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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models 1 , 2 . Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence. In a cohort of 87 individuals with COVID-19, the memory B cell response at 6.2 months after the onset of disease evolves in a manner that is consistent with the persistence of SARS-CoV-2 antigen.

Here we report on the antibody and memory B cell responses of a cohort of 20 volunteers who received the Moderna (mRNA-1273) or Pfizer–BioNTech (BNT162b2) vaccine against SARS-CoV-2 1 – 4 . Eight weeks after the second injection of vaccine, volunteers showed high levels of IgM and IgG anti-SARS-CoV-2 spike protein (S) and receptor-binding-domain (RBD) binding titre. Moreover, the plasma neutralizing activity and relative numbers of RBD-specific memory B cells of vaccinated volunteers were equivalent to those of individuals who had recovered from natural infection 5 , 6 . However, activity against SARS-CoV-2 variants that encode E484K-, N501Y- or K417N/E484K/N501-mutant S was reduced by a small—but significant—margin. The monoclonal antibodies elicited by the vaccines potently neutralize SARS-CoV-2, and target a number of different RBD epitopes in common with monoclonal antibodies isolated from infected donors 5 – 8 . However, neutralization by 14 of the 17 most-potent monoclonal antibodies that we tested was reduced or abolished by the K417N, E484K or N501Y mutation. Notably, these mutations were selected when we cultured recombinant vesicular stomatitis virus expressing SARS-CoV-2 S in the presence of the monoclonal antibodies elicited by the vaccines. Together, these results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid a potential loss of clinical efficacy. The Moderna (mRNA-1273) and Pfizer–BioNTech (BNT162b2) vaccines elicit anti-RBD antibodies similar to those elicited through natural infection with SARS-CoV-2, but their potent neutralizing activity was reduced or abolished by new viral variants of concern.

A single injection of four anti-HIV-1-neutralizing monoclonal antibodies blocks repeated weekly low-dose virus challenges of simian/human immunodeficiency virus. Immunoprophylaxis against HIV-1 infection This study assesses the long-term efficacy of a passive antibody transfer approach for the control of human immunodeficiency virus type 1 (HIV-1) infection. Malcolm Martin and colleagues administered single intravenous injections of four different anti-HIV-1 neutralizing monoclonal antibodies in a simian/HIV intrarectal exposure model involving weekly low-dose viral challenge and demonstrate protection from infection lasting almost 6 months. Despite the success of potent anti-retroviral drugs in controlling human immunodeficiency virus type 1 (HIV-1) infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 broadly neutralizing antibodies can protect mice or macaques against a single high-dose challenge with HIV or simian/human (SIV/HIV) chimaeric viruses (SHIVs) respectively 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Here we show, on the basis of the relatively long-term protection conferred by hepatitis A immune globulin, the efficacy of a single injection (20 mg kg −1 ) of four anti-HIV-1-neutralizing monoclonal antibodies (VRC01, VRC01-LS, 3BNC117, and 10-1074 (refs 9 , 10 , 11 , 12 )) in blocking repeated weekly low-dose virus challenges of the clade B SHIV AD8 . Compared with control animals, which required two to six challenges (median = 3) for infection, a single broadly neutralizing antibody infusion prevented virus acquisition for up to 23 weekly challenges. This effect depended on antibody potency and half-life. The highest levels of plasma-neutralizing activity and, correspondingly, the longest protection were found in monkeys administered the more potent antibodies 3BNC117 and 10-1074 (median = 13 and 12.5 weeks, respectively). VRC01, which showed lower plasma-neutralizing activity, protected for a shorter time (median = 8 weeks). The introduction of a mutation that extends antibody half-life into the crystallizable fragment (Fc) domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered to populations at high risk of HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission.

A mutation in VRC01, a broadly neutralizing, HIV-1-specific antibody, confers enhanced binding to the neonatal Fc receptor, increasing the antibody half-life in the serum and localization in mucosal tissues, where it provides superior protection against rectal simian HIV-1 infection in macaques. Enhanced anti-HIV activity in mutant VRC01 antibody The recent discovery of broad and potent anti-HIV-1 antibodies has renewed interest in their use for passive protection against human immunodeficiency virus-1 in humans. This paper describes a mutation in the HIV-specific broadly neutralizing antibody VRC01 that confers enhanced binding to the neonatal Fc receptor and increases the antibody half-life in serum and mucosal tissues. It conferred superior protection in a rectal simian-HIV challenge model in macaques when compared to wild-type VRC01. To protect against human immunodeficiency virus (HIV-1) infection, broadly neutralizing antibodies (bnAbs) must be active at the portals of viral entry in the gastrointestinal or cervicovaginal tracts. The localization and persistence of antibodies at these sites is influenced by the neonatal Fc receptor (FcRn) 1 , 2 , whose role in protecting against infection in vivo has not been defined. Here, we show that a bnAb with enhanced FcRn binding has increased gut mucosal tissue localization, which improves protection against lentiviral infection in non-human primates. A bnAb directed to the CD4-binding site of the HIV-1 envelope (Env) protein (denoted VRC01) 3 was modified by site-directed mutagenesis to increase its binding affinity for FcRn. This enhanced FcRn-binding mutant bnAb, denoted VRC01-LS, displayed increased transcytosis across human FcRn-expressing cellular monolayers in vitro while retaining FcγRIIIa binding and function, including antibody-dependent cell-mediated cytotoxicity (ADCC) activity, at levels similar to VRC01 (the wild type). VRC01-LS had a threefold longer serum half-life than VRC01 in non-human primates and persisted in the rectal mucosa even when it was no longer detectable in the serum. Notably, VRC01-LS mediated protection superior to that afforded by VRC01 against intrarectal infection with simian–human immunodeficiency virus (SHIV). These findings suggest that modification of FcRn binding provides a mechanism not only to increase serum half-life but also to enhance mucosal localization that confers immune protection. Mutations that enhance FcRn function could therefore increase the potency and durability of passive immunization strategies to prevent HIV-1 infection.

The authors describe a 69-year-old man with Covid-19 diagnosed in January 2020 in Wuhan, China, along with two other critically ill patients with Covid-19 who were also seen in the same intensive care unit. Coagulopathy and antiphospholipid antibodies were seen in all three patients.

Infection with Zika virus has occurred in areas previously exposed to dengue virus, a closely related flavivirus. Screaton and colleagues find that monoclonal antibodies to dengue virus cross-react with Zika virus and enhance infection. Zika virus (ZIKV) was discovered in 1947 and was thought to lead to relatively mild disease. The recent explosive outbreak of ZIKV in South America has led to widespread concern, with reports of neurological sequelae ranging from Guillain Barré syndrome to microcephaly. ZIKV infection has occurred in areas previously exposed to dengue virus (DENV), a flavivirus closely related to ZIKV. Here we investigated the serological cross-reaction between the two viruses. Plasma immune to DENV showed substantial cross-reaction to ZIKV and was able to drive antibody-dependent enhancement (ADE) of ZIKV infection. Using a panel of human monoclonal antibodies (mAbs) to DENV, we showed that most antibodies that reacted to DENV envelope protein also reacted to ZIKV. Antibodies to linear epitopes, including the immunodominant fusion-loop epitope, were able to bind ZIKV but were unable to neutralize the virus and instead promoted ADE. Our data indicate that immunity to DENV might drive greater ZIKV replication and have clear implications for disease pathogenesis and future vaccine programs for ZIKV and DENV.

HIV broadly neutralizing antibodies (bnAbs) can suppress viremia and protect against HIV infection. However, their elicitation is made difficult by low frequencies of appropriate precursor B cell receptors and the complex maturation pathways required to generate bnAbs from these precursors. Antibody genes can be engineered into B cells for expression as both a functional antigen receptor on cell surfaces and as secreted antibody. Here, we show that HIV bnAb-engineered primary mouse B cells can be adoptively transferred and vaccinated in immunocompetent mice resulting in the expansion of durable bnAb memory and long-lived plasma cells. Somatic hypermutation after immunization indicates that engineered cells have the capacity to respond to an evolving pathogen. These results encourage further exploration of engineered B cell vaccines as a strategy for durable elicitation of HIV bnAbs to protect against infection and as a contributor to a functional HIV cure. A vaccine to generate durable HIV broadly neutralizing antibodies (bnAb) from engineered B cells holds promise as an HIV functional cure. Here, the authors show that CRISPR/Cas-modified B cells expressing bnAbs as functional antigen receptors can be immunized to generate long-lived, germinal centre matured bnAb memory and plasma cells in mice.

ABSTRACT HIV viremia can be controlled by chronic antiretroviral therapy. As a potentially single-shot alternative, B cells engineered by CRISPR/Cas9 to express anti-HIV broadly neutralizing antibodies (bNAbs) are capable of secreting high antibody titers. Here, we show that, upon immunization of mice, adoptively transferred engineered B cells home to germinal centers (GC) where they predominate over the endogenous response and differentiate into memory and plasma cells while undergoing class switch recombination (CSR). Immunization with a high affinity antigen increases accumulation in GCs and CSR rates. Boost immunization increases the rate of engineered B cells in GCs and antibody secretion, indicating memory retention. Finally, antibody sequences of engineered B cells in the spleen show patterns of clonal selection. Therefore, B cells can be engineered into what could be a living and evolving drug. Chronic antiretroviral therapy does not eradicate HIV infection. Here, the authors describe a potentially one-shot alternative by engineering B cells to express anti-HIV antibodies and undergo memory retention, isotype switching and clonal expansion

In this 52-week randomized trial, the α 4 β 7 integrin antibody vedolizumab was effective in treating Crohn's disease. The incidence of serious adverse events was higher with vedolizumab than with placebo. Crohn's disease is a chronic inflammatory bowel disease. 1 Current treatments include glucocorticoids, immunosuppressive agents (i.e., azathioprine, mercaptopurine, or methotrexate), and tumor necrosis factor (TNF) antagonists. 1 – 3 Many patients do not have a response to therapy, 4 and treatments are associated with important toxic effects. 5 , 6 Natalizumab, a monoclonal antibody that modulates gut and brain lymphocyte migration by antagonizing α 4 β 1 and α 4 β 7 integrin–mediated interactions, 7 is efficacious in the treatment of multiple sclerosis 8 , 9 and Crohn's disease. 10 – 12 Its use in patients with Crohn's disease has been limited by the development in some patients of progressive multifocal . . .

Background Virus neutralising antibodies in serum are considered key correlates of protection for vaccines and monoclonal antibodies against respiratory syncytial virus (RSV). RSM01 is a novel, highly-potent, half-life-extended and fully-human monoclonal antibody candidate targeting the RSV prefusion F protein. Currently in Phase 1 development, RSM01 is primarily being developed to potentially provide an effective and affordable RSV prevention strategy in low- and middle-income countries. To evaluate the ability of dried blood collection to generate data sets and conclusions comparable to serum collection, we compared pharmacokinetics (PK) of RSM01, immunogenicity, and virus neutralisation for dried capillary blood samples with serum samples. Methods RSM01 PK, anti-drug antibodies (ADA), and RSV-neutralising antibodies from the Phase 1 trial were analyzed and compared between matched serum and dried blood samples. Deming regression analysis was performed using baseline-corrected values to evaluate correlation between measurements in liquid serum versus dried blood. Results The analysis showed good correlation (R 2  > 0.95) between individual RSM01 concentrations measured in both serum and capillary blood. Analysis of RSM01 PK parameters in capillary blood yielded equivalent conclusions as from serum. A strong correlation (R 2  > 0.95) was observed between RSV neutralising activity measured in both serum and capillary blood. In addition, RSV neutralising activity was correlated with RSM01 concentrations in both serum and capillary blood data sets. For ADA, individual sample results had 96% agreement (290/302) and overall participant ADA status had 93% agreement (52/56). Conclusions Both RSM01 concentrations and RSV neutralising activity showed a strong correlation between the serum and blood measurements. ADA measurements also had an agreement of > 90% for individual samples and overall participant status. Our results demonstrate that dried blood is a suitable specimen type for collection and evaluation in the RSM01 clinical development program and shows promise as a useful approach to reduce patient burden in clinical trials, particularly for infants in low- and middle-income countries. Trial Registration Clinicaltrials.gov NCT05118386 November 12, 2021.