ABSTRACT
IntroductionHyaluronic acid (HA) is one of the main components of glycosaminoglycan (GAG) in proteoglycans. Among patients with novel coronavirus pneumonia, the serum HA content of severe patients was significantly higher than that of mild patients. Therefore, hyaluronic acid inhibitors have the potential to be the treatment of novel coronavirus pneumonia. This study plans to carry out a study on the optimization of the hyaluronic acid inhibitor Hymecromone in the treatment of COVID-19 to improve the therapeutic effect.Methods and analysisThis is a single-center, randomized, parallel controlled, double-blind clinical trial designed to evaluate the efficacy and safety of hymecromone tablets in subjects who confirmed to be infected by the SARS-CoV-2 virus and diagnosed as mild or moderate novel coronavirus pneumonia in China. The subjects in the experimental arm shall receive necessary routine treatment and hymecromone tablets while the control arm shall receive placebo. The study aims to compare the proportion of subjects in the experimental group and the control group who developed disease progression within 28 days after initial treatment. Meanwhile, all subjects will be monitored for safety constantly during the whole study phases.Ethics and disseminationThe study protocol was approved by the Ethics Committee of Zhongshan Hospital Fudan University (identifiers: Clinical Ethical Approval No. B2022-251R).Trial registrationClinicalTrails.org, NCT05386420. Registered 24 May 2022, https://clinicaltrials.gov/ct2/show/NCT05386420Strengths and limitations of this studyThis is one of the first prospective randomized controlled double-blind studies of the efficacy and safety of the hyaluronic acid inhibitor Hymecromone for the treatment of COVID-19. This study will be an innovative clinical intervention strategy, and is expected to provide an effective new treatment plan for the clinical treatment of severe infection with COVID-19. The limitation is it is a single center study, it might need more centers cases to be further external validated.INTRODUCTION
Subject(s)
COVID-19ABSTRACT
Background: The ongoing outbreak of SARS-CoV-2 Omicron BA.2 infections in Hong Kong, the world model city of universal masking, has resulted in a major public health crisis. Although the third heterologous BNT162b2 vaccination after 2-dose CoronaVac generated higher neutralizing antibody responses than the third homologous CoronaVac booster, vaccine efficacy and corelates of immune protection against the major circulating Omicron BA.2 remains to be investigated. Methods: : We investigated the vaccine efficacy against the Omicron BA.2 breakthrough infection among 481 public servants who had been received with SARS-CoV-2 vaccines including two-dose BNT162b2 (2×BNT, n=169), three-dose BNT162b2 (2×BNT, n=175), two-dose CoronaVac (2×CorV, n=37), three-dose CoronaVac (3×CorV, n=68) and third-dose BNT162b2 following 2×CorV (2×CorV+1BNT, n=32). Humoral and cellular immune responses after three-dose vaccination were characterized and correlated with clinical characteristics of BA.2 infection. Results: : During the BA.2 outbreak, 29.3% vaccinees were infected. Three-dose vaccination provided protection with lower incidence rates of breakthrough infections (2×BNT 49.2% vs 3×BNT 16.6%, p<0.0001; 2×CorV 48.6% vs 3×CoV 20.6%, p=0.003). The third heterologous vaccination showed the lowest incidence (2×CorV+1×BNT 6.3%). Although BA.2 conferred the highest neutralization resistance compared with variants of concern tested, the third dose vaccination-activated spike-specific memory B and Omicron cross-reactive T cell responses contributed to reduced frequencies of breakthrough infection and disease severity. Conclusions: : Our results have implications to timely boost vaccination and immune responses likely required for vaccine-mediated protection against Omicron BA.2 pandemic.
Subject(s)
Breakthrough PainABSTRACT
The ongoing outbreak of SARS-CoV-2 Omicron BA.2 infections in Hong Kong, the world model city of universal masking, has resulted in a major public health crisis. In this study, we investigate public servants who had been vaccinated with two dose (82.7%) or three dose (14%) of either CoronaVac (CorV) or BNT162b2 (BNT). During the BA.2 outbreak, 29.3% vaccinees were infected. Three-dose vaccination provided protection with lower incidence rates of breakthrough infections (2xBNT 49.2% vs 3xBNT 16.6%, p<0.0001; 2xCorV 48.6% vs 3xCoV 20.6%, p=0.003). The third heterologous vaccination showed the lowest incidence (2xCorV+1xBNT 6.3%). Although BA.2 conferred the highest neutralization resistance compared with variants of concern tested, the third dose vaccination-activated spike-specific memory B and Omicron cross-reactive T cell responses contributed to reduced frequencies of breakthrough infection and disease severity. Our results have implications to timely boost vaccination and immune responses likely required for vaccine-mediated protection against Omicron BA.2 pandemic.
Subject(s)
Breakthrough PainABSTRACT
Highly transmissible SARS-CoV-2 Omicron variant has posted a new crisis for COVID-19 pandemic control. Within a month, Omicron is dominating over Delta variant in several countries probably due to immune evasion. It remains unclear whether vaccine-induced memory responses can be recalled by Omicron infection. Here, we investigated host immune responses in the first vaccine-breakthrough case of Omicron infection in Hong Kong. We found that the breakthrough infection rapidly recruited potent cross-reactive broad neutralizing antibodies (bNAbs) against current VOCs, including Alpha, Beta, Gamma, Delta and Omicron, from unmeasurable IC50 values to mean 1:2929 at around 9-12 days, which were higher than the mean peak IC50 values of BioNTech-vaccinees. Cross-reactive spike- and nucleocapsid-specific CD4 and CD8 T cell responses were detected. Similar results were also obtained in the second vaccine-breakthrough case of Omicron infection. Our preliminary findings may have timely implications to booster vaccine optimization and preventive strategies of pandemic control.
Subject(s)
Breakthrough Pain , COVID-19ABSTRACT
Background: Nearly 4 billion doses of the BioNTech-mRNA and Sinovac-inactivated vaccines have been administrated globally, yet different vaccine-induced immunity against SARS-CoV-2 variants of concern (VOCs) remain incompletely investigated. Methods: We compare the immunogenicity and durability of these two vaccines among fully vaccinated Hong Kong people. Findings: Standard BioNTech and Sinovac vaccinations were tolerated and induced neutralizing antibody (NAb) (100% and 85.7%) and spike-specific CD4 T cell responses (96.7% and 82.1%), respectively. The geometric mean NAb IC 50 and median frequencies of reactive CD4 subsets were consistently lower among Sinovacvaccinees than BioNTech-vaccinees. Against VOCs, NAb response rate and geometric mean IC 50 against B1.351 and B.1.617.2 were significantly lower for Sinovac (14.3%, 15 and 50%, 23.2) than BioNTech (79.4%, 107 and 94.1%, 131). Three months after vaccinations, NAbs to VOCs dropped near to detection limit, along with waning memory T cell responses, mainly among Sinovac-vaccinees. Interpretation: Our results indicate that Sinovac-vaccinees may face higher risk to pandemic VOCs breakthrough infection.
Subject(s)
Breakthrough PainABSTRACT
Background Vaccines in emergency use are efficacious against COVID-19, yet vaccine-induced prevention against nasal SARS-CoV-2 infection remains suboptimal. Methods Since mucosal immunity is critical for nasal prevention, we investigated an intramuscular PD1-based receptor-binding domain (RBD) DNA vaccine (PD1-RBD-DNA) and intranasal live attenuated influenza-based vaccines (LAIV-CA4-RBD and LAIV-HK68-RBD) against SARS-CoV-2. Findings Substantially higher systemic and mucosal immune responses, including bronchoalveolar lavage IgA/IgG and lung polyfunctional memory CD8 T cells, were induced by the heterologous PD1-RBD-DNA/LAIV-HK68-RBD as compared with other regimens. When vaccinated animals were challenged at the memory phase, prevention of robust SARS-CoV-2 infection in nasal turbinate was achieved primarily by the heterologous regimen besides consistent protection in lungs. The regimen-induced antibodies cross-neutralized variants of concerns. Furthermore, LAIV-CA4-RBD could boost the BioNTech vaccine for improved mucosal immunity. Interpretation Our results demonstrated that intranasal influenza-based boost vaccination is required for inducing mucosal and systemic immunity for effective SARS-CoV-2 prevention in both upper and lower respiratory systems. Funding This study was supported by the Research Grants Council Collaborative Research Fund (C7156-20G, C1134-20G and C5110-20G), General Research Fund (17107019) and Health and Medical Research Fund (19181052 and 19181012) in Hong Kong; Outbreak Response to Novel Coronavirus (COVID-19) by the Coalition for Epidemic Preparedness Innovations; Shenzhen Science and Technology Program (JSGG20200225151410198); the Health@InnoHK, Innovation and Technology Commission of Hong Kong; and National Program on Key Research Project of China (2020YFC0860600, 2020YFA0707500 and 2020YFA0707504); and donations from the Friends of Hope Education Fund. Z.C.’s team was also partly supported by the Theme-Based Research Scheme (T11-706/18-N).
Subject(s)
COVID-19ABSTRACT
Background The outbreak of coronavirus disease 2019 (COVID-19) has become a global pandemic acute infectious disease, especially with the features of possible asymptomatic carriers and high contagiousness. It causes acute respiratory distress syndrome and results in a high mortality rate if pneumonia is involved. Currently, it is difficult to quickly identify asymptomatic cases or COVID-19 patients with pneumonia due to limited access to reverse transcription-polymerase chain reaction (RT-PCR) nucleic acid tests and CT scans, which facilitates the spread of the disease at the community level, and contributes to the overwhelming of medical resources in intensive care units. Goal This study aimed to develop a scientific and rigorous clinical diagnostic tool for the rapid prediction of COVID-19 cases based on a COVID-19 clinical case database in China, and to assist global frontline doctors to efficiently and precisely diagnose asymptomatic COVID-19 patients and cases who had a false-negative RT-PCR test result. Methods With online consent, and the approval of the ethics committee of Zhongshan Hospital Fudan Unversity (approval number B2020-032R) to ensure that patient privacy is protected, clinical information has been uploaded in real-time through the New Coronavirus Intelligent Auto-diagnostic Assistant Application of cloud plus terminal (nCapp) by doctors from different cities (Wuhan, Shanghai, Harbin, Dalian, Wuxi, Qingdao, Rizhao, and Bengbu) during the COVID-19 outbreak in China. By quality control and data anonymization on the platform, a total of 3,249 cases from COVID-19 high-risk groups were collected. These patients had SARS-CoV-2 RT-PCR test results and chest CT scans, both of which were used as the gold standard for the diagnosis of COVID-19 and COVID-19 pneumonia. In particular, the dataset included 137 indeterminate cases who initially did not have RT-PCR tests and subsequently had positive RT-PCR results, 62 suspected cases who initially had false-negative RT-PCR test results and subsequently had positive RT-PCR results, and 122 asymptomatic cases who had positive RT-PCR test results, amongst whom 31 cases were diagnosed. We also integrated the function of a survey in nCapp to collect user feedback from frontline doctors. Findings We applied the statistical method of a multi-factor regression model to the training dataset (1,624 cases) and developed a prediction model for COVID-19 with 9 clinical indicators that are fast and accessible: 'Residing or visiting history in epidemic regions', 'Exposure history to COVID-19 patient', 'Dry cough', 'Fatigue', 'Breathlessness', 'No body temperature decrease after antibiotic treatment', 'Fingertip blood oxygen saturation<=93%', 'Lymphopenia', and 'C-reactive protein (CRP) increased'. The area under the receiver operating characteristic (ROC) curve (AUC) for the model was 0.88 (95% CI: 0.86, 0.89) in the training dataset and 0.84 (95% CI: 0.82, 0.86) in the validation dataset (1,625 cases). To ensure the sensitivity of the model, we used a cutoff value of 0.09. The sensitivity and specificity of the model were 98.0% (95% CI: 96.9%, 99.1%) and 17.3% (95% CI: 15.0%, 19.6%), respectively, in the training dataset, and 96.5% (95% CI: 95.1%, 98.0%) and 18.8% (95% CI: 16.4%, 21.2%), respectively, in the validation dataset. In the subset of the 137 indeterminate cases who initially did not have RT-PCR tests and subsequently had positive RT-PCR results, the model predicted 132 cases, accounting for 96.4% (95% CI: 91.7%, 98.8%) of the cases. In the subset of the 62 suspected cases who initially had false-negative RT-PCR test results and subsequently had positive RT-PCR results, the model predicted 59 cases, accounting for 95.2% (95% CI: 86.5%, 99.0%) of the cases. Considering the specificity of the model, we used a cutoff value of 0.32. The sensitivity and specificity of the model were 83.5% (95% CI: 80.5%, 86.4%) and 83.2% (95% CI: 80.9%, 85.5%), respectively, in the training dataset, and 79.6% (95% CI: 76.4%, 82.8%) and 81.3% (95% CI: 78.9%, 83.7%), respectively, in the validation dataset, which is very close to the published AI model. The results of the online survey 'Questionnaire Star' showed that 90.9% of nCapp users in WeChat mini programs were 'satisfied' or 'very satisfied' with the tool. The WeChat mini program received a significantly higher satisfaction rate than other platforms, especially for 'availability and sharing convenience of the App' and 'fast speed of log-in and data entry'. Discussion With the assistance of nCapp, a mobile-based diagnostic tool developed from a large database that we collected from COVID-19 high-risk groups in China, frontline doctors can rapidly identify asymptomatic patients and avoid misdiagnoses of cases with false-negative RT-PCR results. These patients require timely isolation or close medical supervision. By applying the model, medical resources can be allocated more reasonably, and missed diagnoses can be reduced. In addition, further education and interaction among medical professionals can improve the diagnostic efficiency for COVID-19, thus avoiding the transmission of the disease from asymptomatic patients at the community level.