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1.
Nat Commun ; 14(1): 3440, 2023 Jun 10.
Artigo em Inglês | MEDLINE | ID: covidwho-20244495

RESUMO

The overall success of worldwide mass vaccination in limiting the negative effect of the COVID-19 pandemics is inevitable, however, recent SARS-CoV-2 variants of concern, especially Omicron and its sub-lineages, efficiently evade humoral immunity mounted upon vaccination or previous infection. Thus, it is an important question whether these variants, or vaccines against them, induce anti-viral cellular immunity. Here we show that the mRNA vaccine BNT162b2 induces robust protective immunity in K18-hACE2 transgenic B-cell deficient (µMT) mice. We further demonstrate that the protection is attributed to cellular immunity depending on robust IFN-γ production. Viral challenge with SARS-CoV-2 Omicron BA.1 and BA.5.2 sub-variants induce boosted cellular responses in vaccinated µMT mice, which highlights the significance of cellular immunity against the ever-emerging SARS-CoV-2 variants evading antibody-mediated immunity. Our work, by providing evidence that BNT162b2 can induce significant protective immunity in mice that are unable to produce antibodies, thus highlights the importance of cellular immunity in the protection against SARS-CoV-2.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Imunidade Celular , Animais , Humanos , Camundongos , Anticorpos , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacina BNT162 , COVID-19/prevenção & controle , Interferon gama , SARS-CoV-2 , Vacinas contra COVID-19/imunologia
2.
ACS Infect Dis ; 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: covidwho-2116865

RESUMO

The ongoing coronavirus disease 2019 pandemic has raised concerns about the risk of re-infection. Non-neutralizing epitopes are one of the major reasons for antibody-dependent enhancement. Past studies on the ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have revealed an infectivity-enhancing site on the ancestral SARS-CoV-2 spike protein. However, infection enhancement associated with the SARS-CoV-2 Omicron strain remains elusive. In this study, we examined the antibodies induced by a multiple epitope-based vaccine, which showed infection enhancement for the Omicron strain but not for the ancestral SARS-CoV-2 or Delta strain. By examining the antibodies induced by single epitope-based vaccines, we identified a conserved epitope, IDf (450-469), with neutralizing activity against ancestral SARS-CoV-2, Delta, and Omicron. Although neutralizing epitopes are present in the multiple epitope-based vaccine, other immunodominant non-neutralizing epitopes such as IDg (480-499) can shade their neutralizing activity, leading to infection enhancement of Omicron. Our study provides up-to-date epitope information on SARS-CoV-2 variants to help design better vaccines or antibody-based therapeutics against future variants.

3.
JCI Insight ; 7(11)2022 06 08.
Artigo em Inglês | MEDLINE | ID: covidwho-1892019

RESUMO

SARS-CoV-2 has been confirmed in over 450 million confirmed cases since 2019. Although several vaccines have been certified by the WHO and people are being vaccinated on a global scale, it has been reported that multiple SARS-CoV-2 variants can escape neutralization by antibodies, resulting in vaccine breakthrough infections. Bacillus Calmette-Guérin (BCG) is known to induce heterologous protection based on trained immune responses. Here, we investigated whether BCG-induced trained immunity protected against SARS-CoV-2 in the K18-hACE2 mouse model. Our data demonstrate that i.v. BCG (BCG-i.v.) vaccination induces robust trained innate immune responses and provides protection against WT SARS-CoV-2, as well as the B.1.617.1 and B.1.617.2 variants. Further studies suggest that myeloid cell differentiation and activation of the glycolysis pathway are associated with BCG-induced training immunity in K18-hACE2 mice. Overall, our study provides the experimental evidence that establishes a causal relationship between BCG-i.v. vaccination and protection against SARS-CoV-2 challenge.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Vacina BCG , COVID-19/prevenção & controle , Humanos , Melfalan , Camundongos , gama-Globulinas
4.
Acta Biomater ; 148: 133-141, 2022 08.
Artigo em Inglês | MEDLINE | ID: covidwho-1885570

RESUMO

Microneedles can realize the intradermal and transdermal delivery of drugs. However, most conventional microneedles made of metal, polymer and ceramics are unsuitable for the delivery of mRNA drugs that are fragile and temperature-sensitive. This study explores the usage of cryomicroneedles (CryoMNs) for the intradermal delivery of mRNA molecules. Taking luciferase mRNA as an example, we first optimize the formulation of CryoMNs to maximize mRNA stability. Later, in the mouse model, we compare the delivery efficiency with the conventional subcutaneous injection for both the luciferase mRNA and COVID-19 Comirnaty mRNA vaccines, where CryoMNs delivered mRNA vaccines successfully induce specific B-cell antibody, neutralizing activity and T-cell responses. STATEMENT OF SIGNIFICANCE: mRNA vaccines are fragile and temperature-sensitive, so they are mainly delivered by intramuscular injection that often causes pain and requires clinical expertise to immunize patients. Microneedles permit convenient, fast and safe vaccination. However, existing microneedle platforms are ineffective to protect the integrity of mRNA vaccines in fabrication, storage, and administration. This work utilizes cryomicroneedles (CryoMNs) technology to intradermally deliver mRNA. In the mouse model, CryoMNs are compared with the subcutaneous injection for the delivery efficiency of both the luciferase mRNA and COVID-19 Comirnaty mRNA vaccines, where CryoMNs delivered mRNA vaccines successfully produce specific B-cell antibodies, T-cell responses, and neutralizing activity. This work is expected to provide a new delivery strategy for the emerging mRNA therapeutics.


Assuntos
COVID-19 , Animais , COVID-19/prevenção & controle , Sistemas de Liberação de Medicamentos , Injeções Intradérmicas , Camundongos , Agulhas , RNA Mensageiro/genética , Vacinação
5.
Front Immunol ; 13: 861050, 2022.
Artigo em Inglês | MEDLINE | ID: covidwho-1785349

RESUMO

It has been reported that multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) including Alpha, Beta, Gamma, and Delta can reduce neutralization by antibodies, resulting in vaccine breakthrough infections. Virus-antiserum neutralization assays are typically performed to monitor potential vaccine breakthrough strains. However, experiment-based methods took several weeks whether newly emerging variants can break through current vaccines or therapeutic antibodies. To address this, we sought to establish a computational model to predict the antigenicity of SARS-CoV-2 variants by sequence alone. In this study, we firstly identified the relationship between the antigenic difference transformed from the amino acid sequence and the antigenic distance from the neutralization titers. Based on this correlation, we obtained a computational model for the receptor-binding domain (RBD) of the spike protein to predict the fold decrease in virus-antiserum neutralization titers with high accuracy (~0.79). Our predicted results were comparable to experimental neutralization titers of variants, including Alpha, Beta, Delta, Gamma, Epsilon, Iota, Kappa, and Lambda, as well as SARS-CoV. Here, we predicted the fold of decrease of Omicron as 17.4-fold less susceptible to neutralization. We visualized all 1,521 SARS-CoV-2 lineages to indicate variants including Mu, B.1.630, B.1.633, B.1.649, and C.1.2, which can induce vaccine breakthrough infections in addition to reported VOCs Beta, Gamma, Delta, and Omicron. Our study offers a quick approach to predict the antigenicity of SARS-CoV-2 variants as soon as they emerge. Furthermore, this approach can facilitate future vaccine updates to cover all major variants. An online version can be accessed at http://jdlab.online.


Assuntos
Antígenos Virais , Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Anticorpos Neutralizantes , Anticorpos Antivirais , Antígenos Virais/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Humanos , Soros Imunes , Testes de Neutralização , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética
6.
J Immunol Res ; 2021: 5531220, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1232374

RESUMO

The nucleocapsid protein (NP) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains immunogenic epitopes that can induce cytotoxic T lymphocyte (CTL) against viral infection. This makes the nucleocapsid protein a suitable candidate for developing a vaccine against SARS-CoV-2 infection. This article reports the intradermal delivery of NP antigen using dissolvable microneedle skin patches that could induce both significant B cell and T cell responses.


Assuntos
Anticorpos Antivirais/sangue , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , SARS-CoV-2/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Linfócitos B/imunologia , Vacinas contra COVID-19/administração & dosagem , Proteínas do Nucleocapsídeo de Coronavírus/administração & dosagem , Ensaio de Imunoadsorção Enzimática , Injeções Intradérmicas/métodos , Camundongos , Camundongos Endogâmicos BALB C , Fosfoproteínas/administração & dosagem , Fosfoproteínas/imunologia
7.
Emerg Microbes Infect ; 10(1): 874-884, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: covidwho-1199439

RESUMO

The Coronavirus Disease 2019 (COVID-19) pandemic is unlikely to abate until sufficient herd immunity is built up by either natural infection or vaccination. We previously identified ten linear immunodominant sites on the SARS-CoV-2 spike protein of which four are located within the RBD. Therefore, we designed two linkerimmunodominant site (LIS) vaccine candidates which are composed of four immunodominant sites within the RBD (RBD-ID) or all the 10 immunodominant sites within the whole spike (S-ID). They were administered by subcutaneous injection and were tested for immunogenicity and in vivo protective efficacy in a hamster model for COVID-19. We showed that the S-ID vaccine induced significantly better neutralizing antibody response than RBD-ID and alum control. As expected, hamsters vaccinated by S-ID had significantly less body weight loss, lung viral load, and histopathological changes of pneumonia. The S-ID has the potential to be an effective vaccine for protection against COVID-19.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Epitopos Imunodominantes/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Cricetinae , Feminino , Células HEK293 , Humanos , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos BALB C , Vacinação
8.
Bioeng Transl Med ; 6(1): e10202, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: covidwho-985967

RESUMO

The S1 subunit of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein contains an immunogenic receptor-binding domain (RBD), which is a promising candidate for the development of a potential vaccine. This study demonstrated that intradermal delivery of an S-RBD vaccine using a dissolvable microneedle skin patch can induce both significant B-cell and significant T-cell responses against S-RBD. Importantly, the outcomes were comparable to that of conventional bolus injection.

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