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1.
Sci Bull (Beijing) ; 67(13): 1372-1387, 2022 Jul 15.
Article in English | MEDLINE | ID: covidwho-1867754

ABSTRACT

Remarkable progress has been made in developing intramuscular vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, they are limited with respect to eliciting local immunity in the respiratory tract, which is the primary infection site for SARS-CoV-2. To overcome the limitations of intramuscular vaccines, we constructed a nasal vaccine candidate based on an influenza vector by inserting a gene encoding the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2, named CA4-dNS1-nCoV-RBD (dNS1-RBD). A preclinical study showed that in hamsters challenged 1 d after single-dose vaccination or 9 months after booster vaccination, dNS1-RBD largely mitigated lung pathology, with no loss of body weight. Moreover, such cellular immunity is relatively unimpaired for the most concerning SARS-CoV-2 variants, especially for the latest Omicron variant. In addition, this vaccine also provides cross-protection against H1N1 and H5N1 influenza viruses. The protective immune mechanism of dNS1-RBD could be attributed to the innate immune response in the nasal epithelium, local RBD-specific T cell response in the lung, and RBD-specific IgA and IgG response. Thus, this study demonstrates that the intranasally delivered dNS1-RBD vaccine candidate may offer an important addition to the fight against the ongoing coronavirus disease 2019 pandemic and influenza infection, compensating limitations of current intramuscular vaccines.

2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-324812

ABSTRACT

Background: The pandemic of SARS-CoV-2 has turned into a global public health crisis. Acute SARS-CoV-2 infection is associated with severe pneumonia, multiple-organ failures and deaths. Currently, treatment for SARS-CoV-2 infection and severe pneumonia is largely lacking. Several clinical trials demonstrated that glucocorticoid dexamethasone is effective to reduce disease severity and mortality. However, whether dexamethasone is clinically sufficient to treat COVID-19 is unknown.Methods: We tested the therapeutic effect of dexamethasone on SARS-CoV-2 infection and pneumonia in a Syrian hamster model. Survival rate, body weight loss, viral RNA, antibody responses, severity of lung inflammation and injury were measured in a 7-day acute infection course.Findings: Dexamethasone reduces body weight loss and relieves the diffusion of lung injury in SARS-CoV-2-infected hamster by inhibiting the excessive proinflammatory cytokines including IL-4, IL-6, IL-10, IL-13, TNF-α and IFN-γ. Dexamethasone rescues hamsters from the lethal infection of SARS-CoV-2 variant D614G. Dexamethasone attenuates serum neutralizing antibody and RBD-specific antibody titers, and slightly increases viral RNA level in lung tissues.Interpretation: Overall, using the hamster model, this study improves our understanding of the therapeutic mechanisms and drawbacks of dexamethasone treatment of COVID-19, and suggests that an antiviral is needed to accompany the dexamethasone treatment regimen.Funding: National Science Key Research and Development Project of China, National Natural Science Foundation of China, the CAMS Innovation Fund for Medical Sciences and China Postdoctoral Science Foundation.Declaration of Interest: The authors declare no competing interests.Ethical Approval: All the animal experiments were approved by the Medical Ethics Committee(SUCM2021-112).

4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-292884

ABSTRACT

Remarkable progress has been made in developing intramuscular vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2);however, they are limited with respect to eliciting local immunity in the respiratory tract, which is the primary infection site for SARS-CoV-2. To overcome the limitations of intramuscular vaccines, we constructed a nasal vaccine candidate based on an influenza vector by inserting a gene encoding the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2, named CA4-dNS1-nCoV-RBD (dNS1-RBD). A preclinical study showed that in hamsters challenged 1 day and 7 days after single-dose vaccination or 6 months after booster vaccination, dNS1-RBD largely mitigated lung pathology, with no loss of body weight, caused by either the prototype-like strain or beta variant of SARS-CoV-2. Lasted data showed that the animals could be well protected against beta variant challenge 9 months after vaccination. Notably, the weight loss and lung pathological changes of hamsters could still be significantly reduced when the hamster was vaccinated 24 h after challenge. Moreover, such cellular immunity is relatively unimpaired for the most concerning SARS-CoV-2 variants. The protective immune mechanism of dNS1-RBD could be attributed to the innate immune response in the nasal epithelium, local RBD-specific T cell response in the lung, and RBD-specific IgA and IgG response. Thus, this study demonstrates that the intranasally delivered dNS1-RBD vaccine candidate may offer an important addition to fight against the ongoing COVID-19 pandemic, compensating limitations of current intramuscular vaccines, particularly at the start of an outbreak.

6.
Sci Transl Med ; 13(606)2021 08 11.
Article in English | MEDLINE | ID: covidwho-1319371

ABSTRACT

Multiple safe and effective vaccines that elicit immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary to respond to the ongoing coronavirus disease 2019 (COVID-19) pandemic. Here, we developed a protein subunit vaccine composed of spike ectodomain protein (StriFK) plus a nitrogen bisphosphonate-modified zinc-aluminum hybrid adjuvant (FH002C). StriFK-FH002C generated substantially higher neutralizing antibody titers in mice, hamsters, and cynomolgus monkeys than those observed in plasma isolated from COVID-19 convalescent individuals. StriFK-FH002C also induced both TH1- and TH2-polarized helper T cell responses in mice. In hamsters, StriFK-FH002C immunization protected animals against SARS-CoV-2 challenge, as shown by the absence of virus-induced weight loss, fewer symptoms of disease, and reduced lung pathology. Vaccination of hamsters with StriFK-FH002C also reduced within-cage virus transmission to unvaccinated, cohoused hamsters. In summary, StriFK-FH002C represents an effective, protein subunit-based SARS-CoV-2 vaccine candidate.


Subject(s)
COVID-19 , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , Cricetinae , Humans , Mice , Protein Subunits , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics
7.
Theranostics ; 11(13): 6607-6615, 2021.
Article in English | MEDLINE | ID: covidwho-1231569

ABSTRACT

SARS-CoV-2 infection, which is responsible for the current COVID-19 pandemic, can cause life-threatening pneumonia, respiratory failure and even death. Characterizing SARS-CoV-2 pathogenesis in primary human target cells and tissues is crucial for developing vaccines and therapeutics. However, given the limited access to clinical samples from COVID-19 patients, there is a pressing need for in vitro/in vivo models to investigate authentic SARS-CoV-2 infection in primary human lung cells or tissues with mature structures. The present study was designed to evaluate a humanized mouse model carrying human lung xenografts for SARS-CoV-2 infection in vivo. Methods: Human fetal lung tissue surgically grafted under the dorsal skin of SCID mice were assessed for growth and development after 8 weeks. Following SARS-CoV-2 inoculation into the differentiated lung xenografts, viral replication, cell-type tropism and histopathology of SARS-CoV-2 infection, and local cytokine/chemokine expression were determined over a 6-day period. The effect of IFN-α treatment against SARS-CoV-2 infection was tested in the lung xenografts. Results: Human lung xenografts expanded and developed mature structures closely resembling normal human lung. SARS-CoV-2 replicated and spread efficiently in the lung xenografts with the epithelial cells as the main target, caused severe lung damage, and induced a robust pro-inflammatory response. IFN-α treatment effectively inhibited SARS-CoV-2 replication in the lung xenografts. Conclusions: These data support the human lung xenograft mouse model as a useful and biological relevant tool that should facilitate studies on the pathogenesis of SARS-CoV-2 lung infection and the evaluation of potential antiviral therapies.


Subject(s)
COVID-19/immunology , Disease Models, Animal , Lung/pathology , Respiratory Mucosa/cytology , SARS-CoV-2/immunology , Aborted Fetus , Animals , COVID-19/pathology , COVID-19/virology , Cells, Cultured , Epithelial Cells/virology , Heterografts , Humans , Lung/immunology , Lung/virology , Lung Transplantation , Male , Mice , Mice, SCID , Primary Cell Culture , SARS-CoV-2/pathogenicity , Virus Replication
8.
Signal Transduct Target Ther ; 6(1): 136, 2021 03 31.
Article in English | MEDLINE | ID: covidwho-1164823

ABSTRACT

Epidemiological studies of the COVID-19 patients have suggested the male bias in outcomes of lung illness. To experimentally demonstrate the epidemiological results, we performed animal studies to infect male and female Syrian hamsters with SARS-CoV-2. Remarkably, high viral titer in nasal washings was detectable in male hamsters who presented symptoms of weight loss, weakness, piloerection, hunched back and abdominal respiration, as well as severe pneumonia, pulmonary edema, consolidation, and fibrosis. In contrast with the males, the female hamsters showed much lower shedding viral titers, moderate symptoms, and relatively mild lung pathogenesis. The obvious differences in the susceptibility to SARS-CoV-2 and severity of lung pathogenesis between male and female hamsters provided experimental evidence that SARS-CoV-2 infection and the severity of COVID-19 are associated with gender.


Subject(s)
COVID-19 , SARS-CoV-2/metabolism , Sex Characteristics , Animals , COVID-19/metabolism , COVID-19/pathology , Disease Models, Animal , Disease Susceptibility , Female , Male , Mesocricetus
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