Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002)
In the version of this article initially published, the numbers of cells in the third sentence of... more In the version of this article initially published, the numbers of cells in the third sentence of the second paragraph of the Methods subsection ' Antibody-dependent neutrophil phagocytosis' (500,000) and in the fifth sentence of the first paragraph of the Methods subsection ' Antibody-dependent monocyte phagocytosis' (250,000) were incorrect. The correct numbers are 50,000 and 25,000 (respectively). The errors have been corrected in the HTML and PDF versions of the article.
f 198 coronavirus disease 2019 (COVID-19) vaccine candidates at various developmental stages, 44 ... more f 198 coronavirus disease 2019 (COVID-19) vaccine candidates at various developmental stages, 44 are in clinical trials, 10 of which are in late-stage clinical development 1. The majority of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidates in development are designed to induce immune responses against the spike surface antigen with many demonstrating early encouraging immunogenicity readouts from clinical trials 2-6. Much work has been carried out to characterize the immune response to infection with SARS-CoV-2 and in this manner delineate potential correlates of protection. Importantly, in a rhesus macaque challenge model, neutralizing antibody (NAb) levels following vaccination using the spike antigen correlated with protection against SARS-CoV-2 (refs. 7,8). It is therefore generally accepted that NAb levels against spike protein are likely to be critically important in protecting against overt disease, and these Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses
Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK
Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial
Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus ... more 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 needed 1. Strong, Th1-skewed T cell responses can drive protective humoral and cell-mediated immune responses 2 and might reduce the potential for disease enhancement 3. Cytotoxic T cells clear virus-infected host cells and contribute to control of infection 4. 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. Efforts to develop a vaccine against SARS-CoV-2 to control the global COVID-19 disease pandemic have been underway since January 2020, with more than 40 vaccine candidates in clinical trials by October 2020 1. The past decade has seen an expansion and acceleration in the development of tools to support pandemic preparedness, including the development of vaccines against novel and emerging pathogens 8,9. This acceleration, spurred on by numerous outbreaks of diseases, including SARS-CoV, MERS-CoV, Ebola and Zika, has leveraged the use of platform technologies and blueprints for target product profiles for priority diseases 10. Replication-deficient adenoviruses 11 are attractive for use as COVID-19 vaccine candidates, as they can be manufactured at scale, have favorable safety profiles and are highly immunogenic. Importantly, viral vectored vaccines can induce strong immune responses in older adults and immunocompromised individuals 12,13. Replication-deficient adenovirus vectors are also potent inducers of both antibodies as well as cytotoxic T cells; the latter can clear virus-infected host cells and contribute to the control of infection, alleviating disease symptoms 4,14. Importantly, high-frequency T cell responses targeting the SARS-CoV-2 spike protein have been detected in patients who recover from COVID-19, with recent data suggesting a role for T cells during COVID-19 (refs. 15-17). Previous efforts to develop vaccines against human coronaviruses have faced challenges, with several preclinical studies demonstrating disease enhancement in vaccinated animals after viral
For fixed finite graphs $G$, $H$, a common problem in Ramsey theory is to study graphs $F$ such t... more For fixed finite graphs $G$, $H$, a common problem in Ramsey theory is to study graphs $F$ such that $F \to (G,H)$, i.e. every red-blue coloring of the edges of $F$ produces either a red $G$ or a blue $H$. We generalize this study to infinite graphs $G$, $H$; in particular, we want to determine if there is a minimal such $F$. This problem has strong connections to the study of self-embeddable graphs: infinite graphs which properly contain a copy of themselves. We prove some compactness results relating this problem to the finite case, then give some general conditions for a pair $(G,H)$ to have a Ramsey-minimal graph. We use these to prove, for example, that if $G=S_\infty$ is an infinite star and $H=nK_2$, $n \geqslant 1$ is a matching, then the pair $(S_\infty,nK_2)$ admits no Ramsey-minimal graphs.
Effector CD4 + T cells coordinate protective immunity during bloodstage malaria by promoting para... more Effector CD4 + T cells coordinate protective immunity during bloodstage malaria by promoting parasite phagocytosis and antibody production. 1,2 However, it is now evident that effector CD4 + T cell function is strongly regulated during the course of blood-stage malaria by the activity of co-inhibitory receptors, which are upregulated on activated CD4 + T cells as infection progresses. 3-7 The expression of co-inhibitory molecules (including PD-1, CTLA-4 and LAG-3), dampens effector CD4 + T cell cytokine production and proliferation, impairs memory T cell formation and promotes infection chronicity. 8,9 Consequently, there is currently major interest in
Through major histocompatibility complex class Ia leader sequence-derived (VL9) peptide binding a... more Through major histocompatibility complex class Ia leader sequence-derived (VL9) peptide binding and CD94/NKG2 receptor engagement, human leucocyte antigen E (HLA-E) reports cellular health to NK cells. Previous studies demonstrated a strong bias for VL9 binding by HLA-E, a preference subsequently supported by structural analyses. However, Mycobacteria tuberculosis (Mtb) infection and Rhesus cytomegalovirus-vectored SIV vaccinations revealed contexts where HLA-E and the rhesus homologue, Mamu-E, presented diverse pathogenderived peptides to CD8 + T cells, respectively. Here we present crystal structures of HLA-E in complex with HIV and Mtb-derived peptides. We show that despite the presence of preferred primary anchor residues, HLA-E-bound peptides can adopt alternative conformations within the peptide binding groove. Furthermore, combined structural and mutagenesis analyses illustrate a greater tolerance for hydrophobic and polar residues in the primary pockets than previously appreciated. Finally, biochemical studies reveal HLA-E peptide binding and exchange characteristics with potential relevance to its alternative antigen presenting function in vivo.
Book Review: Divine Simplicity: A Dogmatic Account. By Steven J. DubyDivine Simplicity: A Dogmatic Account. By DubySteven J. T & T Clark Studies in Systematic Theology, 30. New York: Bloomsbury T & T Clark, 2015. Pp. viii + 260. $120
This paper considers the nineteen planar discrete topological relations that apply to regions bou... more This paper considers the nineteen planar discrete topological relations that apply to regions bounded by a digital Jordan curve. Rather than modeling the topological relations with purely topological means, metrics are developed that determine the topological relations. Two sets of five such metrics are found to be minimal and sufficient to uniquely identify each of the nineteen topological relations. Key to distinguishing all nineteen relations are regions' margins (i.e., the neighborhood of their boundaries). Deriving topological relations from metric properties in ℝ ! vs. ℤ ! reveals that the eight binary topological relations between two simple regions in ℝ ! can be distinguished by a minimal set of six metrics, whereas in ℤ ! , a more fine-grained set of relations (19) can be distinguished by a smaller set of metrics (5). Determining discrete topological relations from metrics enables not only the refinement of the set of known topological relations in the digital plane, but further enables the processing of raster images where the topological relation is not explicitly stored by reverting to mere pixel counts.
Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002)
In the version of this article initially published, the numbers of cells in the third sentence of... more In the version of this article initially published, the numbers of cells in the third sentence of the second paragraph of the Methods subsection ' Antibody-dependent neutrophil phagocytosis' (500,000) and in the fifth sentence of the first paragraph of the Methods subsection ' Antibody-dependent monocyte phagocytosis' (250,000) were incorrect. The correct numbers are 50,000 and 25,000 (respectively). The errors have been corrected in the HTML and PDF versions of the article.
f 198 coronavirus disease 2019 (COVID-19) vaccine candidates at various developmental stages, 44 ... more f 198 coronavirus disease 2019 (COVID-19) vaccine candidates at various developmental stages, 44 are in clinical trials, 10 of which are in late-stage clinical development 1. The majority of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidates in development are designed to induce immune responses against the spike surface antigen with many demonstrating early encouraging immunogenicity readouts from clinical trials 2-6. Much work has been carried out to characterize the immune response to infection with SARS-CoV-2 and in this manner delineate potential correlates of protection. Importantly, in a rhesus macaque challenge model, neutralizing antibody (NAb) levels following vaccination using the spike antigen correlated with protection against SARS-CoV-2 (refs. 7,8). It is therefore generally accepted that NAb levels against spike protein are likely to be critically important in protecting against overt disease, and these Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses
Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK
Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial
Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus ... more 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 needed 1. Strong, Th1-skewed T cell responses can drive protective humoral and cell-mediated immune responses 2 and might reduce the potential for disease enhancement 3. Cytotoxic T cells clear virus-infected host cells and contribute to control of infection 4. 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. Efforts to develop a vaccine against SARS-CoV-2 to control the global COVID-19 disease pandemic have been underway since January 2020, with more than 40 vaccine candidates in clinical trials by October 2020 1. The past decade has seen an expansion and acceleration in the development of tools to support pandemic preparedness, including the development of vaccines against novel and emerging pathogens 8,9. This acceleration, spurred on by numerous outbreaks of diseases, including SARS-CoV, MERS-CoV, Ebola and Zika, has leveraged the use of platform technologies and blueprints for target product profiles for priority diseases 10. Replication-deficient adenoviruses 11 are attractive for use as COVID-19 vaccine candidates, as they can be manufactured at scale, have favorable safety profiles and are highly immunogenic. Importantly, viral vectored vaccines can induce strong immune responses in older adults and immunocompromised individuals 12,13. Replication-deficient adenovirus vectors are also potent inducers of both antibodies as well as cytotoxic T cells; the latter can clear virus-infected host cells and contribute to the control of infection, alleviating disease symptoms 4,14. Importantly, high-frequency T cell responses targeting the SARS-CoV-2 spike protein have been detected in patients who recover from COVID-19, with recent data suggesting a role for T cells during COVID-19 (refs. 15-17). Previous efforts to develop vaccines against human coronaviruses have faced challenges, with several preclinical studies demonstrating disease enhancement in vaccinated animals after viral
For fixed finite graphs $G$, $H$, a common problem in Ramsey theory is to study graphs $F$ such t... more For fixed finite graphs $G$, $H$, a common problem in Ramsey theory is to study graphs $F$ such that $F \to (G,H)$, i.e. every red-blue coloring of the edges of $F$ produces either a red $G$ or a blue $H$. We generalize this study to infinite graphs $G$, $H$; in particular, we want to determine if there is a minimal such $F$. This problem has strong connections to the study of self-embeddable graphs: infinite graphs which properly contain a copy of themselves. We prove some compactness results relating this problem to the finite case, then give some general conditions for a pair $(G,H)$ to have a Ramsey-minimal graph. We use these to prove, for example, that if $G=S_\infty$ is an infinite star and $H=nK_2$, $n \geqslant 1$ is a matching, then the pair $(S_\infty,nK_2)$ admits no Ramsey-minimal graphs.
Effector CD4 + T cells coordinate protective immunity during bloodstage malaria by promoting para... more Effector CD4 + T cells coordinate protective immunity during bloodstage malaria by promoting parasite phagocytosis and antibody production. 1,2 However, it is now evident that effector CD4 + T cell function is strongly regulated during the course of blood-stage malaria by the activity of co-inhibitory receptors, which are upregulated on activated CD4 + T cells as infection progresses. 3-7 The expression of co-inhibitory molecules (including PD-1, CTLA-4 and LAG-3), dampens effector CD4 + T cell cytokine production and proliferation, impairs memory T cell formation and promotes infection chronicity. 8,9 Consequently, there is currently major interest in
Through major histocompatibility complex class Ia leader sequence-derived (VL9) peptide binding a... more Through major histocompatibility complex class Ia leader sequence-derived (VL9) peptide binding and CD94/NKG2 receptor engagement, human leucocyte antigen E (HLA-E) reports cellular health to NK cells. Previous studies demonstrated a strong bias for VL9 binding by HLA-E, a preference subsequently supported by structural analyses. However, Mycobacteria tuberculosis (Mtb) infection and Rhesus cytomegalovirus-vectored SIV vaccinations revealed contexts where HLA-E and the rhesus homologue, Mamu-E, presented diverse pathogenderived peptides to CD8 + T cells, respectively. Here we present crystal structures of HLA-E in complex with HIV and Mtb-derived peptides. We show that despite the presence of preferred primary anchor residues, HLA-E-bound peptides can adopt alternative conformations within the peptide binding groove. Furthermore, combined structural and mutagenesis analyses illustrate a greater tolerance for hydrophobic and polar residues in the primary pockets than previously appreciated. Finally, biochemical studies reveal HLA-E peptide binding and exchange characteristics with potential relevance to its alternative antigen presenting function in vivo.
Book Review: Divine Simplicity: A Dogmatic Account. By Steven J. DubyDivine Simplicity: A Dogmatic Account. By DubySteven J. T & T Clark Studies in Systematic Theology, 30. New York: Bloomsbury T & T Clark, 2015. Pp. viii + 260. $120
This paper considers the nineteen planar discrete topological relations that apply to regions bou... more This paper considers the nineteen planar discrete topological relations that apply to regions bounded by a digital Jordan curve. Rather than modeling the topological relations with purely topological means, metrics are developed that determine the topological relations. Two sets of five such metrics are found to be minimal and sufficient to uniquely identify each of the nineteen topological relations. Key to distinguishing all nineteen relations are regions' margins (i.e., the neighborhood of their boundaries). Deriving topological relations from metric properties in ℝ ! vs. ℤ ! reveals that the eight binary topological relations between two simple regions in ℝ ! can be distinguished by a minimal set of six metrics, whereas in ℤ ! , a more fine-grained set of relations (19) can be distinguished by a smaller set of metrics (5). Determining discrete topological relations from metrics enables not only the refinement of the set of known topological relations in the digital plane, but further enables the processing of raster images where the topological relation is not explicitly stored by reverting to mere pixel counts.
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Papers by Jordan Barrett