Safety and immunogenicity of a SARS-CoV-2 recombinant protein nanoparticle vaccine (GBP510) adjuvanted with AS03: A randomised, placebo-controlled, observer-blinded phase 1/2 trial.

Background: Vaccination has helped to mitigate the COVID-19 pandemic. Ten traditional and novel vaccines have been listed by the World Health Organization for emergency use. Additional alternative approaches may better address ongoing vaccination globally, where there remains an inequity in vaccine distribution. GBP510 is a recombinant protein vaccine, which consists of self-assembling, two-component nanoparticles, displaying the receptor-binding domain (RBD) in a highly immunogenic array. Methods: This randomised, placebo-controlled, observer-blinded phase 1/2 study was conducted to evaluate the safety and immunogenicity of GBP510 (2-doses at a 28-day interval) adjuvanted with or without AS03 in adults aged 19-85 years at 14 hospital sites in Korea. This study was consisted of two stages (stage I, healthy adults aged 19-55 years; stage II, 240 healthy adults aged 19-85 years). Healthy participants who did not previously receive any vaccine within 4 weeks (2 weeks for flu vaccine) prior to the study, no history of COVID-19 vaccination/medication, and were naïve to SARS-CoV-2 infection at screening were eligible for the study enrollment. Participants were block-randomized in a 2:2:1 ratio to receive 2 doses of 10 µg GBP510 adjuvanted with AS03 (group 1), 10 µg unadjuvanted GBP510 (group 2) or placebo intramuscularly in stage I, while they were block-randomized in a 2:2:1:1 ratio to receive 10 µg GBP510 adjuvanted with AS03 (group 1), 25 µg GBP510 adjuvanted with AS03 (group 3), 25 µg unadjuvanted GBP510 (group 4) or placebo in stage II. The primary safety outcomes were solicited and unsolicited adverse events, while primary immunogenicity outcomes included anti-SARS-CoV-2 RBD IgG antibodies; neutralizing antibody responses; and T-cell immune responses. Safety assessment included all participants who received at least 1 dose of study intervention (safety set). Immunogenicity assessment included all participants who completed the vaccination schedule and had valid immunogenicity assessment results without any major protocol deviations (per-protocol set). This study was registered with ClinicalTrials.gov (NCT04750343). Findings: Of 328 participants who were enrolled between February 1 and May 28, 2021, 327 participants received at least 1 dose of vaccine. Each received either 10 µg GBP510 adjuvanted with AS03 (Group 1, n = 101), 10 µg unadjuvanted GBP510 (Group 2, n = 10), 25 µg GBP510 adjuvanted with AS03 (Group 3, n = 104), 25 µg unadjuvanted GBP510 (Group 4, n = 51), or placebo (n = 61). Higher reactogenicity was observed in the GBP510 adjuvanted with AS03 groups compared to the non-adjuvanted and placebo groups. The most frequently reported solicited local adverse event (AE) was injection site pain after any vaccination: (88·1% in group 1; 50·0% in group 2; 92·3% in group 3; 66·7% in group 4). Fatigue and myalgia were two most frequently reported systemic AEs and more frequently reported in GBP510 adjuvanted with AS03 recipients (79·2% and 78·2% in group 1; 75·0% and 79·8% in group 3, respectively) than in the unadjuvanted vaccine recipients (40·0% and of 40·0% in group 2; 60·8% and 47·1% in group 4) after any vaccination. Reactogenicity was higher post-dose 2 compared to post-dose 1, particularly for systemic AEs. The geometric mean concentrations of anti-SARS-CoV-2-RBD IgG antibody reached 2163·6/2599·2 BAU/mL in GBP510 adjuvanted with AS03 recipients (10 µg/25 µg) by 14 days after the second dose. Two-dose vaccination of 10 µg or 25 µg GBP510 adjuvanted with AS03 induced high titres of neutralizing antibody via pseudovirus (1369·0/1431·5 IU/mL) and wild-type virus (949·8/861·0 IU/mL) assay. Interpretation: GBP510 adjuvanted with AS03 was well tolerated and highly immunogenic. These results support further development of the vaccine candidate, which is currently being evaluated in Phase 3. Funding: This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investment ID OPP1148601. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.

Relationship between the appropriateness of antibiotic treatment and clinical outcomes/medical costs of patients with community-acquired acute pyelonephritis: a multicenter prospective cohort study.

BACKGROUND: Inappropriate use of antibiotics not only increases antibiotic resistance as collateral damage but also increases clinical failure rates and medical costs. The purpose of this study was to determine the relationship between the appropriateness of antibiotic prescription and outcomes of community-acquired acute pyelonephritis (CA-APN). METHODS: A multicenter prospective cohort study was conducted at eight hospitals in Korea between September 2017 and August 2018. All hospitalized patients aged ≥ 19 years who were diagnosed with CA-APN on admission were recruited. The appropriateness of empirical and definitive antibiotics, as well as the appropriateness of antibiotic treatment duration and route of administration, was evaluated in accordance with the guideline and expert opinions. Clinical outcomes and medical costs were compared between patients who were administered antibiotics 'appropriately' and 'inappropriately.' RESULTS: A total of 397 and 318 patients were eligible for the analysis of the appropriateness of empirical and definitive antibiotics, respectively. Of them, 10 (2.5%) and 18 (5.7%) were administered 'inappropriately' empirical and definitive antibiotics, respectively. Of the 119 patients whose use of both empirical and definitive antibiotics was classified as 'optimal,' 57 (47.9%) received antibiotics over a longer duration than that recommended; 67 (56.3%) did not change to oral antibiotics on day 7 of hospitalization, even after stabilization of the clinical symptoms. Patients who were administered empirical antibiotics 'appropriately' had shorter hospitalization days (8 vs. 10 days, P = 0.001) and lower medical costs (2381.9 vs. 3235.9 USD, P = 0.002) than those who were administered them 'inappropriately.' Similar findings were observed for patients administered both empirical and definitive antibiotics 'appropriately' and those administered either empirical or definitive antibiotics 'inappropriately'. CONCLUSIONS: Appropriate use of antibiotics leads to better outcomes, including reduced hospitalization duration and medical costs.

Clinical outcomes and healthcare costs of inpatients with tetanus in Korea, 2011-2019.

BACKGROUND: Tetanus is a rare, vaccine-preventable but extremely serious disease. We investigated the recent trend of the clinical outcomes and medical costs for inpatients with tetanus in South Korea over 10 years. METHODS: We conducted a retrospective review to determine the clinical factors and medical costs associated with tetanus at two national university hospitals in South Korea between January 2011 and October 2019. RESULTS: Forty-nine patients were admitted for tetanus (mean age, 67.0 years [range, 53.0-80.0 years]; 32 women [57.1%]). All the patients had generalized tetanus, and 5 (10.2%) died during hospitalization. The median duration from symptom onset to hospital admission was 4 days. Trismus (85.7%) was the most common symptom, and the median hospital stay was 39 days. Thirty-two patients (65.3%) required mechanical ventilation, and 20 (40.8%) developed aspiration pneumonia. The median total healthcare cost per patient was US $18,011. After discharge, 35 patients (71.4%) recovered sufficiently to walk without disability. CONCLUSIONS: Tetanus requires long hospital stays and high medical expenditures in South Korea; however, the vaccination completion rate is low. Medical staff should therefore promote medical advice and policies on the management of tetanus to the general South Korean population.

How to keep patients and staff safe from accidental SARS-CoV-2 exposure in the emergency room: Lessons from South Korea's explosive COVID-19 outbreak.

OBJECTIVES: We report our experience with an emergency room (ER) shutdown related to an accidental exposure to a patient with coronavirus disease 2019 (COVID-19) who had not been isolated. SETTING: A 635-bed, tertiary-care hospital in Daegu, South Korea. METHODS: To prevent nosocomial transmission of the disease, we subsequently isolated patients with suspected symptoms, relevant radiographic findings, or epidemiology. Severe acute respiratory coronavirus 2 (SARS-CoV-2) reverse-transcriptase polymerase chain reaction assays (RT-PCR) were performed for most patients requiring hospitalization. A universal mask policy and comprehensive use of personal protective equipment (PPE) were implemented. We analyzed effects of these interventions. RESULTS: From the pre-shutdown period (February 10-25, 2020) to the post-shutdown period (February 28 to March 16, 2020), the mean hourly turnaround time decreased from 23:31 ±6:43 hours to 9:27 ±3:41 hours (P < .001). As a result, the proportion of the patients tested increased from 5.8% (N=1,037) to 64.6% (N=690) (P < .001) and the average number of tests per day increased from 3.8±4.3 to 24.7±5.0 (P < .001). All 23 patients with COVID-19 in the post-shutdown period were isolated in the ER without any problematic accidental exposure or nosocomial transmission. After the shutdown, several metrics increased. The median duration of stay in the ER among hospitalized patients increased from 4:30 hours (interquartile range [IQR], 2:17-9:48) to 14:33 hours (IQR, 6:55-24:50) (P < .001). Rates of intensive care unit admissions increased from 1.4% to 2.9% (P = .023), and mortality increased from 0.9% to 3.0% (P = .001). CONCLUSIONS: Problematic accidental exposure and nosocomial transmission of COVID-19 can be successfully prevented through active isolation and surveillance policies and comprehensive PPE use despite longer ER stays and the presence of more severely ill patients during a severe COVID-19 outbreak.

The impact of infection control cost reimbursement policy on central line-associated bloodstream infections.

BACKGROUND: In September 2016, the Korean National Health Insurance Service began reimbursing infection control (IC) costs on the condition that a certain number of doctors and full-time nurses for IC be allocated to supported hospitals. We analyzed the impact of the IC cost reimbursement policy on central line-associated bloodstream infections (CLABSIs). METHODS: A before-and-after study that analyzed the CLABSI rate trends between preintervention (January 2016 to February 2017) and intervention (March to December 2017) periods using autoregression time series analysis was performed in intensive care units (ICUs) at a 750-bed, secondary care hospital in Daegu, Republic of Korea. The enhanced IC team visited ICUs daily, monitored the implementation of CLABSI prevention bundles, and educated all personnel involved in catheter insertion and maintenance from March 2017. RESULTS: Autoregressive analysis revealed that the CLABSI rates per month in the preintervention and intervention periods were -0.256 (95% confidence interval, -0.613 to 0.101; P = .15) and -0.602 (95% confidence interval, -0.972 to -0.232; P = .008), respectively. The rates of compliance with maximal barrier precautions significantly improved from the preintervention (36.2%) to the intervention (77.9%) period (χ² test, P < .001). CONCLUSIONS: The IC cost reimbursement policy accelerated the decline in CLABSI rates significantly in monitored ICUs. A nationwide study to evaluate the effectiveness of the IC cost reimbursement policy for various health care-associated infections is warranted.

Looking back to move forward: a twenty-year audit of herpes zoster in Asia-Pacific.

BACKGROUND: Herpes zoster (HZ) is a prevalent viral disease that inflicts substantial morbidity and associated healthcare and socioeconomic burdens. Current treatments are not fully effective, especially among the most vulnerable patients. Although widely recommended, vaccination against HZ is not routine; barriers in Asia-Pacific include long-standing neglect of adult immunisation and sparse local data. To address knowledge gaps, raise awareness, and disseminate best practice, we reviewed recent data and guidelines on HZ from the Asia-Pacific region. METHODS: We searched PubMed, Scopus, and World Health Organization databases for articles about HZ published from 1994 to 2014 by authors from Australia, China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, New Zealand, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. We selected articles about epidemiology, burden, complications, comorbidities, management, prevention, and recommendations/guidelines. Internet searches retrieved additional HZ immunisation guidelines. RESULTS: From 4007 retrieved articles, we screened-out 1501 duplicates and excluded 1264 extraneous articles, leaving 1242 unique articles. We found guidelines on adult immunisation from Australia, India, Indonesia, Malaysia, New Zealand, the Philippines, South Korea, and Thailand. HZ epidemiology in Asia-Pacific is similar to elsewhere; incidence rises with age and peaks at around 70 years - lifetime risk is approximately one-third. Average incidence of 3-10/1000 person-years is rising at around 5% per year. The principal risk factors are immunosenescence and immunosuppression. HZ almost always causes pain, and post-herpetic neuralgia is its most common complication. Half or more of hospitalised HZ patients have post-herpetic neuralgia, secondary infections, or inflammatory sequelae that are occasionally fatal. These disease burdens severely diminish patients' quality of life and incur heavy healthcare utilisation. CONCLUSIONS: Several countries have abundant data on HZ, but others, especially in South-East Asia, very few. However, Asia-Pacific countries generally lack data on HZ vaccine safety, efficacy and cost-effectiveness. Physicians treating HZ and its complications in Asia-Pacific face familiar challenges but, with a vast aged population, Asia bears a unique and growing burden of disease. Given the strong rationale for prevention, most adult immunisation guidelines include HZ vaccine, yet it remains underused. We urge all stakeholders to give higher priority to adult immunisation in general and HZ in particular.

Radiological Assessment of the Effect of Congenital C3-4 Synostosis on Adjacent Segments.

STUDY DESIGN: Retrospective case series. PURPOSE: To assess the effect of non-kyphotic aligned congenital C3-4 synostosis on the adjacent segment in 10 patients. OVERVIEW OF LITERATURE: In the cervical spine, fusion disease at the adjacent motion segments may be a risk factor for potential neurological compromise and death. METHODS: Radiograms of 10 patients 13 to 69 years of age presenting with neck/shoulder discomfort or pain with or without trauma history were examined. C3-4 synostosis was found incidentally in all patients on routine examination radiographs of cervical spine. RESULTS: Adjacent segment disease (ASD) was not found in the three patients younger than 39 years of age. Five of the 10 (50%) patients, including a 67-year-old man, did not develop spondylosis in any of the cervical mobile segments. Spondylosis was observed only in the caudal 1-2 mobile segments in the remaining five patients. The youngest was a 40-year-old male who had spondylosis in the two caudal mobile segments (C4-5 and C5-6). Spondylosis was limited to the two close caudal mobile segments and was not in the cranial segments. Flaring of the lower part of synostotic vertebra associated with advanced narrowed degenerate disc was evident in five patients. CONCLUSIONS: Mobile segment spondylosis in the individuals with congenital monosegment C3-4 synostosis over age of 40 years may be a natural manifestation of aging and is not solely an adjacent segment disease directly and fully related with congenital C3-4 synostosis.