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Journal articles on the topic 'Broadly neutralizing antibodies (bNAbs)'

Author: Grafiati

Published: 27 July 2024

Last updated: 31 July 2025

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1

Karuna, Shelly T., and Lawrence Corey. "Broadly Neutralizing Antibodies for HIV Prevention." Annual Review of Medicine 71, no. 1 (2020): 329–46. http://dx.doi.org/10.1146/annurev-med-110118-045506.

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In the last decade, over a dozen potent broadly neutralizing antibodies (bnAbs) to several HIV envelope protein epitopes have been identified, and their in vitro neutralization profiles have been defined. Many have demonstrated prevention efficacy in preclinical trials and favorable safety and pharmacokinetic profiles in early human clinical trials. The first human prevention efficacy trials using 10 sequential, every-two-month administrations of a single anti-HIV bnAb are anticipated to conclude in 2020. Combinations of complementary bnAbs and multi-specific bnAbs exhibit improved breadth and

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2

Yang, Guang, Mengfei Liu, Kevin Wiehe, et al. "HIV broadly neutralizing antibodies and immunological tolerance (VAC7P.988)." Journal of Immunology 192, no. 1_Supplement (2014): 141.33. http://dx.doi.org/10.4049/jimmunol.192.supp.141.33.

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Abstract It is generally thought that many human antibodies (Ab) that neutralize multiple clades of HIV-1 (bnAbs) are self-reactive. We previously identified kynureninase as the primary self-antigen recognized by 2F5, suggesting that generation of Ab to the 2F5 epitope of HIV-1 may be proscribed by immune tolerance, a notion supported by impaired B-cell development in mice expressing the 2F5 VH and VL regions. However, there is a lack of quantitative and systemic assessment of polyreactivity among HIV bnAbs. In addition, it is unknown whether other classes of HIV-1 bnAbs and non-neutralizing a

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3

Lubow, Jay, Lisa M. Levoir, Duncan K. Ralph, et al. "Single B cell transcriptomics identifies multiple isotypes of broadly neutralizing antibodies against flaviviruses." PLOS Pathogens 19, no. 10 (2023): e1011722. http://dx.doi.org/10.1371/journal.ppat.1011722.

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Sequential dengue virus (DENV) infections often generate neutralizing antibodies against all four DENV serotypes and sometimes, Zika virus. Characterizing cross-flavivirus broadly neutralizing antibody (bnAb) responses can inform countermeasures that avoid enhancement of infection associated with non-neutralizing antibodies. Here, we used single cell transcriptomics to mine the bnAb repertoire following repeated DENV infections. We identified several new bnAbs with comparable or superior breadth and potency to known bnAbs, and with distinct recognition determinants. Unlike all known flavivirus

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Sprenger, Kayla G., Joy E. Louveau, Pranav M. Murugan, and Arup K. Chakraborty. "Optimizing immunization protocols to elicit broadly neutralizing antibodies." Proceedings of the National Academy of Sciences 117, no. 33 (2020): 20077–87. http://dx.doi.org/10.1073/pnas.1919329117.

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Natural infections and vaccination with a pathogen typically stimulate the production of potent antibodies specific for the pathogen through a Darwinian evolutionary process known as affinity maturation. Such antibodies provide protection against reinfection by the same strain of a pathogen. A highly mutable virus, like HIV or influenza, evades recognition by these strain-specific antibodies via the emergence of new mutant strains. A vaccine that elicits antibodies that can bind to many diverse strains of the virus—known as broadly neutralizing antibodies (bnAbs)—could protect against highly m

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Glazkova, D. V., E. V. Bogoslovskaya, G. A. Shipulin, and S. M. Yudin. "Broadly neutralizing antibodies for the treatment of HIV infection." HIV Infection and Immunosuppressive Disorders 13, no. 3 (2021): 81–95. http://dx.doi.org/10.22328/2077-9828-2021-13-3-81-95.

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Antibodies with neutralizing activity against a wide range of human immunodeficiency virus 1 subtypes (known as broadly neutralizing antibodies — bNAb) are of great interest as a therapeutic agent for the treatment of HIV infection, because they are able to provide natural protection against most HIV-1 strains. The review discusses the mechanisms of formation of bNAbs, their classification by binding to conservative regions of the envelope protein, as well as their intrinsic features. Description of the most promising bNAbs and their combinations is presented.In the last section the results of

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Steichen, Jon M., Ying-Cing Lin, Colin Havenar-Daughton, et al. "A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses." Science 366, no. 6470 (2019): eaax4380. http://dx.doi.org/10.1126/science.aax4380.

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Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer–based immunogens that primed responses from rare bnAb-precursor B cells in a mouse mod

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7

Shrader, Hannah, Sabrina Helmold Hait, Sarah Lovelace, et al. "Phenotypic analysis of HIV-1 resistance to CD4 binding site broadly-neutralizing antibodies." Journal of Immunology 210, no. 1_Supplement (2023): 223.08. http://dx.doi.org/10.4049/jimmunol.210.supp.223.08.

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Abstract Broadly neutralizing antibodies (bNAbs) show strong immunotherapy potential by targeting conserved regions of the HIV-1 envelope. Single bNAb use in viremic individuals quickly results in the emergence of escape variants, likely originating from existing quasispecies. An ex vivo assay was developed to predict bNAb efficacy in viremic individuals. The development of a predictive bNAb efficacy model may assist with the planning of future clinical trials. The ex vivoassay used pre-infusion CD4 +T cells from participants enrolled in the VRC 607/ACTG A5378 phase I study of the CD4 binding

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8

Thavarajah, Jannifer Jasmin, Bo Langhoff Hønge, and Christian Morberg Wejse. "The Use of Broadly Neutralizing Antibodies (bNAbs) in HIV-1 Treatment and Prevention." Viruses 16, no. 6 (2024): 911. http://dx.doi.org/10.3390/v16060911.

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Background: Although antiretroviral therapy (ART) effectively halts disease progression in HIV infection, the complete eradication of the virus remains elusive. Additionally, challenges such as long-term ART toxicity, drug resistance, and the demanding regimen of daily and lifelong adherence required by ART highlight the imperative need for alternative therapeutic and preventative approaches. In recent years, broadly neutralizing antibodies (bNAbs) have emerged as promising candidates, offering potential for therapeutic, preventative, and possibly curative interventions against HIV infection.

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9

Kumar, Rajesh, Huma Qureshi, Suprit Deshpande, and Jayanta Bhattacharya. "Broadly neutralizing antibodies in HIV-1 treatment and prevention." Therapeutic Advances in Vaccines and Immunotherapy 6, no. 4 (2018): 61–68. http://dx.doi.org/10.1177/2515135518800689.

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Antibodies that naturally develop in some individuals infected with human immunodeficiency virus 1 (HIV-1) and are capable of broadly neutralizing diverse strains of HIV-1 are useful for two applications: they can inform the rational design of vaccine immunogens, and they may be capable of preventing and treating HIV-1 infection when administered passively. A phase IIb study has been initiated with the experimental broadly neutralizing antibody (bnAb) VRC01, which has considerable breadth and potency (also referred to as a phase IIb HVTN 703/HPTN 081 and HVTN 704/HPTN 085 AMP efficacy trials)

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10

Xu, Ling, Amarendra Pegu, Ercole Rao, et al. "Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques." Science 358, no. 6359 (2017): 85–90. http://dx.doi.org/10.1126/science.aan8630.

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The development of an effective AIDS vaccine has been challenging because of viral genetic diversity and the difficulty of generating broadly neutralizing antibodies (bnAbs). We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: the CD4 binding site, the membrane-proximal external region (MPER), and the V1V2 glycan site. Trispecific Abs exhibited higher potency and breadth than any previously described single bnAb, showed pharmacokinetics similar to those of human bnAbs, and conferred complete immunity against a

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11

Mayer, Bryan T., Allan C. deCamp, Yunda Huang, et al. "Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention." PLOS Computational Biology 18, no. 4 (2022): e1010003. http://dx.doi.org/10.1371/journal.pcbi.1010003.

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Broadly neutralizing antibodies (bNAbs) are promising agents to prevent HIV infection and achieve HIV remission without antiretroviral therapy (ART). As with ART, bNAb combinations are likely needed to cover HIV’s extensive diversity. Not all bNAbs are identical in terms of their breadth, potency, and in vivo longevity (half-life). Given these differences, it is important to optimally select the composition, or dose ratio, of combination bNAb therapies for future clinical studies. We developed a model that synthesizes 1) pharmacokinetics, 2) potency against a wide HIV diversity, 3) interaction

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Becerra, Juan C., Lauren Hitchcock, Khoa Vu, and Johannes S. Gach. "Neutralizing the threat: harnessing broadly neutralizing antibodies against HIV-1 for treatment and prevention." Microbial Cell 11 (July 3, 2024): 207–20. http://dx.doi.org/10.15698/mic2024.07.826.

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Abstract Broadly neutralizing antibodies (bnAbs) targeting the human immunodeficiency virus-1 (HIV-1) have played a crucial role in elucidating and characterizing neutralization-sensitive sites on the HIV-1 envelope spike and in informing vaccine development. Continual advancements in identifying more potent bnAbs, along with their capacity to trigger antibody-mediated effector functions, coupled with modifications to extend their half-life, position them as promising candidates for both HIV-1 treatment and prevention. While current pharmacological interventions have made significant progress

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Khurana, Surender, Megan Hahn, Laura Klenow, and Hana Golding. "Autoreactivity of Broadly Neutralizing Influenza Human Antibodies to Human Tissues and Human Proteins." Viruses 12, no. 10 (2020): 1140. http://dx.doi.org/10.3390/v12101140.

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Broadly neutralizing monoclonal antibodies (bNAbs) against conserved domains in the influenza hemagglutinin are in clinical trials. Several next generation influenza vaccines designed to elicit such bNAbs are also in clinical development. One of the common features of the isolated bNAbs is the use of restricted IgVH repertoire. More than 80% of stem-targeting bNAbs express IgVH1-69, which may indicate genetic constraints on the evolution of such antibodies. In the current study, we evaluated a panel of influenza virus bNAbs in comparison with HIV-1 MAb 4E10 and anti-RSV MAb Palivizumab (approv

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Smith, S. Abigail, and Cynthia A. Derdeyn. "Harnessing the protective potential of HIV-1 neutralizing antibodies." F1000Research 5 (January 5, 2016): 20. http://dx.doi.org/10.12688/f1000research.7254.1.

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Recent biological, structural, and technical advances are converging within the HIV-1 vaccine field to harness the power of antibodies for prevention and therapy. Numerous monoclonal antibodies with broad neutralizing activity against diverse HIV-1 isolates have now been identified, revealing at least five sites of vulnerability on the envelope (Env) glycoproteins. While there are practical and technological barriers blocking a clear path from broadly neutralizing antibodies (bNAb) to a protective vaccine, this is not a dead end. Scientists are revisiting old approaches with new technology, cu

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15

McGuire, Andrew T., Sam Hoot, Anita M. Dreyer, et al. "Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies." Journal of Experimental Medicine 210, no. 4 (2013): 655–63. http://dx.doi.org/10.1084/jem.20122824.

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Broadly neutralizing antibodies (bnAbs) against HIV are believed to be a critical component of the protective responses elicited by an effective HIV vaccine. Neutralizing antibodies against the evolutionarily conserved CD4-binding site (CD4-BS) on the HIV envelope glycoprotein (Env) are capable of inhibiting infection of diverse HIV strains, and have been isolated from HIV-infected individuals. Despite the presence of anti–CD4-BS broadly neutralizing antibody (bnAb) epitopes on recombinant Env, Env immunization has so far failed to elicit such antibodies. Here, we show that Env immunogens fail

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Mishra, Nitesh, Sanjeev Kumar, Swarandeep Singh, et al. "Cross-neutralization of SARS-CoV-2 by HIV-1 specific broadly neutralizing antibodies and polyclonal plasma." PLOS Pathogens 17, no. 9 (2021): e1009958. http://dx.doi.org/10.1371/journal.ppat.1009958.

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Cross-reactive epitopes (CREs) are similar epitopes on viruses that are recognized or neutralized by same antibodies. The S protein of SARS-CoV-2, similar to type I fusion proteins of viruses such as HIV-1 envelope (Env) and influenza hemagglutinin, is heavily glycosylated. Viral Env glycans, though host derived, are distinctly processed and thereby recognized or accommodated during antibody responses. In recent years, highly potent and/or broadly neutralizing human monoclonal antibodies (bnAbs) that are generated in chronic HIV-1 infections have been defined. These bnAbs exhibit atypical feat

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17

Altman, Pilar X., Gabriel Ozorowski, Robyn L. Stanfield, et al. "Immunization of cows with HIV envelope trimers generates broadly neutralizing antibodies to the V2-apex from the ultralong CDRH3 repertoire." PLOS Pathogens 20, no. 9 (2024): e1012042. http://dx.doi.org/10.1371/journal.ppat.1012042.

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The generation of broadly neutralizing antibodies (bnAbs) to conserved epitopes on HIV Envelope (Env) is one of the cornerstones of HIV vaccine research. The animal models commonly used for HIV do not reliably produce a potent broadly neutralizing serum antibody response, with the exception of cows. Cows have previously produced a CD4 binding site response by homologous prime and boosting with a native-like Env trimer. In small animal models, other engineered immunogens were shown to focus antibody responses to the bnAb V2-apex region of Env. Here, we immunized two groups of cows (n = 4) with

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18

Medina-Ramírez, Max, Fernando Garces, Amelia Escolano, et al. "Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo." Journal of Experimental Medicine 214, no. 9 (2017): 2573–90. http://dx.doi.org/10.1084/jem.20161160.

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Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOSIP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOSIP.v4.1-GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC

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19

An, Zhiyin, Yu Zhang, Xiang Yu, et al. "The Screening of Broadly Neutralizing Antibodies Targeting the SARS-CoV-2 Spike Protein by mRNA Immunization in Mice." Pharmaceutics 15, no. 5 (2023): 1412. http://dx.doi.org/10.3390/pharmaceutics15051412.

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Neutralizing antibodies (nAbs), the popular antiviral drugs used for the treatment of COVID-19, are effective in reducing viral load and hospitalization. Currently, most nAbs are screened from convalescent or vaccinated individuals through single B-cell sequencing which requires cutting-edge facilities. Moreover, owing to the rapid mutation of SARS-CoV-2, some approved nAbs are no longer effective. In the present study, we designed a new approach to acquiring broadly neutralizing antibodies (bnAbs) from mRNA-vaccinated mice. Using the flexibility and speed of mRNA vaccine preparation, we desig

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20

Noailly, Blandine, Melyssa Yaugel-Novoa, Justine Werquin, et al. "Antiviral Activities of HIV-1-Specific Human Broadly Neutralizing Antibodies Are Isotype-Dependent." Vaccines 10, no. 6 (2022): 903. http://dx.doi.org/10.3390/vaccines10060903.

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Broadly neutralizing antibodies (bNAbs) offer promising opportunities for preventing HIV-1 infection. The protection mechanisms of bNAbs involve the Fc domain, as well as their Fab counterpart. Here, different bNAb isotypes including IgG1, IgA1, IgA2, and IgA122 (IgA2 with the hinge of IgA1) were generated and then produced in CHO cells. Their ability to neutralize pseudovirus and primary HIV-1 isolates were measured, as well as their potential ADCC-like activity using a newly developed assay. In our work, gp41-specific IgA seems to be more efficient than IgG1 in inducing ADCC-like activity, b

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Caillat, Christophe, Delphine Guilligay, Guidenn Sulbaran, and Winfried Weissenhorn. "Neutralizing Antibodies Targeting HIV-1 gp41." Viruses 12, no. 11 (2020): 1210. http://dx.doi.org/10.3390/v12111210.

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HIV-1 vaccine research has obtained an enormous boost since the discovery of many broadly neutralizing antibodies (bnAbs) targeting all accessible sites on the HIV-1 envelope glycoprotein (Env). This in turn facilitated high-resolution structures of the Env glycoprotein in complex with bnAbs. Here we focus on gp41, its highly conserved heptad repeat region 1 (HR1), the fusion peptide (FP) and the membrane-proximal external region (MPER). Notably, the broadest neutralizing antibodies target MPER. Both gp41 HR1 and MPER are only fully accessible once receptor-induced conformational changes have

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Sakoi-Mosetlhi, Maureen, Gbolahan Ajibola, Roxanna Haghighat, et al. "Caregivers of children with HIV in Botswana prefer monthly IV Broadly Neutralizing Antibodies (bNAbs) to daily oral ART." PLOS ONE 19, no. 3 (2024): e0299942. http://dx.doi.org/10.1371/journal.pone.0299942.

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Introduction Monthly intravenous infusion of broadly neutralizing monoclonal antibodies may be an attractive alternative to daily oral antiretroviral treatment for children living with HIV. However, acceptability among caregivers remains unknown. Methods We evaluated monthly infusion of dual bNAbs (VRCO1LS and 10–1074) as a treatment alternative to ART among children participating in the Tatelo Study in Botswana. Eligible children aged 2–5 years received 8–32 weeks of bNAbs overlapping with ART, and up to 24 weeks of bNAbs alone as monthly intravenous infusion. Using closed-ended questionnaire

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Igiraneza, Aime Bienfait, Panagiota Zacharopoulou, Robert Hinch, et al. "Learning patterns of HIV-1 resistance to broadly neutralizing antibodies with reduced subtype bias using multi-task learning." PLOS Computational Biology 20, no. 11 (2024): e1012618. http://dx.doi.org/10.1371/journal.pcbi.1012618.

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The ability to predict HIV-1 resistance to broadly neutralizing antibodies (bnAbs) will increase bnAb therapeutic benefits. Machine learning is a powerful approach for such prediction. One challenge is that some HIV-1 subtypes in currently available training datasets are underrepresented, which likely affects models’ generalizability across subtypes. A second challenge is that combinations of bnAbs are required to avoid the inevitable resistance to a single bnAb, and computationally determining optimal combinations of bnAbs is an unsolved problem. Recently, machine learning models trained usin

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Wasilewski, Lisa N., Ramy El-Diwany, Supriya Munshaw, et al. "A Hepatitis C Virus Envelope Polymorphism Confers Resistance to Neutralization by Polyclonal Sera and Broadly Neutralizing Monoclonal Antibodies." Journal of Virology 90, no. 7 (2016): 3773–82. http://dx.doi.org/10.1128/jvi.02837-15.

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ABSTRACTHepatitis C virus (HCV) infection is a global health problem, with millions of chronically infected individuals at risk for cirrhosis and hepatocellular carcinoma. HCV vaccine development is vital in the effort toward disease control and eradication, an undertaking aided by an increased understanding of the mechanisms of resistance to broadly neutralizing antibodies (bNAbs). In this study, we identified HCV codons that vary deep in a phylogenetic tree of HCV sequences and showed that a polymorphism at one of these positions renders Bole1a, a computationally derived, ancestral genotype

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Stephenson, Kathryn E., Kshitij Wagh, Bette Korber, and Dan H. Barouch. "Vaccines and Broadly Neutralizing Antibodies for HIV-1 Prevention." Annual Review of Immunology 38, no. 1 (2020): 673–703. http://dx.doi.org/10.1146/annurev-immunol-080219-023629.

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Development of improved approaches for HIV-1 prevention will likely be required for a durable end to the global AIDS pandemic. Recent advances in preclinical studies and early phase clinical trials offer renewed promise for immunologic strategies for blocking acquisition of HIV-1 infection. Clinical trials are currently underway to evaluate the efficacy of two vaccine candidates and a broadly neutralizing antibody (bNAb) to prevent HIV-1 infection in humans. However, the vast diversity of HIV-1 is a major challenge for both active and passive immunization. Here we review current immunologic st

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Ali, Ayub, Scott G. Kitchen, Irvin S. Y. Chen, Hwee L. Ng, Jerome A. Zack, and Otto O. Yang. "HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies." Journal of Virology 90, no. 15 (2016): 6999–7006. http://dx.doi.org/10.1128/jvi.00805-16.

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ABSTRACTAlthough the use of chimeric antigen receptors (CARs) based on single-chain antibodies for gene immunotherapy of cancers is increasing due to promising recent results, the earliest CAR therapeutic trials were done for HIV-1 infection in the late 1990s. This approach utilized a CAR based on human CD4 as a binding domain and was abandoned for a lack of efficacy. The growing number of HIV-1 broadly neutralizing antibodies (BNAbs) offers the opportunity to generate novel CARs that may be more active and revisit this modality for HIV-1 immunotherapy. We used sequences from seven well-define

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Welles, Hugh C., Hannah A. D. King, Leonard Nettey, et al. "Broad coverage of neutralization-resistant SIV strains by second-generation SIV-specific antibodies targeting the region involved in binding CD4." PLOS Pathogens 18, no. 6 (2022): e1010574. http://dx.doi.org/10.1371/journal.ppat.1010574.

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Both SIV and SHIV are powerful tools for evaluating antibody-mediated prevention and treatment of HIV-1. However, owing to a lack of rhesus-derived SIV broadly neutralizing antibodies (bnAbs), testing of bnAbs for HIV-1 prevention or treatment has thus far been performed exclusively in the SHIV NHP model using bnAbs from HIV-1-infected individuals. Here we describe the isolation and characterization of multiple rhesus-derived SIV bnAbs capable of neutralizing most isolates of SIV. Eight antibodies belonging to two clonal families, ITS102 and ITS103 which target unique epitopes in the CD4bs reg

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Klein, Florian, Lilian Nogueira, Yoshiaki Nishimura, et al. "Enhanced HIV-1 immunotherapy by commonly arising antibodies that target virus escape variants." Journal of Experimental Medicine 211, no. 12 (2014): 2361–72. http://dx.doi.org/10.1084/jem.20141050.

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Antibody-mediated immunotherapy is effective in humanized mice when combinations of broadly neutralizing antibodies (bNAbs) are used that target nonoverlapping sites on the human immunodeficiency virus type 1 (HIV-1) envelope. In contrast, single bNAbs can control simian–human immunodeficiency virus (SHIV) infection in immune-competent macaques, suggesting that the host immune response might also contribute to the control of viremia. Here, we investigate how the autologous antibody response in intact hosts can contribute to the success of immunotherapy. We find that frequently arising antibodi

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Brinkkemper, Mitch, and Kwinten Sliepen. "Nanoparticle Vaccines for Inducing HIV-1 Neutralizing Antibodies." Vaccines 7, no. 3 (2019): 76. http://dx.doi.org/10.3390/vaccines7030076.

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The enormous sequence diversity between human immunodeficiency virus type 1 (HIV-1) strains poses a major roadblock for generating a broadly protective vaccine. Many experimental HIV-1 vaccine efforts are therefore aimed at eliciting broadly neutralizing antibodies (bNAbs) that are capable of neutralizing the majority of circulating HIV-1 strains. The envelope glycoprotein (Env) trimer on the viral membrane is the sole target of bNAbs and the key component of vaccination approaches aimed at eliciting bNAbs. Multimeric presentation of Env on nanoparticles often plays a critical role in these st

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Lingwood, Daniel. "Natural gene-encoded affinity for cognate antigen facilitates vaccine-amplification of broadly neutralizing antibodies against influenza virus." Journal of Immunology 202, no. 1_Supplement (2019): 139.22. http://dx.doi.org/10.4049/jimmunol.202.supp.139.22.

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Abstract B cell receptors display V gene-encoded CDRs and hypervariable CDR3, where the former may harbor innate-like antigen recognition characteristics. To test this in vivo, we deployed transgenic mice containing full human CDRH3 diversity but were constrained to single human VH genes: IGHV1-69*01, a human VH reproducibly used to generate broadly neutralizing antibodies (bnAbs) targeting hemagglutinin stalk of Group 1 influenza A viruses or irrelevant IGHV1-2*02. With this system, we could experimentally evaluate the contribution of V gene encoded CDRs to forming the antibody paratope follo

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Foulkes, Caio, Nikolas Friedrich, Branislav Ivan, et al. "Assessing bnAb potency in the context of HIV-1 envelope conformational plasticity." PLOS Pathogens 21, no. 1 (2025): e1012825. https://doi.org/10.1371/journal.ppat.1012825.

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For use in prevention and treatment, HIV-1 broadly neutralizing antibodies (bnAbs) have to overcome Env conformational heterogeneity of viral quasispecies and neutralize with constant high potency. Comparative analysis of neutralization data from the CATNAP database revealed a nuanced relationship between bnAb activity and Env conformational flexibility, with substantial epitope-specific variation of bnAb potency ranging from increased to decreased activity against open, neutralization-sensitive Env. To systematically investigate the impact of variability in Env conformation on bnAb potency we

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Shcherbakov, D. N., A. Yu Bakulina, L. I. Karpenko, and A. A. Ilyichev. "Broadly Neutralizing Antibodies against HIV-1 As a Novel Aspect of the Immune Response." Acta Naturae 7, no. 4 (2015): 11–21. http://dx.doi.org/10.32607/20758251-2015-7-4-11-21.

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The human immunodeficiency virus-1 (HIV-1) has the ability to evade the adaptive immune response due to high mutation rates. Soon after the discovery of HIV-1, it was originally proposed that neutralizing of antibodies to the virus occurs rarely or cannot be elicited at all. In the 1990s, there appeared reports that sera of select HIV-1-infected individuals contained antibodies capable of neutralizing different virus subtypes. Such antibodies were named broadly neutralizing antibodies (bNAbs). Since 2009, the development of new cell technologies has intensified research efforts directed at ide

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Doores, Katie J., Leopold Kong, Stefanie A. Krumm, et al. "Two Classes of Broadly Neutralizing Antibodies within a Single Lineage Directed to the High-Mannose Patch of HIV Envelope." Journal of Virology 89, no. 2 (2014): 1105–18. http://dx.doi.org/10.1128/jvi.02905-14.

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ABSTRACTThe high-mannose patch of human immunodeficiency virus (HIV) envelope (Env) elicits broadly neutralizing antibodies (bnAbs) during natural infection relatively frequently, and consequently, this region has become a major target of vaccine design. However, it has also become clear that antibody recognition of the region is complex due, at least in part, to variability in neighboring loops and glycans critical to the epitopes. bnAbs against this region have some shared features and some distinguishing features that are crucial to understand in order to design optimal immunogens that can

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Biswas, Mrityunjoy, Tatsuya Yamazaki, Joe Chiba, and Sachiko Akashi-Takamura. "Broadly Neutralizing Antibodies for Influenza: Passive Immunotherapy and Intranasal Vaccination." Vaccines 8, no. 3 (2020): 424. http://dx.doi.org/10.3390/vaccines8030424.

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Influenza viruses cause annual epidemics and occasional pandemics. The high diversity of viral envelope proteins permits viruses to escape host immunity. Therefore, the development of a universal vaccine and broadly neutralizing antibodies (bnAbs) is essential for controlling various mutant viruses. Here, we review some potentially valuable bnAbs for influenza; one is a novel passive immunotherapy using a variable domain of heavy chain-only antibody (VHH), and the other is polymeric immunoglobulin A (pIgA) induced by intranasal vaccination. Recently, it was reported that a tetravalent multidom

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Williamson, Brian D., Liana Wu, Yunda Huang, Aaron Hudson, and Peter B. Gilbert. "Predicting neutralization susceptibility to combination HIV-1 monoclonal broadly neutralizing antibody regimens." PLOS ONE 19, no. 9 (2024): e0310042. http://dx.doi.org/10.1371/journal.pone.0310042.

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Combination monoclonal broadly neutralizing antibodies (bnAbs) are currently being developed for preventing HIV-1 acquisition. Recent work has focused on predicting in vitro neutralization potency of both individual bnAbs and combination regimens against HIV-1 pseudoviruses using Env sequence features. To predict in vitro combination regimen neutralization potency against a given HIV-1 pseudovirus, previous approaches have applied mathematical models to combine individual-bnAb neutralization and have predicted this combined neutralization value; we call this the combine-then-predict (CP) appro

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Wang, Qian, and Linqi Zhang. "Broadly neutralizing antibodies and vaccine design against HIV-1 infection." Frontiers of Medicine 14, no. 1 (2019): 30–42. http://dx.doi.org/10.1007/s11684-019-0721-9.

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AbstractRemarkable progress has been achieved for prophylactic and therapeutic interventions against human immunodeficiency virus type I (HIV-1) through antiretroviral therapy. However, vaccine development has remained challenging. Recent discoveries in broadly neutralizing monoclonal antibodies (bNAbs) has led to the development of multiple novel vaccine approaches for inducing bNAbs-like antibody response. Structural and dynamic studies revealed several vulnerable sites and states of the HIV-1 envelop glycoprotein (Env) during infection. Our review aims to highlight these discoveries and rej

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Doria-Rose, Nicole A., Jinal N. Bhiman, Ryan S. Roark, et al. "New Member of the V1V2-Directed CAP256-VRC26 Lineage That Shows Increased Breadth and Exceptional Potency." Journal of Virology 90, no. 1 (2015): 76–91. http://dx.doi.org/10.1128/jvi.01791-15.

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ABSTRACT The epitopes defined by HIV-1 broadly neutralizing antibodies (bNAbs) are valuable templates for vaccine design, and studies of the immunological development of these antibodies are providing insights for vaccination strategies. In addition, the most potent and broadly reactive of these bNAbs have potential for clinical use. We previously described a family of 12 V1V2-directed neutralizing antibodies, CAP256-VRC26, isolated from an HIV-1 clade C-infected donor at years 1, 2, and 4 of infection (N. A. Doria-Rose et al., Nature 509:55–62, 2014, http://dx.doi.org/10.1038/nature13036 ). H

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van Dongen, Maria J. P., Rameshwar U. Kadam, Jarek Juraszek, et al. "A small-molecule fusion inhibitor of influenza virus is orally active in mice." Science 363, no. 6431 (2019): eaar6221. http://dx.doi.org/10.1126/science.aar6221.

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Recent characterization of broadly neutralizing antibodies (bnAbs) against influenza virus identified the conserved hemagglutinin (HA) stem as a target for development of universal vaccines and therapeutics. Although several stem bnAbs are being evaluated in clinical trials, antibodies are generally unsuited for oral delivery. Guided by structural knowledge of the interactions and mechanism of anti-stem bnAb CR6261, we selected and optimized small molecules that mimic the bnAb functionality. Our lead compound neutralizes influenza A group 1 viruses by inhibiting HA-mediated fusion in vitro, pr

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Malbec, Marine, Françoise Porrot, Rejane Rua, et al. "Broadly neutralizing antibodies that inhibit HIV-1 cell to cell transmission." Journal of Experimental Medicine 210, no. 13 (2013): 2813–21. http://dx.doi.org/10.1084/jem.20131244.

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The neutralizing activity of anti–HIV-1 antibodies is typically measured in assays where cell-free virions enter reporter cell lines. However, HIV-1 cell to cell transmission is a major mechanism of viral spread, and the effect of the recently described broadly neutralizing antibodies (bNAbs) on this mode of transmission remains unknown. Here we identify a subset of bNAbs that inhibit both cell-free and cell-mediated infection in primary CD4+ lymphocytes. These antibodies target either the CD4-binding site (NIH45-46 and 3BNC60) or the glycan/V3 loop (10-1074 and PGT121) on HIV-1 gp120 and act

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VanderVeen, Laurie A., Lisa Selzer, Brian Moldt, et al. "HIV-1 envelope diversity and sensitivity to broadly neutralizing antibodies across stages of acute HIV-1 infection." AIDS 38, no. 4 (2023): 607–10. http://dx.doi.org/10.1097/qad.0000000000003792.

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We studied the relationship between viral diversity and susceptibility to broadly neutralizing antibodies (bNAbs) in longitudinal plasma and peripheral blood mononuclear cells from 89 people with HIV who initiated antiretroviral therapy (ART) during acute and early HIV-1 infection (AEHI). HIV-1 diversity and predicted bNAb susceptibility were comparable across AEHI. Diversity evolution was not observed during ART, suggesting (pro)viruses at initiation or during treatment may identify individuals with susceptible virus for bNAb interventional trials.

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Tian, Ming, Kelly McGovern, Hwei-Ling Cheng, et al. "Conditional antibody expression to avoid central B cell deletion in humanized HIV-1 vaccine mouse models." Proceedings of the National Academy of Sciences 117, no. 14 (2020): 7929–40. http://dx.doi.org/10.1073/pnas.1921996117.

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HIV-1 vaccine development aims to elicit broadly neutralizing antibodies (bnAbs) against diverse viral strains. In some HIV-1–infected individuals, bnAbs evolved from precursor antibodies through affinity maturation. To induce bnAbs, a vaccine must mediate a similar antibody maturation process. One way to test a vaccine is to immunize mouse models that express human bnAb precursors and assess whether the vaccine can convert precursor antibodies into bnAbs. A major problem with such mouse models is that bnAb expression often hinders B cell development. Such developmental blocks may be attribute

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Liu, Mengfei, Guang Yang, Kevin Wiehe, et al. "Polyreactivity and Autoreactivity among HIV-1 Antibodies." Journal of Virology 89, no. 1 (2014): 784–98. http://dx.doi.org/10.1128/jvi.02378-14.

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ABSTRACTIt is generally acknowledged that human broadly neutralizing antibodies (bNAbs) capable of neutralizing multiple HIV-1 clades are often polyreactive or autoreactive. Whereas polyreactivity or autoreactivity has been proposed to be crucial for neutralization breadth, no systematic, quantitative study of self-reactivity among nonneutralizing HIV-1 Abs (nNAbs) has been performed to determine whether poly- or autoreactivity in bNAbs is a consequence of chronic antigen (Ag) exposure and/or inflammation or a fundamental property of neutralization. Here, we use protein microarrays to assess b

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Walsh, Stephen R., and Michael S. Seaman. "Broadly Neutralizing Antibodies for HIV-1 Prevention." Frontiers in Immunology 12 (July 20, 2021). http://dx.doi.org/10.3389/fimmu.2021.712122.

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Given the absence of an effective vaccine for protection against HIV-1 infection, passive immunization strategies that utilize potent broadly neutralizing antibodies (bnAbs) to block acquisition of HIV-1 are being rigorously pursued in the clinical setting. bnAbs have demonstrated robust protection in preclinical animal models, and several leading bnAb candidates have shown favorable safety and pharmacokinetic profiles when tested individually or in combinations in early phase human clinical trials. Furthermore, passive administration of bnAbs in HIV-1 infected individuals has resulted in prol

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Lorenzi, Julio C. C., Pilar Mendoza, Yehuda Z. Cohen, et al. "Neutralizing Activity of Broadly Neutralizing anti-HIV-1 Antibodies against Primary African Isolates." Journal of Virology, December 9, 2020. http://dx.doi.org/10.1128/jvi.01909-20.

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Novel therapeutic and preventive strategies are needed to contain the HIV-1 epidemic. Broadly neutralizing human antibodies (bNAbs) with exceptional activity against HIV-1 are currently being tested in HIV-1 prevention trials. The selection of anti-HIV-1 bNAbs for clinical development was primarily guided by their in vitro neutralizing activity against HIV-1 Env pseudotyped viruses. Here we report on the neutralizing activity of 9 anti-HIV-1 bNAbs now in clinical development against 126 Clade A, C, D PBMC-derived primary African isolates. The neutralizing potency and breadth of the bNAbs teste

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Anthony, Colin, Talita York, Valerie Bekker, et al. "Cooperation between Strain-Specific and Broadly Neutralizing Responses Limited Viral Escape and Prolonged the Exposure of the Broadly Neutralizing Epitope." Journal of Virology 91, no. 18 (2017). http://dx.doi.org/10.1128/jvi.00828-17.

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ABSTRACT V3-glycan-targeting broadly neutralizing antibodies (bNAbs) are a focus of HIV-1 vaccine development. Understanding the viral dynamics that stimulate the development of these antibodies can provide insights for immunogen design. We used a deep-sequencing approach, together with neutralization phenotyping, to investigate the rate and complexity of escape from V3-glycan-directed bNAbs compared to overlapping early strain-specific neutralizing antibody (ssNAb) responses to the V3/C3 region in donor CAP177. Escape from the ssNAb response occurred rapidly via an N334-to-N332 glycan switch,

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Waters, Laura, Rosa de Miguel-Buckley, Sébastien Poulin, and Jose R. Arribas. "Broadly Neutralizing Antibodies for HIV Treatment: Broad in Theory, Narrow in Reality." Clinical Infectious Diseases, October 28, 2022. http://dx.doi.org/10.1093/cid/ciac835.

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Abstract In this viewpoint we briefly review the status of antiretroviral therapy, its unmet needs, and the role that broadly neutralizing antibodies (bNAbs) might have in the near future for the treatment of HIV. We summarize advances in the development of bNAbs as antiretroviral therapy, the results of main clinical trials of bNAbs for HIV treatment and prevention, and its role in cure trials. The limitations of broadly neutralizing antibodies are the current need for primary resistance testing, the still unclear number of antibodies that must be combined, the lack of penetration in anatomic

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Leggat, David J., Kristen W. Cohen, Jordan R. Willis, et al. "Vaccination induces HIV broadly neutralizing antibody precursors in humans." Science 378, no. 6623 (2022). http://dx.doi.org/10.1126/science.add6502.

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Broadly neutralizing antibodies (bnAbs) can protect against HIV infection but have not been induced by human vaccination. A key barrier to bnAb induction is vaccine priming of rare bnAb-precursor B cells. In a randomized, double-blind, placebo-controlled phase 1 clinical trial, the HIV vaccine–priming candidate eOD-GT8 60mer adjuvanted with AS01 B had a favorable safety profile and induced VRC01-class bnAb precursors in 97% of vaccine recipients with median frequencies reaching 0.1% among immunoglobulin G B cells in blood. bnAb precursors shared properties with bnAbs and gained somatic hypermu

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Schiffner, Torben, Ivy Phung, Rashmi Ray, et al. "Vaccination induces broadly neutralizing antibody precursors to HIV gp41." Nature Immunology, May 30, 2024. http://dx.doi.org/10.1038/s41590-024-01833-w.

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AbstractA key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif.

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Spencer, David A., Mariya B. Shapiro, Nancy L. Haigwood, and Ann J. Hessell. "Advancing HIV Broadly Neutralizing Antibodies: From Discovery to the Clinic." Frontiers in Public Health 9 (May 26, 2021). http://dx.doi.org/10.3389/fpubh.2021.690017.

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Despite substantial progress in confronting the global HIV-1 epidemic since its inception in the 1980s, better approaches for both treatment and prevention will be necessary to end the epidemic and remain a top public health priority. Antiretroviral therapy (ART) has been effective in extending lives, but at a cost of lifelong adherence to treatment. Broadly neutralizing antibodies (bNAbs) are directed to conserved regions of the HIV-1 envelope glycoprotein trimer (Env) and can block infection if present at the time of viral exposure. The therapeutic application of bNAbs holds great promise, a

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Hsu, Denise C., John W. Mellors, and Sandhya Vasan. "Can Broadly Neutralizing HIV-1 Antibodies Help Achieve an ART-Free Remission?" Frontiers in Immunology 12 (July 12, 2021). http://dx.doi.org/10.3389/fimmu.2021.710044.

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Many broadly neutralizing antibodies (bnAbs) targeting the HIV-1 envelope glycoprotein are being assessed in clinical trials as strategies for HIV-1 prevention, treatment, and antiretroviral-free remission. BnAbs can neutralize HIV-1 and target infected cells for elimination. Concerns about HIV-1 resistance to single bnAbs have led to studies of bnAb combinations with non-overlapping resistance profiles. This review focuses on the potential for bnAbs to induce HIV-1 remission, either alone or in combination with latency reversing agents, therapeutic vaccines or other novel therapeutics. Key to

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