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| Open AccessCorrelates of protection for booster doses of the SARS-CoV-2 vaccine BNT162b2
Vaccination with multiple doses has been proven effective against severe COVID-19, but protection levels widely vary among individuals. This study examines the serological and immunological profiles in recipients of multiple doses of Pfizer BNT162b2 vaccine for immune markers that correlate with protection against and susceptibility for SARS-CoV-2 infection.
- Tomer Hertz
- , Shlomia Levy
- & Orly Weinstein
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Article
| Open AccessMonoclonal antibody levels and protection from COVID-19
Monoclonal antibodies (mAbs) have shown efficacy against SARS-CoV-2 infection in clinical trials. Here the authors model the dose-response relationship between the dose of mAbs and protection from symptomatic SARS-CoV-2 infection. Further, the protection is comparable to that achieved by vaccination.
- Eva Stadler
- , Martin T. Burgess
- & David S. Khoury
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| Open AccessA highly potent human neutralizing antibody prevents vertical transmission of Rift Valley fever virus in a rat model
Rift valley fever virus (RVFV) infection during pregnancy has been associated with late-term fetal loss. Here, the authors show that a neutralizing monoclonal antibody can prevent vertical transmission of RVFV when administered either pre- or post-infection in a rodent model.
- Cynthia M. McMillen
- , Nathaniel S. Chapman
- & Amy L. Hartman
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| Open AccessMolecular and phenotypic characteristics of RSV infections in infants during two nirsevimab randomized clinical trials
Nirsevimab binds the respiratory syncytial virus (RSV) fusion protein and has been tested for RSV prevention in clinical trials. Here, the authors analyse RSV from infections and show that binding site substitutions are rare and that over 99% of isolates remain susceptible to nirsevimab.
- Bahar Ahani
- , Kevin M. Tuffy
- & Tonya Villafana
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Article
| Open AccessImmunogenicity and efficacy of vaccine boosters against SARS-CoV-2 Omicron subvariant BA.5 in male Syrian hamsters
Long-term BA.5-specific efficiency of booster vaccination is incompletely understood. Here, analyzing immunity to and efficacy of various COVID-19 vaccination regimens in Syrian hamster, the authors found that heterologous boosting provides more durable immunity and that NVX-CoV2373 provides the strongest boosting effect.
- Rafael R. G. Machado
- , Jordyn L. Walker
- & Scott C. Weaver
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| Open AccessStructural delineation and computational design of SARS-CoV-2-neutralizing antibodies against Omicron subvariants
In this study, the authors isolated SARS-CoV-2 receptor binding site monoclonal antibodies resistant to Omicron mutations. An amino acid in the receptor binding domain, tyrosine-489, is a virus-vulnerable site and a common footprint of broadly neutralizing antibodies.
- Saya Moriyama
- , Yuki Anraku
- & Yoshimasa Takahashi
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| Open AccessWaning and boosting of antibody Fc-effector functions upon SARS-CoV-2 vaccination
Efficiency of SARS-CoV-2 vaccines has long been attributed to the neutralising capacity of the antibodies that are produced upon prime-boost vaccinations. Here authors show that upon vaccination with CoronaVac and BNT162b2 vaccines in prime-boost regimens, antibodies with Fc-effector functions to enhance cellular and innate immunity are also produced, albeit with different kinetics.
- X. Tong
- , R. P. McNamara
- & R. A. Medina
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Article
| Open AccessToll-like receptor mediated inflammation directs B cells towards protective antiviral extrafollicular responses
Compared to germinal centres, extrafollicular plasmablast responses are thought to produce lower affinity antibodies, offering little protection from infection. Here authors show in an influenza infection and immunization mouse model that extrafollicular responses could yield protective antibodies, and that their development depends on signals provided via Toll-like receptor stimulation.
- Jonathan H. Lam
- & Nicole Baumgarth
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| Open AccessImmunological imprinting of humoral immunity to SARS-CoV-2 in children
The immune responses to SARS CoV-2 infection in children are less well understood than in adults. Here the authors characterise immune responses to newer omicron lineages and relate these to previous infection with earlier lineages of SARS-CoV-2, implicating a reduced immunogenicity from omicron variants and imprinting from previous virus strains.
- Alexander C. Dowell
- , Tara Lancaster
- & Paul Moss
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Article
| Open AccessUnmodified rabies mRNA vaccine elicits high cross-neutralizing antibody titers and diverse B cell memory responses
Here the authors show that in non-human primates two doses of an mRNA-based rabies vaccine induce higher levels of vaccine-specific B cells and cross-neutralizing antibodies compared to two doses of a licensed whole inactivated virus vaccine.
- Fredrika Hellgren
- , Alberto Cagigi
- & Karin Loré
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Article
| Open AccessExamining protective effects of SARS-CoV-2 neutralizing antibodies after vaccination or monoclonal antibody administration
Here the authors assess neutralizing antibody (nAb) levels as correlate of protection in a monoclonal antibody prevention trial and a vaccine trial for COVID-19 and show that nAb titers correlate with clinical protection against COVID-19 supporting nAb titer as a surrogate endpoint for authorization of monoclonal antibodies.
- Dean Follmann
- , Meagan P. O’Brien
- & Myron S. Cohen
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| Open AccessDiscovery and characterization of potent pan-variant SARS-CoV-2 neutralizing antibodies from individuals with Omicron breakthrough infection
In this study, the authors isolated and characterized neutralizing antibodies from vaccinated individuals with SARS-CoV-2 BA.1 breakthrough infection and show that elite antibodies derived from specific germlines provide potent pan-variant neutralization capacity and in vivo protection.
- Yu Guo
- , Guangshun Zhang
- & Zihe Rao
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| Open AccessEvolution of antibody immunity following Omicron BA.1 breakthrough infection
Authors longitudinally profile SARS-CoV-2 receptor binding domain-specific antibody responses in mRNA-vaccinated individuals, following Omicron BA.1 breakthrough infection.
- Chengzi I. Kaku
- , Tyler N. Starr
- & Laura M. Walker
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Article
| Open AccessIgh and Igk loci use different folding principles for V gene recombination due to distinct chromosomal architectures of pro-B and pre-B cells
V gene recombination at the immunoglobulin heavy chain locus (Igh) is facilitated by extended loop extrusion. In this study, the authors find that, unlike Igh, the κ light chain locus does not involve extended loop extrusion but instead involves multiple, short-range loops for V gene combination.
- Louisa Hill
- , Gordana Wutz
- & Meinrad Busslinger
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| Open AccessVaccination of SARS-CoV-2-infected individuals expands a broad range of clonally diverse affinity-matured B cell lineages
Here, the authors isolated and characterized genetic features of spike-specific monoclonal antibodies. They show how the antibodies evolve from infection to after vaccination and conclude that highly polyclonal repertoires of affinity-matured memory B cells are efficiently recalled by vaccination.
- Mark Chernyshev
- , Mrunal Sakharkar
- & Gunilla B. Karlsson Hedestam
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Article
| Open AccessInactivated vaccine-elicited potent antibodies can broadly neutralize SARS-CoV-2 circulating variants
In this study, the authors isolate and characterize BBIBPCorV inactivated vaccine-elicited human antibodies. They show that these can broadly neutralize a range of SARS-CoV-2 variants and protect mice from Delta and Omicron infection. The neutralization mechanism of bispecific antibodies were solved structurally.
- Yubin Liu
- , Ziyi Wang
- & Gong Cheng
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| Open AccessA ferritin-based COVID-19 nanoparticle vaccine that elicits robust, durable, broad-spectrum neutralizing antisera in non-human primates
Here the authors develop a ferritin-based protein nanoparticle vaccine candidate for SARS-CoV-2, and show induction of neutralizing antibodies to variants of concern, including Omicron BQ.1, in non-human primates after initial immunization and a booster dose.
- Payton A.-B. Weidenbacher
- , Mrinmoy Sanyal
- & Peter S. Kim
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Article
| Open AccessDelayed generation of functional virus-specific circulating T follicular helper cells correlates with severe COVID-19
T follicular helper cells (Tfh) enhance antibody responses and can circulate or be resident in lymph nodes. Here the authors show that during acute SARS-CoV-2 infection, circulating Tfh cells correlate with antibody titres and plasmablast levels but in more severe COVID-19 cases, cTfh generation is delayed.
- Meng Yu
- , Afandi Charles
- & Anna Smed-Sörensen
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Article
| Open AccessHypoimmune anti-CD19 chimeric antigen receptor T cells provide lasting tumor control in fully immunocompetent allogeneic humanized mice
The development of allogeneic chimaeric antigen receptor (CAR) T cells could overcome manufacturing bottlenecks for immunotherapy. However, immune rejection reduces the persistence and efficacy of these cells. Here, the authors generate allogeneic anti-CD19 CAR T cells that can evade the immune system and provide durable anti-tumour responses.
- Xiaomeng Hu
- , Karl Manner
- & Sonja Schrepfer
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Article
| Open AccessSingle-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimers as HIV-1 vaccine candidates
Here the authors present an HIV-1 vaccine strategy that combines Env stabilization, nanoparticle display, and glycan trimming, which improves neutralizing antibody responses, frequency of vaccine responders, and germinal center reactions in animal models.
- Yi-Nan Zhang
- , Jennifer Paynter
- & Jiang Zhu
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Article
| Open AccessThe RNA-binding protein hnRNP F is required for the germinal center B cell response
The germinal centre (GC) response is characterized by regulated production of high affinity, class-switched antibodies in response to T-cell dependent antigens. Here authors show that the GC response is not only regulated at the transcriptional and protein levels, but also by the RNA-binding protein hnRNP F via alternative splicing of the co-stimulatory molecule CD40.
- Hengjun Huang
- , Yuxing Li
- & Xijun Ou
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Article
| Open AccessmRNA vaccines and hybrid immunity use different B cell germlines against Omicron BA.4 and BA.5
Omicron strains of SARS-CoV-2 have displayed high transmissibility and immunological escape to antibody responses derived from natural infection and vaccination. Here the authors compare the antibody response to vaccination and natural infection, assessing neutralisation after vaccine doses and analyse the repertoire of such responses.
- Emanuele Andreano
- , Ida Paciello
- & Rino Rappuoli
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Article
| Open AccessAffinity maturation generates pathogenic antibodies with dual reactivity to DNase1L3 and dsDNA in systemic lupus erythematosus
Antibodies directed against DNA in systemic lupus erythematosus are functionally diverse. This study demonstrates that DNAse1L3 is the primary target of a subset of autoantibodies previously considered specific for double-stranded DNA.
- Eduardo Gomez-Bañuelos
- , Yikai Yu
- & Felipe Andrade
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Article
| Open AccessB cell class switch recombination is regulated by DYRK1A through MSH6 phosphorylation
Class switch recombination (CSR) is a process by which B cells switch their immunoglobulin isotype and develop pathogen-eliminating antibodies. Here, the authors show that a protein kinase DYRK1A is required for protection from viral infection through the regulation of CSR and effective clonal expansion.
- Liat Stoler-Barak
- , Ethan Harris
- & Ziv Shulman
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Article
| Open AccessHIV vaccine candidate efficacy in female macaques mediated by cAMP-dependent efferocytosis and V2-specific ADCC
HIV vaccine development can be aided by knowledge of correlates of protection. Here the authors identify engagement and reprogramming of tolerogenic CD14+ myeloid cells mediating a spatiotemporal balance of pro- and anti-inflammatory responses, as correlates of efficacy in female macaques vaccinated with the DNA/ALVAC/gp120/Alum platform.
- Massimiliano Bissa
- , Sohyoung Kim
- & Genoveffa Franchini
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| Open AccessStructural basis for a conserved neutralization epitope on the receptor-binding domain of SARS-CoV-2
An antibody, IY-2A, identified from a panel of class-4 SARS-CoV-2-neutralizing antibodies isolated from convalescent and vaccinated individuals, targets and induces partial unfolding of a conserved epitope within the RBD. IY-2A retains activity against BA.4/5 subvariants and neutralizes diverse sarbecoviruses.
- Kuan-Ying A. Huang
- , Xiaorui Chen
- & Che Ma
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Article
| Open AccessB cell analyses after SARS-CoV-2 mRNA third vaccination reveals a hybrid immunity like antibody response
SARS-CoV-2 vaccines and infection induce antibody responses but the evolution of subsequent variants has resulted in the development of escape mutants. Here the authors characterise, at single cell level, the antibody response in donors after a third dose of SARS-CoV-2 mRNA vaccination and show difference in breadth, neutralisation and molecular signature according to the vaccination regimen used.
- Emanuele Andreano
- , Ida Paciello
- & Rino Rappuoli
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Article
| Open AccessAntibodies targeting the neuraminidase active site inhibit influenza H3N2 viruses with an S245N glycosylation site
Antibodies that broadly inhibit influenza virus neuraminidase by binding to its active site could be therapeutic candidates, but circulating viruses have acquired a glycosylation site in that region. Here, the authors show that, while the S245N glycosylation site affects binding of tested monoclonal antibodies, protective activity in a mouse model is maintained.
- Daniel Stadlbauer
- , Meagan McMahon
- & Florian Krammer
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Article
| Open AccessPrimary exposure to SARS-CoV-2 variants elicits convergent epitope specificities, immunoglobulin V gene usage and public B cell clones
Vaccines against the WA1 SARS-CoV2 strain confer protection against other variants. However, the mechanisms underlying cross-protection are not fully understood. Here, the authors develop a method for rapid analysis of single B cells from patient samples and show that infection with a variant elicits convergent, public B cell responses to other variants.
- Noemia S. Lima
- , Maryam Musayev
- & Daniel C. Douek
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Article
| Open AccessA p38α-BLIMP1 signalling pathway is essential for plasma cell differentiation
Plasma cells are terminally differentiated B cells that are specialized for antibody secretion. Authors show here that genomic deletion of the p38α mitogen activated protein kinase specifically in the B cell lineage leads to diminished plasma cell differentiation via impairment of a transcriptional regulatory program by BLIMP1.
- Jianfeng Wu
- , Kang Yang
- & Jiahuai Han
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Article
| Open AccessStructural characterization of protective non-neutralizing antibodies targeting Crimean-Congo hemorrhagic fever virus
There are currently no approved treatments for Crimean-Congo Hemorrhagic Fever Virus (CCHFV) infection. In this study, the authors structurally characterize the epitope targeted by protective non-neutralizing mouse and human antibodies and provide insights into their broad range potential against various CCHFV strains.
- Ian A. Durie
- , Zahra R. Tehrani
- & Scott D. Pegan
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| Open AccessA broadly protective human monoclonal antibody targeting the sialidase activity of influenza A and B virus neuraminidases
Broadly protective antibodies targeting influenza viruses are of interest as potential therapeutics or to inform vaccine development. Here the authors characterize a human mAb (DA03E17) with heterosubtypic binding to neuraminidases from IAVs and IBVs that provides broad protection in vitro and in vivo.
- Atsuhiro Yasuhara
- , Seiya Yamayoshi
- & Yoshihiro Kawaoka
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| Open AccessUse of a glycomics array to establish the anti-carbohydrate antibody repertoire in type 1 diabetes
Type I diabetes is characterized by autoantibodies directed against protein or non-protein self-antigens. Here the authors profile glycan reactive anti-carbohydrate antibodies (ACA) in a longitudinal and cross-sectional childhood diabetes cohort and associate clusters of ACA with disease progression.
- Paul M. H. Tran
- , Fran Dong
- & Sharad Purohit
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Article
| Open AccessCryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin M pentamer
Immunoglobulin M (IgM) is the Ig isotype that serves as the first line of host defence during infection. Here, the authors image the full-length IgM pentamer by cryo-EM, revealing the structure and hinge motion of the antigen binding domains.
- Qu Chen
- , Rajesh Menon
- & Peter B. Rosenthal
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Article
| Open AccessPriming conditions shape breadth of neutralizing antibody responses to sarbecoviruses
Vaccination and infection history determine the breadth of neutralizing antibody response to SARS-CoV-2 variants and other sarbecoviruses with breakthrough or natural infection combined with vaccination or booster vaccination with mRNA vaccine providing highest neutralization.
- Janice Zhirong Jia
- , Chee Wah Tan
- & Sophie A. Valkenburg
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Article
| Open AccessChAd155-RSV vaccine is immunogenic and efficacious against bovine RSV infection-induced disease in young calves
A pediatric RSV vaccine is an unmet medical need, even after >50 years of effort. Here, the authors show that a chimpanzee adenovirus based RSV vaccine candidate protects calves from disease upon RSV infection, regardless of the time after vaccination (1 or 4 months) or the presence of maternal antibodies.
- Rineke de Jong
- , Norbert Stockhofe-Zurwieden
- & Ann-Muriel Steff
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Article
| Open AccessEx vivo engineered human plasma cells exhibit robust protein secretion and long-term engraftment in vivo
Plasma B cells (PC) are a potential source for protein replacement as they could be engineered to secrete protein other than antibody. Here the authors engineer B cells to express exogenous proteins and demonstrate that these cells can persist long term in adoptive transfer experiments in mice.
- Rene Yu-Hong Cheng
- , King L. Hung
- & Richard G. James
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Article
| Open AccessDiscriminating cross-reactivity in polyclonal IgG1 responses against SARS-CoV-2 variants of concern
Profiling antibody repertoires using proteomic approaches may provide a way of screening for antibody cross-reactivity against SARS-CoV-2 variants. Here the authors use a IgG1 specific cleavage method to analyse the IgG1 repertoire within recovered patients and relate this to antibody binding and neutralisation.
- Danique M. H. van Rijswijck
- , Albert Bondt
- & Albert J. R. Heck
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Article
| Open AccessNeutralizing and interfering human antibodies define the structural and mechanistic basis for antigenic diversion
The Plasmodium falciparum Merozoite Surface Protein 1 (MSP-1) is a prime vaccine candidate for malaria. Here, the authors structurally and functionally characterise a panel of naturally acquired MSP-1 specific antibodies to identify one with potent broadly neutralising activity and better understand immune evasion mechanisms.
- Palak N. Patel
- , Thayne H. Dickey
- & Niraj H. Tolia
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Article
| Open AccessSpike-antibody responses to COVID-19 vaccination by demographic and clinical factors in a prospective community cohort study
Vaccination can provide reliable and long-lasting protection against COVID-19, however the immune response to vaccination can vary between individuals and can decline over time, leading to differences in protective effects. Here the authors assess the immune response to COVID-19 vaccination across a large cohort of previously uninfected adults and demonstrate lower post-vaccination antibody levels amongst those with immune-suppressing conditions and medications, as well as those with several other more common chronic conditions.
- Madhumita Shrotri
- , Ellen Fragaszy
- & Robert W. Aldridge
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Article
| Open AccessCombined IgE neutralization and Bifidobacterium longum supplementation reduces the allergic response in models of food allergy
IgE is a critical component of the allergic response and therapeutic targeting can alleviate symptomology. Here the authors propose the combined use of Bifidobacterium longum and a FcεRIα extracellular domain linked to a IgD/IgG4 hybrid Fc domain fusion protein called IgETRAP and show reduction of mast cell and IgE levels in models of food allergy.
- Seong Beom An
- , Bo-Gie Yang
- & Myoung Ho Jang
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Article
| Open AccessCirculating multimeric immune complexes contribute to immunopathology in COVID-19
During viral infections high levels of antibodies can form soluble immune complexes (sICs) with antigen and trigger Fcγ receptors (FcγR) leading to increased immunopathology. Here the authors measure FcγRs activation by sICs and consider how these may lead to excessive immunopathology during severe SARS-CoV-2 infection.
- Jakob Ankerhold
- , Sebastian Giese
- & Valeria Falcone
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Article
| Open AccessEngineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth
Bispecific antibodies can have advantages compared to antibody cocktails. Here, the authors engineer and characterize two different approaches for generating bispecific SARS-CoV-2 specific antibodies and find that only one design increases antigen-binding and virus neutralizing activities.
- Zhiqiang Ku
- , Xuping Xie
- & Zhiqiang An
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Article
| Open AccessMagnitude of venous or capillary blood-derived SARS-CoV-2-specific T cell response determines COVID-19 immunity
The presence of SARS-CoV-2-specific antibodies alone is not an accurate determinant of immunity. In this work, the authors investigate if whole-blood based measurement of SARS-CoV-2 specific T cell responses could prognosticate the risk of possible SARS-CoV-2 infection, and recapitulate their findings in a capillary blood-based assay.
- Martin J. Scurr
- , George Lippiatt
- & Andrew Godkin
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Article
| Open AccessSerum neutralization activity declines but memory B cells persist after cure of chronic hepatitis C
Long-term dynamics of the humoral response to HCV in cured individuals aren’t well understood. Here, Nishio et al. show that virus-neutralizing antibody levels decrease in potency and breadth after cure of chronic hepatitis C, while HCV-specific memory B cells persist.
- Akira Nishio
- , Sharika Hasan
- & Barbara Rehermann
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Article
| Open AccessTherapeutic high affinity T cell receptor targeting a KRASG12D cancer neoantigen
Cancers often harbor mutations in genes encoding important regulatory proteins, but therapeutic targeting of these molecules proves difficult due to their high structural similarity to their non-mutated counterpart. Here authors show the engineering of T cell engaging bispecific protein able to selectively target cancer cells with a high-frequency mutation in the KRAS oncogene.
- Andrew Poole
- , Vijaykumar Karuppiah
- & Chandramouli Chillakuri
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Article
| Open AccessMolecular insights into antibody-mediated protection against the prototypic simian immunodeficiency virus
SIVmac239 infection of macaques is a favored model of human HIV infection, but antibody-mediated protection for SIVmac239 is insufficiently understood. Here, Zhao and Berndsen et al isolated nAbs and confirmed protection against SIVmac239 infection in passive transfer studies in macaques. The nAb was used to provide the first high-resolution structure of a rhesus SIV trimer by CryoEM. Analysis of the glycosylation pattern of this SIV trimer suggests a denser glycan shield on Env for rhesus SIV compared to chimpanzee SIV or HIV-1, which partially explains the poor nAb response of rhesus macaques to SIVmac239 infection.
- Fangzhu Zhao
- , Zachary T. Berndsen
- & Devin Sok
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Article
| Open AccessBNT162b2-boosted immune responses six months after heterologous or homologous ChAdOx1nCoV-19/BNT162b2 vaccination against COVID-19
Vaccines against SARS-CoV-2 have changed the course of the COVID-19 pandemics, but waning immunity necessitates repeated immunization. Authors here show that immunity declines faster following two doses of vector-based vaccine compared to a first dose of vector-based vaccine followed by boosting with an mRNA vaccine, but application of an mRNA vaccine as a third dose minimises the difference between the two groups.
- Georg M. N. Behrens
- , Joana Barros-Martins
- & Reinhold Förster
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Article
| Open AccessOmicron BA.4/BA.5 escape neutralizing immunity elicited by BA.1 infection
Emerging SARS-CoV-2 Omicron sub-lineages BA.4 and BA.5 raise concerns about potential immune evasion. Here, Khan et al. show that both BA.4 and BA.5 are able to escape immune response induced by prior BA.1 infection, but that this effect is less pronounced in vaccinated individuals.
- Khadija Khan
- , Farina Karim
- & Alex Sigal