Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus

By Jessica Marcandalli, B. Fiala, Sebastian Ols, Michela Perotti, Willem de van der Schueren, Joost Snijder, Edgar A Hodge, M. Benhaim, Rashmi Ravichandran, Lauren P. Carter and 14 more. 2019

417 citations recorded by the source corpus.

Summary Respiratory syncytial virus (RSV) is a worldwide public health concern for which no vaccine is available. Elucidation of the prefusion structure of the RSV F glycoprotein and its identification as the main target of neutralizing antibodies have provided new opportunities for development of an effective vaccine. Here, we describe the structure-based design of a self-assembling protein nanoparticle presenting a prefusion-stabilized variant of the F glycoprotein trimer (DS-Cav1) in a repetitive array on the nanoparticle exterior. The two-component nature of the nanoparticle scaffold enabled the production of highly ordered, monodisperse immunogens that display DS-Cav1 at controllable density. In mice and nonhuman primates, the full-valency nanoparticle immunogen displaying 20 DS-Cav1 trimers induced neutralizing antibody responses ∼10-fold higher than trimeric DS-Cav1. These results motivate continued development of this promising nanoparticle RSV vaccine candidate and establish computationally designed two-component nanoparticles as a robust and customizable platform for structure-based vaccine design.

Subfields: Animal Science and Zoology, Epidemiology, Computational Biology & Bioinformatics

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Citations in the corpus

Rethinking Attention with Performers (2020, background): “These approaches could be used to augment existing physics-based design strategies that are of critical importance for example in the development of new nanoparticle vaccines (Marcandalli et al., 2019).”
Robust deep learning based protein sequence design using ProteinMPNN (2022, positive): “Second panel: helical bundle scaffolds were docked to the exposed face of the peptide using RIFDOCK (19), and Rosetta remodel was used to build loops connecting the peptide to the scaffolds.”
Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2 (2020, positive): “In preclinical studies, vaccine candidates based on designed protein nanoparticles have significantly improved the potency or breadth of Ab responses against numerous antigens, including prefusion respiratory syncytial virus (RSV) F (Marcandalli et al., 2019), HIV-1 envelope (Brouwer et al.”
Low-N protein engineering with data-efficient deep learning (2020, background): “Indeed, several previous efforts successfully engineered valuable proteins using high-fidelity assays and low-N design 19,23,24,54–58 .”
Next-Generation Influenza Vaccines. (2020, background): “Recombinant HA and/or NA proteins derived from pandemic strain sequences could also be produced in insect or mammalian cells either as soluble proteins or displayed on nanoparticles (Kanekiyo et al. 2013; Georgiev et al. 2018; Marcandalli et al. 2019).”
Elicitation of broadly protective immunity to influenza by multivalent hemagglutinin nanoparticle vaccines (2020, background): “Multivalent antigen display on these nanoparticles enhanced the potency of vaccine-elicited immune responses against a malaria antigen 43 as well as two trimeric class I viral fusion proteins: prefusion-stabilized respiratory syncytial virus F and HIV envelope 44–46 .”
Vaccine adjuvants: mechanisms and platforms (2023, background): “Notably, the highly ordered and repetitive spatial structure of the delivery systems is highly conducive to the co-aggregation of B cell receptors (BCRs), which can lead to strong activation of B cells and ultimately to the production of high-affinity antibodies and memory B cells.(87,90) In additio”
Generation of ordered protein assemblies using rigid three-body fusion (2020, positive): “T is considerable interest in the design of novel protein assemblies, for example, to develop cryogenic electron microscopy (cryo-EM) scaffolds to aid in structure determination (1, 2) and protein nanoparticle vaccines (3, 4).”
Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens (2020, methodology): “In our previous work with computationally designed nanoparticle immunogens (Marcandalli et al., 2019; Brouwer et al., 2019), the nanoparticles were generated from naturally occurring oligomeric proteins without initial consideration of geometric compatibility for antigen presentation.”
Broadly applicable and accurate protein design by integrating structure prediction networks and diffusion generative models (2022, positive): “There is considerable interest in designing new higher order symmetric oligomers which can serve as vaccine platforms 27 , delivery vehicles 28 , and catalysts 29 .”