A Novel SARS-CoV-2 Multitope Protein/Peptide Vaccine Candidate is Highly Immunogenic and Prevents Lung Infection in an Adeno Associated Virus Human Angiotensin-Converting Enzyme 2 (AAV hACE2) Mouse Model

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.

Changes in clinical indicators among human immunodeficiency virus patients who failed in antiretroviral therapy during 2004-2016 in Yunnan, China: an observational cohort study / 《全球健康杂志（英文）》

Background:This study aimed to investigate the changes in the clinical indicators and influencing factors of treatment duration among human immunodeficiency virus (HIV) patients in whom antiretroviral therapy (ART) was unsuccessful.Methods:In this retrospective study,a total of 9,418 HIV patients who failed in ART during 2004-2016 were included and divided into two treatment groups-Group 1 (treatment time ≤ 3 years,n1 =5,218) and Group 2 (treatment time ＞ 3 years,n2 =4,200).Patient follow-up data,including age,cluster of differentiation 4 (CD4) count,and viral load,glucose,creatinine,and triglyceride levels,were extracted from electronic health record databases.Covariance analysis for repeated measures was used to analyze the biochemical indicators,and multiple logistic regression modeling was used to compare relevant data extracted from the Group 1 and Group 2 HIV patient cohorts with different treatment time.Results:The median initial CD4 count was 175.0 cells/μl (interquartile range,77.0-282.0),while the initial CD4 counts for Group 1 were lower than those for Group 2 (P ＜ 0.05).A significant interaction between group and time effects was observed (P ＜ 0.05) in total cholesterol (TC).Changes in hemoglobin level among HIV patients were also significantly associated with treatment time (P =0.001).The initial CD4 count (odds ratio [OR] =0.756),female sex (OR =0.713),Zerit (d4T) (OR =1.443),TC (OR =1.285),and aspartate aminotransferase level (OR =1.002) were significantly associated with the survival time of dead patients with HIV (P ＜ 0.05).Additionally,the initial CD4 count (OR =1.456),age (OR =1.022),time interval (OR =0.903),patient's living status (OR =0.597),d4T (OR =2.256),and triglyceride (OR =0.930) and hemoglobin levels (OR =0.997) were significantly associated with the treatment time of HIV patients with drug withdrawal (P ＜ 0.05).Conclusion:The initial biochemical parameters can affect the survival and treatment time of HIV patients.With a comprehensive understanding of the physiological and biochemical indicators of patients,we can reduce the probability of drug withdrawal and prolong the survival time of HIV patients.