RESUMO
A novel multitope protein-peptide vaccine against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and disease is described in this report. The initial development and characterization experiments are presented along with proof-of-concept studies for the vaccine candidate UB-612. UB-612 consists of eight components rationally designed for induction of potently neutralizing antibodies and broad T cell responses against SARS-CoV-2: the S1-RBD-sFc fusion protein, six synthetic peptides (one universal peptide and five SARS-CoV-2-derived peptides), a proprietary CpG TLR-9 agonist at low concentration as an excipient, and aluminum phosphate adjuvant. Through immunogenicity studies in Guinea pigs and rats, we optimized the design of protein/peptide immunogens and selected an adjuvant system, yielding a vaccine that provides excellent S1-RBD binding and high neutralizing antibody responses, robust cellular responses, and a Th1-oriented response at low doses. In challenge studies, UB- 612 vaccination reduced viral load and prevented development of disease in mouse and non-human primate challenge models. With a Phase 1 trial completed, a Phase 2 trial ongoing in Taiwan, and additional trials planned to support global authorizations, UB-612 is a highly promising and differentiated vaccine candidate for prevention of SARS-CoV-2 infection and COVID-19 disease. Author SummarySARS-CoV-2 virus, the causative agent of Coronavirus Disease 2019 (COVID-19), has spread globally since its origin in 2019, causing an unprecedented public health crisis that has resulted in greater than 4.7 million deaths worldwide. Many vaccines are under development to limit disease spread and reduce the number of cases, but additional candidates that promote a robust immune response are needed. Here, we describe a multitope protein-peptide vaccine platform that is unique among COVID-19 vaccines. The advantages of our approach are induction of both high levels of neutralizing antibodies as well as a Th/CTL response in the vaccinated host, which mimics the immune response that occurs after natural infection with SARS-CoV-2. We demonstrate that our vaccine is immunogenic and effective in preventing disease in several animal models, including AAV- hACE-2 transduced mice, and both rhesus and cynomolgus macaques. Importantly, no immunopathology was observed in the lungs of immunized animals, therefore showing that antibody-dependent enhancement (ADE) does not occur. Our study provides an additional, novel vaccine candidate for advancement in clinical trials to treat and prevent SARS-CoV-2 infection and COVID-19 disease.
RESUMO
The role of immediate stress testing in low-risk patients with a potential acute coronary syndrome has not been rigorously evaluated with respect to impact on 30-day cardiovascular events. We evaluated the impact of inpatient, outpatient, or no stress testing (ETT) on 30-day cardiovascular outcomes. We performed a prospective cohort study in which consecutive patients with chest pain were admitted to a non-intensive-care telemetry bed over 16 months. Patients were identified in the ED, followed daily through hospitalization, and contacted by telephone at 30 days. Patients were excluded if they were admitted to the coronary care unit, died during hospitalization, sustained an acute myocardial infarction (AMI), or received cardiac catheterization before ETT. Patients were stratified according to whether they received an ETT as an inpatient, outpatient, or no ETT. Main outcomes were 30-day cardiac death, AMI, percutaneous interventions (PCI), and coronary artery bypass graft surgery (CABG). Data are presented as percentages with 95% confidence intervals (CI) for main outcomes. A total of 832 patients were admitted 962 times. A total of 205 patients (21%) received an in-house ETT. Seventy-four patients (10%) without an inpatient ETT received an outpatient ETT. At baseline, the groups were similar with respect to likelihood of ischemia based on mean ACI-TIPI score and Goldman risk score. A total of 98% of patients had 30-day follow-up. The cardiovascular outcomes (with 95% confidence interval) for patients with inpatient ETT versus outpatient ETT versus no ETT were as follows: death, 0% (0-1.5%) vs 0% (0-4.1%) vs 1% (0.3-1.7%); AMI, 1% (0.1-2.4%) vs 1.4% (0.1-4.1%) vs 0.3% (0.1-0.7%); PCI, 0.5% (0.1-1.5%) vs 1.3% (0.1-4.1%) vs 0% (0-0.4%); and CABG, 0.5% (0.1-1.5%) vs 0% (0-4.1%) vs 0.2% (0.1-0.4%). There was no statistical difference in 30-day cardiovascular outcomes among patients who received inpatient, outpatient, or no ETT within 30 days. This suggests that patients with chest pain who are admitted to non-intensive-care telemetry (or observation unit) beds might not need stress testing before hospital release.