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1.
Immunity ; 56(11): 2621-2634.e6, 2023 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-37967533

RESUMO

There is growing appreciation for neuraminidase (NA) as an influenza vaccine target; however, its antigenicity remains poorly characterized. In this study, we isolated three broadly reactive N2 antibodies from the plasmablasts of a single vaccinee, including one that cross-reacts with NAs from seasonal H3N2 strains spanning five decades. Although these three antibodies have diverse germline usages, they recognize similar epitopes that are distant from the NA active site and instead involve the highly conserved underside of NA head domain. We also showed that all three antibodies confer prophylactic and therapeutic protection in vivo, due to both Fc effector functions and NA inhibition through steric hindrance. Additionally, the contribution of Fc effector functions to protection in vivo inversely correlates with viral growth inhibition activity in vitro. Overall, our findings advance the understanding of NA antibody response and provide important insights into the development of a broadly protective influenza vaccine.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza , Influenza Humana , Infecções por Orthomyxoviridae , Humanos , Influenza Humana/prevenção & controle , Neuraminidase , Infecções por Orthomyxoviridae/prevenção & controle , Vírus da Influenza A Subtipo H3N2 , Epitopos , Anticorpos Antivirais , Anticorpos Monoclonais , Vacinação , Glicoproteínas de Hemaglutininação de Vírus da Influenza
2.
Proc Natl Acad Sci U S A ; 121(15): e2317222121, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38557175

RESUMO

Antigenic drift of SARS-CoV-2 is typically defined by mutations in the N-terminal domain and receptor binding domain of spike protein. In contrast, whether antigenic drift occurs in the S2 domain remains largely elusive. Here, we perform a deep mutational scanning experiment to identify S2 mutations that affect binding of SARS-CoV-2 spike to three S2 apex public antibodies. Our results indicate that spatially diverse mutations, including D950N and Q954H, which are observed in Delta and Omicron variants, respectively, weaken the binding of spike to these antibodies. Although S2 apex antibodies are known to be nonneutralizing, we show that they confer protection in vivo through Fc-mediated effector functions. Overall, this study indicates that the S2 domain of SARS-CoV-2 spike can undergo antigenic drift, which represents a potential challenge for the development of more universal coronavirus vaccines.


Assuntos
Deriva e Deslocamento Antigênicos , COVID-19 , Humanos , SARS-CoV-2/genética , Anticorpos , Glicoproteína da Espícula de Coronavírus/genética , Anticorpos Antivirais
3.
Bull World Health Organ ; 99(2): 155-161, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33551509

RESUMO

Restrictive measures imposed because of the coronavirus disease 2019 (COVID-19) pandemic have resulted in severe social, economic and health effects. Some countries have considered the use of immunity certification as a strategy to relax these measures for people who have recovered from the infection by issuing these individuals a document, commonly called an immunity passport. This document certifies them as having protective immunity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus that causes COVID-19. The World Health Organization has advised against the implementation of immunity certification at present because of uncertainty about whether long-term immunity truly exists for those who have recovered from COVID-19 and concerns over the reliability of the proposed serological test method for determining immunity. Immunity certification can only be considered if scientific thresholds for assuring immunity are met, whether based on antibodies or other criteria. However, even if immunity certification became well supported by science, it has many ethical issues in terms of different restrictions on individual liberties and its implementation process. We examine the main considerations for the ethical acceptability of immunity certification to exempt individuals from restrictive measures during the COVID-19 pandemic. As well as needing to meet robust scientific criteria, the ethical acceptability of immunity certification depends on its uses and policy objectives and the measures in place to reduce potential harms, and prevent disproportionate burdens on non-certified individuals and violation of individual liberties and rights.


Les restrictions imposées dans le cadre de la lutte contre la pandémie de maladie à coronavirus 2019 (COVID-19) ont eu de lourdes conséquences économiques, sociales et sanitaires. Certains pays ont envisagé la mise en place d'une stratégie visant à alléger ces restrictions pour les individus guéris en leur octroyant un document communément appelé «passeport d'immunité¼. Ce document atteste qu'ils ont développé une immunité protectrice contre le coronavirus 2 du syndrome respiratoire aigu sévère (SARS-CoV-2), le virus à l'origine de la COVID-19. L'Organisation mondiale de la Santé a déconseillé l'usage du certificat d'immunité pour l'instant, car l'incertitude demeure quant à l'existence réelle d'une immunité à long terme pour ceux qui se sont remis de la COVID-19. En outre, la fiabilité des tests sérologiques censés déterminer si l'individu est immunisé n'est pas avérée. Un tel certificat ne peut être instauré que si les seuils scientifiques en matière d'immunité sont respectés, qu'ils soient fondés sur les anticorps ou sur d'autres critères. Néanmoins, même si le certificat d'immunité est désormais bien accepté par la science, il s'accompagne de nombreuses questions d'ordre éthique en ce qui concerne la limitation des libertés individuelles et la mise en œuvre. Dans le présent document, nous examinons les principales considérations à prendre en compte pour garantir l'acceptabilité éthique du certificat d'immunité visant à lever les mesures de restriction pour certaines personnes durant la pandémie de COVID-19. Cette acceptabilité éthique dépend non seulement de son degré de conformité à des critères scientifiques stricts, mais aussi de son usage, des objectifs politiques ainsi que des mesures mises en place pour atténuer les préjudices potentiels et éviter d'imposer une charge disproportionnée sur les individus dépourvus de certificat, ou de bafouer les droits et libertés de tout un chacun.


Las medidas restrictivas impuestas a causa de la pandemia de la enfermedad coronavirus de 2019 (COVID-19) han tenido graves efectos sociales, económicos y sanitarios. Algunos países han considerado la posibilidad de utilizar la certificación de inmunidad como estrategia para flexibilizar dichas medidas para las personas que se han recuperado de la infección mediante la expedición a dichas personas de un documento, comúnmente denominado pasaporte de inmunidad. Este documento certifica que han desarrollado inmunidad protectora contra el coronavirus-2 del síndrome respiratorio agudo severo (SARS-CoV-2), el virus que causa la COVID-19. La Organización Mundial de la Salud ha desaconsejado la aplicación de la certificación de la inmunidad en la actualidad debido a la incertidumbre sobre si existe realmente una inmunidad a largo plazo para quienes se han recuperado de la COVID-19 y a las preocupaciones sobre la fiabilidad del método de prueba serológica propuesto para determinar la inmunidad. La certificación de la inmunidad solo puede considerarse si se cumplen los umbrales científicos para asegurar la inmunidad, ya sea que se basen en anticuerpos o en otros criterios. Sin embargo, incluso si la certificación de la inmunidad llegara a estar bien respaldada por la ciencia, tiene muchas cuestiones éticas en cuanto a las diferentes restricciones de las libertades individuales y su proceso de aplicación. Examinamos las principales consideraciones sobre la aceptabilidad ética de la certificación de la inmunidad para eximir a los individuos de las medidas restrictivas durante la pandemia de la COVID-19. Además de necesitar cumplir criterios científicos sólidos, la aceptabilidad ética de la certificación de inmunidad depende de sus usos y objetivos de política y de las medidas que se apliquen para reducir los posibles daños y evitar que se impongan cargas desproporcionadas a las personas que no cuenten con dicha certificación y se violen las libertades y derechos individuales.


Assuntos
Teste Sorológico para COVID-19/ética , COVID-19/diagnóstico , Certificação/ética , Pandemias , Saúde Pública/ética , Humanos , Imunidade Humoral
5.
Biotechnol Appl Biochem ; 67(6): 880-891, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33011985

RESUMO

This paper focuses on the ethical and regulatory issues raised by gene editing. In the introduction of this paper, authors provide the background where the ethical and regulatory issues by gene editing have been raised including the scientific dimension of gene-editing techniques. In the second part of the paper, the authors focus on ethical issues in human gene editing with the start of Huang Junjiu case and He Jiankui case. Here, the authors discuss the criteria for evaluating action, general ethical issues in gene editing, and try to answer two crucial questions: is it ethically justifiable to use human embryo in ex vivo genome editing study and is it ethically justifiable to perform heritable human genome editing? In answering the second question, the authors discuss the arguments against and for heritable human genome editing, methodological problem, and the building of an ethical framework for heritable human genome editing. In the third part of the paper, the authors focus on regulatory issues in gene editing including proactionary approach versus ethically thinking ahead approach, self-regulation versus top-down regulation, transparency versus confidentiality, and education versus punishment.


Assuntos
Temas Bioéticos , Edição de Genes , Genoma Humano , China , Edição de Genes/ética , Edição de Genes/legislação & jurisprudência , Humanos
6.
Bioethics ; 34(2): 172-182, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31639227

RESUMO

This article consists of four parts. In the first part it briefly describes the history of body-to-head transplantation (BHT) and the surgical plan proposed by Drs. Sergio Canavero and Ren Xiaoping on a human subject. In the second part it argues that the BHT procedure that they propose is scientifically invalid and technically infeasible so therefore would end in failure. In the third part it argues that the present conceivable procedure of BHT cannot be ethically justified because it would bring great harm to the human subject, it is uncertain who would be the possible beneficiary, and valid informed consent cannot be obtained. In the fourth part it argues that the action of performing the procedure of BHT might violate China's current criminal and civil laws. The conclusion that follows from the arguments above is that BHT should be prohibited now and also in the near future. However, this conclusion does not preclude scientists, neurosurgeons and bioethicists doing research into scientific, technical, surgical and ethical issues raised by BHT.


Assuntos
Pesquisa Biomédica/ética , Pesquisa Biomédica/legislação & jurisprudência , Ética Médica , Ética em Pesquisa , Cabeça/cirurgia , Sujeitos da Pesquisa , Transplante/ética , Anastomose Cirúrgica , China , Humanos
7.
J Org Chem ; 84(6): 3624-3631, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30806513

RESUMO

The Cu(I)- or Ag(I)-catalyzed cycloaddition between 8-ethynyladenine or guanine nucleosides and TMSN3 gave 8-(1- H-1,2,3-triazol-4-yl) nucleosides in good yields. On the other hand, reactions of 5-ethynyluracil or cytosine nucleosides with TMSN3 led to the chemoselective formation of triazoles via Cu(I)-catalyzed cycloaddition or vinyl azides via Ag(I)-catalyzed hydroazidation. These nucleosides with a minimalistic triazolyl modification showed excellent fluorescent properties with 8-(1- H-1,2,3-triazol-4-yl)-2'-deoxyadenosine (8-TrzdA), exhibiting a quantum yield of 44%. The 8-TrzdA 5'-triphosphate was incorporated into duplex DNA containing a one-nucleotide gap by DNA polymerase ß.


Assuntos
Fluorescência , Nucleosídeos de Purina/química , Nucleosídeos de Pirimidina/química , Triazóis/química , Catálise , Cobre/química , Estrutura Molecular , Nucleosídeos de Purina/síntese química , Nucleosídeos de Pirimidina/síntese química , Prata/química
8.
Nat Commun ; 15(1): 4056, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38744813

RESUMO

The fusion peptide of SARS-CoV-2 spike protein is functionally important for membrane fusion during virus entry and is part of a broadly neutralizing epitope. However, sequence determinants at the fusion peptide and its adjacent regions for pathogenicity and antigenicity remain elusive. In this study, we perform a series of deep mutational scanning (DMS) experiments on an S2 region spanning the fusion peptide of authentic SARS-CoV-2 in different cell lines and in the presence of broadly neutralizing antibodies. We identify mutations at residue 813 of the spike protein that reduced TMPRSS2-mediated entry with decreased virulence. In addition, we show that an F823Y mutation, present in bat betacoronavirus HKU9 spike protein, confers resistance to broadly neutralizing antibodies. Our findings provide mechanistic insights into SARS-CoV-2 pathogenicity and also highlight a potential challenge in developing broadly protective S2-based coronavirus vaccines.


Assuntos
Anticorpos Neutralizantes , COVID-19 , Mutação , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Internalização do Vírus , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Humanos , SARS-CoV-2/imunologia , SARS-CoV-2/genética , Anticorpos Neutralizantes/imunologia , COVID-19/virologia , COVID-19/imunologia , Animais , Anticorpos Antivirais/imunologia , Serina Endopeptidases/genética , Serina Endopeptidases/imunologia , Serina Endopeptidases/metabolismo , Chlorocebus aethiops , Células HEK293 , Células Vero , Epitopos/imunologia , Epitopos/genética , Linhagem Celular , Camundongos
9.
Nat Commun ; 15(1): 5175, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890325

RESUMO

The receptor-binding site of influenza A virus hemagglutinin partially overlaps with major antigenic sites and constantly evolves. In this study, we observe that mutations G186D and D190N in the hemagglutinin receptor-binding site have coevolved in two recent human H3N2 clades. X-ray crystallography results show that these mutations coordinately drive the evolution of the hemagglutinin receptor binding mode. Epistasis between G186D and D190N is further demonstrated by glycan binding and thermostability analyses. Immunization and neutralization experiments using mouse and human samples indicate that the evolution of receptor binding mode is accompanied by a change in antigenicity. Besides, combinatorial mutagenesis reveals that G186D and D190N, along with other natural mutations in recent H3N2 strains, alter the compatibility with a common egg-adaptive mutation in seasonal influenza vaccines. Overall, our findings elucidate the role of epistasis in shaping the recent evolution of human H3N2 hemagglutinin and substantiate the high evolvability of its receptor-binding mode.


Assuntos
Epistasia Genética , Evolução Molecular , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Vírus da Influenza A Subtipo H3N2 , Influenza Humana , Humanos , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/metabolismo , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Animais , Camundongos , Sítios de Ligação , Influenza Humana/virologia , Mutação , Cristalografia por Raios X , Vacinas contra Influenza , Ligação Proteica , Receptores Virais/metabolismo , Receptores Virais/genética , Receptores Virais/química , Feminino
10.
Front Genet ; 14: 1261623, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37928244

RESUMO

Background: Human biobanks are an essential resource for contemporary medical research, crucial in treating and preventing human diseases and improving health. Public trust in human biobanks is a vital social prerequisite for their continued operation and related research. Methods: Drawing on the "leap of faith" theory proposed by Georg Simmel and Guido Möllering, this paper first examines the relationship between public trust and human biobanks and the process through which such trust is established. Subsequently, based on the results of this analysis, targeted policy recommendations are put forward to consolidate or enhance public trust in human biobanks. Results: Public trust in human biobanks stems from certain "good reasons," through which uncertainty and vulnerability are "suspended" by faith, leading to a leap toward the "land of expectations." In this progress, the critical factors in building and enhancing public trust in human biobanks are the public's propensity to trust, the inherent trustworthiness of human biobanks, and the security and interactivity of the trust environment. Conclusion: Public trust in human biobanks cannot be determined by any universal formula, as it is influenced by many factors, including intangible elements such as faith that defy empirical understanding. Nonetheless, public trust in human biobanks can be enhanced through measures such as fostering the public's propensity to trust, enhancing the inherent trustworthiness of human biobanks, establishing structural safeguards for the trust environment through ethical norms, systems, and supervision, and promoting public participation.

11.
Front Pharmacol ; 14: 1214590, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37701030

RESUMO

As international academic exchanges and cooperation deepen, China has actively engaged in international biomedical research collaboration and achieved significant success. However, these accomplishments have been accompanied by ethical controversies and issues, with ethics dumping being a recurrently discussed focus among scholars. This paper reviews ethics dumping incidents in China's biomedical research field and analyzes the underlying causes to answer why China is often susceptible to ethics dumping. We argue that the primary reasons include weak ethical awareness among some researchers, an oversimplified research evaluation system, gaps in relevant ethics governance and oversight mechanisms, and limited capabilities of certain ethics committees. To address these issues, we propose five ethics governance recommendations: establishing refined ethics committees at various levels and types; advancing theoretical and practical research on science and technology ethics governance; strengthening legislation and regulation related to emerging science and technology; emphasizing self-regulation and capacity building of research institutions; and providing special protection and healthcare for victims of ethics dumping. The aim is to enhance China's research supervision system and prevent similar ethics dumping incidents from recurring.

12.
bioRxiv ; 2023 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-37461670

RESUMO

IGHV1-69 is frequently utilized by broadly neutralizing influenza antibodies to the hemagglutinin (HA) stem. These IGHV1-69 HA stem antibodies have diverse complementarity-determining region (CDR) H3 sequences. Besides, their light chains have minimal to no contact with the epitope. Consequently, sequence determinants that confer IGHV1-69 antibodies with HA stem specificity remain largely elusive. Using high-throughput experiments, this study revealed the importance of light chain sequence for the IGHV1-69 HA stem antibody CR9114, which is the broadest influenza antibody known to date. Moreover, we demonstrated that the CDR H3 sequences from many other IGHV1-69 antibodies, including those to HA stem, were incompatible with CR9114. Along with mutagenesis and structural analysis, our results indicate that light chain and CDR H3 sequences coordinately determine the HA stem specificity of IGHV1-69 antibodies. Overall, this work provides molecular insights into broadly neutralizing antibody responses to influenza virus, which have important implications for universal influenza vaccine development.

13.
Cell Rep ; 42(11): 113410, 2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-37976161

RESUMO

IGHV1-69 is frequently utilized by broadly neutralizing influenza antibodies to the hemagglutinin (HA) stem. These IGHV1-69 HA stem antibodies have diverse complementarity-determining region (CDR) H3 sequences. Besides, their light chains have minimal to no contact with the epitope. Consequently, sequence determinants that confer IGHV1-69 antibodies with HA stem specificity remain largely elusive. Using high-throughput experiments, this study reveals the importance of light-chain sequence for the IGHV1-69 HA stem antibody CR9114, which is the broadest influenza antibody known to date. Moreover, we demonstrate that the CDR H3 sequences from many other IGHV1-69 antibodies, including those to the HA stem, are incompatible with CR9114. Along with mutagenesis and structural analysis, our results indicate that light-chain and CDR H3 sequences coordinately determine the HA stem specificity of IGHV1-69 antibodies. Overall, this work provides molecular insights into broadly neutralizing antibody responses to influenza virus, which have important implications for universal influenza vaccine development.


Assuntos
Vacinas contra Influenza , Influenza Humana , Humanos , Hemaglutininas , Anticorpos Amplamente Neutralizantes , Anticorpos Neutralizantes , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Anticorpos Antivirais , Regiões Determinantes de Complementaridade
14.
Cell Rep ; 42(1): 111951, 2023 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-36640354

RESUMO

Influenza neuraminidase (NA) has received increasing attention as an effective vaccine target. However, its mutational tolerance is not well characterized. Here, the fitness effects of >6,000 mutations in human H3N2 NA are probed using deep mutational scanning. Our result shows that while its antigenic regions have high mutational tolerance, there are solvent-exposed regions with low mutational tolerance. We also find that protein stability is a major determinant of NA mutational fitness. The deep mutational scanning result correlates well with mutational fitness inferred from natural sequences using a protein language model, substantiating the relevance of our findings to the natural evolution of circulating strains. Additional analysis further suggests that human H3N2 NA is far from running out of mutations despite already evolving for >50 years. Overall, this study advances our understanding of the evolutionary potential of NA and the underlying biophysical constraints, which in turn provide insights into NA-based vaccine design.


Assuntos
Influenza Humana , Humanos , Influenza Humana/genética , Vírus da Influenza A Subtipo H3N2/genética , Neuraminidase/genética , Neuraminidase/metabolismo , Evolução Molecular , Mutação/genética
15.
Nat Commun ; 14(1): 2003, 2023 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-37037866

RESUMO

Designing prefusion-stabilized SARS-CoV-2 spike is critical for the effectiveness of COVID-19 vaccines. All COVID-19 vaccines in the US encode spike with K986P/V987P mutations to stabilize its prefusion conformation. However, contemporary methods on engineering prefusion-stabilized spike immunogens involve tedious experimental work and heavily rely on structural information. Here, we establish a systematic and unbiased method of identifying mutations that concomitantly improve expression and stabilize the prefusion conformation of the SARS-CoV-2 spike. Our method integrates a fluorescence-based fusion assay, mammalian cell display technology, and deep mutational scanning. As a proof-of-concept, we apply this method to a region in the S2 domain that includes the first heptad repeat and central helix. Our results reveal that besides K986P and V987P, several mutations simultaneously improve expression and significantly lower the fusogenicity of the spike. As prefusion stabilization is a common challenge for viral immunogen design, this work will help accelerate vaccine development against different viruses.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Glicoproteína da Espícula de Coronavírus , Mutação , Mamíferos/metabolismo
16.
bioRxiv ; 2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38076875

RESUMO

The fusion peptide of SARS-CoV-2 spike protein is functionally important for membrane fusion during virus entry and is part of a broadly neutralizing epitope. However, sequence determinants at the fusion peptide and its adjacent regions for pathogenicity and antigenicity remain elusive. In this study, we performed a series of deep mutational scanning (DMS) experiments on an S2 region spanning the fusion peptide of authentic SARS-CoV-2 in different cell lines and in the presence of broadly neutralizing antibodies. We identified mutations at residue 813 of the spike protein that reduced TMPRSS2-mediated entry with decreased virulence. In addition, we showed that an F823Y mutation, present in bat betacoronavirus HKU9 spike protein, confers resistance to broadly neutralizing antibodies. Our findings provide mechanistic insights into SARS-CoV-2 pathogenicity and also highlight a potential challenge in developing broadly protective S2-based coronavirus vaccines.

17.
bioRxiv ; 2023 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-37745338

RESUMO

Despite decades of antibody research, it remains challenging to predict the specificity of an antibody solely based on its sequence. Two major obstacles are the lack of appropriate models and inaccessibility of datasets for model training. In this study, we curated a dataset of >5,000 influenza hemagglutinin (HA) antibodies by mining research publications and patents, which revealed many distinct sequence features between antibodies to HA head and stem domains. We then leveraged this dataset to develop a lightweight memory B cell language model (mBLM) for sequence-based antibody specificity prediction. Model explainability analysis showed that mBLM captured key sequence motifs of HA stem antibodies. Additionally, by applying mBLM to HA antibodies with unknown epitopes, we discovered and experimentally validated many HA stem antibodies. Overall, this study not only advances our molecular understanding of antibody response to influenza virus, but also provides an invaluable resource for applying deep learning to antibody research.

18.
mBio ; 14(3): e0008423, 2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37070986

RESUMO

Immune imprinting is a driver known to shape the anti-hemagglutinin (HA) antibody landscape of individuals born within the same birth cohort. With the HA and neuraminidase (NA) proteins evolving at different rates under immune selection pressures, anti-HA and anti-NA antibody responses since childhood influenza virus infections have not been evaluated in parallel at the individual level. This is partly due to the limited knowledge of changes in NA antigenicity, as seasonal influenza vaccines have focused on generating neutralizing anti-HA antibodies against HA antigenic variants. Here, we systematically characterized the NA antigenic variants of seasonal A(H1N1) viruses from 1977 to 1991 and completed the antigenic profile of N1 NAs from 1977 to 2015. We identified that NA proteins of A/USSR/90/77, A/Singapore/06/86, and A/Texas/36/91 were antigenically distinct and mapped N386K as a key determinant of the NA antigenic change from A/USSR/90/77 to A/Singapore/06/86. With comprehensive panels of HA and NA antigenic variants of A(H1N1) and A(H1N1)pdm09 viruses, we determined hemagglutinin inhibition (HI) and neuraminidase inhibition (NI) antibodies from 130 subjects born between 1950 and 2015. Age-dependent imprinting was observed for both anti-HA and anti-NA antibodies, with the peak HI and NI titers predominantly detected from subjects at 4 to 12 years old during the year of initial virus isolation, except the age-independent anti-HA antibody response against A(H1N1)pdm09 viruses. More participants possessed antibodies that reacted to multiple antigenically distinct NA proteins than those with antibodies that reacted to multiple antigenically distinct HA proteins. Our results support the need to include NA proteins in seasonal influenza vaccine preparations. IMPORTANCE Seasonal influenza vaccines have aimed to generate neutralizing anti-HA antibodies for protection since licensure. More recently, anti-NA antibodies have been established as an additional correlate of protection. While HA and NA antigenic changes occurred discordantly, the anti-HA and anti-NA antibody profiles have rarely been analyzed in parallel at the individual level, due to the limited knowledge on NA antigenic changes. By characterizing NA antigenic changes of A(H1N1) viruses, we determined the anti-HA and anti-NA antibody landscape against antigenically distinct A(H1N1) and A(H1N1)pdm09 viruses using sera of 130 subjects born between 1950 and 2015. We observed age-dependent imprinting of both anti-HA and anti-NA antibodies against strains circulated during the first decade of life. A total of 67.7% (88/130) and 90% (117/130) of participants developed cross-reactive antibodies to multiple HA and NA antigens at titers ≥1:40. With slower NA antigenic changes and cross-reactive anti-NA antibody responses, including NA protein in influenza vaccine preparation may enhance vaccine efficacy.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza , Influenza Humana , Humanos , Criança , Pré-Escolar , Hemaglutininas , Formação de Anticorpos , Neuraminidase/genética , Anticorpos Antivirais , Anticorpos Neutralizantes , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética
19.
Synth Syst Biotechnol ; 7(2): 784-790, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35387231

RESUMO

Synthetic biology (SynBio) is a high-profile interdiscipline combining engineering with science. As a dual-purpose discipline, SynBio is bringing large changes to many fields and providing great benefits to humans. However, due to its characteristic of complexity and uncertainty, SynBio also presents potential biosafety and biosecurity risks. Biosecurity risks refer to unauthorized access, loss, theft, misuse, diversion or intentional release. If a biosecurity accident happens, it would pose a huge threat to humans and nature. Therefore, it is crucial to establish a set of regulations and management practices for the biosecurity risks of SynBio. In this paper, we summarized the sources of the biosecurity risks of SynBio, from its research materials, products, technologies, information to Do-it-yourself synthetic biology. We reviewed and analyzed the current situation of regulation and management of biosecurity for SynBio in the international community and in China. We found that in most countries and regions, SynBio risks commonly follow the regulation and management of Genetically Modified Organisms which has loopholes if applied to the regulation for SynBio without any amendments. Here, we proposed suggestions for the Chinese-featured regulation and management of biosecurity for SynBio, including a top-to-bottom governing framework, a think-tank implementation mechanism, a Synthetic Biology Laboratory Biosecurity Manual safeguarding system, and strengthening biosecurity education on synthetic biology and self-regulation awareness among relevant personnel. Through this work, we aim to improve the standardized process of biosecurity regulation and management for SynBio in China and thereby map out a peaceful, profitable, and practical development path for synthetic biology.

20.
Sci Adv ; 8(47): eadd7221, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36417523

RESUMO

Increasing the expression level of the SARS-CoV-2 spike (S) protein has been critical for COVID-19 vaccine development. While previous efforts largely focused on engineering the receptor-binding domain (RBD) and the S2 subunit, the amino-terminal domain (NTD) has been long overlooked because of the limited understanding of its biophysical constraints. In this study, the effects of thousands of NTD single mutations on S protein expression were quantified by deep mutational scanning. Our results revealed that in terms of S protein expression, the mutational tolerability of NTD residues was inversely correlated with their proximity to the RBD and S2. We also identified NTD mutations at the interdomain interface that increased S protein expression without altering its antigenicity. Overall, this study not only advances the understanding of the biophysical constraints of the NTD but also provides invaluable insights into S-based immunogen design.

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