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2. Molecular engineering of a cryptic epitope in Spike RBD improves manufacturability and neutralizing breadth against SARS-CoV-2 variants

Author

Rodriguez-Aponte, Sergio A., Dalvie, Neil C., Wong, Ting Y., Johnston, Ryan S., Naranjo, Christopher A., Bajoria, Sakshi, Kumru, Ozan S., Kaur, Kawaljit, Russ, Brynnan P., Lee, Katherine S., Cyphert, Holly A., Barbier, Mariette, Rao, Harish D., Rajurkar, Meghraj P., Lothe, Rakesh R., Shaligram, Umesh S., Batwal, Saurabh, Chandrasekaran, Rahul, Nagar, Gaurav, Kleanthous, Harry, Biswas, Sumi, Bevere, Justin R., Joshi, Sangeeta B., Volkin, David B., Damron, F. Heath, and Love, J. Christopher

Published
2023
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3. Minimal purification method enables developability assessment of recombinant proteins.

Author

Rodriguez‐Aponte, Sergio A., Naranjo, Christopher A., Johnston, Ryan S., Dalvie, Neil C., Crowell, Laura E., Bajoria, Sakshi, Kumru, Ozan S., Joshi, Sangeeta B., Volkin, David B., and Love, J. Christopher

Abstract

Analytical characterization of proteins is a critical task for developing therapeutics and subunit vaccine candidates. Assessing candidates with a battery of biophysical assays can inform the selection of one that exhibits properties consistent with a given target product profile (TPP). Such assessments, however, require several milligrams of purified protein, and ideal assessments of the physicochemical attributes of the proteins should not include unnatural modifications like peptide tags for purification. Here, we describe a fast two‐stage minimal purification process for recombinant proteins secreted by the yeast host Komagataella phaffii from a 20 mL culture supernatant. This method comprises a buffer exchange and filtration with a Q‐membrane filter and we demonstrate sufficient removal of key supernatant impurities including host‐cell proteins (HCPs) and DNA with yields of 1–2 mg and >60% purity. This degree of purity enables characterizing the resulting proteins using affinity binding, mass spectrometry, and differential scanning calorimetry. We first evaluated this method to purify an engineered SARS‐CoV‐2 subunit protein antigen and compared the purified protein to a conventional two‐step chromatographic process. We then applied this method to compare several SARS‐CoV‐2 RBD sequences. Finally, we show this simple process can be applied to a range of other proteins, including a single‐domain antibody, a rotavirus protein subunit, and a human growth hormone. This simple and fast developability methodology obviates the need for genetic tagging or full chromatographic development when assessing and comparing early‐stage protein therapeutics and vaccine candidates produced in K. phaffii. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Effects of aluminum-salt, CpG and emulsion adjuvants on the stability and immunogenicity of a virus-like particle displaying the SARS-CoV-2 receptor-binding domain (RBD)

Author

Kumru, Ozan S., primary, Bajoria, Sakshi, additional, Kaur, Kawaljit, additional, Hickey, John M., additional, Van Slyke, Greta, additional, Doering, Jennifer, additional, Berman, Katherine, additional, Richardson, Charles, additional, Lien, Hans, additional, Kleanthous, Harry, additional, Mantis, Nicholas J., additional, Joshi, Sangeeta B., additional, and Volkin, David B., additional

Published
2023
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5. Effects of aluminum-salt, CpG and emulsion adjuvants on the stability and immunogenicity of a virus-like particle displaying the SARS-CoV-2 receptor binding domain (RBD)

Author

Kumru, Ozan S, primary, Bajoria, Sakshi, additional, Kaur, Kawaljit, additional, Hickey, John M, additional, Van Slyke, Greta, additional, Doering, Jennifer, additional, Berman, Katherine, additional, Richardson, Charles, additional, Lien, Hans, additional, Kleanthous, Harry, additional, Mantis, Nicholas J, additional, Joshi, Sangeeta B, additional, and Volkin, David B, additional

Published
2023
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6. Nanoalum Formulations Containing Aluminum Hydroxide and Cpg 1018TM Adjuvants: The Effect on Stability and Immunogen-Icity of a Recombinant SARS-CoV-2 Rbd Antigen

Author

Bajoria, Sakshi, primary, Kumru, Ozan S., additional, Doering, Jennifer, additional, Berman, Katherine, additional, Slyke, Greta Van, additional, Prigodich, Anneka, additional, Rodriguez-Aponte, Sergio A., additional, Kleanthous, Harry, additional, Love, J. Christopher, additional, Mantis, Nicholas J., additional, Joshi, Sangeeta B., additional, and Volkin, David B., additional

Published
2023
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8. Nanoalum Formulations Containing Aluminum Hydroxide and CpG 1018TM Adjuvants: The Effect on Stability and Immunogenicity of a Recombinant SARS-CoV-2 RBD Antigen

Author

Massachusetts Institute of Technology. Department of Biological Engineering, Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Department of Chemical Engineering, Bajoria, Sakshi, Kumru, Ozan S., Doering, Jennifer, Berman, Katherine, Slyke, Greta Van, Prigodich, Anneka, Rodriguez-Aponte, Sergio A., Kleanthous, Harry, Love, J. Christopher, Mantis, Nicholas J., Joshi, Sangeeta B., Volkin, David B., Massachusetts Institute of Technology. Department of Biological Engineering, Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Department of Chemical Engineering, Bajoria, Sakshi, Kumru, Ozan S., Doering, Jennifer, Berman, Katherine, Slyke, Greta Van, Prigodich, Anneka, Rodriguez-Aponte, Sergio A., Kleanthous, Harry, Love, J. Christopher, Mantis, Nicholas J., Joshi, Sangeeta B., and Volkin, David B.

Abstract

Aluminum-salt vaccine adjuvants (alum) are commercially available as micron-sized particles with varying chemical composition and crystallinity. There are reports of enhanced adjuvanticity when the alum’s particle size is reduced to the nanometer range. Previously, we demonstrated that a recombinant receptor-binding domain (RBD)-based COVID-19 vaccine candidate (RBD-J; RBD-L452K-F490W) formulated with aluminum hydroxide (Alhydrogel®; AH) and CpG 1018™ (CpG) adjuvants induced potent neutralizing antibody responses in mice yet displayed instability during storage. In this work, we evaluated whether sonication of AH to the nanometer size range (nanoAH) could further enhance immunogenicity or improve storage stability of the above formulation. The addition of CpG to nanoAH (at mouse doses), however, caused re-agglomeration of nanoAH. AH-CpG interactions were evaluated by Langmuir binding isotherms and zeta potential measurements, and stabilized nanoAH + CpG formulations of RBD-J were then designed by (1) optimizing CpG:Aluminum dose ratios or (2) adding a small-molecule polyanion (phytic acid, PA). Compared with the micron-sized AH + CpG formulation, the two stabilized nanoAH + CpG formulations of RBD-J demonstrated no enhancement in SARS-CoV-2 pseudovirus neutralizing titers in mice, but the PA-containing nanoAH + CpG formulation showed improved RBD-J storage stability trends (at 4, 25, and 37 °C). The formulation protocols presented herein can be employed to evaluate the potential benefits of the nanoAH + CpG adjuvant combination with other vaccine antigens in different animal models.

Published
2023

9. Molecular engineering of a cryptic epitope in Spike RBD improves manufacturability and neutralizing breadth against SARS-CoV-2 variants

Author

Rodriguez-Aponte, Sergio A., primary, Dalvie, Neil C., additional, Wong, Ting Y., additional, Johnston, Ryan S., additional, Naranjo, Christopher A., additional, Bajoria, Sakshi, additional, Kumru, Ozan S., additional, Kaur, Kawaljit, additional, Russ, Brynnan P., additional, Lee, Katherine S., additional, Cyphert, Holly A., additional, Barbier, Mariette, additional, Rao, Harish D., additional, Rajurkar, Meghraj P., additional, Lothe, Rakesh R., additional, Shaligram, Umesh S., additional, Batwal, Saurabh, additional, Chandrasekaran, Rahul, additional, Nagar, Gaurav, additional, Kleanthous, Harry, additional, Biswas, Sumi, additional, Bevere, Justin R., additional, Joshi, Sangeeta B., additional, Volkin, David B., additional, Damron, F. Heath, additional, and Love, J. Christopher, additional

Published
2022
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10. Nanoalum Formulations Containing Aluminum Hydroxide and CpG 1018 TM Adjuvants: The Effect on Stability and Immunogenicity of a Recombinant SARS-CoV-2 RBD Antigen.

Author

Bajoria, Sakshi, Kumru, Ozan S., Doering, Jennifer, Berman, Katherine, Slyke, Greta Van, Prigodich, Anneka, Rodriguez-Aponte, Sergio A., Kleanthous, Harry, Love, J. Christopher, Mantis, Nicholas J., Joshi, Sangeeta B., and Volkin, David B.

Subjects
ALUMINUM hydroxide, IMMUNE response, COMBINED vaccines, SARS-CoV-2, PHYTIC acid, TITERS
Abstract

Aluminum-salt vaccine adjuvants (alum) are commercially available as micron-sized particles with varying chemical composition and crystallinity. There are reports of enhanced adjuvanticity when the alum's particle size is reduced to the nanometer range. Previously, we demonstrated that a recombinant receptor-binding domain (RBD)-based COVID-19 vaccine candidate (RBD-J; RBD-L452K-F490W) formulated with aluminum hydroxide (Alhydrogel®; AH) and CpG 1018™ (CpG) adjuvants induced potent neutralizing antibody responses in mice yet displayed instability during storage. In this work, we evaluated whether sonication of AH to the nanometer size range (nanoAH) could further enhance immunogenicity or improve storage stability of the above formulation. The addition of CpG to nanoAH (at mouse doses), however, caused re-agglomeration of nanoAH. AH-CpG interactions were evaluated by Langmuir binding isotherms and zeta potential measurements, and stabilized nanoAH + CpG formulations of RBD-J were then designed by (1) optimizing CpG:Aluminum dose ratios or (2) adding a small-molecule polyanion (phytic acid, PA). Compared with the micron-sized AH + CpG formulation, the two stabilized nanoAH + CpG formulations of RBD-J demonstrated no enhancement in SARS-CoV-2 pseudovirus neutralizing titers in mice, but the PA-containing nanoAH + CpG formulation showed improved RBD-J storage stability trends (at 4, 25, and 37 °C). The formulation protocols presented herein can be employed to evaluate the potential benefits of the nanoAH + CpG adjuvant combination with other vaccine antigens in different animal models. [ABSTRACT FROM AUTHOR]

Published
2023
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11. Antigen-adjuvant interactions, stability, and immunogenicity profiles of a SARS-CoV-2 receptor-binding domain (RBD) antigen formulated with aluminum salt and CpG adjuvants

Author

Bajoria, Sakshi, primary, Kaur, Kawaljit, additional, Kumru, Ozan S., additional, Van Slyke, Greta, additional, Doering, Jennifer, additional, Novak, Hayley, additional, Rodriguez Aponte, Sergio A., additional, Dalvie, Neil C., additional, Naranjo, Christopher A., additional, Johnston, Ryan S., additional, Silverman, Judith Maxwell, additional, Kleanthous, Harry, additional, Love, J. Christopher, additional, Mantis, Nicholas J., additional, Joshi, Sangeeta B., additional, and Volkin, David B., additional

Published
2022
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12. SARS-CoV-2 receptor binding domain displayed on HBsAg virus–like particles elicits protective immunity in macaques

Author

Dalvie, Neil C., primary, Tostanoski, Lisa H., additional, Rodriguez-Aponte, Sergio A., additional, Kaur, Kawaljit, additional, Bajoria, Sakshi, additional, Kumru, Ozan S., additional, Martinot, Amanda J., additional, Chandrashekar, Abishek, additional, McMahan, Katherine, additional, Mercado, Noe B., additional, Yu, Jingyou, additional, Chang, Aiquan, additional, Giffin, Victoria M., additional, Nampanya, Felix, additional, Patel, Shivani, additional, Bowman, Lesley, additional, Naranjo, Christopher A., additional, Yun, Dongsoo, additional, Flinchbaugh, Zach, additional, Pessaint, Laurent, additional, Brown, Renita, additional, Velasco, Jason, additional, Teow, Elyse, additional, Cook, Anthony, additional, Andersen, Hanne, additional, Lewis, Mark G., additional, Camp, Danielle L., additional, Silverman, Judith Maxwell, additional, Nagar, Gaurav S., additional, Rao, Harish D., additional, Lothe, Rakesh R., additional, Chandrasekharan, Rahul, additional, Rajurkar, Meghraj P., additional, Shaligram, Umesh S., additional, Kleanthous, Harry, additional, Joshi, Sangeeta B., additional, Volkin, David B., additional, Biswas, Sumi, additional, Love, J. Christopher, additional, and Barouch, Dan H., additional

Published
2022
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13. A modular protein subunit vaccine candidate produced in yeast confers protection against SARS-CoV-2 in non-human primates

Author

Dalvie, Neil C., primary, Tostanoski, Lisa H., additional, Rodriguez-Aponte, Sergio A, additional, Kaur, Kawaljit, additional, Bajoria, Sakshi, additional, Kumru, Ozan S., additional, Martinot, Amanda J., additional, Chandrashekar, Abishek, additional, McMahan, Katherine, additional, Mercado, Noe B., additional, Yu, Jingyou, additional, Chang, Aiquan, additional, Giffin, Victoria M., additional, Nampanya, Felix, additional, Patel, Shivani, additional, Bowman, Lesley, additional, Naranjo, Christopher A., additional, Yun, Dongsoo, additional, Flinchbaugh, Zach, additional, Pessaint, Laurent, additional, Brown, Renita, additional, Velasco, Jason, additional, Teow, Elyse, additional, Cook, Anthony, additional, Andersen, Hanne, additional, Lewis, Mark G., additional, Camp, Danielle L., additional, Silverman, Judith Maxwell, additional, Kleanthous, Harry, additional, Joshi, Sangeeta B., additional, Volkin, David B., additional, Biswas, Sumi, additional, Love, J. Christopher, additional, and Barouch, Dan H., additional

Published
2021
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14. Prophylactic Activity of Orally Administered FliD-Reactive Monoclonal SIgA Against Campylobacter Infection

Author

Perruzza, Lisa, Jaconi, Stefano, Lombardo, Gloria, Pinna, Debora, Strati, Francesco, Morone, Diego, Seehusen, Frauke, Hu, Yue, Bajoria, Sakshi, Xiong, Jian, Kumru, Ozan Selahattin, Joshi, Sangeeta Bagai, Volkin, David Bernard, Piantanida, Renato, Benigni, Fabio, Grassi, Fabio, Corti, Davide, Pizzuto, Matteo Samuele, Perruzza, Lisa, Jaconi, Stefano, Lombardo, Gloria, Pinna, Debora, Strati, Francesco, Morone, Diego, Seehusen, Frauke, Hu, Yue, Bajoria, Sakshi, Xiong, Jian, Kumru, Ozan Selahattin, Joshi, Sangeeta Bagai, Volkin, David Bernard, Piantanida, Renato, Benigni, Fabio, Grassi, Fabio, Corti, Davide, and Pizzuto, Matteo Samuele

Abstract

Campylobacter infection is one of the most common causes of bacterial gastroenteritis worldwide and a major global health threat due to the rapid development of antibiotic resistance. Currently, there are no vaccines approved to prevent campylobacteriosis, and rehydration is the main form of therapy. Secretory immunoglobulin A (SIgA) is the main antibody class found in mucous secretions, including human milk, and serves as the first line of defense for the gastrointestinal epithelium against enteric pathogens. In this study, we describe the prophylactic activity of orally delivered recombinant SIgA generated from two human monoclonal antibodies (CAA1 and CCG4) isolated for their reactivity against the flagellar-capping protein FliD, which is essential for bacteria motility and highly conserved across Campylobacter species associated with severe enteritis. In an immunocompetent weaned mouse model, a single oral administration of FliD-reactive SIgA CAA1 or CCG4 at 2 h before infection significantly enhances Campylobacter clearance at early stages post-infection, reducing the levels of inflammation markers associated with epithelial damage and polymorphonuclear (PMN) cells infiltration in the cecum lamina propria. Our data indicate that the prophylactic activity of CAA1 and CCG4 is not only dependent on the specificity to FliD but also on the use of the SIgA format, as the immunoglobulin G (IgG) versions of the same antibodies did not confer a comparable protective effect. Our work emphasizes the potential of FliD as a target for the development of vaccines and supports the concept that orally administered FliD-reactive SIgA can be developed to prevent or mitigate the severity of Campylobacter infections as well as the development of post-infection syndromes.

Published
2020

15. Prophylactic Activity of Orally Administered FliD-Reactive Monoclonal SIgA Against Campylobacter Infection

Author

Perruzza, Lisa, primary, Jaconi, Stefano, additional, Lombardo, Gloria, additional, Pinna, Debora, additional, Strati, Francesco, additional, Morone, Diego, additional, Seehusen, Frauke, additional, Hu, Yue, additional, Bajoria, Sakshi, additional, Xiong, Jian, additional, Kumru, Ozan Selahattin, additional, Joshi, Sangeeta Bagai, additional, Volkin, David Bernard, additional, Piantanida, Renato, additional, Benigni, Fabio, additional, Grassi, Fabio, additional, Corti, Davide, additional, and Pizzuto, Matteo Samuele, additional

Published
2020
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16. Antigen-adjuvant interactions, stability, and immunogenicity profiles of a SARS-CoV-2 receptor-binding domain (RBD) antigen formulated with aluminum salt and CpG adjuvants (Datasets)

Author

Bajoria, Sakshi, primary, Kaur, Kawaljit, additional, Kumru, Ozan S., additional, Van Slyke, Greta, additional, Doering, Jennifer, additional, Novak, Hayley, additional, Rodriguez-Aponte, Sergio A., additional, Dalvie, Neil C., additional, Naranjo, Christopher A., additional, Johnston, Ryan S., additional, Maxwell Silverman, Judith, additional, Kleanthous, Harry, additional, Love, J. Christopher, additional, Mantis, Nicholas J., additional, Joshi, Sangeeta B., additional, and Volkin, David B., additional

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17. Effects of aluminum-salt, CpG and emulsion adjuvants on the stability and immunogenicity of a virus-like particle displaying the SARS-CoV-2 receptor-binding domain (RBD) (Dataset)

Author

Kumru, Ozan S., primary, Bajoria, Sakshi, additional, Kaur, Kawaljit, additional, Hickey, John M., additional, Van Slyke, Greta, additional, Doering, Jennifer, additional, Berman, Katherine, additional, Richardson, Charles, additional, Lien, Hans, additional, Kleanthous, Harry, additional, Mantis, Nicholas J., additional, Joshi, Sangeeta B., additional, and Volkin, David B., additional

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19. A modular protein subunit vaccine candidate produced in yeast confers protection against SARS-CoV-2 in non-human primates.

Author

Dalvie NC, Tostanoski LH, Rodriguez-Aponte SA, Kaur K, Bajoria S, Kumru OS, Martinot AJ, Chandrashekar A, McMahan K, Mercado NB, Yu J, Chang A, Giffin VM, Nampanya F, Patel S, Bowman L, Naranjo CA, Yun D, Flinchbaugh Z, Pessaint L, Brown R, Velasco J, Teow E, Cook A, Andersen H, Lewis MG, Camp DL, Silverman JM, Kleanthous H, Joshi SB, Volkin DB, Biswas S, Love JC, and Barouch DH

Abstract

Vaccines against SARS-CoV-2 have been distributed at massive scale in developed countries, and have been effective at preventing COVID-19. Access to vaccines is limited, however, in low- and middle-income countries (LMICs) due to insufficient supply, high costs, and cold storage requirements. New vaccines that can be produced in existing manufacturing facilities in LMICs, can be manufactured at low cost, and use widely available, proven, safe adjuvants like alum, would improve global immunity against SARS-CoV-2. One such protein subunit vaccine is produced by the Serum Institute of India Pvt. Ltd. and is currently in clinical testing. Two protein components, the SARS-CoV-2 receptor binding domain (RBD) and hepatitis B surface antigen virus-like particles (VLPs), are each produced in yeast, which would enable a low-cost, high-volume manufacturing process. Here, we describe the design and preclinical testing of the RBD-VLP vaccine in cynomolgus macaques. We observed titers of neutralizing antibodies (>10 4 ) above the range of protection for other licensed vaccines in non-human primates. Interestingly, addition of a second adjuvant (CpG1018) appeared to improve the cellular response while reducing the humoral response. We challenged animals with SARS-CoV-2, and observed a ~3.4 and ~2.9 log 10 reduction in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, compared to sham controls. These results inform the design and formulation of current clinical COVID-19 vaccine candidates like the one described here, and future designs of RBD-based vaccines against variants of SARS-CoV-2 or other betacoronaviruses., Competing Interests: Competing interests J.C.L. has interests in Sunflower Therapeutics PBC, Pfizer, Honeycomb Biotechnologies, OneCyte Biotechnologies, QuantumCyte, Amgen, and Repligen. J.C.L’s interests are reviewed and managed under MIT’s policies for potential conflicts of interest. J.M.S. is an employee of the Bill & Melinda Gates Medical Research Institute. H.K. is an employee of the Bill & Melinda Gates Foundation. Sumi Biswas is the CEO and co-founder of SpyBiotech Ltd. which holds the exclusive rights for the use of Spytag/Spyctacher in the field of vaccines. Lesley Bowman is an employee of SpyBiotech Ltd.

Published
2021
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