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1.
Medicina (B Aires) ; 81(5): 683-687, 2021.
Artigo em Espanhol | MEDLINE | ID: mdl-34633939

RESUMO

The rapid spread of the SARS-CoV-2, the causative agent of the emergent pandemic disease COVID-19, requires the urgent commitment of the immunology community to understand the adaptive immune response developed by COVID-19 convalescent patients and individuals vaccinated with different strategies and schemes, with the ultimate goal of implementing and optimizing health care and prevention policies. Currently, assessment of SARS-CoV-2-specific immunity is mainly focused on the measurement of the antibody titers and analysis of their neutralizing capacity. However, a considerable proportion of individuals lack humoral responses or show a progressive decline of SARS-CoV-2-specific neutralizing antibodies. In order to study the cellular response of convalescent patients and vaccinated individuals, we have developed the "COVID-T Platform", an optimized strategy to study SARS-CoV-2-specific T cell responses. This platform allows assessment of the nature, magnitude and persistence of antigen-specific T-cell immunity in COVID-19-convalescent patients and vaccinated individuals. Moreover, it gives the opportunity to study cellular responses against emerging coronavirus variants and to identify individuals with cross-reactive immunity against seasonal coronaviruses.


Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Neutralizantes , Anticorpos Antivirais , Humanos , Linfócitos T
2.
PLoS Med ; 18(10): e1003769, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34597298

RESUMO

BACKGROUND: NVX-CoV2373 is a recombinant severe acute respiratory coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. METHODS AND FINDINGS: The phase 2 component of our randomized, placebo-controlled, phase 1 to 2 trial was designed to identify which dosing regimen of NVX-CoV2373 should move forward into late-phase studies and was based on immunogenicity and safety data through Day 35 (14 days after the second dose). The trial was conducted at 9 sites in Australia and 8 sites in the United States. Participants in 2 age groups (aged 18 to 59 and 60 to 84 years) were randomly assigned to receive either 1 or 2 intramuscular doses of 5-µg or 25-µg NVX-CoV2373 or placebo, 21 days apart. Primary endpoints were immunoglobulin G (IgG) anti-spike protein response, 7-day solicited reactogenicity, and unsolicited adverse events. A key secondary endpoint was wild-type virus neutralizing antibody response. After enrollment, 1,288 participants were randomly assigned to 1 of 4 vaccine groups or placebo, with 1,283 participants administered at least 1 study treatment. Of these, 45% were older participants 60 to 84 years. Reactogenicity was predominantly mild to moderate in severity and of short duration (median <3 days) after first and second vaccination with NVX-CoV2373, with higher frequencies and intensity after second vaccination and with the higher dose. Reactogenicity occurred less frequently and was of lower intensity in older participants. Both 2-dose regimens of 5-µg and 25-µg NVX-CoV2373 induced robust immune responses in younger and older participants. For the 2-dose regimen of 5 µg, geometric mean titers (GMTs) for IgG anti-spike protein were 65,019 (95% confidence interval (CI) 55,485 to 76,192) and 28,137 (95% CI 21,617 to 36,623) EU/mL and for wild-type virus neutralizing antibody (with an inhibitory concentration of 50%-MN50%) were 2,201 (95% CI 1,343 to 3,608) and 981 (95% CI 560 to 1,717) titers for younger and older participants, respectively, with seroconversion rates of 100% in both age groups. Neutralizing antibody responses exceeded those seen in a panel of convalescent sera for both age groups. Study limitations include the relatively short duration of safety follow-up to date and current lack of immune persistence data beyond the primary vaccination regimen time point assessments, but these data will accumulate over time. CONCLUSIONS: The study confirmed the phase 1 findings that the 2-dose regimen of 5-µg NVX-CoV2373 is highly immunogenic and well tolerated in younger adults. In addition, in older adults, the 2-dose regimen of 5 µg was also well tolerated and showed sufficient immunogenicity to support its use in late-phase efficacy studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT04368988.


Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Imunogenicidade da Vacina , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto Jovem
3.
Sheng Wu Gong Cheng Xue Bao ; 37(9): 3211-3220, 2021 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-34622629

RESUMO

To develop Senecavirus A (SVA) virus-like particles (VLPs), a recombinant prokaryotic expression plasmid pET28a-SVA-VP031 was constructed to co-express SVA structural proteins VP0, VP3 and VP1, according to the genomic sequence of the field isolate CH-FJ-2017 after the recombinant proteins were expressed in E .coli system, and purified by Ni+ ion chromatographic method. The SVA VLPs self-assemble with a high yield in vitro buffer. A typical VLPs with an average diameter of 25-30 nm which is similar to native virions by using TEM detection. Animals immunized by SVA VLPs shown that the VLPs induced high titers neutralizing antibodies in Guinea pigs. This study indicated that the VLPs produced with co-expressing SVA structural proteins VP0, VP3 and VP1 in prokaryotic system is a promising candidate and laid an important foundation for the development of a novel SVA VLPs vaccine.


Assuntos
Picornaviridae , Animais , Anticorpos Neutralizantes , Escherichia coli/genética , Genômica , Cobaias , Picornaviridae/genética
4.
Vaccine ; 39(44): 6520-6528, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34620531

RESUMO

BACKGROUND: The WHO declared COVID-19 a pandemic on March 11th, 2020. This serious outbreak and the precipitously increasing numbers of deaths worldwide necessitated the urgent need to develop an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. The development of COVID-19 vaccines has moved quickly. In this study, we assessed the efficacy, safety, and immunogenicity of an inactivated (SARS-CoV-2) vaccine. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to evaluate the efficacy, immunogenicity, and safety of an inactivated SARS-CoV-2 vaccine and its lot-to-lot consistency. A total of 1620 healthy adults aged 18-59 years were randomly assigned to receive 2 injections of the trial vaccine or placebo on a day 0 and 14 schedule. This article was based on an interim report completed within 3 months following the last dose of study vaccine. The interim analysis includes safety and immunogenicity data for 540 participants in the immunogenicity subset and an efficacy analysis of the 1620 subjects. For the safety evaluation, solicited and unsolicited adverse events were collected after the first and second vaccination within 14 and 28 days, respectively. Blood samples were collected for an antibody assay before and 14 days following the second dose. RESULTS: Most of the adverse reactions were in the solicited category and were mild in severity. Pain at the injection site was the most frequently reported symptom. Antibody IgG titer determined by enzyme-linked immunosorbent assay was 97.48% for the seroconversion rate. Using a neutralization assay, the seroconversion rate was 87.15%. The efficacy in preventing symptomatic confirmed cases of COVID-19 occurring at least 14 days after the second dose of vaccine using an incidence rate was 65.30%. CONCLUSIONS: From the 3-month interim analysis, the vaccine exhibited a 65.30% efficacy at preventing COVID-19 illness with favorable safety and immunogenicity profiles.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Adulto , Anticorpos Neutralizantes , Anticorpos Antivirais , Método Duplo-Cego , Humanos , Imunogenicidade da Vacina , Indonésia/epidemiologia , SARS-CoV-2 , Vacinas de Produtos Inativados/efeitos adversos
5.
FASEB J ; 35(11): e21970, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34637549

RESUMO

Single domain shark variable domain of new antigen receptor (VNAR) antibodies can offer a viable alternative to conventional Ig-based monoclonal antibodies in treating COVID-19 disease during the current pandemic. Here we report the identification of neutralizing single domain VNAR antibodies selected against the severe acute respiratory syndrome coronavirus 2 spike protein derived from the Wuhan variant using phage display. We identified 56 unique binding clones that exhibited high affinity and specificity to the spike protein. Of those, 10 showed an ability to block both the spike protein receptor binding domain from the Wuhan variant and the N501Y mutant from interacting with recombinant angiotensin-converting enzyme 2 (ACE2) receptor in vitro. In addition, three antibody clones retained in vitro blocking activity when the E484K spike protein mutant was used. The inhibitory property of the VNAR antibodies was further confirmed for all 10 antibody clones using ACE2 expressing cells with spike protein from the Wuhan variant. The viral neutralizing potential of the VNAR clones was also confirmed for the 10 antibodies tested using live Wuhan variant virus in in vitro cell infectivity assays. Single domain VNAR antibodies, due to their low complexity, small size, unique epitope recognition, and formatting flexibility, should be a useful adjunct to existing antibody approaches to treat COVID-19.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19 , SARS-CoV-2/imunologia , Anticorpos de Domínio Único/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , COVID-19/imunologia , COVID-19/prevenção & controle , Chlorocebus aethiops , Humanos , Ligação Proteica , Tubarões/imunologia , Células Vero
6.
Front Immunol ; 12: 709759, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603283

RESUMO

The clinical features of SARS-CoV-2 infection range from asymptomatic to severe disease with life-threatening complications. Understanding the persistence of immune responses in asymptomatic individuals merit special attention because of their importance in controlling the spread of the infections. We here studied the antibody and T cell responses, and a wide range of inflammation markers, in 56 SARS-CoV-2 antibody-positive individuals, identified by a population screen after the first wave of SARS-CoV-2 infection. These, mostly asymptomatic individuals, were reanalyzed 7-8 months after their infection together with 115 age-matched seronegative controls. We found that 7-8 months after the infection their antibodies to SARS-CoV-2 Nucleocapsid (N) protein declined whereas we found no decrease in the antibodies to Spike receptor-binding domain (S-RBD) when compared to the findings at seropositivity identification. In contrast to antibodies to N protein, the antibodies to S-RBD correlated with the viral neutralization capacity and with CD4+ T cell responses as measured by antigen-specific upregulation of CD137 and CD69 markers. Unexpectedly we found the asymptomatic antibody-positive individuals to have increased serum levels of S100A12, TGF-alpha, IL18, and OSM, the markers of activated macrophages-monocytes, suggesting long-term persistent inflammatory effect associated with the viral infection in asymptomatic individuals. Our results support the evidence for the long-term persistence of the inflammation process and the need for post-infection clinical monitoring of SARS-CoV-2 infected asymptomatic individuals.


Assuntos
Anticorpos Antivirais/sangue , Infecções Assintomáticas , Linfócitos T CD4-Positivos/imunologia , COVID-19/patologia , Mediadores da Inflamação/sangue , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Contagem de Linfócito CD4 , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Humanos , Inflamação/imunologia , Interleucina-18/sangue , Macrófagos/imunologia , Monócitos/imunologia , Oncostatina M/sangue , Fosfoproteínas/imunologia , Domínios Proteicos/imunologia , Proteína S100A12/sangue , Glicoproteína da Espícula de Coronavírus/imunologia , Fator de Crescimento Transformador alfa/sangue
7.
Front Immunol ; 12: 729189, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603303

RESUMO

Several SARS-CoV-2 vaccines have received EUAs, but many issues remain unresolved, including duration of conferred immunity and breadth of cross-protection. Adjuvants that enhance and shape adaptive immune responses that confer broad protection against SARS-CoV-2 variants will be pivotal for long-term protection as drift variants continue to emerge. We developed an intranasal, rationally designed adjuvant integrating a nanoemulsion (NE) that activates TLRs and NLRP3 with an RNA agonist of RIG-I (IVT DI). The combination adjuvant with spike protein antigen elicited robust responses to SARS-CoV-2 in mice, with markedly enhanced TH1-biased cellular responses and high virus-neutralizing antibody titers towards both homologous SARS-CoV-2 and a variant harboring the N501Y mutation shared by B1.1.7, B.1.351 and P.1 variants. Furthermore, passive transfer of vaccination-induced antibodies protected naive mice against heterologous viral challenge. NE/IVT DI enables mucosal vaccination, and has the potential to improve the immune profile of a variety of SARS-CoV-2 vaccine candidates to provide effective cross-protection against future drift variants.


Assuntos
Adjuvantes Imunológicos/farmacologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacinas Sintéticas/imunologia , Imunidade Adaptativa/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Chlorocebus aethiops , Proteção Cruzada/imunologia , Proteína DEAD-box 58 , Células HEK293 , Humanos , Imunidade Humoral/imunologia , Imunização Passiva , Camundongos , Camundongos Endogâmicos C57BL , Receptores Imunológicos/agonistas , Proteínas Recombinantes/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação , Células Vero
8.
Front Immunol ; 12: 729837, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603305

RESUMO

We have developed a dual-antigen COVID-19 vaccine incorporating genes for a modified SARS-CoV-2 spike protein (S-Fusion) and the viral nucleocapsid (N) protein with an Enhanced T-cell Stimulation Domain (N-ETSD) to increase the potential for MHC class II responses. The vaccine antigens are delivered by a human adenovirus serotype 5 platform, hAd5 [E1-, E2b-, E3-], previously demonstrated to be effective in the presence of Ad immunity. Vaccination of rhesus macaques with the hAd5 S-Fusion + N-ETSD vaccine by subcutaneous prime injection followed by two oral boosts elicited neutralizing anti-S IgG and T helper cell 1-biased T-cell responses to both S and N that protected the upper and lower respiratory tracts from high titer (1 x 106 TCID50) SARS-CoV-2 challenge. Notably, viral replication was inhibited within 24 hours of challenge in both lung and nasal passages, becoming undetectable within 7 days post-challenge.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adenovírus Humanos/genética , Adenovírus Humanos/imunologia , Adenovírus Humanos/metabolismo , Administração Oral , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Vacinas contra COVID-19/administração & dosagem , Citocinas/sangue , Imunização Secundária/métodos , Imunoglobulina G/sangue , Pulmão/virologia , Macaca mulatta , Nariz/virologia , Fosfoproteínas/imunologia , Domínios Proteicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinação , Replicação Viral/imunologia
9.
Front Immunol ; 12: 731100, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603308

RESUMO

Coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious infectious disease that has led to a global pandemic with high morbidity and mortality. High-affinity neutralizing antibody is important for controlling infection, which is closely regulated by follicular helper T (Tfh) cells. Tfh cells play a central role in promoting germinal center reactions and driving cognate B cell differentiation for antibody secretion. Available studies indicate a close relationship between virus-specific Tfh cell-mediated immunity and SARS-CoV-2 infection progression. Although several lines of evidence have suggested that Tfh cells contribute to the control of SARS-CoV-2 infection by eliciting neutralizing antibody productions, further studies are needed to elucidate Tfh-mediated effector mechanisms in anti-SARS-CoV-2 immunity. Here, we summarize the functional features and roles of virus-specific Tfh cells in the immunopathogenesis of SARS-CoV-2 infection and in COVID-19 vaccines, and highlight the potential of targeting Tfh cells as therapeutic strategy against SARS-CoV-2 infection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Células T Auxiliares Foliculares/imunologia , Formação de Anticorpos/imunologia , Linfócitos B/imunologia , COVID-19/patologia , Vacinas contra COVID-19/imunologia , Diferenciação Celular/imunologia , Centro Germinativo/citologia , Centro Germinativo/imunologia , Humanos , Ativação Linfocitária/imunologia , Células T Auxiliares Foliculares/citologia
10.
Nat Commun ; 12(1): 5769, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599175

RESUMO

Distinct SARS-CoV-2 lineages, discovered through various genomic surveillance initiatives, have emerged during the pandemic following unprecedented reductions in worldwide human mobility. We here describe a SARS-CoV-2 lineage - designated B.1.620 - discovered in Lithuania and carrying many mutations and deletions in the spike protein shared with widespread variants of concern (VOCs), including E484K, S477N and deletions HV69Δ, Y144Δ, and LLA241/243Δ. As well as documenting the suite of mutations this lineage carries, we also describe its potential to be resistant to neutralising antibodies, accompanying travel histories for a subset of European cases, evidence of local B.1.620 transmission in Europe with a focus on Lithuania, and significance of its prevalence in Central Africa owing to recent genome sequencing efforts there. We make a case for its likely Central African origin using advanced phylogeographic inference methodologies incorporating recorded travel histories of infected travellers.


Assuntos
COVID-19/transmissão , COVID-19/virologia , SARS-CoV-2/genética , África Central/epidemiologia , Anticorpos Neutralizantes/imunologia , COVID-19/epidemiologia , Europa (Continente)/epidemiologia , Humanos , Evasão da Resposta Imune/genética , Mutação , Filogenia , Filogeografia , SARS-CoV-2/classificação , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Viagem/estatística & dados numéricos
11.
Zhonghua Yu Fang Yi Xue Za Zhi ; 55(2): 171-176, 2021 Feb 06.
Artigo em Chinês | MEDLINE | ID: mdl-34645175

RESUMO

Antibody-dependent enhancement (ADE) refers to the process in which some virus-specific antibodies (generally non-neutralizing antibodies) bind to the virus and bind to some cells expressing FcR on the surface through their Fc segment, thereby mediating the endocytosis and replication of the virus and enhancing the infection of the virus. This review summarized experience of ADE in respiratory syncytial virus, dengue virus, influenza virus infection and explored the possible mechanism of COVID-19 high incidence and severity of the disease, which implied challenges in the process of vaccine development and provided some insights for COVID-19 pathogenesis.


Assuntos
COVID-19 , Vírus da Dengue , Dengue , Anticorpos Neutralizantes , Anticorpos Antivirais , Anticorpos Facilitadores , Humanos , SARS-CoV-2
12.
Nat Commun ; 12(1): 5877, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620860

RESUMO

Several COVID-19 vaccines have recently gained authorization for emergency use. Limited knowledge on duration of immunity and efficacy of these vaccines is currently available. Data on other coronaviruses after natural infection suggest that immunity to SARS-CoV-2 might be short-lived, and preliminary evidence indicates waning antibody titers following SARS-CoV-2 infection. In this work, we model the relationship between immunogenicity and protective efficacy of a series of Ad26 vectors encoding stabilized variants of the SARS-CoV-2 Spike protein in rhesus macaques and validate the analyses by challenging macaques 6 months after immunization with the Ad26.COV2.S vaccine candidate that has been selected for clinical development. We show that Ad26.COV2.S confers durable protection against replication of SARS-CoV-2 in the lungs that is predicted by the levels of Spike-binding and neutralizing antibodies, indicating that Ad26.COV2.S could confer durable protection in humans and immunological correlates of protection may enable the prediction of durability of protection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação , Animais , Feminino , Células HEK293 , Humanos , Imunidade Humoral , Modelos Logísticos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta , Masculino , Nariz/imunologia , Nariz/virologia , SARS-CoV-2/fisiologia , Replicação Viral/fisiologia
13.
Nat Commun ; 12(1): 5868, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620866

RESUMO

We investigated ChAdOx1 nCoV-19 (AZD1222) vaccine efficacy against SARS-CoV-2 variants of concern (VOCs) B.1.1.7 and B.1.351 in Syrian hamsters. We previously showed protection against SARS-CoV-2 disease and pneumonia in hamsters vaccinated with a single dose of ChAdOx1 nCoV-19. Here, we observe a 9.5-fold reduction of virus neutralizing antibody titer in vaccinated hamster sera against B.1.351 compared to B.1.1.7. Vaccinated hamsters challenged with B.1.1.7 or B.1.351 do not lose weight compared to control animals. In contrast to control animals, the lungs of vaccinated animals do not show any gross lesions. Minimal to no viral subgenomic RNA (sgRNA) and no infectious virus can be detected in lungs of vaccinated animals. Histopathological evaluation shows extensive pulmonary pathology caused by B.1.1.7 or B.1.351 replication in the control animals, but none in the vaccinated animals. These data demonstrate the effectiveness of the ChAdOx1 nCoV-19 vaccine against clinical disease caused by B.1.1.7 or B.1.351 VOCs.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Administração Intranasal , Substituição de Aminoácidos , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/virologia , Feminino , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Mesocricetus , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação
14.
Commun Biol ; 4(1): 1196, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645933

RESUMO

Emerging mutations in SARS-CoV-2 cause several waves of COVID-19 pandemic. Here we investigate the infectivity and antigenicity of ten emerging SARS-CoV-2 variants-B.1.1.298, B.1.1.7(Alpha), B.1.351(Beta), P.1(Gamma), P.2(Zeta), B.1.429(Epsilon), B.1.525(Eta), B.1.526-1(Iota), B.1.526-2(Iota), B.1.1.318-and seven corresponding single amino acid mutations in the receptor-binding domain using SARS-CoV-2 pseudovirus. The results indicate that the pseudovirus of most of the SARS-CoV-2 variants (except B.1.1.298) display slightly increased infectivity in human and monkey cell lines, especially B.1.351, B.1.525 and B.1.526 in Calu-3 cells. The K417N/T, N501Y, or E484K-carrying variants exhibit significantly increased abilities to infect mouse ACE2-overexpressing cells. The activities of furin, TMPRSS2, and cathepsin L are increased against most of the variants. RBD amino acid mutations comprising K417T/N, L452R, Y453F, S477N, E484K, and N501Y cause significant immune escape from 11 of 13 monoclonal antibodies. However, the resistance to neutralization by convalescent serum or vaccines elicited serum is mainly caused by the E484K mutation. The convalescent serum from B.1.1.7- and B.1.351-infected patients neutralized the variants themselves better than other SARS-CoV-2 variants. Our study provides insights regarding therapeutic antibodies and vaccines, and highlights the importance of E484K mutation.


Assuntos
COVID-19/virologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , COVID-19/terapia , Linhagem Celular , Células HEK293 , Humanos , Imunização Passiva/métodos , Mamíferos/imunologia , Camundongos , Mutação , Pandemias , Primatas/imunologia , Ligação Proteica , Tropismo/genética
15.
Front Immunol ; 12: 739037, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34594341

RESUMO

Background: Transfusion of COVID-19 convalescent plasma (CCP) containing high titers of anti-SARS-CoV-2 antibodies serves as therapy for COVID-19 patients. Transfusions early during disease course was found to be beneficial. Lessons from the SARS-CoV-2 pandemic could inform early responses to future pandemics and may continue to be relevant in lower resource settings. We sought to identify factors correlating to high antibody titers in convalescent plasma donors and understand the magnitude and pharmacokinetic time course of both transfused antibody titers and the endogenous antibody titers in transfused recipients. Methods: Plasma samples were collected up to 174 days after convalescence from 93 CCP donors with mild disease, and from 16 COVID-19 patients before and after transfusion. Using ELISA, anti-SARS-CoV-2 Spike RBD, S1, and N-protein antibodies, as well as capacity of antibodies to block ACE2 from binding to RBD was measured in an in vitro assay. As an estimate for viral load, viral RNA and N-protein plasma levels were assessed in COVID-19 patients. Results: Anti-SARS-CoV-2 antibody levels and RBD-ACE2 blocking capacity were highest within the first 60 days after symptom resolution and markedly decreased after 120 days. Highest antibody titers were found in CCP donors that experienced fever. Effect of transfused CCP was detectable in COVID-19 patients who received high-titer CCP and had not seroconverted at the time of transfusion. Decrease in viral RNA was seen in two of these patients. Conclusion: Our results suggest that high titer CCP should be collected within 60 days after recovery from donors with past fever. The much lower titers conferred by transfused antibodies compared to endogenous production in the patient underscore the importance of providing CCP prior to endogenous seroconversion.


Assuntos
COVID-19/terapia , Convalescença , SARS-CoV-2/imunologia , Soroconversão , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Antígenos Virais/sangue , Doadores de Sangue , COVID-19/sangue , COVID-19/imunologia , Feminino , Humanos , Imunização Passiva , Cinética , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , RNA Viral/sangue
16.
Math Biosci Eng ; 18(5): 6887-6906, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34517562

RESUMO

Eradication and eventually cure of the HIV virus from the infected individual should be the primary goal in all HIV therapy. This has yet to be achieved, however development of broadly neutralizing antibodies (bNabs) and eCD4-Ig and its related particles are promising therapeutic alternatives to eliminate the HIV virus from the host. Past studies have found superior protectivity and efficacy eradicating the HIV virus with the use of eCD4-Igs over bNabs, which has proposed the antibody-dependent cell-mediated cytotoxicity (ADCC) effect as one of the key-factors for antibody design. In this study, we evaluated the dynamics of the HIV virus, CD4 T-cells, and eCD4-Ig in humans using a gene-therapy approach which has been evaluated in primates previously. We utilized a mathematical model to investigate the relationship between eCD4-Ig levels, ADCC effects, and the neutralization effect on HIV elimination. In addition, a balance between ADCC and viral neutralization effect of eCD4-Ig has been investigated in order to understand the condition of which HIV eliminating antibodies needs to satisfy. Our analysis indicated some level of ADCC effect, which was missing from ART, was required for viral elimination. The results will be helpful in designing future drugs or therapeutic strategies.


Assuntos
Infecções por HIV , HIV-1 , Animais , Anticorpos Neutralizantes , Anticorpos Anti-HIV , Infecções por HIV/tratamento farmacológico , Modelos Teóricos
17.
Mil Med Res ; 8(1): 47, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465396

RESUMO

SARS-CoV-2 is a newly identified member of the coronavirus family that has caused the Coronavirus disease 2019 (COVID-19) pandemic. This rapidly evolving and unrelenting SARS-CoV-2 has disrupted the lives and livelihoods of millions worldwide. As of 23 August 2021, a total of 211,373,303 COVID-19 cases have been confirmed globally with a death toll of 4,424,341. A strong understanding of the infection pathway of SARS-CoV-2, and how our immune system responds to the virus is highly pertinent for guiding the development and improvement of effective treatments. In this review, we discuss the current understanding of neutralising antibodies (NAbs) and their implications in clinical practice. The aspects include the pathophysiology of the immune response, particularly humoral adaptive immunity and the roles of NAbs from B cells in infection clearance. We summarise the onset and persistence of IgA, IgM and IgG antibodies, and we explore their roles in neutralising SARS-CoV-2, their persistence in convalescent individuals, and in reinfection. Furthermore, we also review the applications of neutralising antibodies in the clinical setting-from predictors of disease severity to serological testing to vaccinations, and finally in therapeutics such as convalescent plasma infusion.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , COVID-19/terapia , Imunidade Humoral , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/imunologia , COVID-19/epidemiologia , COVID-19/imunologia , Humanos , Imunização Passiva , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Pandemias , Glicoproteína da Espícula de Coronavírus/imunologia
18.
BMC Health Serv Res ; 21(1): 939, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34496836

RESUMO

BACKGROUND: Clostridioides difficile infection (CDI) is one of the leading nosocomial infections, resulting in increased hospital length of stay and additional treatment costs. Bezlotoxumab, the first monoclonal antibody against CDI, has an 1 A guideline recommendation for prevention of CDI, after randomized clinical trials demonstrated its superior efficacy vs. placebo. METHODS: The budget impact analysis at hand is focused on patients at high risk of CDI recurrence. Treatment with standard of care (SoC) + bezlotoxumab was compared with current SoC alone in the 10 most associated Diagnosis Related Groups to identify, analyze, and evaluate potential cost savings per case from the German hospital management perspective. Based on variation in days to rehospitalization, three different case consolidation scenarios were assessed: no case consolidation, case consolidation for the SoC + bezlotoxumab treatment arm only, and case consolidation for both treatment arms. RESULTS: On average, the budget impact amounted to € 508.56 [range: € 424.85 - € 642.19] for no case consolidation, € 470.50 [range: € 378.75 - € 601.77] for case consolidation in the SoC + bezlotoxumab treatment arm, and € 618.00 [range: € 557.40 - € 758.41] for case consolidation in both treatment arms. CONCLUSIONS: The study demonstrated administration of SoC + bezlotoxumab in patients at high risk of CDI recurrence is cost-saving from a hospital management perspective. Reduced length of stay in bezlotoxumab treated patients creates free spatial and personnel capacities for the treating hospital. Yet, a requirement for hospitals to administer bezlotoxumab is the previously made request for additional fees and a successful price negotiation.


Assuntos
Antibacterianos , Clostridioides difficile , Antibacterianos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes , Anticorpos Amplamente Neutralizantes , Alemanha/epidemiologia , Hospitais , Humanos , Recidiva , Padrão de Cuidado
20.
Front Immunol ; 12: 739025, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531877

RESUMO

A rise in adiposity in the United States has resulted in more than 70% of adults being overweight or obese, and global obesity rates have tripled since 1975. Following the 2009 H1N1 pandemic, obesity was characterized as a risk factor that could predict severe infection outcomes to viral infection. Amidst the SARS-CoV-2 pandemic, obesity has remained a significant risk factor for severe viral disease as obese patients have a higher likelihood for developing severe symptoms and requiring hospitalization. However, the mechanism by which obesity enhances viral disease is unknown. In this study, we utilized a diet-induced obesity mouse model of West Nile virus (WNV) infection, a flavivirus that cycles between birds and mosquitoes and incidentally infects both humans and mice. Likelihood for severe WNV disease is associated with risk factors such as diabetes that are comorbidities also linked to obesity. Utilizing this model, we showed that obesity-associated chronic inflammation increased viral disease severity as obese female mice displayed higher mortality rates and elevated viral titers in the central nervous system. In addition, our studies highlighted that obesity also dysregulates host acute adaptive immune responses, as obese female mice displayed significant dysfunction in neutralizing antibody function. These studies highlight that obesity-induced immunological dysfunction begins at early time points post infection and is sustained through memory phase, thus illuminating a potential for obesity to alter the differentiation landscape of adaptive immune cells.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Citocinas/sangue , Obesidade/imunologia , Febre do Nilo Ocidental/mortalidade , Vírus do Nilo Ocidental/imunologia , Animais , COVID-19/patologia , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/patologia , Fígado/lesões , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/patologia , Índice de Gravidade de Doença , Febre do Nilo Ocidental/imunologia , Febre do Nilo Ocidental/patologia
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