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

... 2. Using experience gained from studies of the earlier SARS and MERS coronaviruses, it has been shown that introduction of two proline mutations (preS-2P) in the S2 domain prevents the spike protein from refolding to the post-fusion form and thereby stabilizes the prefusion form [58]. ...

... The addition of non-native N-linked glycans onto the H. pylori apoferritin scaffold was another engineered feature that contributed to augmenting the quality of the immune response. In contrast to a recent study that investigated the effect of scaffold glycosylation in the context of viral glycoprotein antigens 53 , we observed that in addition to dampening of the anti-scaffold response, glycan modification of the H. pylori apoferritin nanocage boosted anti-PfCSP responses and increased the frequency of PfCSP-reactive B cells compared to the non-glycosylated immunogen. Both effects were also evident in the BM plasma cell compartment indicating a long-lasting effect and qualitative difference in the response. ...

... Nanoparticle vaccine platforms allow multivalent antigen presentation and can elicit more potent immune responses than protein immunogens 17 . Several nanoparticle platforms using lumazine synthase, ferritin or I53-50 displaying SARS-CoV-2 spike or its RBD domain elicit potent nAb responses against SARS-CoV-2 [18][19][20][21] . HBsAg can self-assemble into a 22 nm nanoparticle and has been used successfully in multiple vaccines including Hepaccine B and Recombivax HB 22 . ...

... We started our pseudosymmetric design with a homotrimeric aldolase from the hyperthermophilic bacterium Thermotoga maritima that is remarkably stable and tolerant of modification (PDB ID 1WA3; 68 ). This trimer has previously been used to design multiple one-and two-component protein assemblies 12,16,69 , which as we show below makes possible the re-use of these previously designed interfaces in the creation of large pseudosymmetric assemblies. We set out to identify the minimum set of mutations necessary to drive 2 formation of a pseudosymmetric heterotrimer. ...

... Neuraminidase, located on the virus's surface and belongs to glycoproteins, next to HA and matrix protein2(M2), is also called sialidase [21]. NA is a tetramer of four identical polypeptides, presenting the mushroom-like structure consisting of four domains: an N-terminal cytoplasmic sequence, followed by a membrane-anchoring hydrophobic transmembrane domain (TMD) and a thin stalk of variable length, ending in a globular head domain, the binding site for sialic acid is located in the head domain [21][22][23][24]. Each protomer comprises approximately 470 amino acid residues [23]. ...

... Methods like the Degreaser that encode improved yield or performance in the sequence of the molecule itself are especially desirable, as they make the improvements "automatic": They do not require other actions like the use of specialized cell culture media or co-transfection of chaperones. Numerous examples of enzyme and antigen redesign to improve yield highlight the utility of this approach (19,(73)(74)(75)(76)(77)(78)(79)(80). Methods that encode improvements genetically are of increasing importance now that genetic delivery of biologics has become clinical reality with the recent licensure of several AAV-based gene therapies and mRNA vaccines (81,82). ...

... 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). ...

... The induction of a broad range of HI and neutralizing antibodies against the structural domains of the HA head and stem is an attractive target for the development of universal influenza vaccines. Vaccines that induce a broad range of antibodies are being developed as new universal influenza vaccines in various countries [10][11][12][13] . In addition, NA exhibits a slower rate of antigenic drift, which makes its antigenic sites more conservative, and antibodies to NA often show a broader cross-1 talk 14 , so optimizing influenza vaccines to improve the targeting of NA, and thus to protect different influenza strains consistently and broadly, is becoming a new direction in the development of universal influenza vaccines. ...

... While hydrophobic packing provides a strong driving force for assembly, it also tends to make the unassembled protein building blocks prone to aggregation, which can complicate their manufacture. By contrast, the interfaces in naturally occurring hierarchically structured protein complexes often include a higher fraction of polar residues, which maximizes assembly fidelity by minimizing off-target aggregation [28][29][30] . Methods capable of designing custom multi-component protein assemblies with native-like interfaces would promote the development of new protein-based technologies. ...

... Despite also sharing the N501Y mutation, omicron showed much weaker binding affinity than WT. A computational modeling study suggested that nine other mutations in the omicron RBD would decrease its binding affinity to ACE2 [64]. The weaker binding of omicron S protein to ACE2 implicates other interactions such as omicron's preference for cathepsin L instead of TMPRSS2 as the driving force behind its enhanced infectivity and transmissibility [65]. ...