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4.
Emerg Microbes Infect ; 10(1): 1156-1168, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1249264

ABSTRACT

ABSTRACTThe risk of secondary infection with SARS-CoV-2 and influenza A virus is becoming a practical problem that must be addressed as the flu season merges with the COVID-19 pandemic. As SARS-CoV-2 and influenza A virus have been found in patients, understanding the in vivo characteristics of the secondary infection between these two viruses is a high priority. Here, hACE2 transgenic mice were challenged with the H1N1 virus at a nonlethal dose during the convalescent stage on 7 and 14 days post SARS-CoV-2 infection, and importantly, subsequent H1N1 infection showed enhanced viral shedding and virus tissue distribution. Histopathological observation revealed an extensive pathological change in the lungs related to H1N1 infection in mice recovered from SARS-CoV-2 infection, with severe inflammation infiltration and bronchiole disruption. Moreover, upon H1N1 exposure on 7 and 14 dpi of SARS-CoV-2 infection, the lymphocyte population activated at a lower level with T cell suppressed in both PBMC and lung. These findings will be valuable for evaluating antiviral therapeutics and vaccines as well as guiding public health work.


Subject(s)
Acute Lung Injury/pathology , Angiotensin-Converting Enzyme 2/genetics , COVID-19/pathology , Orthomyxoviridae Infections/pathology , Acute Lung Injury/virology , Animals , COVID-19/therapy , Coinfection/pathology , Coinfection/virology , Cytokines/blood , Disease Models, Animal , Female , Humans , Influenza A Virus, H1N1 Subtype/isolation & purification , Lung/pathology , Lymphocyte Count , Lymphocytes/immunology , Mice , Mice, Transgenic , Orthomyxoviridae Infections/therapy , SARS-CoV-2/isolation & purification , Viral Load , Virus Replication/physiology , Virus Shedding/physiology
5.
Bioconjug Chem ; 32(5): 1034-1046, 2021 05 19.
Article in English | MEDLINE | ID: covidwho-1217668

ABSTRACT

SARS-CoV-2 caused the COVID-19 pandemic that lasted for more than a year. Globally, there is an urgent need to use safe and effective vaccines for immunization to achieve comprehensive protection against SARS-CoV-2 infection. Focusing on developing a rapid vaccine platform with significant immunogenicity as well as broad and high protection efficiency, we designed a SARS-CoV-2 spike protein receptor-binding domain (RBD) displayed on self-assembled ferritin nanoparticles. In a 293i cells eukaryotic expression system, this candidate vaccine was prepared and purified. After rhesus monkeys are immunized with 20 µg of RBD-ferritin nanoparticles three times, the vaccine can elicit specific humoral immunity and T cell immune response, and the neutralizing antibodies can cross-neutralize four SARS-CoV-2 strains from different sources. In the challenge protection test, after nasal infection with 2 × 105 CCID50 SARS-CoV-2 virus, compared with unimmunized control animals, virus replication in the vaccine-immunized rhesus monkeys was significantly inhibited, and respiratory pathology observations also showed only slight pathological damage. These analyses will benefit the immunization program of the RBD-ferritin nanoparticle vaccine in the clinical trial design and the platform construction to present a specific antigen domain in the self-assembling nanoparticle in a short time to harvest stable, safe, and effective vaccine candidates for new SARS-CoV-2 isolates.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Nanoparticles/chemistry , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocytes/immunology , Animals , Antibodies, Neutralizing/immunology , Binding Sites , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Ferritins/chemistry , Ferritins/metabolism , Immunity, Humoral , Macaca mulatta , Male , Nanoparticles/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/metabolism , Ultracentrifugation
6.
Food Chem Toxicol ; 152: 112239, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1202176

ABSTRACT

The outbreak of COVID-19 has posed a serious threat to global public health. Vaccination may be the most effective way to prevent and control the spread of the virus. The safety of vaccines is the focus of preclinical research, and the repeated dose toxicity test is the key safety test to evaluate the vaccine before clinical trials. The purpose of this study was (i) to observe the toxicity and severity of an inactivated SARS-CoV-2 vaccine (Vero cells) in rodent Sprague Dawley rats after multiple intramuscular injections under the premise of Good Laboratory Practice principles and (ii) to provide a basis for the formulation of a clinical trial scheme. The results showed that all animals in the experimental group were in good condition, no regular changes related to the vaccine were found in the detection of various toxicological indexes, and no noticeable stimulating reaction related to the vaccine was found in the injected local tissues. The neutralizing antibodies in the low- and high-dose vaccine groups began to appear 14 days after the last administration. In the negative control group, no neutralizing antibodies were observed from the administration period to the recovery period. Therefore, the repeated administration toxicity test of the inactivated SARS-CoV-2 vaccine (Vero cells) in Sprague Dawley rats showed no obvious toxic reaction. It was preliminarily confirmed that the vaccine can stimulate production of neutralizing antibodies and is safe in Sprague Dawley rats.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Vaccines/immunology , Animals , COVID-19 , COVID-19 Vaccines/toxicity , Female , Male , Rats, Sprague-Dawley , Toxicity Tests , Vaccines, Inactivated/immunology , Vaccines, Inactivated/toxicity
7.
PLoS Pathog ; 16(11): e1008949, 2020 11.
Article in English | MEDLINE | ID: covidwho-922716

ABSTRACT

The COVID-19 has emerged as an epidemic, causing severe pneumonia with a high infection rate globally. To better understand the pathogenesis caused by SARS-CoV-2, we developed a rhesus macaque model to mimic natural infection via the nasal route, resulting in the SARS-CoV-2 virus shedding in the nose and stool up to 27 days. Importantly, we observed the pathological progression of marked interstitial pneumonia in the infected animals on 5-7 dpi, with virus dissemination widely occurring in the lower respiratory tract and lymph nodes, and viral RNA was consistently detected from 5 to 21 dpi. During the infection period, the kinetics response of T cells was revealed to contribute to COVID-19 progression. Our findings implied that the antiviral response of T cells was suppressed after 3 days post infection, which might be related to increases in the Treg cell population in PBMCs. Moreover, two waves of the enhanced production of cytokines (TGF-α, IL-4, IL-6, GM-CSF, IL-10, IL-15, IL-1ß), chemokines (MCP-1/CCL2, IL-8/CXCL8, and MIP-1ß/CCL4) were detected in lung tissue. Our data collected from this model suggested that T cell response and cytokine/chemokine changes in lung should be considered as evaluation parameters for COVID-19 treatment and vaccine development, besides of observation of virus shedding and pathological analysis.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/pathology , Pneumonia, Viral/pathology , Animals , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cytokines/immunology , Disease Models, Animal , Lung/immunology , Lung/pathology , Macaca mulatta , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , Viral Load/methods , Virulence , Virus Shedding
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