Efficacious human metapneumovirus vaccine based on AI-guided engineering of a closed prefusion trimer

Mark J. G. Bakkers, Tina Ritschel, Machteld Tiemessen, Jacobus Dijkman, Angelo A. Zuffianò, Xiaodi Yu, Daan Overveld, Lam Le, Richard Voorzaat, Marlies M. Haaren, Martijn Man, Sem Tamara, Leslie Fits, Roland Zahn, Jarek Juraszek and Johannes P. M. Langedijk ()
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Mark J. G. Bakkers: Janssen Vaccines & Prevention BV
Tina Ritschel: Janssen Vaccines & Prevention BV
Machteld Tiemessen: Janssen Vaccines & Prevention BV
Jacobus Dijkman: Janssen Vaccines & Prevention BV
Angelo A. Zuffianò: Janssen Vaccines & Prevention BV
Xiaodi Yu: Janssen Research and Development
Daan Overveld: Janssen Vaccines & Prevention BV
Lam Le: Janssen Vaccines & Prevention BV
Richard Voorzaat: Janssen Vaccines & Prevention BV
Marlies M. Haaren: Janssen Vaccines & Prevention BV
Martijn Man: Janssen Vaccines & Prevention BV
Sem Tamara: Janssen Vaccines & Prevention BV
Leslie Fits: Janssen Vaccines & Prevention BV
Roland Zahn: Janssen Vaccines & Prevention BV
Jarek Juraszek: Janssen Vaccines & Prevention BV
Johannes P. M. Langedijk: Janssen Vaccines & Prevention BV

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract The prefusion conformation of human metapneumovirus fusion protein (hMPV Pre-F) is critical for eliciting the most potent neutralizing antibodies and is the preferred immunogen for an efficacious vaccine against hMPV respiratory infections. Here we show that an additional cleavage event in the F protein allows closure and correct folding of the trimer. We therefore engineered the F protein to undergo double cleavage, which enabled screening for Pre-F stabilizing substitutions at the natively folded protomer interfaces. To identify these substitutions, we developed an AI convolutional classifier that successfully predicts complex polar interactions often overlooked by physics-based methods and visual inspection. The combination of additional processing, stabilization of interface regions and stabilization of the membrane-proximal stem, resulted in a Pre-F protein vaccine candidate without the need for a heterologous trimerization domain that exhibited high expression yields and thermostability. Cryo-EM analysis shows the complete ectodomain structure, including the stem, and a specific interaction of the newly identified cleaved C-terminus with the adjacent protomer. Importantly, the protein induces high and cross-neutralizing antibody responses resulting in near complete protection against hMPV challenge in cotton rats, making the highly stable, double-cleaved hMPV Pre-F trimer an attractive vaccine candidate.

Date: 2024
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DOI: 10.1038/s41467-024-50659-5

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