Bettina Gröschel

Scripps Research Institute

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William R. Schief

Scripps Research Institute

Shane Crotty

La Jolla Institute for Immunology

JČ

Jindřich Činátl

Goethe University Frankfurt

Erik Georgeson

Scripps Research Institute

Hans Wilhelm Doerr

Goethe University Frankfurt

Michael Kubitz

Scripps Research Institute

Darrell J. Irvine

Massachusetts Institute of Technology

Christopher A. Cottrell

Scripps Research Institute

Alessia Liguori

Scripps Research Institute

Torben Schiffner

Scripps Research Institute

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Scripps Research Institute

117

International AIDS Vaccine Initiative

Ragon Institute of MGH, MIT and Harvard

Goethe University Frankfurt

Scripps Institution of Oceanography

Massachusetts Institute of Technology

Harvard University

Massachusetts General Hospital

Scripps (United States)

National Institutes of Health

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B cells expressing IgM B cell receptors of HIV-1 neutralizing antibodies discriminate antigen affinities by sensing binding association rates

Cell Reports (2022)

Md. Alamgir Hossain Kara Anasti Brian Watts Kenneth Cronin Ronald Derking

HIV-1 envelope (Env) proteins designed to induce neutralizing antibody responses allow study of the role of affinities (equilibrium dissociation constant [KD]) and kinetic rates (association/dissociation rates) on B cell antigen recognition. It is unclear whether affinity discrimination during B cell activation is based solely on Env protein binding KD and whether B cells discriminate among proteins of similar affinities that bind with different kinetic rates. Here, we use a panel of Env proteins and Ramos B cell lines expressing immunoglobulin M (IgM) B cell receptors (BCRs) with specificity for CD4-binding-site broadly neutralizing antibodies to study the role of antigen binding kinetic rates on both early (proximal/distal signaling) and late events (BCR/antigen internalization) in B cell activation. Our results support a kinetic model for B cell activation in which Env protein affinity discrimination is based not on overall KD but on sensing of association rate and a threshold antigen-BCR half-life.

Internalization

Affinities

10.1016/j.celrep.2022.111021

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Citations (10)

3′-Azido-2′,3′-dideoxythymidine induced deficiency of thymidine kinases 1, 2 and deoxycytidine kinase in H9 T-lymphoid cells

Biochemical Pharmacology (2002)

Bettina Gröschel Andreas M. Kaufmann Gerold Höver Jaroslav Činátl Hans Wilhelm Doerr

Deoxycytidine kinase

Thymidine kinase

Thymidine

10.1016/s0006-2952(02)01109-7

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Citations (16)

Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Aleksandar Antanasijevic Leigh M. Sewall Christopher A. Cottrell Diane G. Carnathan Luis Jiménez

In Brief Herein, we evaluated the immunogenicity of several BG505 SOSIP-based HIV Env immunogens in the rhesus macaque animal model using a combination of serology and biophysical approaches. We applied electron cryo-microscopy for high-resolution mapping of elicited polyclonal antibody responses, which provided detailed insights into the binding modes of the most common classes of antibodies elicited by BG505 SOSIP immunogens as well as the critical differences in immunogenicity that can occur as a consequence of engineered stabilizing mutations and partial glycan occupancy at different sites. Summary Engineered ectodomain trimer immunogens based on BG505 envelope glycoprotein are widely utilized as components of HIV vaccine development platforms. In this study, we used rhesus macaques to evaluate the immunogenicity of several stabilized BG505 SOSIP constructs both as free trimers and presented on a nanoparticle. We applied a cryoEM-based method for high-resolution mapping of polyclonal antibody responses elicited in immunized animals (cryoEMPEM). Mutational analysis coupled with neutralization assays were used to probe the neutralization potential at each epitope. We demonstrate that cryoEMPEM data can be used for rapid, high-resolution analysis of polyclonal antibody responses without the need for monoclonal antibody isolation. This approach allowed to resolve structurally distinct classes of antibodies that bind overlapping sites. In addition to comprehensive mapping of commonly targeted neutralizing and non-neutralizing epitopes in BG505 SOSIP immunogens, our analysis revealed that epitopes comprising engineered stabilizing mutations and of partially occupied glycosylation sites can be immunogenic. Graphical abstract

Polyclonal antibodies

Epitope mapping

HIV vaccine

10.1101/2021.01.28.428677

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Citations (3)

Use of the ecf1 Gene To Detect Shiga Toxin–Producing Escherichia coli in Beef Samples

Journal of Food Protection (2015)

Kristin Livezey Bettina Gröschel Michael Becker

STX2

Shiga-like toxin

10.4315/0362-028x.jfp-14-417

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Citations (11)

Highly mutated antibodies capable of neutralizing N276 glycan-deficient HIV after a single immunization with an Env trimer

Cell Reports (2022)

Jeong Hyun Lee Catherine Nakao Michael Y. Appel Amber Le Elise Landais

Elicitation of HIV broadly neutralizing antibodies (bnAbs) is challenging because unmutated bnAb precursors are rare and seldom bind HIV envelope glycoprotein (Env) trimers. One strategy to initiate bnAb responses is to use germline-targeting (GT) immunogens with high affinity to bnAb-class precursor B cells and then shepherd affinity maturation with booster immunogens that successively look more like native Env. In a mouse model where the frequency of VRC01-precursor (VRC01gHL) B cells mimics that of humans, we show that following a GT HIV Env trimer protein prime, VRC01-class B cells in the germinal center (GC) acquire high-affinity VRC01-class B cell somatic hypermutations (SHMs). Many GC-derived VRC01gHL antibodies robustly bind N276 glycan-deficient Env trimers and neutralize several N276 glycan-deficient tier 2 HIV strains. These results are encouraging for GT Env trimer vaccine designs and demonstrate accumulation of substantial SHMs, including deletions, uncommon point mutations, and functional bnAb features, after a single immunization.

Trimer

HIV vaccine

Affinity maturation

Naive B cell

Memory B cell

10.1016/j.celrep.2022.110485

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Citations (7)

Optimization of an alum-anchored clinical HIV vaccine candidate

npj Vaccines (2023)

Kristen A. Rodrigues Christopher A. Cottrell Jon M. Steichen Bettina Gröschel Wuhbet Abraham

Abstract In the ongoing effort to develop a vaccine against HIV, vaccine approaches that promote strong germinal center (GC) responses may be critical to enable the selection and affinity maturation of rare B cell clones capable of evolving to produce broadly neutralizing antibodies. We previously demonstrated an approach for enhancing GC responses and overall humoral immunity elicited by alum-adjuvanted protein immunization via the use of phosphoserine (pSer) peptide-tagged immunogens that stably anchor to alum particles via ligand exchange with the alum particle surface. Here, using a clinically relevant stabilized HIV Env trimer termed MD39, we systematically evaluated the impact of several parameters relevant to pSer tag composition and trimer immunogen design to optimize this approach, including phosphate valency, amino acid sequence of the trimer C-terminus used for pSer tag conjugation, and structure of the pSer tag. We also tested the impact of co-administering a potent saponin/monophosphoryl lipid A (MPLA) nanoparticle co-adjuvant with alum-bound trimers. We identified MD39 trimer sequences bearing an optimized positively-charged C-terminal amino acid sequence, which, when conjugated to a pSer tag with four phosphates and a polypeptide spacer, bound very tightly to alum particles while retaining a native Env-like antigenicity profile. This optimized pSer-trimer design elicited robust antigen-specific GC B cell and serum IgG responses in mice. Through this optimization, we present a favorable MD39-pSer immunogen construct for clinical translation.

Immunogen

Trimer

Alum

Antigenicity

Virus-like particle

10.1038/s41541-023-00711-0

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Citations (6)

Modulation of antigen delivery and lymph node activation in non-human primates by saponin adjuvant SMNP

PNAS Nexus (2024)

Parisa Yousefpour Yiming Zhang Laura Maiorino Mariane B. Melo Mariluz A. Arainga Ramirez

Abstract Saponin-based vaccine adjuvants are potent in preclinical animal models and humans, but their mechanisms of action remain poorly understood. Here, using a stabilized HIV envelope trimer immunogen, we carried out studies in nonhuman primates (NHPs) comparing the most common clinical adjuvant aluminum hydroxide (alum) with saponin/monophosphoryl lipid A nanoparticles (SMNP), an immune-stimulating complex–like adjuvant. SMNP elicited substantially stronger humoral immune responses than alum, including 7-fold higher peak antigen-specific germinal center B-cell responses, 18-fold higher autologous neutralizing antibody titers, and higher levels of antigen-specific plasma and memory B cells. Positron emission tomography and computed tomography imaging in live NHPs showed that, unlike alum, SMNP promoted rapid antigen accumulation in both proximal and distal lymph nodes (LNs). SMNP also induced strong type I interferon transcriptional signatures, expansion of innate immune cells, and increased antigen-presenting cell activation in LNs. These findings indicate that SMNP promotes multiple facets of the early immune response relevant for enhanced immunity to vaccination.

Modulation (music)

10.1093/pnasnexus/pgae529

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B cells expressing authentic naive human VRC01-class BCRs can be recruited to germinal centers and affinity mature in multiple independent mouse models

Proceedings of the National Academy of Sciences (2020)

Deli Huang Robert Abbott Colin Havenar‐Daughton Patrick Skog Rita Al-Kolla

Significance Rational development of successful vaccines requires utilization of predictive models of vaccination. One approach for development of an HIV vaccine has been to study broadly neutralizing antibodies (bnAbs) and revert the mutations back to germline. However, there are limitations to such models. Therefore, we generated three knockin mice expressing B cell receptors (BCRs) from authentic naive VRC01-class B cells from healthy human donors (“HuGL” mice). This approach revealed that human VRC01-class naive B cell BCRs are indeed competent for antigen-specific responses in vivo. Additionally, a series of experiments shows the importance of precursor frequency and affinity on B cell responses to vaccine antigens. Overall, these HuGL mouse models validate a central tenet of the germline-targeting approach to vaccine design.

Immunogen

breakpoint cluster region

Naive B cell

Priming (agriculture)

10.1073/pnas.2004489117

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Citations (53)

Highly Mutated Antibodies Capable of Neutralizing N276-Glycan Deficient HIV after a Single Immunization with an Env Trimer

SSRN Electronic Journal (2021)

Jeong Hyun Lee Catherine Nakao Michael Y. Appel Amber Le Elise Landais

Elicitation of broadly neutralizing antibodies (bnAbs) is a major challenge in HIV vaccine development, because unmutated precursors to bnAbs are rare and typically do not bind the wildtype HIV Envelope glycoprotein (Env) trimers. One strategy to initiate bnAb type responses is to use germline-targeting immunogens that have high affinity to bnAb-class precursor B cells, then shepherd affinity maturation with booster immunogens that successively look more similar to native Env. Here, we demonstrate in a rare VRC01gHL (inferred germline of bnAb VRC01) B cell precursor model in mouse, starting from a physiological 1 in 1 million VRC01 gHL precursor frequency, a single immunization with a germline targeting soluble Env trimer can generate a significant number of high affinity bnAb-class somatic hypermutations (SHM). Notably, deletions in the light chain complementarity determining region 1 were observed in multiple germinal center (GC) B cell clones after a single immunization. Many of the GC-derived VRC01gHL antibodies developed binding to the wildtype Env trimer without an N276 glycan. Antibodies elicited after a single priming immunization neutralized several N276 glycan-deficient tier-2 HIV strains. These results are encouraging for germline-targeting Env trimer vaccine designs, demonstrating it can be possible to accumulate substantial SHM, including indels, and functional bnAb features after a single immunization.

Trimer

AIDS Vaccines

10.2139/ssrn.3805158

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Zidovudine induces alterations of apoptosis and resistance to antineoplastic agents in T-cell lymphoma cells

Antiviral Research (1997)

Rouslan Kotchetkov Bettina Gröschel Jaroslav Činátl B. Kornhuber Holger F. Rabenau

10.1016/s0166-3542(97)83203-2

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Citations (0)