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Rempe, Coordination numbers of alkali metal ions in aqueous solutions. Persson, A study of the hydration of the alkali metal ions in aqueous solution. Dang, Mechanism and thermodynamics of ion selectivity in aqueous solutions of 18-crown-6 ether: A molecular dynamics study. Einstein, Investigations on the Ferumoxytol Injection (Feraheme)- FDA of the Brownian movement. Sahebdelfar, Interaction effects in multicomponent separation by reverse osmosis.

Walch, Donnan-membrane effects in Ferumoxytol Injection (Feraheme)- FDA of ternary systems. Freeman, Ion diffusion coefficients in ion exchange membranes: Significance of counterion condensation. Cinacalcet (Sensipar)- FDA, Design principles of ion selective nanostructured membranes for the extraction of lithium ions.

Plimpton, Fast parallel algorithms for short-range molecular dynamics. Ferumoxytol Injection (Feraheme)- FDA, Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. Cabeza de Vaca, J. Jorgensen, LigParGen web server: An automatic OPLS-AA parameter generator for organic ligands.

Cheatham III, Determination of alkali and halide monovalent ion parameters for use in explicitly solvated biomolecular simulations. Warnock, Rahul Ferumoxytol Injection (Feraheme)- FDA, Everett S. Zofchak, Shou Zhao, Theodore J. Zeneca astrazeneca, Sanjoy Mukherjee, Venkat Ganesan, Benny D. BatesProceedings of the National Academy of Sciences Sep 2021, 118 (37) e2022197118; DOI: 10.

Tirrell, The University of Chicago, Chicago, IL, and approved July 21, 2021 (received for review April Ferumoxytol Injection (Feraheme)- FDA, 2021)Most of the global population resides in low- and middle-income countries, where current vaccines for COVID-19 remain largely unavailable. Many vaccine candidates use the SARS-CoV-2 receptor-binding domain (RBD) antigen. Here, we Ferumoxytol Injection (Feraheme)- FDA an Ferumoxytol Injection (Feraheme)- FDA RBD with improved production titers in Pichia pastoris, a yeast commonly used for large-scale, low-cost manufacturing by vaccine manufacturers.

The modified RBD also raises an enhanced immune response in mice Ferumoxytol Injection (Feraheme)- FDA to the Wuhan-Hu-1 sequence used in current candidates. These combined traits make it a promising candidate for next-generation vaccines addressing emerging variants of the virus. Global containment of COVID-19 still requires accessible and affordable vaccines for low- and middle-income countries (LMICs). Recently approved vaccines provide needed interventions, albeit at prices that may limit their global access.

Subunit vaccines based on recombinant proteins are suited for large-volume microbial manufacturing to yield billions of doses annually, minimizing their manufacturing cost.

These types of vaccines are well-established, proven interventions with multiple safe and efficacious commercial examples. Many vaccine candidates of this type for SARS-CoV-2 rely on sequences containing the receptor-binding domain (RBD), which mediates viral entry to cells via ACE2.

Here we report an engineered sequence variant of RBD that exhibits high-yield manufacturability, high-affinity binding to ACE2, and enhanced immunogenicity after a single dose in mice compared to the Wuhan-Hu-1 variant used in current vaccines.

Antibodies raised against the engineered protein exhibited heterotypic binding to the RBD from two recently reported SARS-CoV-2 variants of concern (501Y. Presentation of the engineered RBD on a designed virus-like particle (VLP) also reduced weight loss in hamsters upon viral challenge.

To ensure adequate supply and global access, vaccine manufacturers must select highly immunogenic vaccine antigens that offer broad protection against emerging variants and are compatible with large-volume production in existing manufacturing facilities (2, 3).

Vaccines using mRNA have established the efficacy of vaccines for SARS-CoV-2 based on full-length trimeric spike (S) protein (4, 5). Recombinant S protein produced in mammalian or insect cells has also shown immunogenicity and efficacy in nonhuman primates (6). Antibodies to RBD account for most of the neutralizing Urofollitropin for Injection (Metrodin)- Multum elicited in natural infections, and several potent monoclonal antibodies have been discovered from convalescent patients (14, 15).

A His-tagged SARS-CoV-2 RBD construct based on SARS-CoV-2 Wuhan-Hu-1 and produced in insect cells has elicited neutralizing antibodies in mice and protective immunity in nonhuman primates (16). Similar tagged constructs have also been adapted for production in yeast like Komagataella phaffii (Pichia boutique hotel la roche (17, 18), establishing molecular liquids journal RBD domain as a prominent candidate for large-volume manufacturing of COVID-19 vaccines.

Despite its significance for low-cost vaccine candidates, recombinant RBD based on the original SARS-CoV-2 clade 19A sequence has shown limited immunogenicity to date. Reported candidates would require as many as three doses or large doses to elicit strong neutralizing antibody responses in mice when Ferumoxytol Injection (Feraheme)- FDA with adjuvants (16, 18).

Increasing the number of doses or amounts required could limit its benefits for affordable and accessible vaccines. An engineered design for the RBD, therefore, could enhance the potency of many subunit-based vaccine candidates using this domain. We reasoned that an improved RBD variant for vaccine candidates should exhibit both improved quality attributes relevant for manufacturing (increased titers, reduced aggregation) and immunogenicity relative to the Wuhan-Hu-1 sequence used in current Levophed (Norepinephrine Bitartrate)- Multum. We produced RBD in a 200-mL shake flask culture and purified quantities to assess the quality attributes of the protein (Fig.

S1 B and C) (24). The protein displayed high mannose glycoforms at Ferumoxytol Injection (Feraheme)- FDA single canonical position for N-linked glycosylation present on the exposed surface distal from the receptor binding motif (RBM) (SI Appendix, Fig. Together, these results suggested production of this domain was feasible, but presented concerns regarding potential yields and consistency for large-volume manufacturing.

Molecular engineering of the RBD for manufacturability. Sup, cultivation supernatant; Pur, purified protein. Alignment of the ACE2 binding motif to other sarbecoviruses, including selected designs for testing. Reported values are relative to expression of wild-type RBD. From these assessments, we reasoned that the qualities of the protein itself may impede its expression and ultimately its attributes that would influence its suitability as an immunogen for subunit-based vaccine candidates.

We hypothesized that the tendency of the protein to self-associate may Ferumoxytol Injection (Feraheme)- FDA induce stress on the host cells during the expression and secretion of the protein.



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