data.

The frailty model is increasingly popular for analyzing multivariate time-to-event data. The most common model is the shared frailty model. Although study design consideration is as important as analysis strategies, sample size determination methodology in studies with multivariate time-to-event data is greatly lacking in the literature. In this article, we develop a sample size determination method for the shared frailty model to investigate the treatment effect on multivariate event times. We analyzed the data using both a parametric model and a piecewise model with unknown baseline hazard, and compare the empirical power with the calculated power. Last, we discuss the formula for testing the treatment effect on recurrent events.

Flexible stopping boundaries when changing primary endpoints after unblinded interim analyses.

It has been widely recognized that interim analyses of accumulating data in a clinical trial can inflate type I error. Different methods, from group sequential boundaries to flexible alpha spending functions, have been developed to control the overall type I error at prespecified level. These methods mainly apply to testing the same endpoint in multiple interim analyses. In this article, we consider a group sequential design with preplanned endpoint switching after unblinded interim analyses. We extend the alpha spending function method to group sequential stopping boundaries when the parameters can be different between interim, or between interim and final analyses.

Sample size and power determination in joint modeling of longitudinal and survival data.

Owing to the rapid development of biomarkers in clinical trials, joint modeling of longitudinal and survival data has gained its popularity in the recent years because it reduces bias and provides improvements of efficiency in the assessment of treatment effects and other prognostic factors. Although much effort has been put into inferential methods in joint modeling, such as estimation and hypothesis testing, design aspects have not been formally considered. Statistical design, such as sample size and power calculations, is a crucial first step in clinical trials. In this paper, we derive a closed-form sample size formula for estimating the effect of the longitudinal process in joint modeling, and extend Schoenfeld's sample size formula to the joint modeling setting for estimating the overall treatment effect. The sample size formula we develop is quite general, allowing for p-degree polynomial trajectories. The robustness of our model is demonstrated in simulation studies with linear and quadratic trajectories. We discuss the impact of the within-subject variability on power and data collection strategies, such as spacing and frequency of repeated measurements, in order to maximize the power. When the within-subject variability is large, different data collection strategies can influence the power of the study in a significant way. Optimal frequency of repeated measurements also depends on the nature of the trajectory with higher polynomial trajectories and larger measurement error requiring more frequent measurements.

Basic concepts and methods for joint models of longitudinal and survival data.

Joint models for longitudinal and survival data are particularly relevant to many cancer clinical trials and observational studies in which longitudinal biomarkers (eg, circulating tumor cells, immune response to a vaccine, and quality-of-life measurements) may be highly associated with time to event, such as relapse-free survival or overall survival. In this article, we give an introductory overview on joint modeling and present a general discussion of a broad range of issues that arise in the design and analysis of clinical trials using joint models. To demonstrate our points throughout, we present an analysis from the Eastern Cooperative Oncology Group trial E1193, as well as examine some operating characteristics of joint models through simulation studies.

Characteristics and outcomes for critically ill patients with prolonged intensive care unit stays.

OBJECTIVE: Prolonged stay in the intensive care unit (ICU) is associated with high mortality, morbidity, and costs. Identifying those patients who are most likely to benefit from an extended ICU stay would be helpful in guiding clinical decisions. We sought to describe the characteristics and outcomes for a heterogeneous group of patients who required a prolonged ICU stay. DESIGN: Observational study. SETTING: Adult ICUs of three teaching and five community hospitals. PATIENTS: The study group comprised 5,881 patients consecutively admitted to the ICUs during a 10-month period. MEASUREMENTS AND MAIN RESULTS: A prolonged stay was defined as one >21 days at teaching hospitals and >10 days at community hospitals. For patients meeting the criteria of prolonged stay, Therapeutic Intervention Scoring System (TISS) score and Multiple Organ Dysfunction Score (MODS) were measured prospectively from days 10 and 21 in community and teaching hospitals, respectively, and retrospectively before this. Prolonged-stay patients represented 5.6% of ICU admissions and 39.7% of ICU bed-days. Compared with short-stay patients, they were significantly older and had higher admission Acute Physiology and Chronic Health Evaluation (APACHE) II scores (p < .01). ICU and hospital mortality for prolonged-stay patients were 24.4% and 35.2%, respectively, compared with 11% and 15.9% for short-stay patients (p < .001). Mean admission TISS and MODS scores for prolonged-stay patients were 30.8 (sd, 11.1) and 4.8 (sd, 3.3) respectively. For prolonged-stay patients the dominant reason for ICU care was multiple organ failure (37.8%), ventilator support (30.7%), or nonventilated single organ failure (31.5%). Hospital mortality was highest in the group with multiple organ failure (53%). CONCLUSIONS: We developed a method to broadly classify a heterogeneous population of prolonged-stay ICU patients on the basis of MODS and the ICU interventions received. Mortality among prolonged-stay patients was highest for those with multiple organ failure. Future research should evaluate whether the proposed classification system can be used to influence the delivery of ICU care.

Attitudes regarding organ donation from non-heart-beating donors.

PURPOSE: To determine the attitudes toward organ donation from non-heart-beating cadaver donors in a sample of the general public and health care workers. MATERIALS AND METHODS: A moderator-administered questionnaire was completed by members of the general public, recruited randomly from a professional consumer research group's database, and health care workers recruited from the same database, family practice clinics, and local hospitals. Two primary scenarios were tested: (1) patient in coma, not going to survive intensive care unit (ICU), and (2) patient lapsing in and out of consciousness, lifetime institutional care. RESULTS: Sixty members of the general public and 68 health care workers completed the questionnaire. The majority of both groups were aware life support could be withdrawn in Scenario 1, however, significantly fewer were aware life support could also be withdrawn in Scenario 2 (83% general public vs 34% general public, P <.001 and 94% health care workers vs 78% health care workers, P =.012). Uncertainty in prognosis was cited as the primary concern. The issue of organ donation was directly linked with withdrawal of life support. The majority of both groups believed that organ donation would be permissible if further life support were deemed to be not in the patient's best interest because of poor short-term prognosis (94% health care workers and 98% general public for Scenario 1 and 87% health care workers and 81% general public for Scenario 2). The greatest difficulty arose in defining futility of care. Expected quality of life, patient's and family's values, opinions, and religious beliefs were felt to be most important in determining decisions regarding futility and withdrawal of life support. Physician beliefs and values were felt to influence decisions more than they should. CONCLUSIONS: Both the general public and health care workers support the use of non-heart-beating cadaver donors once a decision has been made to withdraw life support. However, both groups raised concerns regarding how the decision to withdraw life support is made.

A simplified sensitive method for the analysis of renal calculi.

A simple, convenient method for the analysis of renal calculi is presented. The method allows the quantitative estimation of oxalate, urate, calcium, magnesium, xanthine, and phosphate; a qualitative analysis for ammonia, carbonate, and cystine is also done. The estimations can be done with specimens of calculi as small as 1 mg. The results of analyses of some calculi from patients are presented and discussed.