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T follicular regulatory (Tfr) cells can counteract the B cell helper activity of T follicular helper (Tfh) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (Treg) cells into Tfr cells is still missing. Herein, we report that low doses of the pro-Tfh cytokine interleukin-12 (IL-12) drive the induction of a Tfr cell program on activated human Treg cells while also preserving their regulatory function. Mechanistically, we found that IL-12 led to STAT4 (signal transducer and activator of transcription 4) phosphorylation and binding to IL-12-driven follicular signature genes. Patients with inborn errors of immunity in the IL12RB1 gene presented with a strong decrease in circulating Tfr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of Tfr cell differentiation in vivo and provides an approach for the in vitro generation of human Tfr-like cells.
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Diferenciación Celular , Interleucina-12 , Linfocitos T Reguladores , Humanos , Interleucina-12/inmunología , Diferenciación Celular/inmunología , Linfocitos T Reguladores/inmunología , Factor de Transcripción STAT4/inmunología , Factor de Transcripción STAT4/genética , Receptores de Interleucina-12/inmunología , Receptores de Interleucina-12/genética , Femenino , MasculinoRESUMEN
Viral haemorrhagic fevers (VHF) pose a significant threat to human health. In recent years, VHF outbreaks caused by Ebola, Marburg and Lassa viruses have caused substantial morbidity and mortality in West and Central Africa. In 2022, an Ebola disease outbreak in Uganda caused by Sudan virus resulted in 164 cases with 55 deaths. In 2023, a Marburg disease outbreak was confirmed in Equatorial Guinea and Tanzania resulting in over 49 confirmed or suspected cases; 41 of which were fatal. There are no clearly defined correlates of protection against these VHF, impeding targeted vaccine development. Any vaccine developed should therefore induce strong and preferably long-lasting humoral and cellular immunity against these viruses. Ideally this immunity should also cross-protect against viral variants, which are known to circulate in animal reservoirs and cause human disease. We have utilized two viral vectored vaccine platforms, an adenovirus (ChAdOx1) and Modified Vaccinia Ankara (MVA), to develop a multi-pathogen vaccine regime against three filoviruses (Ebola virus, Sudan virus, Marburg virus) and an arenavirus (Lassa virus). These platform technologies have consistently demonstrated the capability to induce robust cellular and humoral antigen-specific immunity in humans, most recently in the rollout of the licensed ChAdOx1-nCoV19/AZD1222. Here, we show that our multi-pathogen vaccines elicit strong cellular and humoral immunity, induce a diverse range of chemokines and cytokines, and most importantly, confers protection after lethal Ebola virus, Sudan virus and Marburg virus challenges in a small animal model.
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Ebolavirus , Fiebre Hemorrágica Ebola , Fiebre de Lassa , Virus Lassa , Enfermedad del Virus de Marburg , Marburgvirus , Animales , Ratones , Ebolavirus/inmunología , Virus Lassa/inmunología , Marburgvirus/inmunología , Fiebre Hemorrágica Ebola/prevención & control , Fiebre Hemorrágica Ebola/inmunología , Fiebre de Lassa/inmunología , Fiebre de Lassa/prevención & control , Enfermedad del Virus de Marburg/inmunología , Enfermedad del Virus de Marburg/prevención & control , Vacunas Virales/inmunología , Humanos , Vacunación , Femenino , Anticuerpos Antivirales/inmunología , Inmunogenicidad Vacunal , Vacunas contra el Virus del Ébola/inmunologíaRESUMEN
Although licensed vaccines against influenza virus have been successful in reducing pathogen-mediated disease, they have been less effective at preventing viral infection of the airways and current seasonal updates to influenza vaccines do not always successfully accommodate viral drift. Most licensed influenza and recently licensed RSV vaccines are administered via the intramuscular route. Alternative immunisation strategies, such as intranasal vaccinations, and "prime-pull" regimens, may deliver a more sterilising form of protection against respiratory viruses. A bivalent ChAdOx1-based vaccine (ChAdOx1-NP + M1-RSVF) encoding conserved nucleoprotein and matrix 1 proteins from influenza A virus and a modified pre-fusion stabilised RSV A F protein, was designed, developed and tested in preclinical animal models. The aim was to induce broad, cross-protective tissue-resident T cells against heterotypic influenza viruses and neutralising antibodies against RSV in the respiratory mucosa and systemically. When administered via an intramuscular prime-intranasal boost (IM-IN) regimen in mice, superior protection was generated against challenge with either RSV A, Influenza A H3N2 or H1N1. These results support further clinical development of a pan influenza & RSV vaccine administered in a prime-pull regimen.
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Many human activities contaminate terrestrial and aquatic environments with numerous chemical pollutants that not only directly alter the environment but also affect microbial communities in ways that are potentially concerning to human health, such as selecting for the spread of antibiotic-resistance genes (ARGs) through horizontal gene transfer. In the present study, metagenomes available in the public domain from polluted (with antibiotics, with petroleum, with metal mining, or with coal-mining effluents) and unpolluted terrestrial and aquatic environments were compared to examine whether pollution has influenced the abundance and composition of ARGs and mobile elements, with specific focus on IS26 and class 1 integrons (intI1). When aggregated together, polluted environments had a greater relative abundance of ARGs than unpolluted environments and a greater relative abundance of IS26 and intI1. In general, chemical pollution, notably with petroleum, was associated with an increase in the prevalence of ARGs linked to multidrug efflux pumps. Included in the suite of efflux pumps were mexK, mexB, mexF, and mexW that are polyspecific and whose substrate ranges include multiple classes of critically important antibiotics. Also, in some instances, ß-lactam resistance (TEM181 and OXA-541) genes increased, and genes associated with rifampicin resistance (RNA polymerases subunits rpoB and rpoB2) decreased in relative abundance. This meta-analysis suggests that different types of chemical pollution can enrich populations that carry efflux pump systems associated with resistance to multiple classes of medically critical antibiotics.IMPORTANCEThe United Nations has identified chemical pollution as being one of the three greatest threats to environmental health, through which the evolution of antimicrobial resistance, a seminally important public health challenge, may be favored. While this is a very plausible outcome of continued chemical pollution, there is little evidence or research evaluating this risk. The objective of the present study was to examine existing metagenomes from chemically polluted environments and evaluate whether there is evidence that pollution increases the relative abundance of genes and mobile genetic elements that are associated with antibiotic resistance. The key finding is that for some types of pollution, particularly in environments exposed to petroleum, efflux pumps are enriched, and these efflux pumps can confer resistance to multiple classes of medically important antibiotics that are typically associated with Pseudomonas spp. or other Gram-negative bacteria. This finding makes clear the need for more investigation on the impact of chemical pollution on the environmental reservoir of ARGs and their association with mobile genetic elements that can contribute to horizontal gene transfer events.
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Metagenoma , Petróleo , Humanos , Antibacterianos/farmacología , Farmacorresistencia Microbiana/genética , Genes Bacterianos , Secuencias Repetitivas EsparcidasRESUMEN
It is generally thought that antibiotics confer upon the producing bacteria the ability to inhibit or kill neighboring microorganisms, thereby providing the producer with a significant competitive advantage. Were this to be the case, the concentrations of emitted antibiotics in the vicinity of producing bacteria might be expected to fall within the ranges of MICs that are documented for a number of bacteria. Furthermore, antibiotic concentrations that bacteria are punctually or chronically exposed to in environments harboring antibiotic-producing bacteria might fall within the range of minimum selective concentrations (MSCs) that confer a fitness advantage to bacteria carrying acquired antibiotic resistance genes. There are, to our knowledge, no available in situ measured antibiotic concentrations in the biofilm environments that bacteria typically live in. The objective of the present study was to use a modeling approach to estimate the antibiotic concentrations that might accumulate in the vicinity of bacteria that are producing an antibiotic. Fick's law was used to model antibiotic diffusion using a series of key assumptions. The concentrations of antibiotics within a few microns of single producing cells could not reach MSC (8 to 16 µg/L) or MIC (500 µg/L) values, whereas the concentrations around aggregates of a thousand cells could reach these concentrations. The model outputs suggest that single cells could not produce an antibiotic at a rate sufficient to achieve a bioactive concentration in the vicinity, whereas a group of cells, each producing the antibiotic, could do so. IMPORTANCE It is generally assumed that a natural function of antibiotics is to provide their producers with a competitive advantage. If this were the case, sensitive organisms in proximity to producers would be exposed to inhibitory concentrations. The widespread detection of antibiotic resistance genes in pristine environments suggests that bacteria are indeed exposed to inhibitory antibiotic concentrations in the natural world. Here, a model using Fick's law was used to estimate potential antibiotic concentrations in the space surrounding producing cells at the micron scale. Key assumptions were that per-cell production rates drawn from the pharmaceutical manufacturing industry are applicable in situ, that production rates were constant, and that produced antibiotics are stable. The model outputs indicate that antibiotic concentrations in proximity to aggregates of a thousand cells can indeed be in the minimum inhibitory or minimum selective concentration range.
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Antibacterianos , Farmacorresistencia Bacteriana , Antibacterianos/farmacología , Pruebas de Sensibilidad Microbiana , Bacterias/genéticaRESUMEN
Cytomegalovirus (CMV) is a globally ubiquitous pathogen with a seroprevalence of approximately 50% in the United Kingdom. CMV infection induces expansion of immunosenescent T cell and NK cell populations, with these cells demonstrating lower responsiveness to activation and reduced functionality upon infection and vaccination. In this study, we found that CMV+ participants had normal T cell responses after a single-dose or homologous vaccination with the viral vector chimpanzee adenovirus developed by the University of Oxford (ChAdOx1). CMV seropositivity was associated with reduced induction of IFN-γ-secreting T cells in a ChAd-Modified Vaccinia Ankara (ChAd-MVA) viral vector vaccination trial. Analysis of participants receiving a single dose of ChAdOx1 demonstrated that T cells from CMV+ donors had a more terminally differentiated profile of CD57+PD1+CD4+ T cells and CD8+ T cells expressing less IL-2Rα (CD25) and fewer polyfunctional CD4+ T cells 14 days after vaccination. NK cells from CMV-seropositive individuals also had a reduced activation profile. Overall, our data suggest that although CMV infection enhances immunosenescence of T and NK populations, it does not affect antigen-specific T cell IFN-γ secretion or antibody IgG production after vaccination with the current ChAdOx1 nCoV-19 vaccination regimen, which has important implications given the widespread use of this vaccine, particularly in low- and middle-income countries with high CMV seroprevalence.
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Infecciones por Citomegalovirus , Citomegalovirus , ChAdOx1 nCoV-19 , Humanos , Células Asesinas Naturales , Estudios Seroepidemiológicos , VacunaciónRESUMEN
Pathogenic spore-forming Firmicutes are commonly present in animal and human wastes that are used as fertilizers in crop production. Pre-treatments of organic waste prior to land application offer the potential to abate enteric microorganisms, and therefore reduce the risk of contamination of crops or adjacent water resources with pathogens carried in these materials. The inactivation and reduction of gram-positive spore formers such as Clostridium spp., Clostridioides spp. and Bacillus spp. from animal and human waste can be challenging given the recalcitrance of the spores these bacteria produce. Given the significance of these organisms to human and animal health, information concerning spore-forming bacteria inactivation during anaerobic digestion (AD) and aerobic composting (AC) is required as the basis for recommending safe organic waste management practices. In this review, an assessment of the inactivation of spore-forming Firmicutes during AD and AC was conducted to provide guidance for practical management of organic matrices of animal or human origin. Temperature and pH may be the main factors contributing to the inactivation of spore-forming Firmicutes during batch lab-scale AD (log reduction <0.5-5 log). In continuous digesters, wet AD systems do not effectively inactivate spore-forming Firmicutes even under thermopholic conditions (log reduction -1.09 - 0.98), but dry AD systems could be a feasible management practice to inactivate spore-forming Firmicutes from organic materials with high solid content (log reduction 1.77-3.1). In contrast, composting is an effective treatment to abate spore-forming Firmicutes (log reduction 1.7-6.5) when thermophilic conditions last at least six consecutive days. Temperature, moisture content and composting scale are the key operating conditions influencing the inactivation of spore-forming Firmicutes during composting. Where possible, undertaking AD with subsequent composting to ensure the biosafety of digestate before its downstream processing and recycling is recommended to abate recalcitrant bacteria in digestate.
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Clostridium , Compostaje , Anaerobiosis , Esporas BacterianasRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines drive the generation of affinity-matured B cell responses through germinal center (GC) reactions in vaccine draining lymph nodes. Herein, we describe a procedure for the acquisition of human lymph node samples via an ultrasound-guided fine needle aspiration-based approach. Additionally, we outline a suggested approach for the analysis of CD4 T helper cell subsets as well as antigen-specific GC B cells, memory B cells, and plasmablasts by high-parameter spectral flow cytometry. For complete details on the use and execution of this protocol, please refer to Lederer et al. (2022).1.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Vacunas contra la COVID-19 , Citometría de Flujo , Biopsia con Aguja Fina/métodos , COVID-19/prevención & control , COVID-19/patología , Centro Germinal , VacunaciónRESUMEN
Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease.
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Enfermedades Inflamatorias del Intestino/patología , Interleucina-1/metabolismo , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Células del Estroma/inmunología , Adulto , Anciano , Femenino , Fibroblastos/metabolismo , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/genética , Masculino , Persona de Mediana Edad , Receptores de Interleucina-1/metabolismo , Transducción de Señal/fisiología , Remodelación Vascular/fisiologíaRESUMEN
Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49-14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08-18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 -a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.
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COVID-19/inmunología , COVID-19/mortalidad , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/inmunología , Linfocitos B/inmunología , Biomarcadores/sangre , Proteínas Sanguíneas/metabolismo , Estudios de Cohortes , Enfermedad Crítica/mortalidad , Femenino , Humanos , Inmunofenotipificación , Gripe Humana/inmunología , Lectinas Tipo C/inmunología , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Células T Invariantes Asociadas a Mucosa/inmunología , Gravedad del PacienteRESUMEN
Vaccines against SARS-CoV-2 are urgently required, but early development of vaccines against SARS-CoV-1 resulted in enhanced disease after vaccination. Careful assessment of this phenomena is warranted for vaccine development against SARS CoV-2. Here we report detailed immune profiling after ChAdOx1 nCoV-19 (AZD1222) and subsequent high dose challenge in two animal models of SARS-CoV-2 mediated disease. We demonstrate in rhesus macaques the lung pathology caused by SARS-CoV-2 mediated pneumonia is reduced by prior vaccination with ChAdOx1 nCoV-19 which induced neutralising antibody responses after a single intramuscular administration. In a second animal model, ferrets, ChAdOx1 nCoV-19 reduced both virus shedding and lung pathology. Antibody titre were boosted by a second dose. Data from these challenge models on the absence of enhanced disease and the detailed immune profiling, support the continued clinical evaluation of ChAdOx1 nCoV-19.
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Vacunas contra la COVID-19/inmunología , SARS-CoV-2/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , ChAdOx1 nCoV-19 , Hurones , Macaca mulattaRESUMEN
Several vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.
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Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , ARN Viral/administración & dosificación , SARS-CoV-2/inmunología , Vacunación/métodos , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , Vacunas contra la COVID-19/genética , Vacunas contra la COVID-19/inmunología , ChAdOx1 nCoV-19 , Inmunización Secundaria , Inmunogenicidad Vacunal , Ratones , ARN Viral/genética , ARN Viral/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Linfocitos T Citotóxicos/inmunología , Células TH1/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunologíaRESUMEN
Outbreaks that occur as a result of zoonotic spillover from an animal reservoir continue to highlight the importance of studying the disease interface between species. One Health approaches recognise the interdependence of human and animal health and the environmental interplay. Improving the understanding and prevention of zoonotic diseases may be achieved through greater consideration of these relationships, potentially leading to better health outcomes across species. In this review, special emphasis is given on the emerging and outbreak pathogen Crimean-Congo Haemorrhagic Fever virus (CCHFV) that can cause severe disease in humans. We discuss the efforts undertaken to better understand CCHF and the importance of integrating veterinary and human research for this pathogen. Furthermore, we consider the use of closely related nairoviruses to model human disease caused by CCHFV. We discuss intervention approaches with potential application for managing CCHFV spread, and how this concept may benefit both animal and human health.
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Fiebre Hemorrágica de Crimea/prevención & control , Animales , Modelos Animales de Enfermedad , Reservorios de Enfermedades , Virus de la Fiebre Hemorrágica de Crimea-Congo/patogenicidad , Fiebre Hemorrágica de Crimea/epidemiología , Fiebre Hemorrágica de Crimea/transmisión , Humanos , Vacunas Virales/inmunología , Zoonosis Virales/prevención & controlRESUMEN
Mucosal-associated invariant T (MAIT) cells are innate sensors of viruses and can augment early immune responses and contribute to protection. We hypothesized that MAIT cells may have inherent adjuvant activity in vaccine platforms that use replication-incompetent adenovirus vectors. In mice and humans, ChAdOx1 (chimpanzee adenovirus Ox1) immunization robustly activated MAIT cells. Activation required plasmacytoid dendritic cell (pDC)-derived interferon (IFN)-α and monocyte-derived interleukin-18. IFN-α-induced, monocyte-derived tumor necrosis factor was also identified as a key secondary signal. All three cytokines were required in vitro and in vivo. Activation of MAIT cells positively correlated with vaccine-induced T cell responses in human volunteers and MAIT cell-deficient mice displayed impaired CD8+ T cell responses to multiple vaccine-encoded antigens. Thus, MAIT cells contribute to the immunogenicity of adenovirus vectors, with implications for vaccine design.
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Adenoviridae/inmunología , Inmunogenicidad Vacunal , Células T Invariantes Asociadas a Mucosa/inmunología , Vacunas Virales/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Vectores Genéticos/inmunología , Humanos , Interferón-alfa/metabolismo , Interleucina-18/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), has caused a global pandemic, and safe, effective vaccines are urgently needed1. Strong, Th1-skewed T cell responses can drive protective humoral and cell-mediated immune responses2 and might reduce the potential for disease enhancement3. Cytotoxic T cells clear virus-infected host cells and contribute to control of infection4. Studies of patients infected with SARS-CoV-2 have suggested a protective role for both humoral and cell-mediated immune responses in recovery from COVID-19 (refs. 5,6). ChAdOx1 nCoV-19 (AZD1222) is a candidate SARS-CoV-2 vaccine comprising a replication-deficient simian adenovirus expressing full-length SARS-CoV-2 spike protein. We recently reported preliminary safety and immunogenicity data from a phase 1/2 trial of the ChAdOx1 nCoV-19 vaccine (NCT04400838)7 given as either a one- or two-dose regimen. The vaccine was tolerated, with induction of neutralizing antibodies and antigen-specific T cells against the SARS-CoV-2 spike protein. Here we describe, in detail, exploratory analyses of the immune responses in adults, aged 18-55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1 nCoV-19 in this trial, demonstrating an induction of a Th1-biased response characterized by interferon-γ and tumor necrosis factor-α cytokine secretion by CD4+ T cells and antibody production predominantly of IgG1 and IgG3 subclasses. CD8+ T cells, of monofunctional, polyfunctional and cytotoxic phenotypes, were also induced. Taken together, these results suggest a favorable immune profile induced by ChAdOx1 nCoV-19 vaccine, supporting the progression of this vaccine candidate to ongoing phase 2/3 trials to assess vaccine efficacy.
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Formación de Anticuerpos/inmunología , Vacunas contra la COVID-19/inmunología , Linfocitos T/inmunología , Adolescente , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , COVID-19/inmunología , COVID-19/virología , ChAdOx1 nCoV-19 , Relación Dosis-Respuesta Inmunológica , Femenino , Humanos , Inmunidad Celular , Inmunidad Humoral , Inmunoglobulina A/inmunología , Inmunoglobulina M/inmunología , Interferón gamma/metabolismo , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Subunidades de Proteína/inmunología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunación , Adulto JovenRESUMEN
Clinical development of the COVID-19 vaccine candidate ChAdOx1 nCoV-19, a replication-deficient simian adenoviral vector expressing the full-length SARS-CoV-2 spike (S) protein was initiated in April 2020 following non-human primate studies using a single immunisation. Here, we compared the immunogenicity of one or two doses of ChAdOx1 nCoV-19 in both mice and pigs. Whilst a single dose induced antigen-specific antibody and T cells responses, a booster immunisation enhanced antibody responses, particularly in pigs, with a significant increase in SARS-CoV-2 neutralising titres.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 20191,2 and is responsible for the coronavirus disease 2019 (COVID-19) pandemic3. Vaccines are an essential countermeasure and are urgently needed to control the pandemic4. Here we show that the adenovirus-vector-based vaccine ChAdOx1 nCoV-19, which encodes the spike protein of SARS-CoV-2, is immunogenic in mice and elicites a robust humoral and cell-mediated response. This response was predominantly mediated by type-1 T helper cells, as demonstrated by the profiling of the IgG subclass and the expression of cytokines. Vaccination with ChAdOx1 nCoV-19 (using either a prime-only or a prime-boost regimen) induced a balanced humoral and cellular immune response of type-1 and type-2 T helper cells in rhesus macaques. We observed a significantly reduced viral load in the bronchoalveolar lavage fluid and lower respiratory tract tissue of vaccinated rhesus macaques that were challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated SARS-CoV-2-infected animals. However, there was no difference in nasal shedding between vaccinated and control SARS-CoV-2-infected macaques. Notably, we found no evidence of immune-enhanced disease after viral challenge in vaccinated SARS-CoV-2-infected animals. The safety, immunogenicity and efficacy profiles of ChAdOx1 nCoV-19 against symptomatic PCR-positive COVID-19 disease will now be assessed in randomized controlled clinical trials in humans.
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Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Modelos Animales de Enfermedad , Macaca mulatta , Pandemias/prevención & control , Neumonía Viral/prevención & control , Vacunas Virales/inmunología , Adenoviridae/genética , Animales , Líquido del Lavado Bronquioalveolar , COVID-19 , Vacunas contra la COVID-19 , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/virología , Citocinas/inmunología , Femenino , Inmunidad Celular , Inmunidad Humoral , Inmunoglobulina G/inmunología , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Macaca mulatta/inmunología , Macaca mulatta/virología , Masculino , Ratones , Neumonía Viral/inmunología , Neumonía Viral/virología , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Células TH1/inmunología , Vacunación , Carga Viral , Vacunas Virales/administración & dosificación , Vacunas Virales/genéticaRESUMEN
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in December 20191,2 and is responsible for the COVID-19 pandemic3. Vaccines are an essential countermeasure urgently needed to control the pandemic4. Here, we show that the adenovirus-vectored vaccine ChAdOx1 nCoV-19, encoding the spike protein of SARS-CoV-2, is immunogenic in mice, eliciting a robust humoral and cell-mediated response. This response was not Th2 dominated, as demonstrated by IgG subclass and cytokine expression profiling. A single vaccination with ChAdOx1 nCoV-19 induced a humoral and cellular immune response in rhesus macaques. We observed a significantly reduced viral load in bronchoalveolar lavage fluid and respiratory tract tissue of vaccinated animals challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated rhesus macaques. Importantly, no evidence of immune-enhanced disease following viral challenge in vaccinated animals was observed. ChAdOx1 nCoV-19 is currently under investigation in a phase I clinical trial. Safety, immunogenicity and efficacy against symptomatic PCR-positive COVID-19 disease will now be assessed in randomised controlled human clinical trials.