SARS-CoV-2 RBD trimer protein adjuvanted with Alum-3M-052 protects from SARS-CoV-2 infection and immune pathology in the lung

Nanda Kishore Routhu; Narayanaiah Cheedarla; Venkata Satish Bollimpelli; Sailaja Gangadhara; Venkata Viswanadh Edara; Lilin Lai; Anusmita Sahoo; Ayalnesh Shiferaw; Tiffany M. Styles; Katharine Floyd; Stephanie Fischinger; Caroline Atyeo; Sally A. Shin; Sanjeev Gumber; Shannon Kirejczyk; Kenneth H. Dinnon; Pei Yong Shi; Vineet D. Menachery; Mark Tomai; Christopher B. Fox; Galit Alter; Thomas H. Vanderford; Lisa Gralinski; Mehul S. Suthar; Rama Rao Amara

doi:10.1038/s41467-021-23942-y

SARS-CoV-2 RBD trimer protein adjuvanted with Alum-3M-052 protects from SARS-CoV-2 infection and immune pathology in the lung

Nanda Kishore Routhu, Narayanaiah Cheedarla, Venkata Satish Bollimpelli, Sailaja Gangadhara, Venkata Viswanadh Edara, Lilin Lai, Anusmita Sahoo, Ayalnesh Shiferaw, Tiffany M. Styles, Katharine Floyd, Stephanie Fischinger, Caroline Atyeo, Sally A. Shin, Sanjeev Gumber, Shannon Kirejczyk, Kenneth H. Dinnon, Pei Yong Shi, Vineet D. Menachery, Mark Tomai, Christopher B. FoxGalit Alter, Thomas H. Vanderford, Lisa Gralinski, Mehul S. Suthar, Rama Rao Amara

Research output: Contribution to journal › Article › peer-review

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Abstract

There is a great need for the development of vaccines that induce potent and long-lasting protective immunity against SARS-CoV-2. Multimeric display of the antigen combined with potent adjuvant can enhance the potency and longevity of the antibody response. The receptor binding domain (RBD) of the spike protein is a primary target of neutralizing antibodies. Here, we developed a trimeric form of the RBD and show that it induces a potent neutralizing antibody response against live virus with diverse effector functions and provides protection against SARS-CoV-2 challenge in mice and rhesus macaques. The trimeric form induces higher neutralizing antibody titer compared to monomer with as low as 1μg antigen dose. In mice, adjuvanting the protein with a TLR7/8 agonist formulation alum-3M-052 induces 100-fold higher neutralizing antibody titer and superior protection from infection compared to alum. SARS-CoV-2 infection causes significant loss of innate cells and pathology in the lung, and vaccination protects from changes in innate cells and lung pathology. These results demonstrate RBD trimer protein as a suitable candidate for vaccine against SARS-CoV-2.

Original language	English (US)
Article number	3587
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23942-y
State	Published - Dec 1 2021

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Routhu, N. K., Cheedarla, N., Bollimpelli, V. S., Gangadhara, S., Edara, V. V., Lai, L., Sahoo, A., Shiferaw, A., Styles, T. M., Floyd, K., Fischinger, S., Atyeo, C., Shin, S. A., Gumber, S., Kirejczyk, S., Dinnon, K. H., Shi, P. Y., Menachery, V. D., Tomai, M., ... Amara, R. R. (2021). SARS-CoV-2 RBD trimer protein adjuvanted with Alum-3M-052 protects from SARS-CoV-2 infection and immune pathology in the lung. Nature communications, 12(1), [3587]. https://doi.org/10.1038/s41467-021-23942-y

Routhu, NK, Cheedarla, N, Bollimpelli, VS, Gangadhara, S, Edara, VV, Lai, L, Sahoo, A, Shiferaw, A, Styles, TM, Floyd, K, Fischinger, S, Atyeo, C, Shin, SA, Gumber, S, Kirejczyk, S, Dinnon, KH, Shi, PY, Menachery, VD, Tomai, M, Fox, CB, Alter, G, Vanderford, TH, Gralinski, L, Suthar, MS & Amara, RR 2021, 'SARS-CoV-2 RBD trimer protein adjuvanted with Alum-3M-052 protects from SARS-CoV-2 infection and immune pathology in the lung', Nature communications, vol. 12, no. 1, 3587. https://doi.org/10.1038/s41467-021-23942-y

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title = "SARS-CoV-2 RBD trimer protein adjuvanted with Alum-3M-052 protects from SARS-CoV-2 infection and immune pathology in the lung",

abstract = "There is a great need for the development of vaccines that induce potent and long-lasting protective immunity against SARS-CoV-2. Multimeric display of the antigen combined with potent adjuvant can enhance the potency and longevity of the antibody response. The receptor binding domain (RBD) of the spike protein is a primary target of neutralizing antibodies. Here, we developed a trimeric form of the RBD and show that it induces a potent neutralizing antibody response against live virus with diverse effector functions and provides protection against SARS-CoV-2 challenge in mice and rhesus macaques. The trimeric form induces higher neutralizing antibody titer compared to monomer with as low as 1μg antigen dose. In mice, adjuvanting the protein with a TLR7/8 agonist formulation alum-3M-052 induces 100-fold higher neutralizing antibody titer and superior protection from infection compared to alum. SARS-CoV-2 infection causes significant loss of innate cells and pathology in the lung, and vaccination protects from changes in innate cells and lung pathology. These results demonstrate RBD trimer protein as a suitable candidate for vaccine against SARS-CoV-2.",

author = "Routhu, {Nanda Kishore} and Narayanaiah Cheedarla and Bollimpelli, {Venkata Satish} and Sailaja Gangadhara and Edara, {Venkata Viswanadh} and Lilin Lai and Anusmita Sahoo and Ayalnesh Shiferaw and Styles, {Tiffany M.} and Katharine Floyd and Stephanie Fischinger and Caroline Atyeo and Shin, {Sally A.} and Sanjeev Gumber and Shannon Kirejczyk and Dinnon, {Kenneth H.} and Shi, {Pei Yong} and Menachery, {Vineet D.} and Mark Tomai and Fox, {Christopher B.} and Galit Alter and Vanderford, {Thomas H.} and Lisa Gralinski and Suthar, {Mehul S.} and Amara, {Rama Rao}",

note = "Funding Information: We thank Traci Legere, Brenda Wehrle, and Zeba Momin for help with processing of blood and tissue samples, Shelly Wang for help with viral RNA mesurements, the Yerkes Division of Pathology and Research Resources for outstanding animal care during the pandemic and Histology and Molecular Pathology Lab for help with tissue sectioning. The following reagent was produced under HHSN272201400008C and obtained through BEI Resources, NIAID, NIH: Vector pCAGGS Containing the SARS-Related Coronavirus 2, Wuhan-Hu-1 Spike Glycoprotein Receptor Binding Domain (RBD), NR-52309. This work was supported in part by National Institutes of Health Grants RO1 AI148378-01S1 and Fast Grants Award #2166 to R.R.A., and NCRR/NIH base grant P51 OD011132 to theYerkes National Primate Research Center. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s41467-021-23942-y",

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T1 - SARS-CoV-2 RBD trimer protein adjuvanted with Alum-3M-052 protects from SARS-CoV-2 infection and immune pathology in the lung

AU - Routhu, Nanda Kishore

AU - Cheedarla, Narayanaiah

AU - Bollimpelli, Venkata Satish

AU - Gangadhara, Sailaja

AU - Edara, Venkata Viswanadh

AU - Lai, Lilin

AU - Sahoo, Anusmita

AU - Shiferaw, Ayalnesh

AU - Styles, Tiffany M.

AU - Floyd, Katharine

AU - Fischinger, Stephanie

AU - Atyeo, Caroline

AU - Shin, Sally A.

AU - Gumber, Sanjeev

AU - Kirejczyk, Shannon

AU - Dinnon, Kenneth H.

AU - Shi, Pei Yong

AU - Menachery, Vineet D.

AU - Tomai, Mark

AU - Fox, Christopher B.

AU - Alter, Galit

AU - Vanderford, Thomas H.

AU - Gralinski, Lisa

AU - Suthar, Mehul S.

AU - Amara, Rama Rao

N1 - Funding Information: We thank Traci Legere, Brenda Wehrle, and Zeba Momin for help with processing of blood and tissue samples, Shelly Wang for help with viral RNA mesurements, the Yerkes Division of Pathology and Research Resources for outstanding animal care during the pandemic and Histology and Molecular Pathology Lab for help with tissue sectioning. The following reagent was produced under HHSN272201400008C and obtained through BEI Resources, NIAID, NIH: Vector pCAGGS Containing the SARS-Related Coronavirus 2, Wuhan-Hu-1 Spike Glycoprotein Receptor Binding Domain (RBD), NR-52309. This work was supported in part by National Institutes of Health Grants RO1 AI148378-01S1 and Fast Grants Award #2166 to R.R.A., and NCRR/NIH base grant P51 OD011132 to theYerkes National Primate Research Center. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - There is a great need for the development of vaccines that induce potent and long-lasting protective immunity against SARS-CoV-2. Multimeric display of the antigen combined with potent adjuvant can enhance the potency and longevity of the antibody response. The receptor binding domain (RBD) of the spike protein is a primary target of neutralizing antibodies. Here, we developed a trimeric form of the RBD and show that it induces a potent neutralizing antibody response against live virus with diverse effector functions and provides protection against SARS-CoV-2 challenge in mice and rhesus macaques. The trimeric form induces higher neutralizing antibody titer compared to monomer with as low as 1μg antigen dose. In mice, adjuvanting the protein with a TLR7/8 agonist formulation alum-3M-052 induces 100-fold higher neutralizing antibody titer and superior protection from infection compared to alum. SARS-CoV-2 infection causes significant loss of innate cells and pathology in the lung, and vaccination protects from changes in innate cells and lung pathology. These results demonstrate RBD trimer protein as a suitable candidate for vaccine against SARS-CoV-2.

AB - There is a great need for the development of vaccines that induce potent and long-lasting protective immunity against SARS-CoV-2. Multimeric display of the antigen combined with potent adjuvant can enhance the potency and longevity of the antibody response. The receptor binding domain (RBD) of the spike protein is a primary target of neutralizing antibodies. Here, we developed a trimeric form of the RBD and show that it induces a potent neutralizing antibody response against live virus with diverse effector functions and provides protection against SARS-CoV-2 challenge in mice and rhesus macaques. The trimeric form induces higher neutralizing antibody titer compared to monomer with as low as 1μg antigen dose. In mice, adjuvanting the protein with a TLR7/8 agonist formulation alum-3M-052 induces 100-fold higher neutralizing antibody titer and superior protection from infection compared to alum. SARS-CoV-2 infection causes significant loss of innate cells and pathology in the lung, and vaccination protects from changes in innate cells and lung pathology. These results demonstrate RBD trimer protein as a suitable candidate for vaccine against SARS-CoV-2.

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SARS-CoV-2 RBD trimer protein adjuvanted with Alum-3M-052 protects from SARS-CoV-2 infection and immune pathology in the lung

Abstract

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