Characterization of prefusion-F-specific antibodies elicited by natural infection with human metapneumovirus

Rush, Scott A.; Brar, Gurinder Singh; Hsieh, Ching-Lin; Chautard, Émilie; Rainho-Tomko, Jennifer N; Slade, Chris; Bricault, Christine A.; Kume, Ana; Kearns, James; Groppo, Rachel; Mundle, Sophia T.; Zhang, Linong; Casimiro, Danilo R.; Fu, Tong-Ming; DiNapoli, Joshua; McLellan, Jason S.

doi:10.1101/2022.03.28.486060

Cited by 3 publications

(3 citation statements)

References 77 publications

(116 reference statements)

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“…These data would be most powerful if they included nucleotide sequences (enabling, for example, consistent VDJ gene identification) and enough donor information to distinguish bona fide recurrence from clonal expansion within given individuals. The generation of such truth data at scale is feasible using existing methods 21,35,[46][47][48] . The immunoglobulin loci and their products are complex and challenging to analyse.…”

Section: Discussionmentioning

confidence: 99%

Functional antibodies exhibit light chain coherence

Jaffe

Shahi

Adams

et al. 2022

Nature

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The vertebrate adaptive immune system modifies the genome of individual B cells to encode antibodies that bind particular antigens1. In most mammals, antibodies are composed of heavy and light chains that are generated sequentially by recombination of V, D (for heavy chains), J and C gene segments. Each chain contains three complementarity-determining regions (CDR1–CDR3), which contribute to antigen specificity. Certain heavy and light chains are preferred for particular antigens2–22. Here we consider pairs of B cells that share the same heavy chain V gene and CDRH3 amino acid sequence and were isolated from different donors, also known as public clonotypes23,24. We show that for naive antibodies (those not yet adapted to antigens), the probability that they use the same light chain V gene is around 10%, whereas for memory (functional) antibodies, it is around 80%, even if only one cell per clonotype is used. This property of functional antibodies is a phenomenon that we call light chain coherence. We also observe this phenomenon when similar heavy chains recur within a donor. Thus, although naive antibodies seem to recur by chance, the recurrence of functional antibodies reveals surprising constraint and determinism in the processes of V(D)J recombination and immune selection. For most functional antibodies, the heavy chain determines the light chain.

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Section: Discussionmentioning

confidence: 99%

Functional antibodies exhibit light chain coherence

Jaffe

Shahi

Adams

et al. 2022

Nature

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“…consistent VDJ gene identification) and enough donor information to distinguish bona fide recurrence from clonal expansion within given individuals. Generation of such truth data at scale is feasible using existing methods 21,[38][39][40][41] .…”

Section: Discussionmentioning

confidence: 99%

Functional antibodies exhibit light chain coherence

Jaffe

Shahi

Adams

et al. 2022

Preprint

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The vertebrate adaptive immune system modifies the genome of individual B cells to encode antibodies binding particular antigens1. In most mammals, antibodies are composed of a heavy and a light chain which are sequentially generated by recombination of V, D (for heavy chains), J, and C gene segments. Each chain contains three complementarity-determining regions (CDR1-3), contributing to antigen specificity. Certain heavy and light chains are preferred for particular antigens2–21. We considered pairs of B cells sharing the same heavy chain V gene and CDRH3 amino acid sequence and isolated from different donors, also known as public clonotypes22,23. We show that for naive antibodies (not yet adapted to antigens), the probability that they use the same light chain V gene is ∼10%, whereas for memory (functional) antibodies it is ∼80%. This property of functional antibodies is a phenomenon we call light chain coherence. We also observe it when similar heavy chains recur within a donor. Thus, though naive antibodies appear to recur by chance, the recurrence of functional antibodies reveals surprising constraint and determinism in the processes of V(D)J recombination and immune selection. For most functional antibodies, the heavy chain determines the light chain.

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“…The prefusion hMPV F construct DS-CavEs2-IPDS (hMPV F A1 NL/1/00, residues 1–490) used for structural studies includes the previously described G294E, A185P, L219K, V231I, E453Q, and furin cleavage site substitutions ( 31 , 49 , 50 ). Disulfide substitutions included are L110C/N322C, T127C/N153C, A140C/A147C, and T365C/V463C ( 50 ) as well as an interprotomer disulfide at V84C/A249C ( 51 ).…”

Section: Methodsmentioning

confidence: 99%

Structural basis for ultrapotent antibody-mediated neutralization of human metapneumovirus

Banerjee

Huang

Rush

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Human metapneumovirus (hMPV) is a leading cause of morbidity and hospitalization among children worldwide, however, no vaccines or therapeutics are currently available for hMPV disease prevention and treatment. The hMPV fusion (F) protein is the sole target of neutralizing antibodies. To map the immunodominant epitopes on the hMPV F protein, we isolated a panel of human monoclonal antibodies (mAbs), and the mAbs were assessed for binding avidity, neutralization potency, and epitope specificity. We found the majority of the mAbs target diverse epitopes on the hMPV F protein, and we discovered multiple mAb binding approaches for antigenic site III. The most potent mAb, MPV467, which had picomolar potency, was examined in prophylactic and therapeutic mouse challenge studies, and MPV467 limited virus replication in mouse lungs when administered 24 h before or 72 h after viral infection. We determined the structure of MPV467 in complex with the hMPV F protein using cryo-electron microscopy to a resolution of 3.3 Å, which revealed a complex novel prefusion-specific epitope overlapping antigenic sites II and V on a single protomer. Overall, our data reveal insights into the immunodominant antigenic epitopes on the hMPV F protein, identify a mAb therapy for hMPV F disease prevention and treatment, and provide the discovery of a prefusion-specific epitope on the hMPV F protein.

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Characterization of prefusion-F-specific antibodies elicited by natural infection with human metapneumovirus

Cited by 3 publications

References 77 publications

Functional antibodies exhibit light chain coherence

Functional antibodies exhibit light chain coherence

Functional antibodies exhibit light chain coherence

Structural basis for ultrapotent antibody-mediated neutralization of human metapneumovirus

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