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1.
J Med Virol ; 94(1): 82-87, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34524688

RESUMO

The rapid spread of the Delta variant suggests that SARS-CoV-2 will likely be rampant for months or years and could claim millions of more lives. All the known vaccines cannot well defeat SARS-CoV-2 due to their limited efficacy and production efficiency, except for the neglected live-attenuated vaccines (LAVs), which could have a much higher efficacy and much higher production efficiency than other vaccines. LAVs, like messiahs, have defeated far more pathogenic viruses than other vaccines in history, and most current human vaccines for viral diseases are safe LAVs. LAVs can block completely infection and transmission of relevant viruses and their variants. They can hence inhibit the emergence of vaccine-escape and virulence-enhancing variants and protect immunologically abnormal individuals better in general. The safety of COVID-19 LAVs, which could save millions of more lives, can be solidly guaranteed through animal experiments and clinical trials. The safety of COVID-19 LAVs could be greatly enhanced with intramuscular or oral administration, or administration along with humanized neutralizing monoclonal antibodies. Together, extensive global collaboration, which can greatly accelerate the development of safe COVID-19 LAVs, is imminently needed.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacinas Atenuadas/imunologia , Desenvolvimento de Medicamentos , Humanos , Vacinação em Massa
2.
Vet Res ; 52(1): 139, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34772449

RESUMO

Chicken immune responses to infectious bronchitis virus (IBV) vaccination can depend on route of administration, vaccine strain and bird age. Typically for layer chickens, IBV vaccinations are administered by spray in the hatchery at day-old and boosted at intervals with live vaccines via drinking water (DW). Knowledge of live attenuated IBV vaccine virus kinetics and the immune response in egg-laying hens is exceptionally limited. Here, we demonstrated dissemination of vaccine viruses and differences in hen innate, mucosal, cellular and humoral immune responses following vaccination with Massachusetts or 793B strains, administered by DW or oculonasal (ON) routes. Detection of IBV in the Mass-vaccinated groups was greater during early time-points, however, 793B was detected more frequently at later timepoints. Viral RNA loads in the Harderian gland and turbinate tissues were significantly higher for ON-Mass compared to all other vaccinated groups. Lachrymal fluid IgY levels were significantly greater than the control at 14 days post-vaccination (dpv) for both vaccine serotypes, and IgA mRNA levels were significantly greater in ON-vaccinated groups compared to DW-vaccinated groups, demonstrating robust mucosal immune responses. Cell mediated immune gene transcripts (CD8-α and CD8-ß) were up-regulated in turbinate and trachea tissues. For both vaccines, dissemination and vaccine virus clearance was slower when given by DW compared to the ON route. For ON administration, both vaccines induced comparable levels of mucosal immunity. The Mass vaccine induced cellular immunity to similar levels regardless of vaccination method. When given either by ON or DW, 793B vaccination induced significantly higher levels of humoral immunity.


Assuntos
Galinhas/imunologia , Infecções por Coronavirus/veterinária , Doenças das Aves Domésticas/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/imunologia , Infecções por Coronavirus/imunologia , Feminino , Imunidade Celular , Imunidade Humoral , Imunidade nas Mucosas , Vírus da Bronquite Infecciosa , Doenças das Aves Domésticas/virologia , Vacinação/veterinária , Vacinas Atenuadas/imunologia
3.
Expert Rev Vaccines ; 20(9): 1059-1063, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34365880

RESUMO

INTRODUCTION: The Development of the SARS-CoV-2 virus vaccine and its update on an ongoing pandemic is the first subject of the world health agenda. AREAS COVERED: First, we will scrutinize the biological features of the measles virus (MV), variola virus (smallpox virus), influenza virus, and their vaccines to compare them with the SARS-CoV-2 virus and vaccine. Next, we will discuss the statistical details of measuring the effectiveness of an improved vaccine. EXPERT OPINION: Amidst the pandemic, we ought to acknowledge our prior experiences with respiratory viruses and vaccines. In the planning stage of observational Phase-III vaccine effectiveness studies, the sample size, sampling method, statistical model, and selection of variables are crucial in obtaining high-quality and valid results.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Imunidade Celular/imunologia , SARS-CoV-2/imunologia , COVID-19/patologia , Humanos , Vacinas contra Influenza/imunologia , Vacinação em Massa/métodos , Vírus do Sarampo/imunologia , Vacina contra Sarampo-Caxumba-Rubéola/imunologia , Orthomyxoviridae/imunologia , Vacina Antivariólica/imunologia , Vacinação , Vacinas Atenuadas/imunologia , Vírus da Varíola/imunologia
4.
mBio ; 12(4): e0141521, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34425707

RESUMO

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) possesses a discriminative polybasic cleavage motif in its spike protein that is recognized by the host furin protease. Proteolytic cleavage activates the spike protein, thereby affecting both the cellular entry pathway and cell tropism of SARS-CoV-2. Here, we investigated the impact of the furin cleavage site on viral growth and pathogenesis using a hamster animal model infected with SARS-CoV-2 variants bearing mutations at the furin cleavage site (S gene mutants). In the airway tissues of hamsters, the S gene mutants exhibited low growth properties. In contrast to parental pathogenic SARS-CoV-2, hamsters infected with the S gene mutants showed no body weight loss and only a mild inflammatory response, thereby indicating the attenuated variant nature of S gene mutants. This transient infection was sufficient for inducing protective neutralizing antibodies that cross-react with different SARS-CoV-2 lineages. Consequently, hamsters inoculated with S gene mutants showed resistance to subsequent infection with both the parental strain and the currently emerging SARS-CoV-2 variants belonging to lineages B.1.1.7 and P.1. Taken together, our findings revealed that the loss of the furin cleavage site causes attenuation in the airway tissues of hamsters and highlighted the potential benefits of S gene mutants as potential immunogens. IMPORTANCE SARS-CoV-2 uses its spike protein to enter target cells. The spike protein is cleaved by a host protease, and this event facilitates viral entry and broadens cell tropism. In this study, we employed SARS-CoV-2 mutants lacking the S protein cleavage site and characterized their growth and pathogenicity using hamsters, a laboratory animal model for SARS-CoV-2 infection. These mutants exerted low pathogenicity but induced sufficient levels of neutralizing antibodies in hamsters, which protected hamsters from rechallenge with pathogenic clinical SARS-CoV-2 strains. These virus mutants may be used as protective immunogens against SARS-CoV-2 infection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/patologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética , Animais , Linhagem Celular , Chlorocebus aethiops , Reações Cruzadas/imunologia , Furina/metabolismo , Humanos , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Vacinas Atenuadas/imunologia , Células Vero , Virulência/genética
5.
Avian Dis ; 65(3): 364-372, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34427409

RESUMO

We previously reported that recombinant Newcastle disease virus LaSota (rLS) expressing infectious bronchitis virus (IBV) Arkansas (Ark)-type trimeric spike (S) ectodomain (Se; rLS/ArkSe) provides suboptimal protection against IBV challenge. We have now developed rLS expressing chicken granulocyte-macrophage colony-stimulating factor (GMCSF) and IBV Ark Se in an attempt to enhance vaccine effectiveness. In the current study, we first compared protection conferred by vaccination with rLS/ArkSe and rLS/ArkSe.GMCSF. Vaccinated chickens were challenged with virulent Ark, and protection was determined by clinical signs, viral load, and tracheal histomorphometry. Results showed that coexpression of GMCSF and the Se from rLS significantly reduced tracheal viral load and tracheal lesions compared with chickens vaccinated with rLS/ArkSe. In a second experiment, we evaluated enhancement of cross-protection of a Massachusetts (Mass) attenuated vaccine by priming or boosting with rLS/ArkSe.GMCSF. Vaccinated chickens were challenged with Ark, and protection was evaluated. Results show that priming or boosting with the recombinant virus significantly increased cross-protection conferred by Mass against Ark virulent challenge. Greater reductions of viral loads in both trachea and lachrymal fluids were observed in chickens primed with rLS/ArkSe.GMCSF and boosted with Mass. Consistently, Ark Se antibody levels measured with recombinant Ark Se protein-coated ELISA plates 14 days after boost were significantly higher in these chickens. Unexpectedly, the inverse vaccination scheme, that is, priming with Mass and boosting with the recombinant vaccine, proved somewhat less effective. We concluded that a prime and boost strategy by using rLS/ArkSe.GMCSF and the worldwide ubiquitous Mass attenuated vaccine provides enhanced cross-protection. Thus, rLS/GMCSF coexpressing the Se of regionally relevant IBV serotypes could be used in combination with live Mass to protect against regionally circulating IBV variant strains.


Assuntos
Infecções por Coronavirus/veterinária , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Vírus da Bronquite Infecciosa/imunologia , Vírus da Doença de Newcastle/genética , Doenças das Aves Domésticas/prevenção & controle , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Antivirais/imunologia , Galinhas/genética , Galinhas/imunologia , Galinhas/virologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Proteção Cruzada , Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Vírus da Bronquite Infecciosa/química , Vírus da Bronquite Infecciosa/genética , Vírus da Bronquite Infecciosa/fisiologia , Vírus da Doença de Newcastle/metabolismo , Doenças das Aves Domésticas/imunologia , Doenças das Aves Domésticas/virologia , Domínios Proteicos , Glicoproteína da Espícula de Coronavírus/administração & dosagem , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Traqueia/imunologia , Traqueia/virologia , Vacinação , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Carga Viral
6.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445493

RESUMO

Classical swine fever (CSF) is a highly contagious disease caused by the classical swine fever virus (CSFV). The live attenuated C-strain vaccine is highly efficacious, initiating protection within several days of delivery. The vaccine strain is detected in the tonsil early after inoculation, yet little is known of the role that tonsillar immune cells might play in initiating protection. Comparing the C-strain vaccine with the pathogenic CSFV Alfort-187 strain, changes in the myeloid cell compartment of the tonsil were observed. CSFV infection led to the emergence of an additional CD163+CD14+ cell population, which showed the highest levels of Alfort-187 and C-strain infection. There was also an increase in both the frequency and activation status (as shown by increased MHC-II expression) of the tonsillar conventional dendritic cells 1 (cDC1) in pigs inoculated with the C-strain. Notably, the activation of cDC1 cells coincided in time with the induction of a local CSFV-specific IFN-γ+ CD8 T cell response in C-strain vaccinated pigs, but not in pigs that received Alfort-187. Moreover, the frequency of CSFV-specific IFN-γ+ CD8 T cells was inversely correlated to the viral load in the tonsils of individual animals. Accordingly, we hypothesise that the activation of cDC1 is key in initiating local CSFV-specific CD8 T cell responses which curtail early virus replication and dissemination.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Vírus da Febre Suína Clássica/imunologia , Peste Suína Clássica/prevenção & controle , Tonsila Palatina/imunologia , Vacinas Virais/administração & dosagem , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Peste Suína Clássica/imunologia , Peste Suína Clássica/virologia , Vírus da Febre Suína Clássica/fisiologia , Células Dendríticas/metabolismo , Interferon gama/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Células Mieloides/metabolismo , Tonsila Palatina/citologia , Tonsila Palatina/virologia , Receptores de Superfície Celular/metabolismo , Suínos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia , Carga Viral , Vacinas Virais/imunologia
7.
Emerg Microbes Infect ; 10(1): 1626-1637, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34365904

RESUMO

Coronaviruses (CoVs) can infect a variety of hosts, including humans, livestock and companion animals, and pose a serious threat to human health and the economy. The current COVID-19 pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed millions of people. Unfortunately, effective treatments for CoVs infection are still lacking, suggesting the importance of coronavirus vaccines. Our previous work showed that CoV nonstuctural protein 14 (nsp14) functions as (guanine-N7)-methyltransferase (N7-MTase), which is involved in RNA cap formation. Moreover, we found that N7-MTase is well conserved among different CoVs and is a universal target for developing antivirals against CoVs. Here, we show that N7-MTase of CoVs can be an ideal target for designing live attenuated vaccines. Using murine hepatitis virus strain A59 (MHV-A59), a representative and well-studied model of coronaviruses, we constructed N7-MTase-deficient recombinant MHV D330A and Y414A. These two mutants are highly attenuated in mice and exhibit similar replication efficiency to the wild-type (WT) virus in the cell culture. Furthermore, a single dose immunization of D330A or Y414A can induce long-term humoral immune responses and robust CD4+ and CD8+ T cell responses, which can provide full protection against the challenge of a lethal-dose of MHV-A59. Collectively, this study provides an ideal strategy to design live attenuated vaccines for coronavirus by abolishing viral RNA N7-MTase activity. This approach may apply to other RNA viruses that encode their own conservative viral N7-methyltransferase.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacinas Atenuadas/imunologia , Animais , Vacinas contra COVID-19/administração & dosagem , Citocinas/biossíntese , Humanos , Imunidade Celular , Imunidade Humoral , Imunogenicidade da Vacina , Interferon Tipo I/biossíntese , Masculino , Camundongos , Mutação , Vacinas Atenuadas/administração & dosagem , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/imunologia
8.
Vet Microbiol ; 261: 109214, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34461358

RESUMO

Novel duck reovirus (NDRV) causes high morbidity in ducklings, and recovered ducklings are often remarkably stunted in growth. In this study, four NDRV strains were isolated from the NDRV outbreaks that occurred in different regions of Shandong province, China. The biological characteristics and pathogenicity of the four NDRV strains were elucidated, and the N20 was identified as a naturally attenuated strain. Three-day-old ducklings were immunized with live N20 strain (100 ELD50/duck), and challenged with 104.52 ELD50 of virulent N19 strain at 7 days post immunization. The vaccinated ducklings showed no evidence of clinical signs, gross and histopathological lesions, or loss of body weight, and 100 % protection against the virulent NDRV N19 infection. The NDRV-specific antibodies were generated in the immunized ducklings and could neutralize different NDRV strains. These results indicated that the N20 strain was a promising live attenuated vaccine candidate against highly pathogenic NDRV infection.


Assuntos
Orthoreovirus Aviário/imunologia , Doenças das Aves Domésticas/prevenção & controle , Infecções por Reoviridae/veterinária , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/sangue , China , Patos , Orthoreovirus Aviário/genética , Orthoreovirus Aviário/isolamento & purificação , Doenças das Aves Domésticas/virologia , Infecções por Reoviridae/prevenção & controle , Vacinas Atenuadas/imunologia
9.
PLoS Med ; 18(7): e1003655, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34214095

RESUMO

BACKGROUND: Rotavirus vaccination is recommended in all countries to reduce the burden of diarrhea-related morbidity and mortality in children. In resource-limited settings, rotavirus vaccination in the national immunization program has important cost implications, and evidence for protection beyond the first year of life and against the evolving variety of rotavirus strains is important. We assessed the extended and strain-specific vaccine efficacy of a heat-stable, affordable oral rotavirus vaccine (Rotasiil, Serum Institute of India, Pune, India) against severe rotavirus gastroenteritis (SRVGE) among healthy infants in Niger. METHODS AND FINDINGS: From August 2014 to November 2015, infants were randomized in a 1:1 ratio to receive 3 doses of Rotasiil or placebo at approximately 6, 10, and 14 weeks of age. Episodes of gastroenteritis were assessed through active and passive surveillance and graded using the Vesikari score. The primary endpoint was vaccine efficacy of 3 doses of vaccine versus placebo against a first episode of laboratory-confirmed SRVGE (Vesikari score ≥ 11) from 28 days after dose 3, as previously reported. At the time of the primary analysis, median age was 9.8 months. In the present paper, analyses of extended efficacy were undertaken for 3 periods (28 days after dose 3 to 1 year of age, 1 to 2 years of age, and the combined period 28 days after dose 3 to 2 years of age) and by individual rotavirus G type. Among the 3,508 infants included in the per-protocol efficacy analysis (mean age at first dose 6.5 weeks; 49% male), the vaccine provided significant protection against SRVGE through the first year of life (3.96 and 9.98 cases per 100 person-years for vaccine and placebo, respectively; vaccine efficacy 60.3%, 95% CI 43.6% to 72.1%) and over the entire efficacy follow-up period up to 2 years of age (2.13 and 4.69 cases per 100 person-years for vaccine and placebo, respectively; vaccine efficacy 54.7%, 95% CI 38.1% to 66.8%), but the difference was not statistically significant in the second year of life. Up to 2 years of age, rotavirus vaccination prevented 2.56 episodes of SRVGE per 100 child-years. Estimates of efficacy against SRVGE by individual rotavirus genotype were consistent with the overall protective efficacy. Study limitations include limited generalizability to settings with administration of oral polio virus due to low concomitant administration, limited power to assess vaccine efficacy in the second year of life owing to a low number of events among older children, potential bias due to censoring of placebo children at the time of study vaccine receipt, and suboptimal adapted severity scoring based on the Vesikari score, which was designed for use in settings with high parental literacy. CONCLUSIONS: Rotasiil provided protection against SRVGE in infants through an extended follow-up period of approximately 2 years. Protection was significant in the first year of life, when the disease burden and risk of death are highest, and against a changing pattern of rotavirus strains during the 2-year efficacy period. Rotavirus vaccines that are safe, effective, and protective against multiple strains represent the best hope for preventing the severe consequences of rotavirus infection, especially in resource-limited settings, where access to care may be limited. Studies such as this provide valuable information for the planning of national immunization programs and future vaccine development. TRIAL REGISTRATION: ClinicalTrials.gov NCT02145000.


Assuntos
Gastroenterite/prevenção & controle , Gastroenterite/virologia , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/imunologia , Rotavirus/imunologia , Pré-Escolar , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Programas de Imunização , Lactente , Masculino , Níger , Placebos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia
10.
Front Immunol ; 12: 666543, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211465

RESUMO

Sheeppox (SPP) is a highly contagious disease of small ruminants caused by sheeppox virus (SPPV) and predominantly occurs in Asia and Africa with significant economic losses. SPPV is genetically and immunologically closely related to goatpox virus (GTPV) and lumpy skin disease virus (LSDV), which infect goats and cattle respectively. SPPV live attenuated vaccines (LAVs) are used for vaccination against SPP and goatpox (GTP). Mechanisms related to innate immunity elicited by SPPV are unknown. Although adaptive immunity is responsible for long-term immunity, it is the innate responses that prevent viral invasion and replication before LAVs generate specific long-term protection. We analyzed the relative expression of thirteen selected genes that included pattern recognition receptors (PRRs), Nuclear factor-κß p65 (NF-κß), and cytokines to understand better the interaction between SPPV and its host. The transcripts of targeted genes in sheep PBMC incubated with either wild type (WT) or LAV SPPV were analyzed using quantitative PCR. Among PRRs, we observed a significantly higher expression of RIG-1 in PBMC incubated with both WT and LAV, with the former producing the highest expression level. However, there was high inter-individual variability in cytokine transcripts levels among different donors, with the expression of TNFα, IL-15, and IL-10 all significantly higher in both PBMC infected with either WT or LAV compared to control PBMC. Correlation studies revealed a strong significant correlation between RIG-1 and IL-10, between TLR4, TNFα, and NF-κß, between IL-18 and IL-15, and between NF-κß and IL-10. There was also a significant negative correlation between RIG-1 and IFNγ, between TLR3 and IL-1 ß, and between TLR4 and IL-15 (P< 0.05). This study identified RIG-1 as an important PRR in the signaling pathway of innate immune activation during SPPV infection, possibly through intermediate viral dsRNA. The role of immunomodulatory molecules produced by SPPV capable of inhibiting downstream signaling activation following RIG-1 upregulation is discussed. These findings advance our knowledge of the induction of immune responses by SPPV and will help develop safer and more potent vaccines against SPP and GTP.


Assuntos
Capripoxvirus/imunologia , Imunidade Inata , Infecções por Poxviridae/veterinária , Doenças dos Ovinos/prevenção & controle , Vacinas Virais/imunologia , Animais , Capripoxvirus/genética , Capripoxvirus/isolamento & purificação , Leucócitos Mononucleares/imunologia , Filogenia , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Superfície Celular , Ovinos , Vacinas Atenuadas/imunologia
11.
Expert Rev Vaccines ; 20(9): 1051-1057, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34313516

RESUMO

INTRODUCTION: The COVID-19 pandemic is a globalized health concern caused by a beta-coronavirus named Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Since December 2019, when this outbreak flared in Wuhan, China, COVID-19 cases have been continuously rising all over the world. Due to the emergence of SARS-CoV-2 mutants, subsequent waves are flowing in a faster manner as compared to the primary wave, which is more contagious and causing higher mortality. Recently, India has emerged as the new epicenter of the second wave by mutants of SARS-CoV-2. After almost eighteen months of this outbreak, some COVID-19 dedicated therapeutics and vaccines are available, and a few are under trial, but the situation is still uncontrolled. AREA COVERED: This perspective article covers the repurposing of childhood vaccines like Bacille Calmette-Guerin (BCG), Measles, Mumps, Rubella (MMR), and Oral Polio Vaccine (OPV), which are live attenuated vaccines and have been shown the protective effect through 'trained immunity and 'crossreactivity.' EXPERT OPINION: This perspective article has suggested that combinatorial use of these childhood vaccines might exert a better protective effect along with the available COVID-19 therapeutic and vaccines which could be considered as a preventive option against SARS-CoV-2 infection as well as its subsequent waves.


Assuntos
Vacina BCG/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Reposicionamento de Medicamentos/métodos , SARS-CoV-2/imunologia , Vacinas Atenuadas/imunologia , Reações Cruzadas/imunologia , Vacina contra Difteria, Tétano e Coqueluche/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Vacina contra Sarampo-Caxumba-Rubéola/imunologia , Vacina Antipólio Oral/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação , Vacina contra Febre Amarela/imunologia
12.
Vet Microbiol ; 260: 109178, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34330023

RESUMO

Bovine Pestivirus heterogeneity is a major challenge for vaccines against bovine viral diarrhea (BVD). In breeding herds, fetal protection is a high priority issue. To some degree, fetal infections in vaccinated heifers have been attributed to the antigenic diversity of bovine Pestiviruses. The purpose of this study was to assess fetal protection against a divergent bovine Pestivirus (Hobi-like Pestivirus, HoBiPeV) with a commercially available modified live vaccine (MLV) claiming fetal protection against BVDV 1 and BVDV 2 up to one year after the first inoculation. Five vaccinated and four unvaccinated heifers were challenged by intranasal inoculation with the HoBiPeV Italy-1/10-1 strain between 82 and 89 days after insemination, i.e. between 4 and 6 months after vaccination. At challenge, neutralizing antibody titers to HoBiPeV in vaccinated heifers were low or even undetectable. Of the four unvaccinated heifers, one control animal aborted (fetus not available) and the remaining three gave birth to HoBiPeV positive calves. Among the heifers of the vaccinated group, one aborted the fetus in the sixth month of pregnancy, which tested Pestivirus negative, while three others gave birth to healthy, HoBiPeV negative calves; the remaining heifer delivered one HoBiPeV positive calf. The results suggest that the BVDV vaccine might be able to elicit a partial fetal protection against HobiPeV, even in absence of a strong specific antibody response.


Assuntos
Doença das Mucosas por Vírus da Diarreia Viral Bovina/prevenção & controle , Vírus da Diarreia Viral Bovina Tipo 1/imunologia , Vírus da Diarreia Viral Bovina Tipo 2/imunologia , Síndrome Hemorrágica Bovina/prevenção & controle , Complicações Infecciosas na Gravidez/veterinária , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes , Doença das Mucosas por Vírus da Diarreia Viral Bovina/virologia , Bovinos , Proteção Cruzada , Feminino , Feto/virologia , Síndrome Hemorrágica Bovina/virologia , Gravidez , Complicações Infecciosas na Gravidez/prevenção & controle , Complicações Infecciosas na Gravidez/virologia , Vacinas Atenuadas/imunologia
13.
Nature ; 595(7866): 289-294, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34194041

RESUMO

The global decline in malaria has stalled1, emphasizing the need for vaccines that induce durable sterilizing immunity. Here we optimized regimens for chemoprophylaxis vaccination (CVac), for which aseptic, purified, cryopreserved, infectious Plasmodium falciparum sporozoites (PfSPZ) were inoculated under prophylactic cover with pyrimethamine (PYR) (Sanaria PfSPZ-CVac(PYR)) or chloroquine (CQ) (PfSPZ-CVac(CQ))-which kill liver-stage and blood-stage parasites, respectively-and we assessed vaccine efficacy against homologous (that is, the same strain as the vaccine) and heterologous (a different strain) controlled human malaria infection (CHMI) three months after immunization ( https://clinicaltrials.gov/ , NCT02511054 and NCT03083847). We report that a fourfold increase in the dose of PfSPZ-CVac(PYR) from 5.12 × 104 to 2 × 105 PfSPZs transformed a minimal vaccine efficacy (low dose, two out of nine (22.2%) participants protected against homologous CHMI), to a high-level vaccine efficacy with seven out of eight (87.5%) individuals protected against homologous and seven out of nine (77.8%) protected against heterologous CHMI. Increased protection was associated with Vδ2 γδ T cell and antibody responses. At the higher dose, PfSPZ-CVac(CQ) protected six out of six (100%) participants against heterologous CHMI three months after immunization. All homologous (four out of four) and heterologous (eight out of eight) infectivity control participants showed parasitaemia. PfSPZ-CVac(CQ) and PfSPZ-CVac(PYR) induced a durable, sterile vaccine efficacy against a heterologous South American strain of P. falciparum, which has a genome and predicted CD8 T cell immunome that differs more strongly from the African vaccine strain than other analysed African P. falciparum strains.


Assuntos
Anticorpos Neutralizantes/imunologia , Fígado/imunologia , Fígado/parasitologia , Vacinas Antimaláricas/imunologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/imunologia , Vacinas Atenuadas/imunologia , Adulto , Animais , Formação de Anticorpos/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Estágios do Ciclo de Vida/imunologia , Malária/sangue , Malária/imunologia , Malária/parasitologia , Malária/prevenção & controle , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/efeitos adversos , Vacinas Antimaláricas/química , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/crescimento & desenvolvimento , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo , Vacinação/efeitos adversos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/química
14.
J Immunol ; 207(4): 1033-1043, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34321231

RESUMO

A single dose of the replication-competent, live-attenuated yellow fever virus (YFV) 17D vaccine provides lifelong immunity against human YFV infection. The magnitude, kinetics, and specificity of B cell responses to YFV 17D are relatively less understood than T cell responses. In this clinical study, we focused on early immune events critical for the development of humoral immunity to YFV 17D vaccination in 24 study subjects. More specifically, we studied the dynamics of several immune cell populations over time and the development of neutralizing Abs. At 7 d following vaccination, YFV RNA in serum as well as several antiviral proteins were detected as a sign of YFV 17D replication. Activation of Th1-polarized circulating T follicular helper cells followed germinal center activity, the latter assessed by the surrogate marker CXCL13 in serum. This coincided with a plasmablast expansion peaking at day 14 before returning to baseline levels at day 28. FluoroSpot-based analysis confirmed that plasmablasts were specific to the YFV-E protein. The frequencies of plasmablasts correlated with the magnitude of neutralizing Ab titers measured at day 90, suggesting that this transient B cell subset could be used as an early marker of induction of protective immunity. Additionally, YFV-specific memory B cells were readily detectable at 28 and 90 d following vaccination, and all study subjects tested developed protective neutralizing Ab titers. Taken together, these studies provide insights into key immune events leading to human B cell immunity following vaccination with the YFV 17D vaccine.


Assuntos
Anticorpos Neutralizantes/imunologia , Células T Auxiliares Foliculares/imunologia , Vacina contra Febre Amarela/imunologia , Febre Amarela/imunologia , Vírus da Febre Amarela/imunologia , Adolescente , Adulto , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Linfócitos B/imunologia , Citocinas/imunologia , Feminino , Humanos , Imunidade Humoral/imunologia , Cinética , Masculino , Pessoa de Meia-Idade , Vacinação/métodos , Vacinas Atenuadas/imunologia , Adulto Jovem
15.
Proc Natl Acad Sci U S A ; 118(29)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34193524

RESUMO

Successfully combating the COVID-19 pandemic depends on mass vaccination with suitable vaccines to achieve herd immunity. Here, we describe COVI-VAC, the only live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine currently in clinical development. COVI-VAC was developed by recoding a segment of the viral spike protein with synonymous suboptimal codon pairs (codon-pair deoptimization), thereby introducing 283 silent (point) mutations. In addition, the furin cleavage site within the spike protein was deleted from the viral genome for added safety of the vaccine strain. Except for the furin cleavage site deletion, the COVI-VAC and parental SARS-CoV-2 amino acid sequences are identical, ensuring that all viral proteins can engage with the host immune system of vaccine recipients. COVI-VAC was temperature sensitive in vitro yet grew robustly (>107 plaque forming units/mL) at the permissive temperature. Tissue viral loads were consistently lower, lung pathology milder, and weight loss reduced in Syrian golden hamsters (Mesocricetus auratus) vaccinated intranasally with COVI-VAC compared to those inoculated with wild-type (WT) virus. COVI-VAC inoculation generated spike IgG antibody levels and plaque reduction neutralization titers similar to those in hamsters inoculated with WT virus. Upon challenge with WT virus, COVI-VAC vaccination reduced lung challenge viral titers, resulted in undetectable virus in the brain, and protected hamsters from almost all SARS-CoV-2-associated weight loss. Highly attenuated COVI-VAC is protective at a single intranasal dose in a relevant in vivo model. This, coupled with its large-scale manufacturing potential, supports its potential use in mass vaccination programs.


Assuntos
Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/farmacologia , COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Animais , Anticorpos Antivirais/imunologia , COVID-19/epidemiologia , Chlorocebus aethiops , Feminino , Humanos , Masculino , Mesocricetus , Pandemias , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação , Vacinas Atenuadas/imunologia , Células Vero
16.
Commun Biol ; 4(1): 929, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330999

RESUMO

Visceral Leishmaniasis (VL), a potentially fatal disease is caused by Leishmania donovani parasites with no vaccine available. Here we produced a dermotropic live attenuated centrin gene deleted Leishmania major (LmCen-/-) vaccine under Good Laboratory Practices and demonstrated that a single intradermal injection confers robust and durable protection against lethal VL transmitted naturally via bites of L. donovani-infected sand flies and prevents mortality. Surprisingly, immunogenicity characteristics of LmCen-/- parasites revealed activation of common immune pathways like L. major wild type parasites. Spleen cells from LmCen-/- immunized and L. donovani challenged hamsters produced significantly higher Th1-associated cytokines including IFN-γ, TNF-α, and reduced expression of the anti-inflammatory cytokines like IL-10, IL-21, compared to non-immunized challenged animals. PBMCs, isolated from healthy people from non-endemic region, upon LmCen-/- infection also induced more IFN-γ compared to IL-10, consistent with our immunogenicity data in LmCen-/- immunized hamsters. This study demonstrates that the LmCen-/- parasites are safe and efficacious against VL and is a strong candidate vaccine to be tested in a human clinical trial.


Assuntos
Deleção de Genes , Genes de Protozoários , Leishmania donovani/imunologia , Vacinas contra Leishmaniose/imunologia , Leishmaniose Visceral/prevenção & controle , Leishmania donovani/genética , Leishmaniose Visceral/imunologia , Proteínas de Protozoários , Vacinas Atenuadas/imunologia
17.
Nat Commun ; 12(1): 4355, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272362

RESUMO

Mucosal-associated Invariant T (MAIT) cells are recognized for their antibacterial functions. The protective capacity of MAIT cells has been demonstrated in murine models of local infection, including in the lungs. Here we show that during systemic infection of mice with Francisella tularensis live vaccine strain results in evident MAIT cell expansion in the liver, lungs, kidney and spleen and peripheral blood. The responding MAIT cells manifest a polarised Th1-like MAIT-1 phenotype, including transcription factor and cytokine profile, and confer a critical role in controlling bacterial load. Post resolution of the primary infection, the expanded MAIT cells form stable memory-like MAIT-1 cell populations, suggesting a basis for vaccination. Indeed, a systemic vaccination with synthetic antigen 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil in combination with CpG adjuvant similarly boosts MAIT cells, and results in enhanced protection against both systemic and local infections with different bacteria. Our study highlights the potential utility of targeting MAIT cells to combat a range of bacterial pathogens.


Assuntos
Citocinas/metabolismo , Francisella tularensis/imunologia , Imunidade Inata , Células T Invariantes Associadas à Mucosa/imunologia , Adjuvantes Imunológicos , Animais , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Fígado/imunologia , Pulmão/imunologia , Camundongos , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/imunologia , Células T Invariantes Associadas à Mucosa/metabolismo , Fenótipo , RNA-Seq , Ribitol/análogos & derivados , Ribitol/imunologia , Análise de Célula Única , Baço/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Transcriptoma/genética , Uracila/análogos & derivados , Uracila/imunologia , Vacinas Atenuadas/imunologia
18.
PLoS Negl Trop Dis ; 15(6): e0009484, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34086672

RESUMO

The global spread of Zika virus (ZIKV), which caused a pandemic associated with Congenital Zika Syndrome and neuropathology in newborns and adults, prompted the pursuit of a safe and effective vaccine. Here, three kinds of recombinant rabies virus (RABV) encoding the prM-E protein of ZIKV were constructed: ZI-D (prM-E), ZI-E (transmembrane domain (TM) of prM-E replaced with RABV G) and ZI-F (signal peptide and TM domain of prM-E replaced with the region of RABV G). When the TM of prM-E was replaced with the region of RABV G (termed ZI-E), it promoted ZIKV E protein localization on the cell membrane and assembly on recombinant viruses. In addition, the change in the signal peptide with RABV G (termed ZI-F) was not conducive to foreign protein expression. The immunogenicity of recombinant viruses mixed with a complex adjuvant of ISA 201 VG and poly(I:C) was tested in BALB/c mice. After immunization with ZI-E, the anti-ZIKV IgG antibody lasted for at least 10 weeks. The titers of neutralizing antibodies (NAbs) against ZIKV and RABV at week 6 were all greater than the protective titers. Moreover, ZI-E stimulated the proliferation of splenic lymphocytes and promoted the secretion of cytokines. It also promoted the production of central memory T cells (TCMs) among CD4+/CD8+ T cells and stimulated B cell activation and maturation. These results indicate that ZI-E could induce ZIKV-specific humoral and cellular immune responses, which have the potential to be developed into a promising vaccine for protection against both ZIKV and RABV infections.


Assuntos
Vírus da Raiva/genética , Raiva/prevenção & controle , Proteínas do Envelope Viral/imunologia , Vacinas Virais/imunologia , Infecção por Zika virus/prevenção & controle , Zika virus/imunologia , Animais , Anticorpos Antivirais/imunologia , Feminino , Humanos , Imunidade Celular , Camundongos , Camundongos Endogâmicos BALB C , Raiva/imunologia , Raiva/virologia , Vírus da Raiva/imunologia , Linfócitos T/imunologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Proteínas do Envelope Viral/administração & dosagem , Proteínas do Envelope Viral/genética , Vacinas Virais/administração & dosagem , Vacinas Virais/genética , Zika virus/genética , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia
19.
J Virol ; 95(17): e0040221, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34133899

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the viral pathogen responsible for the current coronavirus disease 2019 (COVID-19) pandemic. As of 19 May 2021, John Hopkins University's COVID-19 tracking platform reported 3.3 million deaths associated with SARS-CoV-2 infection. Currently, the World Health Organization has granted emergency use listing (EUL) to six COVID-19 vaccine candidates. However, much of the pathogenesis observed during SARS-CoV-2 infection remains elusive. To gain insight into the contribution of individual accessory open reading frame (ORF) proteins in SARS-CoV-2 pathogenesis, we used our recently described reverse-genetics system approach to successfully engineer recombinant SARS-CoV-2 (rSARS-CoV-2) constructs; we removed individual viral ORF3a, -6, -7a, -7b, and -8 proteins from them, and we characterized the resulting recombinant viruses in vitro and in vivo. Our results indicate differences in plaque morphology, with ORF-deficient (ΔORF) viruses producing smaller plaques than those of the wild type (rSARS-CoV-2/WT). However, growth kinetics of ΔORF viruses were like those of rSARS-CoV-2/WT. Interestingly, infection of K18 human angiotensin-converting enzyme 2 (hACE2) transgenic mice with the ΔORF rSARS-CoV-2s identified ORF3a and ORF6 as the major contributors of viral pathogenesis, while ΔORF7a, ΔORF7b, and ΔORF8 rSARS-CoV-2s induced pathology comparable to that of rSARS-CoV-2/WT. This study demonstrates the robustness of our reverse-genetics system to generate rSARS-CoV-2 constructs and the major role for ORF3a and ORF6 in viral pathogenesis, providing important information for the generation of attenuated forms of SARS-CoV-2 for their implementation as live attenuated vaccines for the treatment of SARS-CoV-2 infection and associated COVID-19. IMPORTANCE Despite great efforts put forward worldwide to combat the current coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a human health and socioeconomic threat. Insights into the pathogenesis of SARS-CoV-2 and the contribution of viral proteins to disease outcome remain elusive. Our study aims (i) to determine the contribution of SARS-CoV-2 accessory open reading frame (ORF) proteins to viral pathogenesis and disease outcome and (ii) to develop a synergistic platform combining our robust reverse-genetics system to generate recombinant SARS-CoV-2 constructs with a validated rodent model of infection and disease. We demonstrate that SARS-CoV-2 ORF3a and ORF6 contribute to lung pathology and ultimately disease outcome in K18 hACE2 transgenic mice, while ORF7a, ORF7b, and ORF8 have little impact on disease outcome. Moreover, our combinatory platform serves as a foundation for generating attenuated forms of the virus to develop live attenuated vaccines for the treatment of SARS-CoV-2.


Assuntos
Enzima de Conversão de Angiotensina 2/imunologia , Fases de Leitura Aberta/imunologia , SARS-CoV-2 , Proteínas Virais , Células A549 , Enzima de Conversão de Angiotensina 2/genética , Animais , Vacinas contra COVID-19/genética , Vacinas contra COVID-19/imunologia , Chlorocebus aethiops , Células HEK293 , Humanos , Camundongos , Camundongos Transgênicos , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Células Vero , Proteínas Virais/genética , Proteínas Virais/imunologia
20.
Viruses ; 13(5)2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067226

RESUMO

The bluetongue virus (BTV) is transmitted by Culicoides biting midges and causes bluetongue (BT), an OIE-notifiable disease of ruminants. At least 29 BTV serotypes are described as determined by the outer shell proteins VP2 and VP5. Vaccination is the most effective control measure. Inactivated and live-attenuated vaccines (LAVs) are currently available. These vaccines have their specific pros and cons, and both are not DIVA vaccines. The BT Disabled Infectious Single Animal (DISA) vaccine platform is based on LAV without nonessential NS3/NS3a expression and is applicable for many serotypes by the exchange of outer shell proteins. The DISA vaccine is effective and completely safe. Further, transmission of the DISA vaccine by midges is blocked (DISA principle). Finally, the DISA vaccine enables DIVA because of a lack of antibodies against the immunogenic NS3/NS3a protein (DIVA principle). The deletion of 72 amino acids (72aa) in NS3/NS3a is sufficient to block virus propagation in midges. Here, we show that a prototype DISA vaccine based on LAV with the 72aa deletion enables DIVA, is completely safe and induces a long-lasting serotype-specific protection in cattle. In conclusion, the in-frame deletion of 72-aa codons in the BT DISA/DIVA vaccine platform is sufficient to fulfil all the criteria for modern veterinary vaccines.


Assuntos
Vírus Bluetongue/genética , Vírus Bluetongue/imunologia , Doenças dos Bovinos/prevenção & controle , Vacinas Atenuadas/imunologia , Proteínas não Estruturais Virais/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/imunologia , Especificidade de Anticorpos , Bluetongue/prevenção & controle , Bluetongue/virologia , Bovinos , Genoma Viral , Imunização , Sorogrupo , Vacinas Virais/administração & dosagem , Vacinas Virais/efeitos adversos
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