Mateo Reveiz

National Institute of Allergy and Infectious Diseases

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Peter D. Kwong

Columbia University

Reda Rawi

National Institute of Allergy and Infectious Diseases

Baoshan Zhang

National Institute of Allergy and Infectious Diseases

Chen‐Hsiang Shen

National Institute of Allergy and Infectious Diseases

Tracy Liu

West Virginia University

Gwo‐Yu Chuang

National Institute of Allergy and Infectious Diseases

Kai Xu

Lianyungang Runzhong Pharmaceutical (China)

Myungjin Lee

National Institute of Allergy and Infectious Diseases

Shuishu Wang

National Institute of Allergy and Infectious Diseases

Adam S. Olia

National Institute of Allergy and Infectious Diseases

Cooperative Institutions

National Institute of Allergy and Infectious Diseases

National Institutes of Health

Institut de Recherche Vaccinale

Ragon Institute of MGH, MIT and Harvard

Massachusetts General Hospital

Hadassah Medical Center

Harvard University

Government of the United States of America

National Cancer Institute

Frederick National Laboratory for Cancer Research

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Vaccine-elicited and naturally elicited antibodies differ in their recognition of the HIV-1 fusion peptide

Frontiers in Immunology (2024)

Mateo Reveiz Kai Xu Myungjin Lee Shuishu Wang Adam S. Olia

Broadly neutralizing antibodies have been proposed as templates for HIV-1 vaccine design, but it has been unclear how similar vaccine-elicited antibodies are to their naturally elicited templates. To provide insight, here we compare the recognition of naturally elicited and vaccine-elicited antibodies targeting the HIV-1 fusion peptide, which comprises envelope (Env) residues 512–526, with the most common sequence being AVGIGAVFLGFLGAA. Naturally elicited antibodies bound peptides with substitutions to negatively charged amino acids at residue positions 517–520 substantially better than the most common sequence, despite these substitutions rarely appearing in HIV-1; by contrast, vaccine-elicited antibodies were less tolerant of sequence variation, with no substitution of residues 512–516 showing increased binding. Molecular dynamics analysis and cryo-EM structural analysis of the naturally elicited ACS202 antibody in complex with the HIV-1 Env trimer with an alanine 517 to glutamine substitution suggested enhanced binding to result from electrostatic interactions with positively charged antibody residues. Overall, vaccine-elicited antibodies appeared to be more fully optimized to bind the most common fusion peptide sequence, perhaps reflecting the immunization with fusion peptide of the vaccine-elicited antibodies.

Trimer

HIV vaccine

10.3389/fimmu.2024.1484029

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Citations (0)

Structure of an influenza group 2-neutralizing antibody targeting the hemagglutinin stem supersite

Structure (2022)

Crystal Sao‐Fong Cheung Jason Gorman Sarah F. Andrews Reda Rawi Mateo Reveiz

10.1016/j.str.2022.04.003

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Citations (5)

GENETIC MODIFICATION OF PROBIOTIC ESCHERICHIA COLI TO PRODUCE OMEGA-3 FATTY ACIDS

Julianna Greenberg Neha Kalla Roja Kambhampati Erin Murphy Aasheen Qadri

10.13016/vxom-eqdo

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Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domain

mAbs (2023)

Young Do Kwon Amarendra Pegu Eun Sung Yang Baoshan Zhang Michael F. Bender

The amino-acid composition of the immunoglobulin variable region has been observed to impact antibody pharmacokinetics (PK). Here, we sought to improve the PK of the broad HIV−1-neutralizing VRC01-class antibodies, VRC07-523LS and N6LS, by reducing the net positive charge in their variable domains. We used a structure-guided approach to generate a panel of antibody variants incorporating select Arg or Lys substituted to Asp, Gln, Glu, or Ser. The engineered variants exhibited reduced affinity to heparin, reduced polyreactivity, and improved PK in human FcRn-transgenic mice. One variant, VRC07-523LS.v34, with three charge substitutions, had an observed in vivo half-life and an estimated human half-life of 10.8 and 60 days, respectively (versus 5.4 and 38 days for VRC07-523LS) and retained functionality, neutralizing 92% of a 208-strain panel at a geometric mean IC80 <1 µg/mL. Another variant, N6LS.C49, with two charge substitutions, had an observed in vivo half-life and an estimated human half-life of 14.5 and 80 days (versus 9.0 and 44 days for N6LS) and neutralized ~80% of 208 strains at a geometric mean IC80 <1 µg/mL. Since Arg and Lys residues are prevalent in human antibodies, we propose substitution of select Arg or Lys with Asp, Gln, Glu, or Ser in the framework region as a general means to improve PK of therapeutic antibodies.

10.1080/19420862.2023.2223350

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Vaccine-elicited and naturally elicited antibodies differ in their recognition of the HIV-1 fusion peptide

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Mateo Reveiz Kai Xu Myungjin Lee Shuishu Wang Adam S. Olia

ABSTRACT Broadly neutralizing antibodies have been proposed as templates for HIV-vaccine design, but it has been unclear how similar vaccine-elicited antibodies are to their naturally elicited templates. To provide insight, here we compare the recognition of naturally elicited and vaccine-elicited antibodies targeting the HIV-1-fusion peptide, which comprises envelope (Env) residues 512-526, with the most common sequence being AVGIGAVFLGFLGAA. Naturally elicited antibodies bound peptides with negative-charge substitutions around residues 517-520 substantially better than the most common sequence, despite these substitutions rarely appearing in HIV; by contrast, vaccine-elicited antibodies were less tolerant of sequence variation, with no substitution of residues 512-516 showing increased binding. Molecular dynamics analysis and cryo-EM structure of the naturally elicited ACS202 antibody in complex with HIV-Env trimer with A517E suggested enhanced binding to result from electrostatic interactions with positively charged antibody residues. Overall, vaccine-elicited antibodies appeared to be more fully optimized to bind the most common fusion peptide sequence. HIGHLIGHTS Peptide substitution scan reveals naturally elicited antibodies against fusion peptide (FP) can bind select non-canonical FP sequences with high affinity. Peptide substitution scan data for FP antibodies correlates significantly with their differential selection indicating variation in binding relates to neutralization tolerance. Structure and energetic analysis of naturally elicited ACS202 with HIV-Env trimer reveals basis for improved recognition of A517E mutant. Atomic level interactions from MD simulation analysis corroborate trends observed with peptide substitutions. verall, peptide substitution scans reveal vaccine-elicited antibodies against FP to be less permissive to FP-sequence variability than naturally elicited antibodies.

10.1101/2024.06.18.599578

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In Silico Improvement of Highly Protective Anti-Malarial Antibodies

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Mateo Reveiz Prabhanshu Tripathi Lais Pereira Patience Kiyuka Tracy Liu

SUMMARY Antibody CIS43 binds Plasmodium falciparum circumsporozoite protein (PfCSP) and protects against malaria, as recently demonstrated clinically. To improve the efficacy of CIS43, we developed an in silico pipeline to optimize the interaction energy of CIS43 to its junctional epitope (peptide 21: PfCSP residues 101-115). Starting from two improved CIS43 variants, recently elicited from a CIS43-germline knock-in mice, single and double amino acid substitutions in the peptide 21-proximal heavy (VH) and light (VL) variable regions were introduced. CIS43-variants, selected on the basis of improved in silico interface and stability energies, showed increased affinity to peptide 21 and superior malaria-protective efficacy. The best designed variant, antibody P3-43, was significantly more protective than its template antibody m43.151, with greater liver-burden protection than the current best-in-class (antibody iGL-CIS43.D3). Crystal structures of improved antibodies revealed atomic-level interactions explaining gains in binding affinity. The reported pipeline provides a powerful in silico approach to improve antibody functionality.

Circumsporozoite protein

Affinity maturation

10.1101/2022.04.08.487687

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Vaccination in a humanized mouse model elicits highly protective PfCSP-targeting anti-malarial antibodies

Immunity (2021)

Sven Kratochvil Chen‐Hsiang Shen Ying‐Cing Lin Kai Xu Usha Nair

Repeat antigens, such as the Plasmodium falciparum circumsporozoite protein (PfCSP), use both sequence degeneracy and structural diversity to evade the immune response. A few PfCSP-directed antibodies have been identified that are effective at preventing malaria infection, including CIS43, but how these repeat-targeting antibodies might be improved has been unclear. Here, we engineered a humanized mouse model in which B cells expressed inferred human germline CIS43 (iGL-CIS43) B cell receptors and used both vaccination and bioinformatic analysis to obtain variant CIS43 antibodies with improved protective capacity. One such antibody, iGL-CIS43.D3, was significantly more potent than the current best-in-class PfCSP-directed antibody. We found that vaccination with a junctional epitope peptide was more effective than full-length PfCSP at recruiting iGL-CIS43 B cells to germinal centers. Structure-function analysis revealed multiple somatic hypermutations that combinatorically improved protection. This mouse model can thus be used to understand vaccine immunogens and to develop highly potent anti-malarial antibodies.

Circumsporozoite protein

Affinity maturation

10.1016/j.immuni.2021.10.017

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Citations (27)

GLYCO: a tool to quantify glycan shielding of glycosylated proteins

Bioinformatics (2021)

Myungjin Lee Mateo Reveiz Reda Rawi Peter D. Kwong Gwo‐Yu Chuang

Abstract Motivation Glycans play important roles in protein folding and cell–cell interactions—and, furthermore, glycosylation of protein antigens can dramatically impact immune responses. While there have been attempts to quantify the glycan shielding or coverage of a protein surface, none of the publicly available tools analyzes glycan shielding computationally at an atomistic level. Results Here, we developed an in silico approach, GLYCO (GLYcan COverage), to quantify the glycan shielding of a protein surface. The software provides insights into glycan-dense/sparse regions of the entire protein surface or a subset of the protein surface. GLYCO calculates glycan shielding from a single coordinate file or from multiple coordinate files, for instance, as obtained from molecular dynamics simulations or by nuclear magnetic resonance spectroscopy structure determination, enabling analysis of glycan dynamics. Overall, GLYCO provides fundamental insights into the glycan shielding of glycosylated proteins. Availability and implementation GLYCO is freely available at GitHub (https://github.com/myungjinlee/GLYCO). Supplementary information Supplementary data are available at Bioinformatics online.

Glycomics

Surface protein

10.1093/bioinformatics/btab791

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Citations (6)

Diverse Murine Vaccinations Reveal Distinct Antibody Classes to Target Fusion Peptide and Variation in Peptide Length to Improve HIV Neutralization

Journal of Virology (2023)

Mallika Sastry Anita Changela Jason Gorman Kai Xu Gwo‐Yu Chuang

The HIV-1 fusion peptide has been identified as a site for elicitation of broadly neutralizing antibodies, with prior studies demonstrating that priming with fusion peptide-based immunogens and boosting with soluble envelope (Env) trimers can elicit cross-clade HIV-1-neutralizing responses. To improve the neutralizing breadth and potency of fusion peptide-directed responses, we evaluated vaccine regimens that incorporated diverse fusion peptide-conjugates and Env trimers with variation in fusion peptide length and sequence.

Priming (agriculture)

HIV vaccine

10.1128/jvi.01604-22

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Citations (9)