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1.
Proc Natl Acad Sci U S A ; 119(30): e2203659119, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35858456

RESUMO

This study analyzed whole blood samples (n = 56) retrieved from 30 patients at 1 to 21 (median 9) mo after verified COVID-19 to determine the polarity and duration of antigen-specific T cell reactivity against severe acute respiratory syndrome coronavirus 2-derived antigens. Multimeric peptides spanning the entire nucleocapsid protein triggered strikingly synchronous formation of interleukin (IL)-4, IL-12, IL-13, and IL-17 ex vivo until ∼70 d after confirmed infection, whereafter this reactivity was no longer inducible. In contrast, levels of nucleocapsid-induced IL-2 and interferon-γ remained stable and highly correlated at 3 to 21 mo after infection. Similar cytokine dynamics were observed in unvaccinated, convalescent patients using whole-blood samples stimulated with peptides spanning the N-terminal portion of the spike 1 protein. These results unravel two phases of T cell reactivity following natural COVID-19: an early, synchronous response indicating transient presence of multipolar, antigen-specific T helper (TH) cells followed by an equally synchronous and durable TH1-like reactivity reflecting long-lasting T cell memory.


Assuntos
COVID-19 , Citocinas , SARS-CoV-2 , Linfócitos T Auxiliares-Indutores , Anticorpos Antivirais/sangue , Antígenos Virais/imunologia , COVID-19/sangue , COVID-19/imunologia , Convalescença , Citocinas/sangue , Humanos , Interferon gama/sangue , Proteínas do Nucleocapsídeo/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T Auxiliares-Indutores/imunologia
2.
Proc Natl Acad Sci U S A ; 119(31): e2204336119, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35858382

RESUMO

The durability of vaccine-mediated immunity to SARS-CoV-2, the durations to breakthrough infection, and the optimal timings of booster vaccination are crucial knowledge for pandemic response. Here, we applied comparative evolutionary analyses to estimate the durability of immunity and the likelihood of breakthrough infections over time following vaccination by BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), ChAdOx1 (Oxford-AstraZeneca), and Ad26.COV2.S (Johnson & Johnson/Janssen). We evaluated anti-Spike (S) immunoglobulin G (IgG) antibody levels elicited by each vaccine relative to natural infection. We estimated typical trajectories of waning and corresponding infection probabilities, providing the distribution of times to breakthrough infection for each vaccine under endemic conditions. Peak antibody levels elicited by messenger RNA (mRNA) vaccines mRNA-1273 and BNT1262b2 exceeded that of natural infection and are expected to typically yield more durable protection against breakthrough infections (median 29.6 mo; 5 to 95% quantiles 10.9 mo to 7.9 y) than natural infection (median 21.5 mo; 5 to 95% quantiles 3.5 mo to 7.1 y). Relative to mRNA-1273 and BNT1262b2, viral vector vaccines ChAdOx1 and Ad26.COV2.S exhibit similar peak anti-S IgG antibody responses to that from natural infection and are projected to yield lower, shorter-term protection against breakthrough infection (median 22.4 mo and 5 to 95% quantiles 4.3 mo to 7.2 y; and median 20.5 mo and 5 to 95% quantiles 2.6 mo to 7.0 y; respectively). These results leverage the tools from evolutionary biology to provide a quantitative basis for otherwise unknown parameters that are fundamental to public health policy decision-making.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Imunogenicidade da Vacina , SARS-CoV-2 , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Formação de Anticorpos , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/uso terapêutico , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Fatores de Tempo
3.
Front Immunol ; 13: 894700, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35734170

RESUMO

The Korean government decided to schedule heterologous vaccinations on dialysis patients for early achievement of immunization against Coronavirus disease 2019(COVID-19). However, the effects of heterologous immunizations in hemodialysis (HD) patients are unclear. One hundred (HD) patients from Gangdong Kyung Hee University Hospital and Kyung Hee Medical Center and 100 hospital workers from Gangdong Kyung Hee University Hospital were enrolled in this study. The HD patients received the mixing schedule of ChAdOx1/BNT162b2 vaccinations at 10-week intervals, while hospital workers received two doses of ChAdOx1 vaccines at 12-week intervals. Serum IgG to a receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2 was measured 1 month after the first dose, 2 months and 4 months after the second dose. The median [interquartile range] anti-RBD IgG was 82.1[34.5, 176.6] AU/ml in HD patients and 197.1[124.0, 346.0] AU/ml in hospital workers (P < 0.001) after the first dose. The percentage of positive responses (IgG > 50 AU/ml) was 65.0% and 96.0% among the both group, respectively (P < 0.001). The anti-RBD IgG levels increased significantly by 2528.8 [1327.6, 5795.1] AU/ml with a 100.0% positive response rate in HD patients 2 months after the second dose, which was higher than those in hospital workers 981.4[581.5, 1891.4] AU/ml (P < 0.001). Moreover, anti-RBD IgG remains constantly high, and positive response remains 100% in HD patients 4 months after the second dose. This study suggests that heterologous vaccinations with ChAdOx1/BNT162b2 can be an alternative solution on HD patients for early and strong induction of humoral response.


Assuntos
Formação de Anticorpos , Vacina BNT162 , COVID-19 , Falência Renal Crônica , Anticorpos Antivirais/sangue , Vacina BNT162/imunologia , COVID-19/prevenção & controle , Humanos , Imunização , Imunoglobulina G/sangue , Falência Renal Crônica/terapia , Diálise Renal , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus
4.
J Infect Chemother ; 28(9): 1310-1316, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35701330

RESUMO

OBJECTIVE: To evaluate the factors affecting seropositivity and antibody levels after SARS-CoV-2 vaccines in patients with cancer because they were excluded from clinical studies of SARS-CoV-2 vaccines. METHODS: This prospective, observational, single-center study included 290 patients with solid tumors followed up in our medical oncology clinic between March 2021 and August 2021. SARS-CoV-2 antibody status was determined before the first dose of vaccine. Fifty-one patients with positive prevaccine baseline antibody tests were excluded from the study, regardless of whether they had previously confirmed SARS-CoV-2 PCR positivity. To determine the quantitative IgG antibody response of the vaccines, blood samples were collected at least 28 days after each dose of vaccine. Quantitative IgG levels against virus spike protein receptor binding domain (RBD) were measured using chemiluminescent enzyme immunoassay (CLIA). Demographic and clinical features affecting seropositivity were analyzed. RESULTS: One hundred and fifty-one (69.3%) patients were vaccinated with two doses of CoronaVac followed by one dose of BNT162b2 (Biontech) (group 1). Sixty-seven (30.7%) patients were vaccinated with three doses of BNT162b2 (group 2). The proportion of patients who developed seropositivity was significantly higher in group 2 (78.6% vs. 54.9%, p < 0.012). Antibody response increased significantly after the second dose of vaccine in both groups. Female sex, being younger than 65 years, and chemotherapy status were significantly related to higher anti-SARS-CoV-2 S antibody levels (p = 0.033, p = 0.036, and p = 0.047, respectively). Antibody levels were significantly higher in patients who had previously received chemotherapy than in patients receiving active chemotherapy (p = 0.042). CONCLUSIONS: Our study is the first to evaluate basal SARS-CoV-2 IgG levels before the first dose of vaccine and after three doses in patients with solid tumors. The rate of development of seropositivity with two doses of mRNA vaccine was found to be higher than with two doses of inactivated SARS-CoV-2 vaccine. More attention should be paid to preventive measures in addition to vaccination in patients aged over 65 years and men with cancer diagnoses.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Neoplasias , Idoso , Anticorpos Antivirais/sangue , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , SARS-CoV-2 , Vacinação
5.
Vet Microbiol ; 271: 109491, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35714529

RESUMO

Viral infectious pathogens, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus, can cause extremely high infection rates and mortality in humans. Therefore, it is urgent to develop an effective vaccine against coronavirus and influenza virus infection. Herein, we used the influenza virus as a vector to express the SARS-CoV-2 spike receptor-binding domain (RBD) and hemagglutinin-esterase-fusion (HEF) protein of the influenza C virus. We then evaluated the feasibility and effectiveness of this design strategy through experiments in vitro and in vivo. The results showed that the chimeric viruses could stably express the HEF protein and the SARS-CoV-2 spike RBD at a high level. BALB/c mice, infected with the chimeric virus, exhibited mild clinical symptoms, yet produced high specific antibody levels against RBD and HEF, including neutralizing antibodies. Importantly, high neutralizing antibodies could be retained in the sera of mice for at least 20 weeks. Altogether, our data provided a new strategy for developing safe and effective COVID-19 and influenza virus vaccines.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Vacinas contra Influenza , Orthomyxoviridae , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Vacinas contra Influenza/imunologia , Camundongos , Camundongos Endogâmicos BALB C , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus
6.
Future Oncol ; 18(23): 2537-2550, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35678621

RESUMO

Background: SARS-CoV-2 vaccination in cancer patients is crucial to prevent severe COVID-19 disease course. Methods: This study assessed immunogenicity of cancer patients on active treatment receiving mRNA-based SARS-CoV-2 vaccine by detection of anti-SARS-CoV-2 S1 IgG antibodies in serum, before, after the first and second doses and 3 months after a complete primary course of vaccination. Results were compared with healthy controls. Results: Of 112 patients, the seroconversion rate was 96%. A significant reduction in antibody levels was observed 3 months after vaccination in patients receiving immune checkpoint inhibitors versus control participants (p < 0.001). Adverse events were mostly mild. Conclusion: Immunogenicity after mRNA-based vaccine in cancer patients is adequate but influenced by the type of anticancer therapy. Antibody levels decline after 3 months, and thus a third vaccination is warranted.


Because cancer patients are especially endangered by SARS-CoV-2 infection and have worse disease course and outcomes, it is crucial to protect them from this infection. This study was aimed at assessing protective antibodies after patients received mRNA-based SARS-CoV-2 vaccines. Protective antibodies (e.g., anti-SARS-CoV-2 S1 IgG antibodies) were assessed in patients' blood before vaccination, after the first and second doses and 3 months after a complete primary course vaccination. Patients' oncological treatment was unaffected by the vaccination received. The results of protective antibodies were also compared with healthy control subjects who were vaccinated in the same manner. More than 110 cancer patients participated and agreed to have their blood samples analyzed. The rate of antibody production was 96% after a complete primary course of vaccination and was similar with that of healthy control subjects. However, there were some differences noted regarding the oncological treatment that the patients were receiving, with patients who were treated with targeted therapy achieving the highest levels of protective antibodies. Adverse events after vaccination were mostly mild and did not interfere with patients' general performance. The rate of antibody production for cancer patients after SARS-CoV-2 vaccination is high and similar to that in healthy control subjects but varies with regard to the oncological treatment that patients are receiving. However, antibodies decline substantially after 3 months, and thus a third vaccination is desirable. There were no new safety concerns after vaccination, and most adverse events were mild and short-lived.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Imunogenicidade da Vacina , Neoplasias , Anticorpos Antivirais/sangue , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , Humanos , Imunoglobulina G/sangue , SARS-CoV-2 , Vacinação
7.
Artigo em Inglês | MEDLINE | ID: mdl-35728947

RESUMO

BACKGROUND AND OBJECTIVES: Evidence regarding the safety and efficacy of messenger RNA (mRNA) vaccines in patients with myasthenia gravis (MG) after immunosuppressive therapies is scarce. Our aim is to determine whether the mRNA-1273 vaccine is safe and able to induce humoral and cellular responses in patients with MG. METHODS: We performed an observational, longitudinal, prospective study including 100 patients with MG of a referral center for MG in our country, conducted from April 2021 to November 2021 during the vaccination campaign. The mRNA-1273 vaccine was scheduled for all participants. Blood samples were collected before vaccination and 3 months after a second dose. Clinical changes in MG were measured using the MG activities of daily life score at baseline and 1 week after the first and second doses. A surveillance of all symptoms of coronavirus disease 2019 (COVID-19) was conducted throughout the study. Humoral and cellular immune responses after vaccination were assessed using a spike-antibody ELISA and interferon gamma release assay in plasma. The primary outcomes were clinically significant changes in MG symptoms after vaccination, adverse events (AEs), and seroconversion and T-cell immune response rates. RESULTS: Ninety-nine patients completed the full vaccination schedule, and 98 had 2 blood samples taken. A statistically significant worsening of symptoms was identified after the first and second doses of the mRNA-1273 vaccine, but this was not clinically relevant. Mild AEs occurred in 14 patients after the first dose and in 21 patients after the second dose. Eighty-seven patients developed a humoral response and 72 patients showed a T-cell response after vaccination. A combined therapy with prednisone and other immunosuppressive drugs correlated with a lower seroconversion ratio (OR = 5.97, 95% CI 1.46-24.09, p = 0.015) and a lower T-cell response ratio (OR = 2.83, 95% CI 1.13-7.13, p = 0.024). DISCUSSION: Our findings indicate that the mRNA vaccination against COVID-19 is safe in patients with MG and show no negative impact on the disease course. Patients achieved high humoral and cellular immune response levels. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that patients with MG receiving the mRNA-1273 vaccine did not show clinical worsening after vaccination and that most of the patients achieved high cellular or immune response levels.


Assuntos
Vacina de mRNA-1273 contra 2019-nCoV , COVID-19 , Miastenia Gravis , Vacina de mRNA-1273 contra 2019-nCoV/efeitos adversos , Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Anticorpos Antivirais/sangue , COVID-19/prevenção & controle , Humanos , Imunidade Celular , Imunidade Humoral , Estudos Longitudinais , Miastenia Gravis/complicações , Estudos Prospectivos , SARS-CoV-2 , Linfócitos T/imunologia
8.
J Immunother Cancer ; 10(6)2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35732350

RESUMO

BACKGROUND: Patients with cancer were excluded from phase 3 COVID-19 vaccine trials, and the immunogenicity and side effect profiles of these vaccines in this population is not well understood. Patients with cancer can be immunocompromised from chemotherapy, corticosteroids, or the cancer itself, which may affect cellular and/or humoral responses to vaccination. PD-1 is expressed on T effector cells, T follicular helper cells and B cells, leading us to hypothesize that anti-PD-1 immunotherapies may augment antibody or T cell generation after vaccination. METHODS: Antibodies to the SARS-CoV-2 receptor binding domain (RBD) and spike protein were assessed in patients with cancer (n=118) and healthy donors (HD, n=22) after 1, 2 or 3 mRNA vaccine doses. CD4+ and CD8+ T cell reactivity to wild-type (WT) or B.1.617.2 (delta) spike peptides was measured by intracellular cytokine staining. RESULTS: Oncology patients without prior COVID-19 infections receiving immunotherapy (n=36), chemotherapy (n=15), chemoimmunotherapy (n=6), endocrine or targeted therapies (n=6) and those not on active treatment (n=26) had similar RBD and Spike IgG antibody titers to HDs after two vaccinations. Contrary to our hypothesis, PD-1 blockade did not augment antibody titers or T cell responses. Patients receiving B-cell directed therapies (n=14) including anti-CD20 antibodies and multiple myeloma therapies had decreased antibody titers, and 9/14 of these patients were seronegative for RBD antibodies. No differences were observed in WT spike-reactive CD4+ and CD8+ T cell generation between treatment groups. 11/13 evaluable patients seronegative for RBD had a detectable WT spike-reactive CD4+ T cell response. T cells cross-reactive against the B.1.617.2 variant spike peptides were detected in 31/59 participants. Two patients with prior immune checkpoint inhibitor-related adrenal insufficiency had symptomatic hypoadrenalism after vaccination. CONCLUSIONS: COVID-19 vaccinations are safe and immunogenic in patients with solid tumors, who developed similar antibody and T cell responses compared with HDs. Patients on B-cell directed therapies may fail to generate RBD antibodies after vaccination and should be considered for prophylactic antibody treatments. Many seronegative patients do develop a T cell response, which may have an anti-viral effect. Patients with pre-existing adrenal insufficiency may need to take stress dose steroids during vaccination to avoid adrenal crisis.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Neoplasias , Insuficiência Adrenal/complicações , Anticorpos Antivirais/sangue , Formação de Anticorpos , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Humanos , Imunidade Celular , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , SARS-CoV-2 , Linfócitos T/imunologia , Vacinação , Vacinas Sintéticas , Vacinas de mRNA/imunologia
9.
Neurol Neurochir Pol ; 56(3): 236-245, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35726751

RESUMO

INTRODUCTION: Fatigue is the most frequent symptom in multiple sclerosis (MS), although it is still poorly understood due to its complexity and subjective nature. There is an urgent need to identify reliable biomarkers to improve disease prognosis and therapeutic strategies. Epstein-Barr virus (EBV) is the major environmental risk factor associated with MS aetiology, and trials with EBV-targeted T cell therapies have reduced fatigue severity in MS patients. AIM OF THE STUDY: We investigated whether the serum amount of immunoglobulin (Ig)G-specific for EBV antigens could be a suitable prognostic marker for the assessment of MS-related fatigue. MATERIAL AND METHODS: A total of 194 MS patients were enrolled. We quantified EBV nuclear antigen 1 (EBNA1) and EBV viral capsid antigen (VCA) immunoglobulin (Ig) G levels and B cell-activating factor of the tumour necrosis factor family (BAFF) concentration in the serum of patients with relapsing-remitting MS (RRMS) and chronic progressive MS (CPMS), and we analysed their correlation with aspects of fatigue and other clinical disease parameters. RESULTS: A complete EBV seropositivity could be detected in our cohort. After adjusting for confounding variables and covariates, neither EBNA1 nor VCA antibody titres were associated with levels of fatigue, sleepiness, depression, or with any of the clinical values such as expanded disability status scale, lesion count, annual relapse rate, or disease duration. However, patients with RRMS had significantly higher EBNA1 IgG titre than those with CPMS, whereas this was not the case under therapies targeting CD20+ cells. BAFF levels in serum were inversely proportional to anti-EBNA1 IgG. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our results show that EBNA1 IgG titre is not associated with the presence or level of fatigue. Whether the increased EBNA1 titre in RRMS plays a direct role in disease progression, or is only a consequence of excessive B cell activation, remains to be answered in future studies.


Assuntos
Anticorpos Antivirais , Infecções por Vírus Epstein-Barr , Fadiga , Imunoglobulina G , Esclerose Múltipla , Anticorpos Antivirais/sangue , Infecções por Vírus Epstein-Barr/complicações , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Fadiga/complicações , Herpesvirus Humano 4 , Humanos , Imunoglobulina G/sangue , Esclerose Múltipla/complicações , Esclerose Múltipla/virologia
10.
Signal Transduct Target Ther ; 7(1): 172, 2022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35665745

RESUMO

The increased coronavirus disease 2019 (COVID-19) breakthrough cases pose the need of booster vaccination. We conducted a randomised, double-blinded, controlled, phase 2 trial to assess the immunogenicity and safety of the heterologous prime-boost vaccination with an inactivated COVID-19 vaccine (BBIBP-CorV) followed by a recombinant protein-based vaccine (NVSI-06-07), using homologous boost with BBIBP-CorV as control. Three groups of healthy adults (600 individuals per group) who had completed two-dose BBIBP-CorV vaccinations 1-3 months, 4-6 months and ≥6 months earlier, respectively, were randomly assigned in a 1:1 ratio to receive either NVSI-06-07 or BBIBP-CorV boost. Immunogenicity assays showed that in NVSI-06-07 groups, neutralizing antibody geometric mean titers (GMTs) against the prototype SARS-CoV-2 increased by 21.01-63.85 folds on day 28 after vaccination, whereas only 4.20-16.78 folds of increases were observed in control groups. For Omicron variant, the neutralizing antibody GMT elicited by homologous boost was 37.91 on day 14, however, a significantly higher neutralizing GMT of 292.53 was induced by heterologous booster. Similar results were obtained for other SARS-CoV-2 variants of concerns (VOCs), including Alpha, Beta and Delta. Both heterologous and homologous boosters have a good safety profile. Local and systemic adverse reactions were absent, mild or moderate in most participants, and the overall safety was quite similar between two booster schemes. Our findings indicated that NVSI-06-07 is safe and immunogenic as a heterologous booster in BBIBP-CorV recipients and was immunogenically superior to the homologous booster against not only SARS-CoV-2 prototype strain but also VOCs, including Omicron.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Imunização Secundária , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Humanos , SARS-CoV-2
11.
Proc Natl Acad Sci U S A ; 119(24): e2202069119, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35679343

RESUMO

Current vaccines have greatly diminished the severity of the COVID-19 pandemic, even though they do not entirely prevent infection and transmission, likely due to insufficient immunity in the upper respiratory tract. Here, we compare intramuscular and intranasal administration of a live, replication-deficient modified vaccinia virus Ankara (MVA)-based Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike (S) vaccine to raise protective immune responses in the K18-hACE2 mouse model. Using a recombinant MVA expressing firefly luciferase for tracking, live imaging revealed luminescence of the respiratory tract of mice within 6 h and persisting for 3 d following intranasal inoculation, whereas luminescence remained at the site of intramuscular vaccination. Intramuscular vaccination induced S-binding-Immunoglobulin G (IgG) and neutralizing antibodies in the lungs, whereas intranasal vaccination also induced Immunoglobulin A (IgA) and higher levels of antigen-specific CD3+CD8+IFN-γ+ T cells. Similarly, IgG and neutralizing antibodies were present in the blood of mice immunized intranasally and intramuscularly, but IgA was detected only after intranasal inoculation. Intranasal boosting increased IgA after intranasal or intramuscular priming. While intramuscular vaccination prevented morbidity and cleared SARS-CoV-2 from the respiratory tract within several days after challenge, intranasal vaccination was more effective as neither infectious virus nor viral messenger (m)RNAs were detected in the nasal turbinates or lungs as early as 2 d after challenge, indicating prevention or rapid elimination of SARS-CoV-2 infection. Additionally, we determined that neutralizing antibody persisted for more than 6 mo and that serum induced to the Wuhan S protein neutralized pseudoviruses expressing the S proteins of variants, although with less potency, particularly for Beta and Omicron.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Imunoglobulina A , Sistema Respiratório , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Vírus Vaccinia , Administração Intranasal , Enzima de Conversão de Angiotensina 2/genética , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/prevenção & controle , COVID-19/transmissão , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Camundongos , Camundongos Transgênicos , Sistema Respiratório/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação/métodos , Vírus Vaccinia/genética , Vírus Vaccinia/imunologia
12.
J Virol ; 96(13): e0014322, 2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35658531

RESUMO

Differentiation of infected from vaccinated hosts (DIVH) is a critical step in virus eradication programs. DIVH-compatible vaccines, however, take years to develop, and are therefore unavailable for fighting the sudden outbreaks that typically drive pandemics. Here, we establish a protocol for the swift and efficient development of DIVH assays, and show that this approach is compatible with any type of vaccines. Using porcine circovirus 2 (PCV2) as the experimental model, the first step is to use Immunoglobin G (IgG) sero-dynamics (IsD) curves to aid epitope discovery (IsDAED): PCV2 Cap peptides were categorized into three types: null interaction, nonspecific interaction (NSI), and specific interaction (SI). We subsequently compared IsDAED approach and traditional approach, and demonstrated identifying SI peptides and excluding NSI peptides supports efficient diagnostic kit development, specifically using a protein-peptide hybrid microarray (PPHM). IsDAED directed the design of a DIVH protocol for three types of PCV2 vaccines (while using a single PPHM). Finally, the DIVH protocol successfully differentiated infected pigs from vaccinated pigs at five farms. This IsDAED approach is almost certainly extendable to other viruses and host species. IMPORTANCE Sudden outbreaks of pandemics caused by virus, such as SARS-CoV-2, has been determined as a public health emergency of international concern. However, the development of a DIVH-compatible vaccine is time-consuming and full of uncertainty, which is unsuitable for an emergent situation like the ongoing COVID-19 pandemic. Along with the development and public health implementation of new vaccines to prevent human diseases, e.g., human papillomavirus vaccines for cervical cancer; enterovirus 71 vaccines for hand, foot, and mouth disease; and most recently SARS-CoV-2, there is an increasing demand for DIVH. Here, we use the IsDAED approach to confirm SI peptides and to exclude NSI peptides, finally to direct the design of a DIVH protocol. It is plausible that our IsDAED approach is applicable for other infectious disease.


Assuntos
Anticorpos Antivirais , Infecções por Circoviridae , Epitopos , Imunoglobulina G , Vacinas Virais , Animais , Anticorpos Antivirais/sangue , COVID-19 , Infecções por Circoviridae/imunologia , Circovirus , Modelos Animais de Doenças , Epitopos/análise , Epitopos/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Peptídeos , SARS-CoV-2 , Suínos , Doenças dos Suínos/imunologia , Vacinas Virais/imunologia
13.
J Virol ; 96(13): e0038322, 2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35699445

RESUMO

Despite the rapid deployment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, the emergence of SARS-CoV-2 variants and reports of their immune evasion characteristics have led to an urgent need for novel vaccines that confer potent cross-protective immunity. In this study, we constructed three different SARS-CoV-2 spike S1-conjugated nanoparticle vaccine candidates that exhibited high structural homogeneity and stability. Notably, these vaccines elicited up to 50-times-higher neutralizing antibody titers than the S1 monomer in mice. Crucially, it was found that the S1-conjugated nanoparticle vaccine could elicit comparable levels of neutralizing antibodies against wild-type or emerging variant SARS-CoV-2, with cross-reactivity to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), the effect of which could be further enhanced using our designed nanoparticles. Our results indicate that the S1-conjugated nanoparticles are promising vaccine candidates with the potential to elicit potent and cross-reactive immunity against not only wild-type SARS-CoV-2, but also its variants of concern, variants of interest, and even other pathogenic betacoronaviruses. IMPORTANCE The emergence of SARS-CoV-2 variants led to an urgent demand for a broadly effective vaccine against the threat of variant infection. The spike protein S1-based nanoparticle designed in our study could elicit a comprehensive humoral response toward different SARS-CoV-2 variants of concern and variants of interest and will be helpful to combat COVID-19 globally.


Assuntos
Formação de Anticorpos , Vacinas contra COVID-19 , COVID-19 , Nanopartículas , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Formação de Anticorpos/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Humanos , Camundongos , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia
14.
J Virol ; 96(13): e0056622, 2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35703545

RESUMO

The family of human papillomaviruses (HPV) includes over 400 genotypes. Genus α genotypes generally infect the anogenital mucosa, and a subset of these HPV are a necessary, but not sufficient, cause of cervical cancer. Of the 13 high-risk (HR) and 11 intermediate-risk (IR) HPV associated with cervical cancer, genotypes 16 and 18 cause 50% and 20% of cases, respectively, whereas HPV16 dominates in other anogenital and oropharyngeal cancers. A plethora of ßHPVs are associated with cutaneous squamous cell carcinoma (CSCC), especially in sun-exposed skin sites of epidermodysplasia verruciformis (EV), AIDS, and immunosuppressed patients. Licensed L1 virus-like particle (VLP) vaccines, such as Gardasil 9, target a subset of αHPV but no ßHPV. To comprehensively target both α- and ßHPVs, we developed a two-component VLP vaccine, RG2-VLP, in which L2 protective epitopes derived from a conserved αHPV epitope (amino acids 17 to 36 of HPV16 L2) and a consensus ßHPV sequence in the same region are displayed within the DE loop of HPV16 and HPV18 L1 VLP, respectively. Unlike vaccination with Gardasil 9, vaccination of wild-type and EV model mice (Tmc6Δ/Δ or Tmc8Δ/Δ) with RG2-VLP induced robust L2-specific antibody titers and protected against ß-type HPV5. RG2-VLP protected rabbits against 17 αHPV, including those not covered by Gardasil 9. HPV16- and HPV18-specific neutralizing antibody responses were similar between RG2-VLP- and Gardasil 9-vaccinated animals. However, only transfer of RG2-VLP antiserum effectively protected naive mice from challenge with all ßHPVs tested. Taken together, these observations suggest RG2-VLP's potential as a broad-spectrum vaccine to prevent αHPV-driven anogenital, oropharyngeal, and ßHPV-associated cutaneous cancers. IMPORTANCE Licensed preventive HPV vaccines are composed of VLPs derived by expression of major capsid protein L1. They confer protection generally restricted to infection by the αHPVs targeted by the up-to-9-valent vaccine, and their associated anogenital cancers and genital warts, but do not target ßHPV that are associated with CSCC in EV and immunocompromised patients. We describe the development of a two-antigen vaccine protective in animal models against known oncogenic αHPVs as well as diverse ßHPVs by incorporation into HPV16 and HPV18 L1 VLP of 20-amino-acid conserved protective epitopes derived from minor capsid protein L2.


Assuntos
Alphapapillomavirus , Carcinoma de Células Escamosas , Papillomaviridae , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Vacinas de Partículas Semelhantes a Vírus , Alphapapillomavirus/imunologia , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Proteínas do Capsídeo/imunologia , Carcinoma de Células Escamosas/prevenção & controle , Epitopos/imunologia , Feminino , Papillomavirus Humano 16/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Papillomaviridae/imunologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Coelhos , Vacinas de Partículas Semelhantes a Vírus/imunologia
15.
Acta Biochim Biophys Sin (Shanghai) ; 54(4): 556-564, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35607955

RESUMO

Age has been found to be one of the main risk factors for the severity and outcome of COVID-19. However, differences in SARS-CoV-2 specific antibody responses among COVID-19 patients of different age groups remain largely unknown. In this study, we analyzed the IgG/IgM responses to 21 SARS-CoV-2 proteins and 197 peptides that fully cover the spike protein against 731 sera collected from 731 COVID-19 patients aged from 1 to We show that there is no overall difference in SARS-CoV-2 antibody responses in COVID-19 patients in the 4 age groups. By antibody response landscape maps, we find that the IgG response profiles of SARS-CoV-2 proteins are positively correlated with age. The S protein linear epitope map shows that the immunogenicity of the S-protein peptides is related to peptide sequence, disease severity and age of the COVID-19 patients. Furthermore, the enrichment analysis indicates that low S1 IgG responses are enriched in patients aged <50 and high S1 IgG responses are enriched in mild COVID-19 patients aged >60. In addition, high responses of non-structural/accessory proteins are enriched in severe COVID-19 patients aged >70. These results suggest the distinct immune response of IgG/IgM to each SARS-CoV-2 protein in patients of different age, which may facilitate a deeper understanding of the immune responses in COVID-19 patients.


Assuntos
Fatores Etários , Formação de Anticorpos , COVID-19 , Idoso , Anticorpos Antivirais/sangue , COVID-19/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Pessoa de Meia-Idade , Peptídeos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus
16.
Virol Sin ; 37(2): 229-237, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35527224

RESUMO

The Getah virus (GETV), a mosquito-borne RNA virus, is widely distributed in Oceania and Asia. GETV is not the only pathogenic to horses, pigs, cattle, foxes and boars, but it can also cause fever in humans. Since its first reported case in Chinese mainland in 2017, the number of GETV-affected provinces has increased to seventeen till now. Therefore, we performed an epidemiologic investigation of GETV in the Xinjiang region, located in northwestern China, during the period of 2017-2020. ELISA was used to analyze 3299 serum samples collected from thoroughbred horse, local horse, sheep, goat, cattle, and pigs, with thoroughbred horse (74.8%), local horse (67.3%), goat (11.7%), sheep (10.0%), cattle (25.1%) and pigs (51.1%) being positive for anti-GETV antibodies. Interestingly, the neutralizing antibody titer in horses was much higher than in other species. Four samples from horses and pigs were positive for GETV according to RT-PCR. Furthermore, from the serum of a local horse, we isolated GETV which was designated as strain XJ-2019-07, and determined its complete genome sequence. From the phylogenetic relationships, it belongs to the Group III lineage. This is the first evidence of GETV associated to domestic animals in Xinjiang. Overall, GETV is prevalent in Xinjiang and probably has been for several years. Since no vaccine against GETV is available in China, detection and monitoring strategies should be improved in horses and pigs, especially imported and farmed, in order to prevent economic losses.


Assuntos
Alphavirus , Culicidae , Alphavirus/genética , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Bovinos/virologia , China/epidemiologia , Culicidae/virologia , Cabras/virologia , Cavalos/virologia , Masculino , Filogenia , Análise de Sequência de DNA , Estudos Soroepidemiológicos , Ovinos/virologia , Suínos/virologia
17.
N Engl J Med ; 386(21): 2011-2023, 2022 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-35544369

RESUMO

BACKGROUND: Vaccination of children to prevent coronavirus disease 2019 (Covid-19) is an urgent public health need. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age are unknown. METHODS: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, we randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 µg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported. RESULTS: In part 1 of the trial, 751 children received 50-µg or 100-µg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-µg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 µg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-µg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-µg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant. CONCLUSIONS: Two 50-µg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).


Assuntos
Vacina de mRNA-1273 contra 2019-nCoV , COVID-19 , Vacina de mRNA-1273 contra 2019-nCoV/efeitos adversos , Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Vacina de mRNA-1273 contra 2019-nCoV/uso terapêutico , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/complicações , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/uso terapêutico , Criança , Método Duplo-Cego , Humanos , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica , Eficácia de Vacinas , Adulto Jovem
18.
J Med Virol ; 94(9): 4193-4205, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35570330

RESUMO

As one of the most rapidly evolving proteins of the genus Betacoronavirus, open reading frames (ORF8's) function and potential pathological consequence in vivo are still obscure. In this study, we show that the secretion of ORF8 is dependent on its N-terminal signal peptide sequence and can be inhibited by reactive oxygen species scavenger and endoplasmic reticulum-Golgi transportation inhibitor in cultured cells. To trace the effect of its possible in vivo secretion, we examined the plasma samples of coronavirus disease 2019 (COVID-19) convalescent patients and found that the patients aged from 40 to 60 had higher antibody titers than those under 40. To explore ORF8's in vivo function, we administered the mice with ORF8 via tail-vein injection to simulate the circulating ORF8 in the patient. Although no apparent difference in body weight, food intake, and vitality was detected between vehicle- and ORF8-treated mice, the latter displayed morphological abnormalities of testes and epididymides, as indicated by the loss of the central ductal lumen accompanied by a decreased fertility in 5-week-old male mice. Furthermore, the analysis of gene expression in the testes between vehicle- and ORF8-treated mice identified a decreased expression of Col1a1, the loss of which is known to be associated with mice's infertility. Although whether our observation in mice could be translated to humans remains unclear, our study provides a potential mouse model that can be used to investigate the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the human reproductive system.


Assuntos
COVID-19 , Infertilidade Masculina , SARS-CoV-2 , Proteínas Virais , Sequência de Aminoácidos , Animais , Anticorpos Antivirais/sangue , Fertilidade , Humanos , Infertilidade Masculina/virologia , Masculino , Camundongos , Fases de Leitura Aberta
19.
Viruses ; 14(5)2022 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-35632710

RESUMO

Serological detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N), spike (S), and neutralizing antibodies (Abs) is commonly undertaken to evaluate the efficacy of vaccination. However, the relative efficiency of different SARS-CoV-2 Ab detection systems has not been extensively investigated. Here, we evaluated serological test systems in vaccinated Japanese. SARS-CoV-2 N, S, and neutralizing Abs in sera of 375 healthy subjects a mean 253 days after vaccination were assessed. The sensitivity of Elecsys Anti-SARS-CoV-2 S (Roche S) and Anti-SARS-CoV-2 S IgG (Fujirebio S) was 100% and 98.9%, respectively, with a specificity of 100% for both. The sensitivity of Anti-SARS-CoV-2 neutralizing Ab (MBL Neu) was 2.7%, and the specificity was 100%. Fujirebio S correlated with Roche S (rho = 0.9182, p = 3.97 × 10-152). Fujirebio S (rho = 0.1295, p = 0.0121) and Roche S (rho = 0.1232, p = 0.0170) correlated weakly with MBL Neu. However, Roche S did correlate with MBL Neu in patients with COVID-19 (rho = 0.8299, p = 1.01 × 10-12) and in healthy subjects more recently after vaccination (mean of 90 days, rho = 0.5306, p = 0.0003). Thus, the Fujirebio S and Roche S results were very similar, but neither correlated with neutralizing antibody titers by MBL Neu at a later time after vaccination.


Assuntos
Anticorpos Neutralizantes , Vacinas contra COVID-19 , COVID-19 , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/imunologia , COVID-19/prevenção & controle , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Humanos , Imunoglobulina G/sangue , Japão , Fosfoproteínas/imunologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus
20.
Sci Rep ; 12(1): 9045, 2022 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-35641545

RESUMO

Long-term antibody responses to SARS-CoV-2 have focused on responses to full-length spike protein, specific domains within spike, or nucleoprotein. In this study, we used high-density peptide microarrays representing the complete proteome of SARS-CoV-2 to identify binding sites (epitopes) targeted by antibodies present in the blood of COVID-19 resolved cases at 5 months post-diagnosis. Compared to previous studies that evaluated epitope-specific responses early post-diagnosis (< 60 days), we found that epitope-specific responses to nucleoprotein and spike protein have contracted, and that responses to membrane protein have expanded. Although antibody titers to full-length spike and nucleoprotein remain steady over months, taken together our data suggest that the population of epitope-specific antibodies that contribute to this reactivity is dynamic and evolves over time. Further, the spike epitopes bound by polyclonal antibodies in COVID-19 convalescent serum samples aligned with known target sites that can neutralize viral activity suggesting that the maintenance of these antibodies might provide rapid serological immunity. Finally, the most dominant epitopes for membrane protein and spike showed high diagnostic accuracy providing novel biomarkers to refine blood-based antibody tests. This study provides new insights into the specific regions of SARS-CoV-2 targeted by serum antibodies long after infection.


Assuntos
Anticorpos Antivirais , COVID-19 , Convalescença , Anticorpos Antivirais/sangue , COVID-19/sangue , COVID-19/terapia , Proteínas do Nucleocapsídeo de Coronavírus , Epitopos , Humanos , Imunização Passiva , Fosfoproteínas , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus
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