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Paradigm changes are required in HIV vaccine research

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889197279 Year: Pages: 74 DOI: 10.3389/978-2-88919-727-9 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-04-07 11:22:02
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In his 1962 book "The Structure of Scientific Revolutions", Thomas Kuhn famously argued that researchers in every field of scientific enquiry always operate under a set of presuppositions known as paradigms that are rarely explicitly stated. In the field of HIV vaccine research, several prevailing paradigms led scientists for many years to pursue unfruitful lines of investigations that impeded significant progress. The uncritical acceptance of reigning paradigms makes scientists reluctant to abandon their mistaken assumptions even when they obtain results that are not consistent with the paradigms. The following five paradigms which disregard the degeneracy of the immune system were particularly harmful. 1) There is a primary and intrinsic epitope specific for each B cell receptor and for the corresponding monoclonal antibody.In reality, there is no single, intrinsic or "real" epitope for any antibody but only a diverse group of potential ligands. 2) Reactions with monoclonal antibodies are more specific than the combined reactivity of polyclonal antibodies. In reality, a polyclonal antiserum has greater specificity for a multiepitopic protein because different antibodies in the antiserum recognize separate epitopes on the same protein, giving rise to an additive specificity effect. By focusing vaccine design on single epitope-Mab pairs, the beneficial neutralizing synergy that occurs with polyclonal antibody responses is overlooked. 3) The HIV epitope identified by solving the crystallographic structure of a broadly neutralizing Mab – HIV Env complex should be able, when used as immunogen, to elicit antibodies endowed with the same neutralizing capacity as the Mab. Since every anti HIV bnMab is polyspecific, the single epitope identified in the complex is not necessarily the one that elicited the bnMab. Since hypermutated Mabs used in crystallographic studies differ from their germline-like receptor version present before somatic hypermutation, the identified epitope will not be an effective vaccine immunogen. 4) Effective vaccine immunogenicity can be predicted from the antigenic binding capacity of viral epitopes. Most fragments of a viral antigen can induce antibodies that react with the immunogen, but this is irrelevant for vaccination since these antibodies rarely recognize the cognate, intact antigen and even more rarely neutralize the infectivity of the viral pathogen that harbors the antigen. 5) The rational design of vaccine immunogens using reverse vaccinology is superior to the trial-and-error screening of vaccine candidates able to induce protective immunity. One epitope can be designed to increase its structural complementarity to one particular bnMab, but such antigen design is only masquerading as immunogen design because it is assumed that antigenic reactivity necessarily entails the immunogenic capacity to elicit neutralizing antibodies. When HIV Env epitopes, engineered to react with a bnMab are used to select from human donors rare memory B cells secreting bnAbs, this represents antigen design and not immunogen design. The aim of this Research Topic is to replace previous misleading paradigms by novel ones that better fit our current understanding of immunological specificity and will help HIV vaccine development.

HSPs - Ambiguous Mediators of Immunity

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889451524 Year: Pages: 92 DOI: 10.3389/978-2-88945-152-4 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2017-08-28 14:01:09
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Heat shock proteins (HSPs) were discovered as polypeptides induced by stress that can be found in all kingdoms of cellular organisms. Their functions were, a first enigmatic and these proteins were thus classified by molecular weight, as in—Hsp27, Hsp70, Hsp90, Hsp110. More recently, each of these size-classified molecules has attributed a role in protein folding, and they thus came to be known, as a class, as molecular chaperones. However, the they possess properties beyond chaperoning. Indeed, their discovery in the extracellular spaces suggested roles in regulation of the immune responses.

The Schistosomiasis Vaccine - It Is Time to Stand Up

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889197415 Year: Pages: 82 DOI: 10.3389/978-2-88919-741-5 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-04-07 11:22:02
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Schistosomiasis is a severe parasitic disease, endemic in 74 developing countries with up to 600 million people, including many children, infected and 800 million at risk of contracting the disease following infection with Schistosoma mansoni, S. haematobium or S. japonicum. Disease burden is estimated to exceed 70 million disability-adjusted life-years, and leads to remarkably high YLD (years lived with disability) rates. Even more importantly, people with schistosomiasis are highly susceptible to malaria, tuberculosis and hepatic and acquired immunodeficiency viruses. There is only one drug, praziquantel, currently available for treatment and it has high efficacy, low cost, and limited side effects. However, only 13% of the target population has received the drug, and those treated are at continuous risk of reinfection necessitating repeated drug administration and the emergence of drug resistant parasites is a constant threat. There currently is no vaccine. While the target of >40% protection has been achieved with some molecules such as excretory-secretory proteins including calpain, glyceraldehyde 3-phosphate dehydrogenase, and cysteine peptidases, very recent articles reiterate the findings published during the last 2 decades of the last century, contradicting the established data of the pioneers of schistosome biology. A consensus should be reached without delay, in order to propose collaborative independent experiments and proceed ahead to pre- and clinical trials with efficacious candidate vaccine molecules. The proposed plan aims to finally reach an objective and fruitful agreement , via inviting established and young researchers from the United States, Brazil, China, Australia, and Europe who are working with different vaccine antigens, adjuvants, and approaches for immunization against S. mansoni, S. haematobium, and S. japonicum. It is hoped that the forum will end with a very few candidate antigens and a consensus approach regarding target immune responses, thus leading to encouraging the World Health Organization and other international foundations to sponsor the development and implementation of the urgently required, yet still elusive, vaccine for preventing and eliminating the transmission of schistosomiasis.

Control of Visceral Leishmaniasis by Immunotherapeutic and Prophylactic Strategies

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195527 Year: Pages: 144 DOI: 10.3389/978-2-88919-552-7 Language: English
Publisher: Frontiers Media SA
Subject: Public Health --- Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2016-01-19 14:05:46
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Visceral leishmaniasis (VL) or kala-azar is the most dreadful of all forms of leishmaniasis caused by Leishmania donovani in Old World and Leishmania chagasi and/or Leishmania infantum in New World affecting millions of people worldwide. In active VL, macrophages host the replicating amastigotes in phagolysosomal compartments leading to splenomegaly, hepatomegaly, hyperglobulinemia, anemia, weight-loss, incessant fever and ultimately death if not treated. Treatments available against the disease are limited by increased incidence of resistance, serious side-effects, high cost and long course of treatment. Immuno-chemotherapy is an alternative to overcome the limitations of the drugs against VL. Combination of one or more of immunotherapeutic agents like BCG, Alum, IFN-?, antigen-pulsed dendritic cells (DC), etc. with chemotherapeutic drugs have been tested raising hopes for a suitable immuno-chemotherapy against VL and Post Kala-azar Dermal Leishmaniasis (PKDL). Antagonists of IL-10, TGF-ß, IL-13 have been effectively used with pentavalent antimonials in treatment of experimental VL. Some parasitic antigens and liposomal formulations have also been shown to impart superior therapeutic effectiveness to antileishmanial drugs. For socio-economic reasons prophylaxis is always more desirable than therapy. Although no vaccine against any form of leishmaniasis in humans is available, patients successfully treated show considerable protection from reinfection highlighting the possibility of developing prophylactic measures against the disease. Subsequently a lot of interest has been focused recently towards developing vaccines against VL and many potential vaccine candidates like whole cell (attenuated or heat killed), crude fractions, purified subunits, DNAs, recombinant proteins, fusion proteins, and genetically modified live attenuated parasites etc. have been reported. These vaccine candidates are either activators of CD4+Th1 cells and/or CD8+ T cells or neutralizers of immuno-suppression. Cationic liposomal formulations, nanoparticle and virosome delivery systems, etc. have been used to increase potency and durability of various vaccine candidates. Immuno-modulators like TLR agonists have been shown to be promising adjuvants in enhancing efficacy and overcoming the challenge of human administrable vaccine formulations. Recently role of sand fly salivary gland proteins as immune-modulators also has been explored. Various strategies such as heterologous prime boosting, targeted antigen delivery, adjuvant mediated protection, have been undertaken. Likewise, precise role of regulatory T cells (Tregs) in VL disease progression needs to be investigated and exploited to develop both immuno-therapeutic and prophylactic methods. A breakthrough in immunotherapy and prophylactic strategy would help in eradication of the parasites from the pool of natural reservoirs namely VL and PKDL patients, asymptomatic carrier individuals and infected dogs ensuring success of global VL control programs.

Influenza Virus Vaccines and Immunotherapies

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889198115 Year: Pages: 185 DOI: 10.3389/978-2-88919-811-5 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-01-19 14:05:46
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Influenza virus infections lead to thousands of deaths worldwide annually and billions of dollars economic burden. Despite continuing advances in our understanding of the immune evasion mechanism, the disease remains one of the foremost threat for human being. Traditional vaccines (attenuated and inactivated) mainly provide protection by inducing virus neutralizing antibodies, targeting ever changing surface antigens: Haemagultinin (HA) and Neuraminidase (NA). Due to genetic shift and immune selection pressure, prevalence of circulating influenza virus subtypes changes every year. Therefore, mismatch between circulating strain and vaccine strain can critically affect the success rate of these conventional flu vaccines, and requires continuous monitoring of circulating influenza virus subtypes and change in the vaccine formulations accordingly. The collective limitations of existing flu vaccines urgently call for the development of a novel universal vaccines that might provide the required protective immunity to a range of influenza virus subtypes. New approaches are being investigated mainly targeting conserved regions of flu proteins. Some of these approaches include universally conserved epitopes of HA, nucleoprotein (NP), capsid protein (M1) and ion channel protein (M2) that induced strong immune responses in animal models. Some attention and progress appears to be focused on vaccines based on the M2 ectodomain (M2e) employing a variety of constructs, adjuvants and delivery systems, including M2e-hepatitis B core antigen, flagellin constructs, and virus-like particles (VLP). Animal studies with these M2e candidate vaccines demonstrated that these vaccine candidates can prevent severe illness and death but not infection, which may pose difficulties in both the evaluation of clinical efficacy and approval by the regulatory authorities. VLP vaccines appear to be promising, but still are mostly limited to animal studies. The discovery and development of new and improved vaccines have been greatly facilitated by the application of new technologies. The use of nucleic acid-based vaccines, to combine the benefits of in-situ expression of antigens with the safety of inactivated and subunit vaccines, has been a key advancement. Upon their discovery more than 20 years ago, nucleic acid vaccines promised to be a safe and effective mean to mimic immunization with a live organism vaccine, particularly for induction of T cell immunity. In addition, the manufacturing of nucleic acid-based vaccines offered the potential to be relatively simple, inexpensive and generic. Reverse Vaccinology and in-silico designing of vaccines are very innovative approaches and being considered as future of vaccines. Furthermore, various immuno-therapeutic agents also being developed to treat and minimize immuno-pathological damage in patients suffering from life threatening complications. For the treatment of such pathological conditions, various novel approaches such as administration of immune suppressive cytokines, blocking co-stimulatory signals or activating co-inhibitory signal of T cell activation, are being tested both in lab and clinics. The Research Topic on influenza virus vaccine and therapeutics will give an insight in to the current status and future scope of these new innovative approaches and technologies. Moreover, these new methods will also serve as a reference tool for the development of future vaccines against several other pathogens.

Why vaccines to HIV, HCV and Malaria have so far failed - Challenges to developing vaccines against immunoregulating pathogens

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889199662 Year: Pages: 157 DOI: 10.3389/978-2-88919-966-2 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Microbiology --- Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2016-01-19 14:05:46
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Despite continuous progress in the development of anti-viral and anti-bacterial/parasite drugs, the high cost of medicines and the potential for re-infection, especially in high risk groups, suggest that protective vaccines to some of the most dangerous persistent infections are still highly desirable. There are no vaccines available for HIV, HCV and Malaria, and all attempts to make a broadly effective vaccine have failed so far. In this Research Topic we look into why vaccines have failed over the years, and what we have learn from these attempts. Rather than only showing positive results, this issue aims to reflect on failed efforts in vaccine development. Coming to understand our limitations will have theoretical and practical implications for the future development of vaccines to these major global disease burdens.

Keywords

Vaccine --- Infectious Disease --- HIV --- HCV --- Malaria --- influenza --- immunology --- Genetics

Mysteries of Type I IFN response: benefits versus detriments

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196296 Year: Pages: 74 DOI: 10.3389/978-2-88919-629-6 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2016-08-16 10:34:25
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Successful containment of an infection is dependent on both innate and adaptive immune response. Cytokines are essential effectors of both of these systems. In particular, type I interferons (IFN-I) are important components of early innate immunity against an infection. However, the production of IFN-I could serve as a double edge sword, either containing an infection or enhancing susceptibility. For example, IFN-I, which is essential for early containment of viral infections, has been shown to be detrimental to the host during bacterial infections. In fact, recent significant reports have shown that influenza virus induced IFN-I responses can enhance the host susceptibility to secondary bacterial infections. These recent reports highlight the expanding immunoregulatory role of IFN-I in the host immunity. With these recent findings in mind, the aim of this research topic is to welcome novel data, opinion and literature reviews on the newly identified dual functions of IFN-I. This research topic wills focus on the following areas of IFN-I: 1) a detrimental role of IFN-I during primary bacterial infection; 2) a detrimental role of viral infection induced IFN-I during secondary bacterial infections; 3) evolutionary pressure that drove detrimental IFN-I response during primary bacterial infection; and 4) does benefit of IFN-I responses during primary viral infections outweigh the adverse consequences of IFN-I mediated enhanced susceptibility to secondary bacterial infections.

The Neonatal Immune System: A Unique Host-Microbial Interface

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889454037 Year: Pages: 175 DOI: 10.3389/978-2-88945-403-7 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Pediatrics --- Allergy and Immunology --- Science (General) --- Microbiology
Added to DOAB on : 2018-11-16 17:17:57
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Emerging from the protective environment of the uterus, the newborn is exposed to a myriad of microbes, and quickly establishes a complex microbiome that shapes the infant’s biology in ways that are only now beginning to come to light. Among these exposures are a number of potential pathogens. The host responses to these pathogens in the neonatal period are unique, reflecting a developing immune system even with delivery at term. Preterm infants are delivered at a time when host defense mechanisms are even less developed and therefore face additional risk. As such, the organisms that cause disease in this period are different from the pathogens that are common in other age groups, or the disease they cause manifests in more severe fashion. Developmental alterations in both innate and adaptive immune responses in neonates have been documented among many cell types and pathways over the last several decades. Contemporary insights into the human immune system and methodologies that allow an “omics” approach to these questions have continued to provide new information regarding the mechanisms that underlie the human neonate as an “immunocompromised host.” This Research Topic highlights studies related to this unique host-pathogen interface. Contributions include those related to the innate or adaptive immune system of neonates, their response to microbial colonization or infection, and/or the pathogenesis of microbes causing disease in neonates.

Significance of antigen and epitope specificity in tuberculosis

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194513 Year: Pages: 119 DOI: 10.3389/978-2-88919-451-3 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-02-05 17:24:33
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Dissection of the specificity of host immune responses following infection with Mycobacterium tuberculosis is essential for designing effective vaccination and diagnostic biomarkers as well as for better understanding of immunopathogenesis of active tuberculosis. The articles in this volume of the Topics in Microbial Immunology review the significance of this area of research from both experimental models and clinical surveys. This includes T cell recognition of MHC permissive epitopes, use of algorithms for genome-based prediction of immunodominant epitopes, evaluation of candidate antigens/epitopes and adjuvants for vaccination and immunodiagnosis. Future research strategies indicate the need for better understanding of the relationship between epitope specificity and the phenotype of responding T cells and search for biomarkers with a capacity to discriminate and predict the change from latent infection to active disease. These research avenues have important potentials for improving the prevention and control of tuberculosis.

Vaccination Against Mycobacterial Diseases in Animals

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194766 Year: Pages: 94 DOI: 10.3389/978-2-88919-476-6 Language: English
Publisher: Frontiers Media SA
Subject: Internal medicine --- Science (General)
Added to DOAB on : 2016-03-10 08:14:33
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The two most prominent mycobacterial diseases in animals include bovine tuberculosis, caused by Mycobacterium bovis and Johne’s disease, caused by Mycobacterium avium subspecies paratuberculosis. Erradication of both diseases has been hampered by a variety of factors. In many countries, the persistence of tuberculosis in cattle has been attributed to reservoirs of M. bovis in wildlife species. Brushtail possums, deer and badgers are notable examples of wildlife reservoirs for M. bovis. The difficulties in eliminating the wildlife reservoir for M. bovis further suggest the need for vaccination of farmed livestock. Vaccination of wildlife species has also been attempted with mixed results. Delivery of the vaccine to wildlife species appears to be a chief obstacle. Vaccination itself leads to complications for diagnostics. For example, when cattle are vaccinated with both BCG and a commercial Johne’s vaccine there is a biased toward the avian tuberculin skin test reaction. Despite these issues, BCG seems to be the clear standard for vaccination against M. bovis, yet many laboratories are investigating ways to improve on BCG. For Johne’s disease, the available commercial vaccines consist of whole-cell preparations in one form or another. But with the ability to generate directed knockouts of specific genes, a number of defined mutants have been constructed in a few laboratories. These should be tested and directly compared with each other and alongside commercial vaccine formulations to determine not only which vaccine is most protective, but which animal model is best for predicting protection in the target host. To this end, there has been a nation-wide, multi-institutional effort to test the best live, attenuated vaccine against Johne's disease in cattle, sheep and goats. This vaccine trial has spanned six years and was conducted in three phases. The first phase examined attenuation in bovine macrophages, the second phase was colonization of spleen and liver in mice and the third phase was protection from bacterial challenge in goats. Many new ideas and retrospective approaches have emerged from this unprecedented effort. These aspects will be captured in this Research Topic. In this Research Topic, we will seek articles on these above topics, but other issues surrounding vaccination of animals against mycobacteria will also be explored. These include immune parameters, correlates of protection, adjuvants and other vaccine formulations, etc.

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