mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits similar B cell expansion, neutralizing responses, and protection from Omicron.

SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-matched vaccines would enhance protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing titers against D614G were 4,760 and 270 reciprocal ID50 at week 6 (peak) and week 41 (preboost), respectively, and 320 and 110 for Omicron. 2 weeks after the boost, titers against D614G and Omicron increased to 5,360 and 2,980 for mRNA-1273 boost and 2,670 and 1,930 for mRNA-Omicron, respectively. Similar increases against BA.2 were observed. Following either boost, 70%-80% of spike-specific B cells were cross-reactive against WA1 and Omicron. Equivalent control of virus replication in lower airways was observed following Omicron challenge 1 month after either boost. These data show that mRNA-1273 and mRNA-Omicron elicit comparable immunity and protection shortly after the boost.

Mucosal adenovirus vaccine boosting elicits IgA and durably prevents XBB.1.16 infection in nonhuman primates.

A mucosal route of vaccination could prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication at the site of infection and limit transmission. We compared protection against heterologous XBB.1.16 challenge in nonhuman primates (NHPs) ~5 months following intramuscular boosting with bivalent mRNA encoding WA1 and BA.5 spike proteins or mucosal boosting with a WA1-BA.5 bivalent chimpanzee adenoviral-vectored vaccine delivered by intranasal or aerosol device. NHPs boosted by either mucosal route had minimal virus replication in the nose and lungs, respectively. By contrast, protection by intramuscular mRNA was limited to the lower airways. The mucosally delivered vaccine elicited durable airway IgG and IgA responses and, unlike the intramuscular mRNA vaccine, induced spike-specific B cells in the lungs. IgG, IgA and T cell responses correlated with protection in the lungs, whereas mucosal IgA alone correlated with upper airway protection. This study highlights differential mucosal and serum correlates of protection and how mucosal vaccines can durably prevent infection against SARS-CoV-2.

Clinical outcomes and immune responses to SARS-CoV-2 vaccination in severe aplastic anaemia.

Patients with severe aplastic anaemia (SAA) are often not vaccinated against viruses due to concerns of ineffective protective antibody response and potential for pathogenic global immune system activation, leading to relapse. We evaluated the impact of COVID-19 vaccination on haematological indices and disease status and characterized the humoural and cellular responses to vaccination in 50 SAA patients, who were previously treated with immunosuppressive therapy (IST). There was no significant difference in haemoglobin (p = 0.52), platelet count (p = 0.67), absolute lymphocyte (p = 0.42) and neutrophil (p = 0.98) counts prior to and after completion of vaccination series. Relapse after vaccination, defined as a progressive decline in counts requiring treatment, occurred in three patients (6%). Humoural response was detectable in 90% (28/31) of cases by reduction in an in-vitro Angiotensin II Converting Enzyme (ACE2) binding and neutralization assay, even in patients receiving ciclosporin (10/11, 90.1%). Comparison of spike-specific T-cell responses in 27 SAA patients and 10 control subjects revealed qualitatively similar CD4+ Th1-dominant responses to vaccination. There was no difference in CD4+ (p = 0.77) or CD8+ (p = 0.74) T-cell responses between patients on or off ciclosporin therapy at the time of vaccination. Our data highlight appropriate humoural and cellular responses in SAA previously treated with IST and true relapse after vaccination is rare.

Phase 1 dose-escalation trial evaluating a group 2 influenza hemagglutinin stabilized stem nanoparticle vaccine.

The relative conservation of the influenza hemagglutinin (HA) stem compared to that of the immunodominant HA head makes the HA stem an attractive target for broadly protective influenza vaccines. Here we report the first-in-human, dose-escalation, open-label trial (NCT04579250) evaluating an unadjuvanted group 2 stabilized stem ferritin nanoparticle vaccine based on the H10 A/Jiangxi-Donghu/346/2013 influenza HA, H10ssF, in healthy adults. Participants received a single 20 mcg dose (n = 3) or two 60 mcg doses 16 weeks apart (n = 22). Vaccination with H10ssF was safe and well tolerated with only mild systemic and local reactogenicity reported. No serious adverse events occurred. Vaccination significantly increased homologous H10 HA stem binding and neutralizing antibodies at 2 weeks after both first and second vaccinations, and these responses remained above baseline at 40 weeks. Heterologous H3 and H7 binding antibodies also significantly increased after each vaccination and remained elevated throughout the study. These data indicate that the group 2 HA stem nanoparticle vaccine is safe and induces stem-directed binding and neutralizing antibodies.

Acute Traumatic Subdural Hematoma in the Elderly and Associated Factors that May Influence Chronicity.

Traumatic acute subdural hematomas (TASDH) is by far the most common traumatic brain injury in adult patients with blunt trauma, who presented to the Emergency Department (ED). One of the serious sequale of TASDH is the development of Chronic Subdural Hematomas (CSD) with associated deterioration in mental status and convulsion.1,2 Studies to identify the risk factors that favors development of chronicity of TASDH are few and inconclusive. As seen in our prior initial study, there were few factors which were common in those who developed chronicity of their TASDH, and we elected to expand our pool of patients to include those admitted between the years of 2015 and 2021 with ATSDH and identify the common factors associated with development of CSD.

Can Time to Treatment Reduce In-Hospital Mortality and Morbidity Among Surgical and Nonsurgical Elderly Patients With Sepsis.

Sepsis mortality remains high and efforts to reduce it are continuing. We collected data from our patients presented to the emergency department (ED) with sepsis and performed a retrospective analysis of 1079 patients seen in the ED with sepsis during 2018 and 2020, before and after implementation of the new CDC protocol. Statistical analysis was performed using Student's t-test and chi square test as well as Cox regression analysis. The patients were divided into pre-protocol (group 1) and post-protocol (group 2). A total of 1079 patients were included in the study. The mean age was 65 + 16.86 years, divided equally between gender (male 49%, female 51%). Patients with certain comorbidities showed statistically significant survival rate in the protocol group. The current protocol for sepsis when implemented will improve patients' survival, in both surgical and medical patients and significantly in those with comorbid conditions.

Value of Thoracic CT in Blunt Trauma Patients With High Glasgow Coma Scale and Low Injury Severity Scale.

OBJECTIVE: To determine the value of ordering a routine chest CT (CCT) in patients with blunt trauma presenting to the emergency department with a high GCS and low ISS, we retrospectively collected patient data including CT scan results, when physical examination and initial chest X-ray were normal in the trauma bay area. METHODS: A retrospective data collection of 901 consecutive blunt trauma patients seen in the ED between 2017 and 2019 was analyzed. Data included physical examination, age, gender, current use of anticoagulation therapy, comorbid conditions, as well as the result of radiologic images, hospital length of stay, surgical intervention, and mortality. The patients were divided into two groups: group one (patients with negative physical examination; chest x-ray and CT) and group 2 (negative physical examination, positive or negative chest x-ray, and positive CT). Statistical analysis was performed using student's t-test and chi-square test. RESULTS: Of the 901 patients there were 489 (54%) males and 412 (46%) females with a mean age of 56 years. There were 461 patients who had a physical examination, chest x-ray, abdominal and CCT done. Group one included 442 (96%) patients, with negative physical examination, negative chest X-ray and CT scan. In group 2, 19 (4%) patients who had positive CT and or chest x-ray. Both groups were similar in GCS and ISS. Of the 19 patients, sixteen patients had a positive CCT, and thirteen of those had a positive chest x-ray. In the three patients who had negative physical examination and chest x-ray, the CT findings included one with a nondisplaced 10th rib fracture and two patients with osteoporotic compression fractures of dorsal vertebrae. The rate of both chest x-ray and CCT being positive among a group of screened patients was 16% (3/19) and the rate of a negative chest x-ray but positive CT was 16% (3/19). The odds ratio between the two outcomes was one. CONCLUSION: In blunt trauma patients presenting to the ED with a high GCS and low ISS score, when initial physical examination and chest x-ray are negative, routine CCT is of little value.

The Value of Abdominal and Pelvic CT Scan in Trauma Patients With Low Injury Severity Score and High Glasgow Coma Scale.

INTRODUCTION: Computed tomography scans became the mainstay of emergency department (ED) evaluation of trauma patients including those with a high Glasgow Coma Scale (GCS) and a low Injury Severity Score (ISS). We elected to find the value of abdominal and pelvic CT in patients with negative physical examination and Focused Assessment of Sonography for Trauma (FAST) on arrival to the ED. METHODS: This study is a retrospective analysis of 901 consecutive patients from 2017 to 2019 who presented to the ED with level 2 and 3 activation criteria. Each patient received a physical examination, CT abdomen and pelvis, and FAST exam. Data were collected on external factor including GCS, ISS, age, sex, comorbidities, anticoagulation use, and surgical intervention. The patients were divided into 2 groups, Group A and B. Group A consisted of patients with a negative physical exam, FAST, and CT result. Group B included patients with a negative physical exam and FAST exam with positive CT findings. Statistical analysis was done using a Student's t-test and chi-square test for significance value of P < .05. Institutional Review Board approval was obtained for this study. RESULTS: A total of 901 patients were analyzed which included 489 (54.3%) male and 412 (45.7%) female with a mean age of 56.2 (SD = 22.62) years. Out of the 901 patients, 461 patients received a physical, FAST, and CT exam. Group A consisted of 442 (95.9%) patients and Group B had 19 (4.1%) patients. Both groups were similar in GCS and ISS scoring with no significance difference in age, sex, comorbidities, and anticoagulation use. There was a significant difference in the ICU and hospital mean length of stay when CT scan was positive [2 (SD = 4.23) days vs. .6 (SD = 1.33) days with P < .0001 and 4.57 (SD ± 4.17) days vs. 2.5 (SD = 2.00) days with P < .0001, respectively]. The CT findings of the 19 patients in group B consisted of 6 incidentalomas, 5 vertebral compression fractures, 4 pelvic bone fractures, 1 minor liver contusion, 1 non-specific bowel thickening, 1 non-displaced rib fracture, and 1 case of small amount of free fluid in the pelvis. None of the CT findings required surgical intervention. CONCLUSION: Computed tomography of the abdomen and pelvis in trauma patients with high GCS and low ISS with initial negative physical and FAST examination did not provide additional critical information.

Mucosal Adenoviral-vectored Vaccine Boosting Durably Prevents XBB.1.16 Infection in Nonhuman Primates.

Waning immunity and continued virus evolution have limited the durability of protection from symptomatic infection mediated by intramuscularly (IM)-delivered mRNA vaccines against COVID-19 although protection from severe disease remains high. Mucosal vaccination has been proposed as a strategy to increase protection at the site of SARS-CoV-2 infection by enhancing airway immunity, potentially reducing rates of infection and transmission. Here, we compared protection against XBB.1.16 virus challenge 5 months following IM or mucosal boosting in non-human primates (NHP) that had previously received a two-dose mRNA-1273 primary vaccine regimen. The mucosal boost was composed of a bivalent chimpanzee adenoviral-vectored vaccine encoding for both SARS-CoV-2 WA1 and BA.5 spike proteins (ChAd-SARS-CoV-2-S) and delivered either by an intranasal mist or an inhaled aerosol. An additional group of animals was boosted by the IM route with bivalent WA1/BA.5 spike-matched mRNA (mRNA-1273.222) as a benchmark control. NHP were challenged in the upper and lower airways 18 weeks after boosting with XBB.1.16, a heterologous Omicron lineage strain. Cohorts boosted with ChAd-SARS-CoV-2-S by an aerosolized or intranasal route had low to undetectable virus replication as assessed by levels of subgenomic SARS-CoV-2 RNA in the lungs and nose, respectively. In contrast, animals that received the mRNA-1273.222 boost by the IM route showed minimal protection against virus replication in the upper airway but substantial reduction of virus RNA levels in the lower airway. Immune analysis showed that the mucosal vaccines elicited more durable antibody and T cell responses than the IM vaccine. Protection elicited by the aerosolized vaccine was associated with mucosal IgG and IgA responses, whereas protection elicited by intranasal delivery was mediated primarily by mucosal IgA. Thus, durable immunity and effective protection against a highly transmissible heterologous variant in both the upper and lower airways can be achieved by mucosal delivery of a virus-vectored vaccine. Our study provides a template for the development of mucosal vaccines that limit infection and transmission against respiratory pathogens.

Effect of Implementation of an Early Treatment of Sepsis Protocol on Surgical Outcomes.

Sepsis outcomes remain high regarding mortality and morbidity, despite efforts to reduce them. We retrospectively evaluated a protocol in the first 6 months of implementation to measure outcomes. Retrospective data collection and analysis was performed of 200 consecutive patients seen in the ED during the first 4 months of 2020 after implementation of the sepsis protocol (group 1) and compared to another 200 consecutive patients during the same time frame in 2019 before the sepsis protocol (group 2). The collected parameters included age, gender, race, length of stay comorbid conditions, mortality, and therapy received. Statistical significance was determined at a p-value ≤.05. Mean age and gender of the groups were similar, 64 vs 66 years for group 1 and 2, respectively. Each group was 45% male. Mean length of stay were 8.9 and 8.6 days in group 1 and 2, respectively. Group 1 had a mortality rate of 13% vs 18% in group 2 (p = .21). Comorbid conditions including cardiovascular disease, diabetes, renal failure, and COPD were analyzed regarding mortality that influenced outcomes using Cox regression analysis. COPD and diabetic patient mortality were significantly lower in the protocol group. Surgical patients had a survival rate of 92.4%. Therefore, the current protocol for sepsis management did improve mortality. Further studies with a larger number of patients are in progress.

Immune correlates analysis of the ENSEMBLE single Ad26.COV2.S dose vaccine efficacy clinical trial.

Measuring immune correlates of disease acquisition and protection in the context of a clinical trial is a prerequisite for improved vaccine design. We analysed binding and neutralizing antibody measurements 4 weeks post vaccination as correlates of risk of moderate to severe-critical COVID-19 through 83 d post vaccination in the phase 3, double-blind placebo-controlled phase of ENSEMBLE, an international randomized efficacy trial of a single dose of Ad26.COV2.S. We also evaluated correlates of protection in the trial cohort. Of the three antibody immune markers we measured, we found most support for 50% inhibitory dilution (ID50) neutralizing antibody titre as a correlate of risk and of protection. The outcome hazard ratio was 0.49 (95% confidence interval 0.29, 0.81; P = 0.006) per 10-fold increase in ID50; vaccine efficacy was 60% (43%, 72%) at non-quantifiable ID50 (<2.7 IU50 ml-1) and increased to 89% (78%, 96%) at ID50 = 96.3 IU50 ml-1. Comparison of the vaccine efficacy by ID50 titre curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine and the COV002-UK trial of the AZD1222 vaccine supported the ID50 titre as a correlate of protection across trials and vaccine types.

Immune Correlates Analysis of a Single Ad26.COV2.S Dose in the ENSEMBLE COVID-19 Vaccine Efficacy Clinical Trial.

Anti-spike IgG binding antibody, anti-receptor binding domain IgG antibody, and pseudovirus neutralizing antibody measurements four weeks post-vaccination were assessed as correlates of risk of moderate to severe-critical COVID-19 outcomes through 83 days post-vaccination and as correlates of protection following a single dose of Ad26.COV2.S COVID-19 vaccine in the placebo-controlled phase of ENSEMBLE, an international, randomized efficacy trial. Each marker had evidence as a correlate of risk and of protection, with strongest evidence for 50% inhibitory dilution (ID50) neutralizing antibody titer. The outcome hazard ratio was 0.49 (95% confidence interval 0.29, 0.81; p=0.006) per 10-fold increase in ID50; vaccine efficacy was 60% (43, 72%) at nonquantifiable ID50 (< 2.7 IU50/ml) and rose to 89% (78, 96%) at ID50 = 96.3 IU50/ml. Comparison of the vaccine efficacy by ID50 titer curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine, and the COV002-UK trial of the AZD1222 vaccine supported consistency of the ID50 titer correlate of protection across trials and vaccine types.