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1.
Immunity ; 54(12): 2877-2892.e7, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1499988

ABSTRACT

Adjuvants are critical for improving the quality and magnitude of adaptive immune responses to vaccination. Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines have shown great efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the mechanism of action of this vaccine platform is not well-characterized. Using influenza virus and SARS-CoV-2 mRNA and protein subunit vaccines, we demonstrated that our LNP formulation has intrinsic adjuvant activity that promotes induction of strong T follicular helper cell, germinal center B cell, long-lived plasma cell, and memory B cell responses that are associated with durable and protective antibodies in mice. Comparative experiments demonstrated that this LNP formulation outperformed a widely used MF59-like adjuvant, AddaVax. The adjuvant activity of the LNP relies on the ionizable lipid component and on IL-6 cytokine induction but not on MyD88- or MAVS-dependent sensing of LNPs. Our study identified LNPs as a versatile adjuvant that enhances the efficacy of traditional and next-generation vaccine platforms.


Subject(s)
B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Germinal Center/immunology , SARS-CoV-2/physiology , T-Lymphocytes, Helper-Inducer/immunology , /immunology , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adjuvants, Immunologic , Animals , HEK293 Cells , Humans , Immunity, Humoral , Interleukin-6/genetics , Interleukin-6/metabolism , Liposomes/administration & dosage , Mice , Mice, Inbred BALB C , Nanoparticles/administration & dosage , Protein Subunits/genetics , /genetics
2.
J Pediatric Infect Dis Soc ; 10(5): 669-673, 2021 May 28.
Article in English | MEDLINE | ID: covidwho-1262143

ABSTRACT

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) antibody responses in children remain poorly characterized. Here, we show that pediatric patients with multisystem inflammatory syndrome in children (MIS-C) possess higher SARS-CoV-2 spike immunoglobulin G (IgG) titers compared with those with severe coronavirus disease 2019, likely reflecting a longer time since the onset of infection in MIS-C patients.


Subject(s)
Antibodies, Viral/immunology , Antibody Formation , COVID-19/immunology , Spike Glycoprotein, Coronavirus/immunology , Systemic Inflammatory Response Syndrome/immunology , COVID-19 Serological Testing , Child , Female , Humans , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Male , SARS-CoV-2 , Severity of Illness Index
3.
Cell ; 184(7): 1858-1864.e10, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1071140

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread within the human population. Although SARS-CoV-2 is a novel coronavirus, most humans had been previously exposed to other antigenically distinct common seasonal human coronaviruses (hCoVs) before the coronavirus disease 2019 (COVID-19) pandemic. Here, we quantified levels of SARS-CoV-2-reactive antibodies and hCoV-reactive antibodies in serum samples collected from 431 humans before the COVID-19 pandemic. We then quantified pre-pandemic antibody levels in serum from a separate cohort of 251 individuals who became PCR-confirmed infected with SARS-CoV-2. Finally, we longitudinally measured hCoV and SARS-CoV-2 antibodies in the serum of hospitalized COVID-19 patients. Our studies indicate that most individuals possessed hCoV-reactive antibodies before the COVID-19 pandemic. We determined that ∼20% of these individuals possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but they were boosted upon SARS-CoV-2 infection.


Subject(s)
Alphacoronavirus/immunology , Antibodies, Viral , Betacoronavirus/immunology , COVID-19/immunology , Adolescent , Adult , Animals , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19 Serological Testing , Child , Child, Preschool , Chlorocebus aethiops , Cross Protection , Cross Reactions , Disease Susceptibility , HEK293 Cells , Humans , Infant , Infant, Newborn , Vero Cells
4.
Immunity ; 53(6): 1281-1295.e5, 2020 12 15.
Article in English | MEDLINE | ID: covidwho-967679

ABSTRACT

The deployment of effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical to eradicate the coronavirus disease 2019 (COVID-19) pandemic. Many licensed vaccines confer protection by inducing long-lived plasma cells (LLPCs) and memory B cells (MBCs), cell types canonically generated during germinal center (GC) reactions. Here, we directly compared two vaccine platforms-mRNA vaccines and a recombinant protein formulated with an MF59-like adjuvant-looking for their abilities to quantitatively and qualitatively shape SARS-CoV-2-specific primary GC responses over time. We demonstrated that a single immunization with SARS-CoV-2 mRNA, but not with the recombinant protein vaccine, elicited potent SARS-CoV-2-specific GC B and T follicular helper (Tfh) cell responses as well as LLPCs and MBCs. Importantly, GC responses strongly correlated with neutralizing antibody production. mRNA vaccines more efficiently induced key regulators of the Tfh cell program and influenced the functional properties of Tfh cells. Overall, this study identifies SARS-CoV-2 mRNA vaccines as strong candidates for promoting robust GC-derived immune responses.


Subject(s)
Antibodies, Neutralizing/metabolism , B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Germinal Center/immunology , SARS-CoV-2/physiology , T-Lymphocytes, Helper-Inducer/immunology , Vaccines, Synthetic/immunology , Antigens, Viral/genetics , Antigens, Viral/immunology , Cells, Cultured , Epitopes , Humans , Lymphocyte Activation , Polysorbates , RNA, Viral/immunology , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Squalene , Vaccination
5.
medRxiv ; 2020 Aug 18.
Article in English | MEDLINE | ID: covidwho-900749

ABSTRACT

SARS-CoV-2 antibody responses in children remain poorly characterized. Here, we show that pediatric patients with multisystem inflammatory syndrome in children (MIS-C) possess higher SARS-CoV-2 spike IgG titers compared to those with severe coronavirus disease 2019 (COVID-19), likely reflecting a longer time since onset of infection in MIS-C patients.

6.
Immunity ; 53(4): 724-732.e7, 2020 10 13.
Article in English | MEDLINE | ID: covidwho-710374

ABSTRACT

SARS-CoV-2 infection has emerged as a serious global pandemic. Because of the high transmissibility of the virus and the high rate of morbidity and mortality associated with COVID-19, developing effective and safe vaccines is a top research priority. Here, we provide a detailed evaluation of the immunogenicity of lipid nanoparticle-encapsulated, nucleoside-modified mRNA (mRNA-LNP) vaccines encoding the full-length SARS-CoV-2 spike protein or the spike receptor binding domain in mice. We demonstrate that a single dose of these vaccines induces strong type 1 CD4+ and CD8+ T cell responses, as well as long-lived plasma and memory B cell responses. Additionally, we detect robust and sustained neutralizing antibody responses and the antibodies elicited by nucleoside-modified mRNA vaccines do not show antibody-dependent enhancement of infection in vitro. Our findings suggest that the nucleoside-modified mRNA-LNP vaccine platform can induce robust immune responses and is a promising candidate to combat COVID-19.


Subject(s)
Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Betacoronavirus/drug effects , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , RNA, Messenger/immunology , RNA, Viral/immunology , Viral Vaccines/administration & dosage , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , B-Lymphocytes/virology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Disease Models, Animal , Furin/genetics , Furin/immunology , Humans , Immunity, Humoral/drug effects , Immunization/methods , Immunogenicity, Vaccine , Immunologic Memory/drug effects , Lymphocyte Activation/drug effects , Mice , Mice, Inbred BALB C , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , RNA, Messenger/genetics , RNA, Viral/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic , Viral Vaccines/biosynthesis , Viral Vaccines/genetics
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