Daniel Ellis's research while affiliated with Molecular and Cellular Biology Program and other places

Publications (16)

Article
Full-text available
Influenza virus neuraminidase (NA) is a major antiviral drug target and has recently reemerged as a key target of antibody-mediated protective immunity. Here we show that recombinant NAs across non-bat subtypes adopt various tetrameric conformations, including an “open” state that may help explain poorly understood variations in NA stability across...
Article
Full-text available
The unprecedented global demand for SARS-CoV-2 vaccines has demonstrated the need for highly effective vaccine candidates that are thermostable and amenable to large-scale manufacturing. Nanoparticle immunogens presenting the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (S) in repetitive arrays are being advanced as second-generati...
Preprint
Full-text available
Influenza virus neuraminidase (NA) is a major antiviral drug target and has recently reemerged as a key target of antibody-mediated protective immunity. Here we show that recombinant NAs across all non-bat subtypes adopt various tetrameric conformations, including a previously unreported 'open' state that may help explain poorly understood variatio...
Preprint
Full-text available
The unprecedented global demand for SARS-CoV-2 vaccines has demonstrated the need for highly effective vaccine candidates that are thermostable and amenable to large-scale manufacturing. Nanoparticle immunogens presenting the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (S) in repetitive arrays are being advanced as second-generati...
Article
Full-text available
Influenza vaccines that confer broad and durable protection against diverse viral strains would have a major effect on global health, as they would lessen the need for annual vaccine reformulation and immunization¹. Here we show that computationally designed, two-component nanoparticle immunogens² induce potently neutralizing and broadly protective...
Article
Full-text available
Recent advances in computational methods have enabled the predictive design of self-assembling protein nanomaterials with atomic-level accuracy. These design strategies focus exclusively on a single target structure, without consideration of the mechanism or dynamics of assembly. However, understanding the assembly process, and in particular its ro...
Article
Full-text available
Multivalent presentation of viral glycoproteins can substantially increase the elicitation of antigen-specific antibodies. To enable a new generation of anti-viral vaccines, we designed self-assembling protein nanoparticles with geometries tailored to present the ectodomains of influenza, HIV, and RSV viral glycoprotein trimers. We first de novo de...
Article
Full-text available
Multivalent presentation of viral glycoproteins can substantially increase the elicitation of antigen-specific antibodies. To enable a new generation of anti-viral vaccines, we designed self-assembling protein nanoparticles with geometries tailored to present the ectodomains of influenza, HIV, and RSV viral glycoprotein trimers. We first de novo de...
Article
Full-text available
Multivalent presentation of viral glycoproteins can substantially increase the elicitation of antigen-specific antibodies. To enable a new generation of anti-viral vaccines, we designed self-assembling protein nanoparticles with geometries tailored to present the ectodomains of influenza, HIV, and RSV viral glycoprotein trimers. We first de novo de...
Article
Full-text available
The receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor, and is a major determinant of host range and a dominant target of neutralizing antibodies. Here we experimentally measure how all amino-acid mutations to the RBD affect expression of folded protein and its affinity for ACE2. Most mutat...
Preprint
Full-text available
Influenza vaccines that confer broad and durable protection against diverse virus strains would have a major impact on global health. However, next-generation vaccine design efforts have been complicated by challenges including the genetic plasticity of the virus and the immunodominance of certain epitopes in its glycoprotein antigens. Here we show...
Preprint
Full-text available
The adaptive immune system is highly sensitive to arrayed antigens, and multivalent display of viral glycoproteins on symmetric scaffolds has been found to substantially increase the elicitation of antigen-specific antibodies. Motivated by the considerable promise of this strategy for next-generation anti-viral vaccines, we set out to design new se...
Article
Full-text available
The development of native-like HIV-1 envelope (Env) trimer antigens has enabled the induction of neutralizing antibody (NAb) responses against neutralization-resistant HIV-1 strains in animal models. However, NAb responses are relatively weak and narrow in specificity. Displaying antigens in a multivalent fashion on nanoparticles (NPs) is an establ...
Article
Technological advances in immunology, protein design, and genetic delivery have unlocked new possibilities for vaccine concepts and delivery technologies that were previously inaccessible. These next-generation vaccine design efforts are particularly promising in their potential to provide solutions to challenging targets for which conventional app...
Article
Full-text available
The challenges of evolution in a complex biochemical environment, coupling genotype to phenotype and protecting the genetic material, are solved elegantly in biological systems by the encapsulation of nucleic acids. In the simplest examples, viruses use capsids to surround their genomes. Although these naturally occurring systems have been modified...
Article
Nature provides many examples of self- and co-assembling protein-based molecular machines, including icosahedral protein cages that serve as scaffolds, enzymes, and compartments for essential biochemical reactions and icosahedral virus capsids, which encapsidate and protect viral genomes and mediate entry into host cells. Inspired by these natural...

Citations

... The presence of LA in the binding pocket shifts the S protein equilibrium toward closed conformations, which also has an effect on reduced ACE2 binding in vitro. Rational drug design approaches have been directed toward the LA pocket with the aim of stabilizing receptor binding-incompetent closed conformations (Ellis et al., 2021; A B C Figure 1. S protein bending dynamics during simulations without benzene (A) Full-length model of the S glycoprotein with the protein shown in cartoon representation and colored pink (chain A), cyan (chain B), and green (chain C), with the glycans and palmitoylated cysteine residues shown in stick representation and colored yellow and brown, respectively. The different subdomains are labeled as RBD (receptor binding domain), NTD (N-terminal domain), HR1 (heptad repeat 1), CH (central helix), CD (connector domain), HR2 (heptad repeat 2), and TM (transmembrane domain). ...
... Structure-guided stabilization of the closed conformation was performed that improved thermal stability. More importantly, it also enhanced the affinity to protective antibodies elicited by viral infection, indicating that these antigens may elicit antibody responses to vulnerable quaternary epitopes more efficiently (149). ...
... C olloidal solutions composed of dispersed nanoparticles in a continuous liquid medium are important for many applications [1][2][3][4] . The surface of the nanoparticles is usually capped by macromolecules, other particles, or ions to increase their affinity to the solvent and to strengthen the inter-particle repulsion force to form stable colloids 5,6 . ...
... In addition to the structural limitations of naturederived self-assembled hierarchical nanostructures that have not suitable valency or size for various applications, researchers have designed highly ordered de novo supramolecular omnidimensional assembly structures such as nanotubes [55,91,[131][132][133][134] and nanocage [135][136][137][138][139][140][141][142][143] with variable size, shape, and symmetry using computational tools. Designing omidimensional self-assembly structures with regularly repeating subunits in tailor-defined constant valency makes them suitable for use in various fields through interior or exterior surface functionalization. ...
... (Beta), P.1 (Gamma), and B.1.617.2 (Delta) variants, due to the E484 mutation [53,54,85,86]. The use of a yeast display library to comprehensively map mutations in the RBD that allow SARS-CoV-2 to escape Ab binding [91] revealed that the L452R mutation in the B.1.429 (Epsilon) lineage allows escape from bamlanivimab [92]. ...
... Elevated levels of antigen-specific antibodies can also be achieved by multivalent presentation of antigens, and NP systems can serve as the platform for this purpose. Ueda and colleagues have engineered self-assembling NPs for tailoring the optimal geometry for multivalent presentation of viral glycoproteins [114]. ...
... We set out to design proteins that drive the assembly of arbitrary antibodies into symmetric assemblies with well-defined structures. Previous design efforts have successfully built nanocages by computationally fusing (14,15) or docking together (16,17) protein building blocks with cyclic symmetry so that the symmetry axes of the building blocks align with a larger target architecture. For example, an I52 icosahedral assembly is built by bringing together a pentamer and a dimer that align to the icosahedral five-and two-fold symmetry axes, respectively. ...
... The application of various symmetric multivalent antigens presenting designed nanocages as vaccines was developed by genetic conjugation between the N-terminus of the trimer subunit and the C-terminal of trimeric viral glycoproteins and improved immunogenicity. (Fig. 6B) [203,204] In a different way, Divine et al. designed self-assembled nanocage with various symmetry using antibody-Fc binders as a building block. They demonstrated enhanced target avidity experimentally by activating Tie-2 pathway (Fig. 6C) and enhancing SARS-CoV-2 neutralization with self-assembled supramolecular structures with each targeting antibody [135]. ...
... recombinant HA trimer may be less immunogenic compared with the polyvalent HA antigens on a virus particle. This problem could be solved through displays of the HA antigens by a polyvalent protein nanoparticle platform, such as a 24-valent nanoparticle [12][13][14] formed by ferritins that are ubiquitous iron storage proteins, or the 60-valent I53-50 nanoparticle [15] that is one of several computationally designed complexes [16]. Alternatively, the HA antigens were displayed by lipid nanoparticles [17][18][19]. ...
... First, to enhance the formation of ICs, we passively administered, prior to immunization, a high-affinity macaque-derived monoclonal antibody (mAb) that targets the base of the soluble HIV Env trimer immunogen BG505 SOSIP. In a second strategy, to enhance MBL binding and subsequent complement deposition, we multimerized the BG505 SOSIP HIV Env trimer immunogen in a particulate form: we recently described the development and characterization of several different two-component self-assembling nanoparticles that present viral glycoprotein immunogens 37,38 . Here, we assessed the in vivo trafficking properties of one such nanoparticle, T33-dn2, presenting the BG505 SOSIP trimer and compared it to soluble Env trimer immunogen. ...