A randomized phase I/II safety and immunogenicity study of the Montanide-adjuvanted SARS-CoV-2 spike protein-RBD-Fc vaccine, AKS-452.

BACKGROUND: Previous interim data from a phase I study of AKS-452, a subunit vaccine comprising an Fc fusion of the respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor binding domain (SP/RBD) emulsified in the water-in-oil adjuvant, Montanide™ ISA 720, suggested a good safety and immunogenicity profile in healthy adults. This phase I study was completed and two dosing regimens were further evaluated in this phase II study. METHODS: This phase II randomized, open-labelled, parallel group study was conducted at a single site in The Netherlands with 52 healthy adults (18 - 72 years) receiving AKS-452 subcutaneously at one 90 µg dose (cohort 1, 26 subjects) or two 45 µg doses 28 days apart (cohort 2, 26 subjects). Serum samples were collected at the first dose (day 0) and at days 28, 56, 90, and 180. Safety and immunogenicity endpoints were assessed, along with induction of IgG isotypes, cross-reactive immunity against viral variants, and IFN-γ T cell responses. RESULTS: All AEs were mild/moderate (grades 1 or 2), and no SAEs were attributable to AKS-452. Seroconversion rates reached 100% in both cohorts, although cohort 2 showed greater geometric mean IgG titers that were stable through day 180 and associated with enhanced potencies of SP/RBD-ACE2 binding inhibition and live virus neutralization. AKS-452-induced IgG titers strongly bound mutant SP/RBD from several SARS-CoV-2 variants (including Omicrons) that were predominantly of the favorable IgG1/3 isotype and IFN-γ-producing T cell phenotype. CONCLUSION: These favorable safety and immunogenicity profiles of the candidate vaccine as demonstrated in this phase II study are consistent with those of the phase I study (ClinicalTrials.gov: NCT04681092) and suggest that a total of 90 µg received in 2 doses may offer a greater duration of cross-reactive neutralizing titers than when given in a single dose.

Impact of the COVID-19 pandemic on surgical care in the Netherlands.

BACKGROUND: The COVID-19 pandemic caused disruption of regular healthcare leading to reduced hospital attendances, repurposing of surgical facilities, and cancellation of cancer screening programmes. This study aimed to determine the impact of COVID-19 on surgical care in the Netherlands. METHODS: A nationwide study was conducted in collaboration with the Dutch Institute for Clinical Auditing. Eight surgical audits were expanded with items regarding alterations in scheduling and treatment plans. Data on procedures performed in 2020 were compared with those from a historical cohort (2018-2019). Endpoints included total numbers of procedures performed and altered treatment plans. Secondary endpoints included complication, readmission, and mortality rates. RESULTS: Some 12 154 procedures were performed in participating hospitals in 2020, representing a decrease of 13.6 per cent compared with 2018-2019. The largest reduction (29.2 per cent) was for non-cancer procedures during the first COVID-19 wave. Surgical treatment was postponed for 9.6 per cent of patients. Alterations in surgical treatment plans were observed in 1.7 per cent. Time from diagnosis to surgery decreased (to 28 days in 2020, from 34 days in 2019 and 36 days in 2018; P < 0.001). For cancer-related procedures, duration of hospital stay decreased (5 versus 6 days; P < 0.001). Audit-specific complications, readmission, and mortality rates were unchanged, but ICU admissions decreased (16.5 versus 16.8 per cent; P < 0.001). CONCLUSION: The reduction in the number of surgical operations was greatest for those without cancer. Where surgery was undertaken, it appeared to be delivered safely, with similar complication and mortality rates, fewer admissions to ICU, and a shorter hospital stay.

COVID-19 has had a significant impact on healthcare worldwide. Hospital visits were reduced, operating facilities were used for COVID-19 care, and cancer screening programmes were cancelled. This study describes the impact of the COVID-19 pandemic on Dutch surgical healthcare in 2020. Patterns of care in terms of changed or delayed treatment are described for patients who had surgery in 2020, compared with those who had surgery in 2018­2019. The study found that mainly non-cancer surgical treatments were cancelled during months with high COVID-19 rates. Outcomes for patients undergoing surgery were similar but with fewer ICU admissions and shorter hospital stay. These data provide no insight into the burden endured by patients who had postponed or cancelled operations.

Phase I interim results of a phase I/II study of the IgG-Fc fusion COVID-19 subunit vaccine, AKS-452.

To address the coronavirus disease 2019 (COVID-19) pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recombinant subunit vaccine, AKS-452, is being developed comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain (SP/RBD) antigen and human IgG1 Fc emulsified in the water-in-oil adjuvant, Montanide™ ISA 720. A single-center, open-label, phase I dose-finding and safety study was conducted with 60 healthy adults (18-65 years) receiving one or two doses 28 days apart of 22.5 µg, 45 µg, or 90 µg of AKS-452 (i.e., six cohorts, N = 10 subjects per cohort). Primary endpoints were safety and reactogenicity and secondary endpoints were immunogenicity assessments. No AEs ≥ 3, no SAEs attributable to AKS-452, and no SARS-CoV-2 viral infections occurred during the study. Seroconversion rates of anti-SARS-CoV-2 SP/RBD IgG titers in the 22.5, 45, and 90 µg cohorts at day 28 were 70%, 90%, and 100%, respectively, which all increased to 100% at day 56 (except 89% for the single-dose 22.5 µg cohort). All IgG titers were Th1-isotype skewed and efficiently bound mutant SP/RBD from several SARS-CoV-2 variants with strong neutralization potencies of live virus infection of cells (including alpha and delta variants). The favorable safety and immunogenicity profiles of this phase I study (ClinicalTrials.gov: NCT04681092) support phase II initiation of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain.

Obesity is not associated with disease-free interval, melanoma-specific survival, or overall survival in patients with clinical stage IB-II melanoma after SLNB.

BACKGROUND AND OBJECTIVES: Clinicopathologic characteristics have prognostic value in clinical stage IB-II patients with melanoma. Little is known about the prognostic value of obesity that has been associated with an increased risk for several cancer types and worsened prognosis after diagnosis. This study aims to examine effects of obesity on outcome in patients with clinical stage IB-II melanoma. METHODS: Prospectively recorded data of patients with clinical stage IB-II melanoma who underwent sentinel lymph node biopsy (SLNB) between 1995 and 2018 at the University Medical Center of Groningen were collected from medical files and retrospectively analyzed. Cox-regression analyses were used to determine associations between obesity (body mass index> 30), tumor (location, histology, Breslow-thickness, ulceration, mitotic rate, SLN-status) and patient-related variables (gender, age, and social-economic-status [SES]) and disease-free interval (DFI), melanoma-specific survival (MSS), and overall survival (OS). RESULTS: Of the 715 patients, 355 (49.7%) were women, median age was 55 (range 18.6-89) years, 149 (20.8%) were obese. Obesity did not significantly affect DFI (adjusted hazard ratio [HR] = 1.40; 95% confidence interval [CI] = 0.98-2.00; p = 0.06), MSS (adjusted HR = 1.48;95%CI = 0.97-2.25; p = 0.07), and OS (adjusted HR = 1.25; 95% CI = 0.85-1.85; p = 0.25). Increased age, arm location, increased Breslow-thickness, ulceration, increased mitotic rate, and positive SLN-status were significantly associated with decreased DFI, MSS, and OS. Histology, sex, and SES were not associated. CONCLUSION: Obesity was not associated with DFI, MSS, or OS in patients with clinical stage IB-II melanoma who underwent SLNB.

The immediate impact of the coronavirus disease 2019 (COVID-19) pandemic on burn-out, work-engagement, and surgical training in the Netherlands.

BACKGROUND: The coronavirus disease 2019 pandemic led to major changes in health care and education options for all health care employees. The aim of this study is to achieve insight into coronavirus disease-care participation of surgical residents in the Netherlands, the impact of coronavirus disease 2019 on the experienced quality of surgical training, and the influence on Burn-out and Work Engagement compared with the non-coronavirus disease 2019 period in January 2020. METHODS: In this study, we have conducted 2 digital surveys immediately before and 2 months after the start of the coronavirus disease 2019 pandemic. We surveyed a validated Dutch questionnaire 'Utrecht Burn-out Scale,' derived from the Maslach Burn-out Inventory, and also collected the 'Utrecht Work Engagement Scale' measuring work engagement. Additionally, we describe the coronavirus disease-care participation of surgical residents, the impact on how they experienced the quality of their surgical training, and the influence on 'Burn-out and Work Engagement' compared with the pre-coronavirus disease 2019 period for surgical residents in the Netherlands. RESULTS: In January 2020, a total of 317 residents completed the online survey, and in April 2020, a total of 313 residents completed the online survey. Of the responders, 48.6%, in April, participated in coronavirus disease-care in both the coronavirus disease ward as well as the coronavirus disease intensive care unit. Residents experienced that the coronavirus disease 2019 influenced their surgical training in 85.2% of responders. In only 5% of the residents did the pandemic not affect the exposure to surgical training in the operating theater. More burn-out symptoms were noted amongst coronavirus disease ward deployed residents versus no coronavirus disease ward deployment, (16.0% vs 7.6%, P = .06). The Work-Engagement questionnaire showed a significantly lower work engagement score of 4.2 for residents who were deployed in a coronavirus disease-care intensive care unit versus a score of 4.6 for residents scheduled in a coronavirus disease ward (P = .02). CONCLUSION: This study shows a significant impact of the first months of the coronavirus disease 2019 pandemic on the Dutch surgical trainee program, with a major redistribution of residents with a decrease of surgical exposure and education. We emphasize the need for adequate guidance of all surgical residents and potentially lengthening the surgical training program.

Perioperative SARS-CoV-2 infections increase mortality, pulmonary complications, and thromboembolic events: A Dutch, multicenter, matched-cohort clinical study.

BACKGROUND: A direct comparison of severe acute respiratory syndrome coronavirus 2 positive patients with a severe acute respiratory syndrome coronavirus 2 negative control group undergoing an operative intervention during the current pandemic is lacking, and a reliable estimate of the assumed difference in morbidity and mortality between both patient categories remains unknown. METHODS: We included all consecutive patients with a confirmed pre- or postoperative severe acute respiratory syndrome coronavirus 2 positive status (operated in 27 hospitals) and negative control patients (operated in 4 hospitals) undergoing emergency or elective operations. A propensity score-matched comparison of clinical outcomes was performed between severe acute respiratory syndrome coronavirus 2 positive and negative tested patients (control group). Primary outcome was overall 30-day mortality rate between both groups. Main secondary outcomes were overall, pulmonary, and thromboembolic complications. RESULTS: In total, 161 severe acute respiratory syndrome coronavirus 2 positive and 342 control severe acute respiratory syndrome coronavirus 2 negative patients were included in this study. The 30-day overall postoperative mortality rate was greater in the severe acute respiratory syndrome coronavirus 2 positive cohort compared with the negative control group (16% vs 4% respectively; P = .007). After propensity score matching, the severe acute respiratory syndrome coronavirus 2 positive group consisted of 123 patients (median 70 years of age [interquartile range 59-77] and 55% male) were compared with 196 patients in the matched control group (median 69 years (interquartile range 58-75] and 53% male). The 30-day mortality rate and risk were greater in the severe acute respiratory syndrome coronavirus 2 positive group compared with the matched control group (12% vs 4%; P = .009 and odds ratio 3.4 [95% confidence interval 1.5-8.5]; P = .005, respectively). Overall, pulmonary and thromboembolic complications occurred more often in severe acute respiratory syndrome coronavirus 2 positive patients (P < .01). CONCLUSION: Patients diagnosed with perioperative severe acute respiratory syndrome coronavirus 2 have an increased risk of 30-day mortality, pulmonary complications, and thromboembolic events. These findings serve as an evidence-based argument to postpone elective surgery and selected emergency cases.