1,721,214 research outputs found
The HIV-1 Glycan Shield: Strategically Placed Kinks in the Armor Improve Antigen Design
Full text linkDense glycosylation on the HIV-1 envelope glycoprotein hampers the induction of broadly neutralizing antibodies against HIV-1. Zhou et al. remove key glycans to unmask sites of vulnerability and enable the induction of neutralizing antibodies
NK Cells in HIV Disease
Full text linkNatural killer (NK) cells play a critical role in viral immunity. In the setting of HIV infection, epidemiologic and functional evidence support a role for NK cells in both protection from new infection and in viral control. Specifically, NK cells directly mediate immune pressure leading to virus evolution, and NK cell receptor genotypic profiles, clonal repertoires, and functional capacity have all been implicated in virus containment. In addition, indirect NK cell-mediated antibody-dependent cellular cytotoxicity has been linked to vaccine-induced protective immunity against HIV infection. With recent advances in our understanding of NK cell deficiency, development, memory-like responses, and editing of the adaptive immune system, the opportunities to direct and exploit NK cell antiviral immunity to target HIV have exponentially grown. In this review, we seek to highlight the intersections between discoveries in basic NK cell biology and the challenges of HIV chronic infection, vaccine development, and cure/eradication strategies
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The development of humoral breadth and protection against influenza
No full textInfluenza remains a serious global health concern, both as a seasonal pathogen and as a possible pandemic threat arising from novel strains against which the human population has no immunity. Current seasonal influenza vaccines provide a moderate level of protection, but complete protection is not achieved even where vaccination uptake is high. Furthermore, protection induced by both vaccines and infection is limited by lack of recognition of emerging zoonotic strains and seasonal strains that have undergone antigenic shift and/or drift. The current correlate of protection, hemagglutination inhibition, does not fully explain protection, particularly in high-risk groups. Emerging data suggests that antibody extra-neutralizing functions, which activate the innate immune system via interactions with Fc receptors (FcRs), can provide protection against seasonal and emerging pandemic strains. This work used an unbiased, polyclonal humoral profiling approach to explore the effects of an adjuvant, MF59, on the immune response to vaccination and define correlates of protection across multiple high-risk groups. In neonates, vaccine-induced maternal antibodies capable of binding to FcRs and transferring across the placenta provided increased protection. Similarly, in older adults, hemagglutinin- and neuraminidase-specific antibodies capable of activating NK cells provided increased protection. Linked to the importance of these mechanistic correlates of protection, the identification of strategies to broaden immunity is also key for the development of protective vaccines. Thus, to extend the correlates work, analysis of the role of antibody Fc-biology in the evolution of breadth of immunity across both influenza A and B revealed that antibodies capable of binding to FcRs, and especially Fc receptor 2B, are both a correlate and a predictor of seroconversion to vaccine strains and seroconversion breadth. These antibodies, in addition to marking a matured humoral immune response, also act to promote this maturation upon repeated exposure, highlighting a target for increasing the potency of influenza vaccines. The data presented here implicate vaccine-induced Fc biology in tuning both the direct control and clearance of virus, but also, indirectly, the evolution of the Fab to recognize the breadth of influenza strain diversity, providing strategies for next generation vaccines, particularly in the context of universal influenza vaccine candidates.Medical SciencesMedical Science
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Maternal:fetal functional antibody transfer for protection against SARS-CoV-2
No full textThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus
disease 2019 (COVID-19), has posed a serious global health threat since its emergence in late
2019, resulting in millions of infections across the world. Specifically, pregnant individuals and their
infants are particularly at risk for severe COVID-19. A lack of inclusion of these populations in vaccine
trials has limited our ability to optimize protection through humoral immunity. The emergence
of SARS-CoV-2 offered an unprecedented opportunity to characterize maternal transfer of antibodies
to neonates in response to both infection and vaccination with a novel pathogen. Using an unbiased,
comprehensive antibody profiling approach, this work explores the correlates of protection
against SARS-CoV-2 to understand the antibody qualities that are crucial for maternal:fetal antibody
transfer. We found that third trimester infection drove inefficient antibody transfer through the placenta
and resulted in a limited titer of inflammatory antibodies in breastmilk. Although vaccination in
pregnancy and lactation induced less inflammatory antibodies than in nonpregnant women, boosting
during pregnancy induced comparable antibody immunity to nonpregnant populations. Subtle differences
were observed between vaccine platforms and trimester of vaccination in both the induction
of vaccine-induced immunity in pregnant populations and in the transfer of antibodies to the neonate.
These data provide novel insights for further optimization of maternal immunization strategies and
increase our understanding of the transfer of humoral defenses at the maternal:fetal barrier.Medical SciencesMedical Science
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Assessing the Potential of Monoclonal Antibodies Against Mycobacterium Tuberculosis
No full textTuberculosis infects approximately one-quarter of the world’s population and is the leading cause of death by a single infectious disease, responsible for a reported 1.3 million deaths in 2017. Though Mycobacterium tuberculosis, the causative bacteria, is treatable with antibiotic therapy, the increased prevalence of drug resistant strains as well as the variable efficacy of the only widely approved vaccine have highlighted the need for novel approaches to therapeutic and vaccine development. Historically, it has been believed that the protective immune response against M. tuberculosis is attributed almost exclusively by cell-mediated immunity with humoral immunity being largely dismissed. Despite the skepticism that has surrounded the role of antibodies against this intracellular pathogen, there has been an increase in evidence suggesting that they can be involved in a variety of protective capacities. In particular, extensive study of the variable (Fab) and constant (Fc) domains has become possible in recent years, and there is a strong possibility that antigen-specificity, innate immune signaling, glycosylation patterns and other related characteristics impact a monoclonal antibody’s protective abilities. Utilizing a specially optimized version of the Golden Gate cloning system, production of mAbs with chosen Fab domains and immunoglobulin subclasses is possible, allowing for the assessment of the influence of each component. By confirming antigen-specific binding, ability to induce innate cell effector functions, and protection conferred against live bacterial challenge, results indicate that antibodies can potentially be important mediators of defense against this global pandemic.Master of Medical Sciences in Immunolog
Determining the Phagocytic Activity of Clinical Antibody Samples
No full textAntibody-driven phagocytosis is induced via the engagement of Fc receptors on professional phagocytes, and can contribute to both clearance as well as pathology of disease. While the properties of the variable domains of antibodies have long been considered critical to in vivo function, the ability of antibodies to recruit innate immune cells via their Fc domains has become increasingly appreciated as a major factor in their efficacy, both in the setting of recombinant monoclonal antibody therapy, as well as in the course of natural infection or vaccination1-3.
Importantly, despite its nomenclature as a constant domain, the antibody Fc domain does not have constant function, and is strongly modulated by IgG subclass (IgG1-4) and glycosylation at Asparagine 2974-6. Thus, this method to study functional differences of antigen-specific antibodies in clinical samples will facilitate correlation of the phagocytic potential of antibodies to disease state, susceptibility to infection, progression, or clinical outcome.
Furthermore, this effector function is particularly important in light of the documented ability of antibodies to enhance infection by providing pathogens access into host cells via Fc receptor-driven phagocytosis7. Additionally, there is some evidence that phagocytic uptake of immune complexes can impact the Th1/Th2 polarization of the immune response8.
Here, we describe an assay designed to detect differences in antibody-induced phagocytosis, which may be caused by differential IgG subclass, glycan structure at Asn297, as well as the ability to form immune complexes of antigen-specific antibodies in a high-throughput fashion. To this end, 1 μm fluorescent beads are coated with antigen, then incubated with clinical antibody samples, generating fluorescent antigen specific immune complexes. These antibody-opsonized beads are then incubated with a monocytic cell line expressing multiple FcγRs, including both inhibitory and activating. Assay output can include phagocytic activity, cytokine secretion, and patterns of FcγRs usage, and are determined in a standardized manner, making this a highly useful system for parsing differences in this antibody-dependent effector function in both infection and vaccine-mediated protection9.National Institutes of Health (U.S.) (NIH 3R01AI080289-02S1)Harvard University. Center for AIDS Research (Research Scholar Fellowship under NIH/NIAID 2P30AI060354-07
Impact of aging on immunity in the context of COVID-19, HIV, and tuberculosis
Full text linkKnowledge of aging biology needs to be expanded due to the continuously growing number of elderly people worldwide. Aging induces changes that affect all systems of the body. The risk of cardiovascular disease and cancer increases with age. In particular, the age-induced adaptation of the immune system causes a greater susceptibility to infections and contributes to the inability to control pathogen growth and immune-mediated tissue damage. Since the impact of aging on immune function, is still to be fully elucidated, this review addresses some of the recent understanding of age-related changes affecting key components of immunity. The emphasis is on immunosenescence and inflammaging that are impacted by common infectious diseases that are characterized by a high mortality, and includes COVID-19, HIV and tuberculosis
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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