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1.
Nat Commun ; 12(1): 3587, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1387350

ABSTRACT

There is a great need for the development of vaccines that induce potent and long-lasting protective immunity against SARS-CoV-2. Multimeric display of the antigen combined with potent adjuvant can enhance the potency and longevity of the antibody response. The receptor binding domain (RBD) of the spike protein is a primary target of neutralizing antibodies. Here, we developed a trimeric form of the RBD and show that it induces a potent neutralizing antibody response against live virus with diverse effector functions and provides protection against SARS-CoV-2 challenge in mice and rhesus macaques. The trimeric form induces higher neutralizing antibody titer compared to monomer with as low as 1µg antigen dose. In mice, adjuvanting the protein with a TLR7/8 agonist formulation alum-3M-052 induces 100-fold higher neutralizing antibody titer and superior protection from infection compared to alum. SARS-CoV-2 infection causes significant loss of innate cells and pathology in the lung, and vaccination protects from changes in innate cells and lung pathology. These results demonstrate RBD trimer protein as a suitable candidate for vaccine against SARS-CoV-2.


Subject(s)
Adjuvants, Immunologic/administration & dosage , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Heterocyclic Compounds, 3-Ring/administration & dosage , Stearic Acids/administration & dosage , Alum Compounds/administration & dosage , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Formation/immunology , COVID-19 Vaccines/administration & dosage , Disease Models, Animal , Heterocyclic Compounds, 3-Ring/immunology , Humans , Macaca mulatta , Mice , Protein Binding , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/immunology , Stearic Acids/immunology
2.
Sci Immunol ; 6(61)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1315792

ABSTRACT

Ongoing SARS-CoV-2 vaccine development is focused on identifying stable, cost-effective, and accessible candidates for global use, specifically in low and middle-income countries. Here, we report the efficacy of a rapidly scalable, novel yeast expressed SARS-CoV-2 specific receptor-binding domain (RBD) based vaccine in rhesus macaques. We formulated the RBD immunogen in alum, a licensed and an emerging alum adsorbed TLR-7/8 targeted, 3M-052-alum adjuvants. The RBD+3M-052-alum adjuvanted vaccine promoted better RBD binding and effector antibodies, higher CoV-2 neutralizing antibodies, improved Th1 biased CD4+T cell reactions, and increased CD8+ T cell responses when compared to the alum-alone adjuvanted vaccine. RBD+3M-052-alum induced a significant reduction of SARS-CoV-2 virus in respiratory tract upon challenge, accompanied by reduced lung inflammation when compared with unvaccinated controls. Anti-RBD antibody responses in vaccinated animals inversely correlated with viral load in nasal secretions and BAL. RBD+3M-052-alum blocked a post SARS-CoV-2 challenge increase in CD14+CD16++ intermediate blood monocytes, and Fractalkine, MCP-1, and TRAIL in the plasma. Decreased plasma analytes and intermediate monocyte frequencies correlated with reduced nasal and BAL viral loads. Lastly, RBD-specific plasma cells accumulated in the draining lymph nodes and not in the bone marrow, contrary to previous findings. Together, these data show that a yeast expressed, RBD-based vaccine+3M-052-alum provides robust immune responses and protection against SARS-CoV-2, making it a strong and scalable vaccine candidate.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Alum Compounds/administration & dosage , COVID-19 Vaccines , COVID-19/prevention & control , SARS-CoV-2 , Saccharomycetales/genetics , Spike Glycoprotein, Coronavirus/genetics , Administration, Inhalation , Administration, Intranasal , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Cell Line , Cytokines/immunology , Humans , Immunoglobulin G/immunology , Lung/pathology , Macaca mulatta , Male , Protein Binding , Protein Domains , Spike Glycoprotein, Coronavirus/immunology , Viral Load
3.
J Med Virol ; 93(2): 892-898, 2021 02.
Article in English | MEDLINE | ID: covidwho-1206802

ABSTRACT

Since its emergence in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed into a global pandemic within a matter of months. While subunit vaccines are one of the prominent options for combating coronavirus disease 2019 (COVID-19), the immunogenicity of spike protein-based antigens remains unknown. When immunized in mice, the S1 domain induced much higher IgG and IgA antibody levels than the receptor-binding domain (RBD) and more efficiently neutralized SARS-CoV-2 when adjuvanted with alum. It is inferred that a large proportion of these neutralization epitopes are located in the S1 domain but outside the RBD and that some of these are spatial epitopes. This finding indicates that expression systems with posttranslational modification abilities are important to maintain the natural configurations of recombinant spike protein antigens and are critical for effective COVID-19 vaccines. Further, adjuvants prone to a Th1 response should be considered for S1-based subunit COVID-19 vaccines to reduce the potential risk of antibody-dependent enhancement of infection.


Subject(s)
Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Antigens, Viral/immunology , COVID-19 Vaccines/biosynthesis , COVID-19/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adjuvants, Immunologic/administration & dosage , Alum Compounds/administration & dosage , Animals , Antigens, Viral/genetics , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Female , HEK293 Cells , Humans , Immunity, Humoral/drug effects , Immunization , Immunization Schedule , Immunogenicity, Vaccine , Immunoglobulin A/biosynthesis , Immunoglobulin G/biosynthesis , Mice , Mice, Inbred BALB C , Protein Domains/immunology , Recombinant Proteins/administration & dosage , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Spike Glycoprotein, Coronavirus/genetics , Th1 Cells/drug effects , Th1 Cells/immunology , Th2 Cells/drug effects , Th2 Cells/immunology
4.
Turk J Med Sci ; 50(8): 1771-1780, 2020 12 17.
Article in English | MEDLINE | ID: covidwho-976378

ABSTRACT

Background/aim: Based on the antiviral and antibacterial properties of aluminum salts, we aimed to find out the influence of aluminum salts on COVID-19 infected patients. Materials and methods: We performed an observational retrospective cohort study which includes the patients diagnosed as COVID-19 and received aluminum salts in addition to actual treatments during hospitalization as the treatment group (Alum Group). Patients who received standard COVID-19 treatment protocols in the Infectious Diseases Clinics were included as the Control Group. Clinical findings, laboratory parameters, length of stay, survival, radiological follow-up, intensive care and mechanical ventilation needs, the presence of comorbidity, polymerase chain reaction (PCR) tests, symptoms, symptom recovery times, hospital stay times, treatment protocols, and clinical presence of pneumonia were examined in all patients. Advanced chemical composition analyzes of existing aluminum salts were also performed. Results: A total of 109 patients, 54 in the alum group and 55 in the control group, were included in the study. None of the patients in the aluminum group developed side effects due to the intake of aluminum salt. Survival status was significantly different between the two groups as there were 5 loss in the Control Group and none in the Alum Group (P = 0.023). The symptom recovery time was significantly shorter in the Alum Group; 2 (1­3) vs. 1 (1­2) days, P = 0.003. According to the paired samples analyses of the comparison between hospitalization and discharge, CRP levels significantly drops in the Alum Group (from 54.09 to 27, P = 0.001) but not in the Control Group. The drop was significantly same for the lactate dehydrogenase (LDH) and procalcitonin levels with P = 0.001. Conclusion: It has been observed that aluminum salts have beneficial effects in COVID-19 infected cases. Considering the low systemic toxicity of intermittent oral intake of aluminum salts as food supplements and the fact that pandemic control is still not achieved, the use of aluminum salts is promising.


Subject(s)
Alum Compounds , COVID-19 , Hospitalization/statistics & numerical data , Recovery of Function/drug effects , Alum Compounds/administration & dosage , Alum Compounds/adverse effects , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/physiopathology , COVID-19 Testing/methods , Critical Care/methods , Critical Care/statistics & numerical data , Female , Humans , Male , Middle Aged , Respiration, Artificial/statistics & numerical data , Retrospective Studies , SARS-CoV-2/drug effects , Survival Analysis , Treatment Outcome , Turkey/epidemiology
5.
J Med Virol ; 93(2): 892-898, 2021 02.
Article in English | MEDLINE | ID: covidwho-661060

ABSTRACT

Since its emergence in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed into a global pandemic within a matter of months. While subunit vaccines are one of the prominent options for combating coronavirus disease 2019 (COVID-19), the immunogenicity of spike protein-based antigens remains unknown. When immunized in mice, the S1 domain induced much higher IgG and IgA antibody levels than the receptor-binding domain (RBD) and more efficiently neutralized SARS-CoV-2 when adjuvanted with alum. It is inferred that a large proportion of these neutralization epitopes are located in the S1 domain but outside the RBD and that some of these are spatial epitopes. This finding indicates that expression systems with posttranslational modification abilities are important to maintain the natural configurations of recombinant spike protein antigens and are critical for effective COVID-19 vaccines. Further, adjuvants prone to a Th1 response should be considered for S1-based subunit COVID-19 vaccines to reduce the potential risk of antibody-dependent enhancement of infection.


Subject(s)
Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Antigens, Viral/immunology , COVID-19 Vaccines/biosynthesis , COVID-19/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adjuvants, Immunologic/administration & dosage , Alum Compounds/administration & dosage , Animals , Antigens, Viral/genetics , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Female , HEK293 Cells , Humans , Immunity, Humoral/drug effects , Immunization , Immunization Schedule , Immunogenicity, Vaccine , Immunoglobulin A/biosynthesis , Immunoglobulin G/biosynthesis , Mice , Mice, Inbred BALB C , Protein Domains/immunology , Recombinant Proteins/administration & dosage , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Spike Glycoprotein, Coronavirus/genetics , Th1 Cells/drug effects , Th1 Cells/immunology , Th2 Cells/drug effects , Th2 Cells/immunology
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