ABSTRACT
Background: This study has assessed the protective effect of a new Anti-COVID-19 SA58 Nasal Spray (SA58 Nasal Spray) against SARS-CoV-2 infection under continuous exposure. Methods: This is an exploratory open-label, single-arm trial. To evaluate the safety and effectiveness of SA58 against SARS-CoV-2 family transmission, SA58 was administered to all enrolled family contacts at 3~6-hour intervals. The frequency of administration and adverse events (AEs) were self-reported by online questionnaire, and RT-PCR tests were used to diagnose SARS-CoV-2 infection. The effectiveness was assessed in comparison to a contemporaneous control group whose information was collected through three follow-up visits. Total effectiveness and single-day effectiveness were calculated. Results: The incidence of SARS-CoV-2 infection was 62.9% (44/70) in the experimental group and 94.8% (343/362) in the control group. Using SA58 nasal spray at least three times per day could possibly reduce the risk of household transmission of SARS-CoV-2 by 46.7%~56.5%. The incidence of AEs was 41.4% and the severity of all AEs was mild. Conclusion: Even under the scenario of continuous exposure to SARS-CoV-2, SA58 nasal spray remained effective in blocking viral transmission and was well tolerated.
Subject(s)
COVID-19ABSTRACT
Background: Many issues, such as severity assessment and antibody responses, remain to be answered eagerly for evaluation and understanding of COVID-19. Immune lesion is one of key pathogenesis of the disease. It would be helpful to understand the disease if an investigation on antigenemia and association was conducted in the patients with SARS-CoV-2 infection. Methods: A total of 156 patients admitted to the First People's Hospital of Hefei or Anhui Provincial Hospital on January to February 2020 were involved in this study. SARS-CoV-2 nucleocapsid (NP) antigen, specific IgM/IgG antibodies, and RNA were detected in sequential sera from three COVID-19 patients, and additional 153 COVID-19 patients by means of NP-antigen capture enzyme-linked immunosorbent assay, colloidal gold quick diagnosis, and real-time RT-PCR, respectively. The clinical types of COVID-19 patients were classified into asymptomatic, mild, moderate, severe, and critical, following on the Chinese guideline of COVID-19 diagnosis and treatment. The demographic and clinical data of patients were obtained for comparable analysis. Results: NP antigen was detected in 5 of 20 sequential sera collected from three COVID-19 patients with typically clinical symptoms, and 60.13% (92/153) expanded samples collected within 17 days after illness onset. No SARS-CoV-2 RNA segment was detected in these sera. The NP positive proportion reached a peak (84.85%, 28/33) on 6 to 8 days after illness onset. Both NP concentration and positive proportion were increased with the increase of clinical severity of COVID-19. Compared to NP negative patients, NP positive patients had older age [years, medians (interquartile ranges (IQR)), 49 (6) vs. 31 (11)], lower positive proportion of NP specific IgM [27.17% (25/92) vs. 59.02% (36/61)], and IgG [21.74% (20/92) vs. 59.02% (36/61)] antibodies, and longer duration [days, medians (IQR), 24 (10) vs. 21 (13)] from illness to recovery. Conclusions: SARS-CoV-2 NP antigenemia occurred in COVID-19, and presented highly prevalent at early stage of the disease. The antigenemia was related to clinical severity of the disease, and may be responsible for the delay of detectable SARS-Cov-2 IgM.
ABSTRACT
Emergence of variants of concern (VOC) with altered antigenic structures and waning humoral immunity to SARS-CoV-2 are harbingers of a long pandemic. Administration of a third dose of an inactivated virus vaccine can boost the immune response. Here, we have dissected the immunogenic profiles of antibodies from 3-dose vaccinees, 2-dose vaccinees and convalescents. Better neutralization breadth to VOCs, expeditious recall and long-lasting humoral response bolster 3-dose vaccinees in warding off COVID-19. Analysis of 171 complex structures of SARS-CoV-2 neutralizing antibodies identified structure-activity correlates, revealing ultrapotent, VOCs-resistant and broad-spectrum antigenic patches. Construction of immunogenic and mutational heat maps revealed a direct relationship between "hot" immunogenic sites and areas with high mutation frequencies. Ongoing antibody somatic mutation, memory B cell clonal turnover and antibody composition changes in B cell repertoire driven by prolonged and repeated antigen stimulation confer development of monoclonal antibodies with enhanced neutralizing potency and breadth. Our findings rationalize the use of 3-dose immunization regimens for inactivated vaccines. One sentence summaryA third booster dose of inactivated vaccine produces a highly sifted humoral immune response via a sustained evolution of antibodies capable of effectively neutralizing SARS-CoV-2 variants of concern.
Subject(s)
COVID-19ABSTRACT
Background: The COVID-19 vaccine for children and adolescents, who are indispensable populations to curb the pandemic, would protect this population against rare severe COVID-19 and infectious conditions. Here we aimed to assess the safety, tolerability and immunogenicity of a candidate COVID-19 vaccine, CoronaVac, containing inactivated SARS-CoV-2, in children and adolescents aged 3-17 years old. Methods: We did a randomised, double-blind, placebo-controlled phase 1/2 clinical trial of CoronaVac in healthy children and adolescents aged 3-17 years old in Zanhuang (Hebei, China). Vaccine (in 0 ·5ml aluminum hydroxide adjuvant) or placebo (adjuvant only) was given by intramuscular injection in two doses (day 0 and day 28). We conducted phase 1 trial in 71 participants with an age de-escalation in tree groups and dose-escalation in two blocks (1.5ug or 3ug per injection). Within each block, participants were randomly assigned (3:1) using block randomisation to receive CoronaVac or placebo. In phase 2, participants were randomly assigned (2:2:1) using block randomisation to receive either CoronaVac at 1.5ug or 3ug per dose, or placebo. The primary safety endpoint was adverse reactions within 28 days after each injection in all participants who received at least one dose. The primary immunogenicity endpoint was seroconversion rate at 28 days after the second injection and its GMT as the secondary endpoint. This study is ongoing and is registered with ClinicalTrials.gov (NCT04551547).Findings: Between October 31 and December 2, 2020, 72 participants were enrolled in phase 1, and between December 12 and December 30, 2020, 480 participants were enrolled in phase 2. 500 participants received at least one dose of vaccine or placebo (n=71 for phase 1 and n=479 for phase 2; safety population). In the combined safety profile of phase 1 and phase 2, any adverse reactions within 28 days after injection occurred in 56 (26%) of 219 participants in the 1·5ug group, 63 (29%) of 217 in the 3ug group and 27 (24%) of 114 in the placebo group, without significant difference. Most adverse reactions were mild and moderate in severity and injection site pain (73[13%]) of 550 participants was the most frequently reported event. As of March 12, 2021, only one serious adverse event has been reported, which was considered unrelated to vaccination. In phase 1, seroconversion after the second dose was observed in 27 of 27 participants (100·0% [95%CI 87·3-100·0]) in the 1·5ug groups and 26 of 26 participants (100·0% [86·8-100·0]) in the 3ug group, with the geometric mean titers of 55·0 (95%CI 38·9-77·9) and 117·4 (87·8-157·0). In phase 2, seroconversion was seen in 180 of 186 participants (96·8% [93·1-98·8]) in the 1·5ug group and 180 of 180 participants (100·0% [98·0-100·0]) in the 3ug group, with the geometric mean titers of 86·4 (73·9-101·0) and 142·2 (124·7-162·1). There were no detectable antibody responses in the placebo groups. Interpretation: CoronaVac was well tolerated and induced strong neutralising antibody responses in children and adolescents aged 3-17 years. The study has provided solid safety and immunogenicity data to support the further study and use of CoronaVac in children and adolescents.Trial Registration: NCT04551547Funding Statement: Chinese National Key Research and Development Program and Beijing Science and Technology Program.Declaration of Interests: QG and XL are employees of Sinovac Life Sciences Co., Ltd. YS, WY and LW are employees of Sinovac Biotech Ltd. All other authors declare no competing interests.Ethics Approval Statement: The clinical trial protocol and informed consent form were approved by the Ethics Committee of Hebei CDC (IRB2020-005).
Subject(s)
COVID-19ABSTRACT
Background: Safe and effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed to halt the spread of coronavirus disease 2019 (COVID-19) pandemic. As a promising inactivated SARS-CoV-2 vaccine, CoronaVac (developed by Sinovac Life Sciences, Beijing, China) is currently undergoing its clinical trials in several countries and showing good results. We investigated the immune mechanisms underlying CoronaVac from the perspective of single-cell gene expressions and immune function features.Methods: In this controlled study, 13 healthy participants aged 21–54 years were recruited in the vaccination group and intramuscularly injected with two doses of CoronaVac (3 μg / 0·5 mL per dose, at Day00 and Day28, right after blood sampling), with peripheral blood samples collected at Day00, Day14, Day28, Day35, and Day45 to monitor dynamic changes. As positive control, 12 participants aged 28–75 years that had recovered from COVID-19 for approximately eight months were recruited in the recovery group with peripheral blood samples collected. Considering the high cost of sequencing, 11 samples from two healthy participants (H1 and H2) with four timepoints (Day00, Day14, Day28, and Day35) and three recovered participants (R1, R2, and R3) with one timepoint (Month8) were randomly chosen for single-cell RNA sequencing of peripheral blood mononuclear cells (PBMC). The transcriptomics of PBMC and its constituent cells were analyzed as gene expression responses. For samples from all 25 participants, the serum neutralizing antibody titer to live SARS-CoV-2 and the in vitro cytokine release activity of CD4+T cells were assayed as immune function responses.Findings: Single-cell RNA sequencing showed that the PBMC transcriptomics after vaccination resembled the COVID-19 recovery control more than that before vaccination, which also applied to its constituent cells such as B cells, T cells, NK cells, and myeloid cells. Gradual transitions of PBMC transcriptomics were observed from Day14 to Day28 and Day35 in vaccination groups, which finally approached the recovery control. The B cell levels in PBMC increased after each vaccination, while the T cell levels mainly increased within four weeks after the first vaccination and peaked at Day28. The serum neutralizing antibody titer to live SARS-CoV-2 was low within four weeks after the first vaccination, but the second vaccination could induce significantly higher serum neutralizing antibody titers due to the immune memory. For both vaccinated participants and recovered participants, the upregulated JUN/FOS network and tuned expressions of immunoglobulin fragments such as IGHV3-30 and IGLV2-23 were observed in B cells. By purifying CD4+T cells from PBMC and re-stimulating them with CoronaVac in vitro, five cytokines were significantly released, including Th1 cytokines (IFN-γ and IL-2) and Th2 cytokines (IL-4, IL-6, and IL-10). Th1 cytokines were mainly activated at Day14, Day28, and Day35, supporting cellular immune responses at early stages when the serum neutralizing antibody titer was low. Th2 cytokines were mainly activated at Day28, Day35, and Day45, supporting humoral immune responses at later stages, especially after the second vaccination.Interpretation: Two vaccinations of CoronaVac (3 µg per dose, with an interval of 28 days) could make positive gene expression and immune responses in healthy participants, as revealed by single-cell PBMC transcriptomics and immune function assays.Funding Statement: China’s National Science and Technology Major Projects for Major New Drugs Innovation and Development.Declaration of Interests: QG, YH, XM, and SZ are employees of Sinovac Life Sciences, Beijing, China. The other authors declare no competing interests.Ethics Approval Statement: This study was approved by the Peking University Biomedical Ethics Committee.
Subject(s)
Coronavirus Infections , T-Lymphocytopenia, Idiopathic CD4-Positive , COVID-19ABSTRACT
ObjectiveTo estimate the prevalence of disability and anxiety in Covid-19 survivors at discharge from hospital and analyze relative risk by exposures. DesignMulti-center retrospective cohort study. SettingTwenty-eight hospitals located in eight provinces of China. MethodsA total of 432 survivors with laboratory-confirmed SARS CoV-2 infection participated in this study. At discharge, we assessed instrumental activities of daily living (IADL) with Lawtons IADL scale, dependence in activities of daily living (ADL) with the Barthel Index, and anxiety with Zungs self-reported anxiety scale. Exposures included comorbidity, smoking, setting (Hubei vs. others), disease severity, symptoms, and length of hospital stay. Other risk factors considered were age, gender, and ethnicity (Han vs. Tibetan). ResultsPrevalence of at least one IADL problem was 36.81% (95% CI: 32.39-41.46). ADL dependence was present in 16.44% (95% CI: 13.23-20.23) and 28.70% (95% CI: 24.63-33.15) were screened positive for clinical anxiety. Adjusted risk ratio (RR) of IADL limitations (RR 2.48, 95% CI: 1.80-3.40), ADL dependence (RR 2.07, 95% CI 1.15-3.76), and probable clinical anxiety (RR 2.53, 95% CI 1.69-3.79) were consistently elevated in survivors with severe Covid-19. Age was an additional independent risk factor for IADL limitations and ADL dependence; and setting (Hubei) for IADL limitations and anxiety. Tibetan ethnicity was a protective factor for anxiety but a risk factor for IADL limitations. ConclusionA significant proportion of Covid-19 survivors had disability and anxiety at discharge from hospital. Health systems need to be prepared for an additional burden resulting from rehabilitation needs of Covid-19 survivors.
Subject(s)
COVID-19ABSTRACT
BACKGROUND The top priority for the control of COVID-19 pandemic currently is the development of a vaccine. A phase 2 trial conducted to further evaluate the immunogenicity and safety of a SARS-CoV-2 inactivated vaccine (CoronaVac). METHODS We conducted a randomized, double-blind, placebo-controlled trial to evaluate the optimal dose, immunogenicity and safety of the CoronaVac. A total of 600 healthy adults aged 18-59 years were randomly assigned to receive 2 injections of the trial vaccine at a dose of 3 g/0.5 mL or 6 g /0.5mL, or placebo on Day 0,14 schedule or Day 0,28 schedule. For safety evaluation, solicited and unsolicited adverse events were collected after each vaccination within 7 days and 28 days, respectively. Blood samples were taken for antibody assay. RESULTS CoronaVac was well tolerated, and no dose-related safety concerns were observed. Most of the adverse reactions fell in the solicited category and were mild in severity. Pain at injection site was the most frequently reported symptoms. No Grade 3 adverse reaction or vaccine related SAEs were reported. CoronaVac showed good immunogenicity with the lower 3 g dose eliciting 92.4% seroconversion under Day 0,14 schedule and 97.4% under Day 0,28 schedule. 28 days after two-dose vaccination, the Nab levels of individual schedules range from 23.8 to 65.4 among different dosage and vaccination schedules. CONCLUSIONS Favorable safety and immunogenicity of CoronaVac was demonstrated on both schedules and both dosages, which support the conduction of phase 3 trial with optimum schedule/dosage per different scenarios.
Subject(s)
COVID-19 , PainABSTRACT
In order to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in the world, we formulate S1 subunit of the virus with two types of adjuvants, amphiphilic adjuvant monophosphoryl lipid A (MPLA) for Toll-like receptor 4 (TLR4) and CpG ODN for TLR9, into cationic multifunctional liposomes to produce a potent, safer, and translatable nanovaccine. The results show that the nanovaccine can efficiently elicit humoral immune response in mice. The sera from the vaccinated mice significantly inhibit SARS-CoV-2 to infect Vero cells. Moreover, relatively to the free S1 with traditional Alum adjuvant, the nanovaccine can elicit strong T cell immunity by activating both CD4+ and CD8+ cells, which may play critical roles in eliminating viral load in patients. Most importantly, the nanovaccine can elicit strong IgA antibody, providing potential mucosal protection to host. Altogether, this study offers a translatable design for a potent subunit SARS-CoV-2 nanovaccine.
Subject(s)
COVID-19ABSTRACT
COVID-19 has become a global pandemic, but with very little is known about it. In this single-centered, retrospective study, we collected all 37 confirmed cases of COVID-19 diagnosed in Dazhou, Sichuan, China from January 23 to February 25, 2020，and analyzed the demographic, clinical, and laboratory data. All of the cases were either imported from Wuhan and transmitted in family clusters. The average age of the patients was 45.76 ± 13.1 years. The average duration of pharyngeal swabs was 20.65 ± 6.7 days. Four (10.8%) patients were asymptomatic, 33 (89.1%) patients had increased lactic acid, 17 (45.9%) patients had increased fibrinogen C (Fib-C), and 5 (13.5%) patients had increased D-Dimers. 29 (87.9%) cases were positive for new coronavirus-specific antibodies, 4 (10.8%) cases were positive for viral nucleic acid in stool samples, 1 (2.7%) patient had positive culture of Klebsiella pneumonia. Therefore, we can predict that Lopinavir/ritonavir and abidol may not be effective in treating COVID-19.Elevated lactic acid, Fib-C, and D-dimer in patients may be predictors of disease progression. The new coronavirus-specific IgM and IgG antibodies can help to diagnose the disease. We need to pay attention to the risks posed by fecal nucleic acid positive patients.Authors Chun Liu, FanXin Zeng, and PingXi Wang contributed equally to this work.
Subject(s)
COVID-19 , Klebsiella InfectionsABSTRACT
The COVID-19 pandemic caused by SARS-CoV-2 has brought about an unprecedented crisis, taking a heavy toll on human health, lives as well as the global economy. There are no SARS-CoV-2-specific treatments or vaccines available due to the novelty of this virus. Hence, rapid development of effective vaccines against SARS-CoV-2 is urgently needed. Here we developed a pilot-scale production of a purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc), which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats and non-human primates. These antibodies potently neutralized 10 representative SARS-CoV-2 strains, indicative of a possible broader neutralizing ability against SARS-CoV-2 strains circulating worldwide. Immunization with two different doses (3g or 6 g per dose) provided partial or complete protection in macaques against SARS-CoV-2 challenge, respectively, without any antibody-dependent enhancement of infection. Systematic evaluation of PiCoVacc via monitoring clinical signs, hematological and biochemical index, and histophathological analysis in macaques suggests that it is safe. These data support the rapid clinical development of SARS-CoV-2 vaccines for humans. One Sentence SummaryA purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc) confers complete protection in non-human primates against SARS-CoV-2 strains circulating worldwide by eliciting potent humoral responses devoid of immunopathology