scholarly journals Recombinant vector vaccines and within-host evolution

2019 ◽  
Author(s):  
James Bull ◽  
Scott L. Nuismer ◽  
Rustom Antia
Keyword(s):  
Immune Response ◽  
Adaptive Immunity ◽  
Computational Models ◽  
Host Population ◽  
Inoculum Size ◽  
Viral Population ◽  
Foreign Antigen ◽  
Recombinant Vector ◽  
Short Period ◽  
Host Evolution

AbstractMany recombinant vector vaccines are capable of replication within the host. They consist of a fully competent vector backbone engineered to express an antigen from a foreign transgene. From the perspective of viral replication, the transgene is not only dispensable but may even be intrinsically detrimental. Thus vaccine revertants that delete the transgene may evolve to dominate the within-host population and in doing so reduce the antigenicity of the vaccine. We apply mathematical and computational models to study this process, including the dynamics of vaccine and revertant growth plus the dynamics of innate and adaptive immunity. Although the selective basis of vaccine evolution is easy to comprehend, the immunological consequences are not. One complication is that, despite possible fitness differences between vaccine and revertant, the opportunity for vaccine evolution is limited by the short period of growth before the viral population is cleared. Even less obvious, revertantper sedoes not interfere with immunity to vaccine except as the revertant suppresses vaccine abundance; the magnitude of this interference depends on mechanisms and timing of viral suppression. Adaptive immunity targeting the foreign antigen is also a possible basis of vaccine inferiority, but it is not worsened by vaccine evolution. Overall, we find that within-host vaccine evolution can sometimes matter to the adaptive immune response targeting the foreign antigen, but even when it does matter, simple principles of vaccine design and the control of inoculum composition can largely mitigate the effects.Author SummaryRecombinant vector vaccines are live replicating viruses that are engineered to carry extra genes derived from a pathogen – and these produce proteins against which we want to generate immunity. These genes may evolve to be lost during the course of replication within an individual, and there is a concern that this can severely limit the vaccine’s efficacy. The dynamics of this process are studied here with mathematical models. The potential for vaccine evolution is somewhat reduced by the short-term growth of the vaccine population before it is suppressed by the immune response. Even when within-host evolution can be a problem, the models show that increasing the vaccine inoculum size or ensuring that the inoculum is mostly pure vaccine can largely avoid the loss of immunity arising from evolution.

scholarly journals Directed attenuation to enhance vaccine immunity

2021 ◽  
Vol 17 (2) ◽  
pp. e1008602
Author(s):  
Rustom Antia ◽  
Hasan Ahmed ◽  
James J. Bull
Keyword(s):  
Immune Response ◽  
Genetic Engineering ◽  
Adaptive Immunity ◽  
Immune Evasion ◽  
Viral Infections ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Innate And Adaptive Immunity ◽  
Live Attenuated Vaccines

Many viral infections can be prevented by immunizing with live, attenuated vaccines. Early methods of attenuation were hit-and-miss, now much improved by genetic engineering. However, even current methods operate on the principle of genetic harm, reducing the virus’s ability to grow. Reduced viral growth has the undesired side-effect of reducing the host immune response below that of infection with wild-type. Might some methods of attenuation instead lead to an increased immune response? We use mathematical models of the dynamics of virus with innate and adaptive immunity to explore the tradeoff between attenuation of virus pathology and immunity. We find that modification of some virus immune-evasion pathways can indeed reduce pathology yet enhance immunity. Thus, attenuated vaccines can, in principle, be directed to be safe yet create better immunity than is elicited by the wild-type virus.

scholarly journals Immunoinflammatory Profile in Patients with Episodic and Continuous Paranoid Schizophrenia

10.17816/cp66 ◽  
2021 ◽  
Vol 2 (1) ◽  
pp. 19-31
Author(s):  
Irina K. Malashenkova ◽  
Sergey A. Krynskiy ◽  
Daniil P. Ogurtsov ◽  
Nikita A. Hailov ◽  
Natalia V. Zakharova ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Adaptive Immunity ◽  
Systemic Inflammation ◽  
Negative Symptoms ◽  
Clinical Course ◽  
Paranoid Schizophrenia ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Positive And Negative Symptoms

Introduction. Associations of disturbances in innate and adaptive immunity during the clinical course of schizophrenia have been found in a number of studies. Yet, the relationship of immune parameters and systemic inflammation in relation to the clinical course of the disease and its prognosis, remains poorly understood, which highlights an interesting topic for further research. The goal of this study was to research the immuno-inflammatory changes in patients with clinical continuous and episodic paranoid schizophrenia, to assess the pathogenetic significance of these changes. Methods. Thirty-six patients with paranoid schizophrenia, of which 20 had episodic symptoms and 16 had continuous symptoms, consented to participate in the study, together with 30 healthy volunteers. In the study we assessed the parameters of innate immune response (serum levels of key pro-inflammatory and anti-inflammatory cytokines, C-reactive protein) and the adaptive immune response, including humoral-mediated immunity (serum immunoglobulins IgA, IgM, IgG, circulating immune complexes), as well as the cell link of adaptive immunity (key lymphocyte subpopulations). Positive and negative symptoms were assessed with the positive and negative symptoms scale; frontal dysfunction was assessed by Frontal Assessment Battery (FAB). Results. Both patient groups had higher than normal levels of C-reactive protein and IL-8. There was a significant elevation of circulating immune complexes among patients with continuous symptoms of schizophrenia, compared to patients with episodic symptoms and healthy controls. Levels of CD45+CD3+ lymphocytes (T-cells) differed between clinical groups, with higher values identified among patients with episodic symptoms and lower values among those with continuous symptoms. In addition, patients with episodic symptoms had significantly increased levels of CD45+CD3+CD4+CD25+CD127- regulatory T-cells. Finally, the level of CD45+CD3-CD19+ B-cells was significantly higher among patients with continuous symptoms vs. patients with episodic symptoms and the control groups. Markers of activation of humoral immunity were associated with the severity of frontal disorders in these patients. Discussion. Comprehensive data on the serum level of cytokines and the parameters of adaptive immunity among individuals with continuous schizophrenia, by comparison with patients with episodic schizophrenia, are practically absent in the literature. We have shown that among those with continuous schizophrenia, there are signs of systemic inflammation and chronic activation of the adaptive humoral immune response, while among patients with episodic symptoms of the disease, there are signs of systemic inflammation and certain activation of cell-mediated immunity, without significant changes in the humoral link of adaptive immunity. Conclusion. More studies are needed, but the data obtained in this study are important for subsequent clinical studies of new treatment methods, based on various immunophenotypes of schizophrenia.

Adaptive Immunity and Genetics of the Host Immune Response

2014 ◽  
pp. 819-994 ◽  
Author(s):  
Craig W. Roberts ◽  
Sheela Prasad ◽  
Farzana Khaliq ◽  
Ricardo T. Gazzinelli ◽  
Imtiaz A. Khan ◽  
...  
Keyword(s):  
Immune Response ◽  
Adaptive Immunity ◽  
Host Immune Response

Introduction to Clinical Immunology: Overview of the Immune Response, Autoimmune Conditions, and Immunosuppressive Therapeutics for Rheumatic Diseases

2016 ◽  
Author(s):  
Steven K. Lundy ◽  
Alison Gizinski ◽  
David A. Fox
Keyword(s):  
Immune Response ◽  
Immune System ◽  
T Cell ◽  
Immune Responses ◽  
Autoimmune Diseases ◽  
Adaptive Immunity ◽  
Cell Populations ◽  
Hematopoietic Stem ◽  
Innate And Adaptive Immunity ◽  
Adaptive Immune

The immune system is a complex network of cells and mediators that must balance the task of protecting the host from invasive threats. From a clinical perspective, many diseases and conditions have an obvious link to improper functioning of the immune system, and insufficient immune responses can lead to uncontrolled acute and chronic infections. The immune system may also be important in tumor surveillance and control, cardiovascular disease, health complications related to obesity, neuromuscular diseases, depression, and dementia. Thus, a working knowledge of the role of immunity in disease processes is becoming increasingly important in almost all aspects of clinical practice. This review provides an overview of the immune response and discusses immune cell populations and major branches of immunity, compartmentalization and specialized immune niches, antigen recognition in innate and adaptive immunity, immune tolerance toward self antigens, inflammation and innate immune responses, adaptive immune responses and helper T (Th) cell subsets, components of the immune response that are important targets of treatment in autoimmune diseases, mechanisms of action of biologics used to treat autoimmune diseases and their approved uses, and mechanisms of other drugs commonly used in the treatment of autoimmune diseases. Figures show the development of erythrocytes, platelets, lymphocytes, and other immune system cells originating from hematopoietic stem cells that first reside in the fetal liver and later migrate to the bone marrow, antigen–major histocompatibility complex recognition by T cell receptor control of T cell survival and activation, and Th cells as central determinants of the adaptive immune response toward different stimuli. Tables list cell populations involved in innate and adaptive immunity, pattern recognition receptors with known ligands, autoantibody-mediated human diseases: examples of pathogenic mechanisms, selected Food and Drug Administration–approved autoimmune disease indications for biologics, and mechanism of action of biologics used to treat autoimmune diseases.   This review contains 3 highly rendered figures, 5 tables, and 64 references.

Adaptive immunity

2010 ◽  
pp. 224-234
Author(s):  
Paul Klenerman
Keyword(s):  
Infectious Disease ◽  
Immune Response ◽  
Pattern Recognition ◽  
Adaptive Immunity ◽  
Adaptive Response ◽  
Critical Role ◽  
Adaptive Immune Response ◽  
Structural Features ◽  
Adaptive Immune ◽  
Single Organism

Following the innate immune response, which acts very rapidly, the adaptive immune response plays a critical role in host defence against infectious disease. Unlike the innate response, which is triggered by pattern recognition of pathogens, i.e. features that are common to many bacteria or viruses, the adaptive response is triggered by structural features—known as antigens or epitopes—that are typically unique to a single organism....

Adaptive immunity

2020 ◽  
pp. 325-336
Author(s):  
Paul Klenerman
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Adaptive Immunity ◽  
Innate Immune Response ◽  
Molecular Basis ◽  
Adaptive Immune Response ◽  
Antigenic Specificity ◽  
Adaptive Immune Responses ◽  
Research Attention ◽  
Adaptive Immune

The adaptive immune response is distinguished from the innate immune response by two main features: its capacity to respond flexibly to new, previously unencountered antigens (antigenic specificity), and its enhanced capacity to respond to previously encountered antigens (immunological memory). These two features have provided the focus for much research attention, from the time of Jenner, through Pasteur onwards. Historically, innate and adaptive immune responses have often been treated as separate, with the latter being considered more ‘advanced’ because of its flexibility. It is now clear this not the case, and in recent years the molecular basis for these phenomena has become much better understood.

scholarly journals Insights into Sensing of Murine Retroviruses

Viruses ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 836
Author(s):  
Eileen A. Moran ◽  
Susan R. Ross
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Nucleic Acid ◽  
Adaptive Immunity ◽  
Innate Immune System ◽  
Innate Immune ◽  
Genetic Tool ◽  
Causes Of Disease ◽  
Retrovirus Infection ◽  
Insight Into

Retroviruses are major causes of disease in animals and human. Better understanding of the initial host immune response to these viruses could provide insight into how to limit infection. Mouse retroviruses that are endemic in their hosts provide an important genetic tool to dissect the different arms of the innate immune system that recognize retroviruses as foreign. Here, we review what is known about the major branches of the innate immune system that respond to mouse retrovirus infection, Toll-like receptors and nucleic acid sensors, and discuss the importance of these responses in activating adaptive immunity and controlling infection.

scholarly journals Evolution of antibody structure during the immune response. The differentiative potential of a single B lymphocyte.

1989 ◽  
Vol 170 (4) ◽  
pp. 1211-1230 ◽  
Author(s):  
T Manser
Keyword(s):  
Immune Response ◽  
B Cell ◽  
Somatic Mutation ◽  
High Efficiency ◽  
Clonal Expansion ◽  
Isotype Switching ◽  
Cell Clones ◽  
Short Period ◽  
V Region ◽  
Neutral Mutations

Changes in the structure and function of antibodies occur during the course of an immune response due to variable (V) region gene somatic mutation and isotype switch recombination. While the end products of both these processes are now well documented, their mechanisms, timing, and regulation during clonal expansion remain unclear. Here I describe the characterization of antibodies expressed by a large number of hybridomas derived from single B cell clones at an intermediate stage of an immune response. These data provide new insights into the mechanism, relative timing, and potential of V gene mutation and isotype switching. The data suggest that somatic mutation and isotype switching are completely independent processes that may, but need not, occur simultaneously during clonal expansion. In addition, the results of this analysis demonstrate that individual B cell clones are far more efficient than previously imagined at generating and fixing particular V region somatic mutations that result in increased affinity for the eliciting epitope. Models to account for this high efficiency are discussed. Taken together with previous data, the results of this analysis also suggest that the "somatic evolution" of V region structure to a single epitope takes place in two stages; the first in which particular mutations are sustained and fixed by antigen selection in the CDR regions of the V region genes expressed in a clone over a short period of clonal expansion, and the second in which these selected CDR mutations are maintained in the growing clone, deleterious mutations are lost, and selectively neutral mutations accumulate throughout the length of V genes over long periods of clonal expansion.

scholarly journals Immunogenicity, Boostability, and Sustainability of the Immune Response after Vaccination against Influenza A Virus (H1N1) 2009 in a Healthy Population

2011 ◽  
Vol 18 (9) ◽  
pp. 1401-1405 ◽  
Author(s):  
Elisabeth Huijskens ◽  
John Rossen ◽  
Paul Mulder ◽  
Ruud van Beek ◽  
Hennie van Vugt ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Virus H1n1 ◽  
Prospective Longitudinal Study ◽  
Virus Vaccination ◽  
Short Period ◽  
Prospective Longitudinal

ABSTRACTThe emergence of a new influenza A virus (H1N1) variant in 2009 led to a worldwide vaccination program, which was prepared in a relatively short period of time. This study investigated the humoral immunity against this virus before and after vaccination with a 2009 influenza A virus (H1N1) monovalent MF59-adjuvanted vaccine, as well as the persistence of vaccine-induced antibodies. Our prospective longitudinal study included 498 health care workers (mean age, 43 years; median age, 44 years). Most (89%) had never or only occasionally received a seasonal influenza virus vaccine, and 11% were vaccinated annually (on average, for >10 years). Antibody titers were determined by a hemagglutination inhibition (HI) assay at baseline, 3 weeks after the first vaccination, and 5 weeks and 7 months after the second vaccination. Four hundred thirty-five persons received two doses of the 2009 vaccine. After the first dose, 79.5% developed a HI titer of ≥40. This percentage increased to 83.3% after the second dose. Persistent antibodies were found in 71.9% of the group that had not received annual vaccinations and in 43.8% of the group that had received annual vaccinations. The latter group tended to have lower HI titers (P=0.09). With increasing age, HI titers decreased significantly, by 2.4% per year. A single dose of the 2009 vaccine was immunogenic in almost 80% of the study population, whereas an additional dose resulted in significantly increased titers only in persons over 50. Finally, a reduced HI antibody response against the 2009 vaccine was found in adults who had previously received seasonal influenza virus vaccination. More studies on the effect of yearly seasonal influenza virus vaccination on the immune response are warranted.

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