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1. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness

Author

Corbett, Kizzmekia S., Edwards, Darin K., Leist, Sarah R., Abiona, Olubukola M., Boyoglu-Barnum, Seyhan, Gillespie, Rebecca A., Himansu, Sunny, Schäfer, Alexandra, Ziwawo, Cynthia T., DiPiazza, Anthony T., Dinnon, Kenneth H., Elbashir, Sayda M., Shaw, Christine A., Woods, Angela, Fritch, Ethan J., Martinez, David R., Bock, Kevin W., Minai, Mahnaz, Nagata, Bianca M., Hutchinson, Geoffrey B., Wu, Kai, Henry, Carole, Bahl, Kapil, Garcia-Dominguez, Dario, Ma, LingZhi, Renzi, Isabella, Kong, Wing-Pui, Schmidt, Stephen D., Wang, Lingshu, Zhang, Yi, Phung, Emily, Chang, Lauren A., Loomis, Rebecca J., Altaras, Nedim Emil, Narayanan, Elisabeth, Metkar, Mihir, Presnyak, Vlad, Liu, Cuiping, Louder, Mark K., Shi, Wei, Leung, Kwanyee, Yang, Eun Sung, West, Ande, Gully, Kendra L., Stevens, Laura J., Wang, Nianshuang, Wrapp, Daniel, Doria-Rose, Nicole A., Stewart-Jones, Guillaume, Bennett, Hamilton, Alvarado, Gabriela S., Nason, Martha C., Ruckwardt, Tracy J., McLellan, Jason S., Denison, Mark R., Chappell, James D., Moore, Ian N., Morabito, Kaitlyn M., Mascola, John R., Baric, Ralph S., Carfi, Andrea, and Graham, Barney S.

Published
2020
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5. Altering the mRNA-1273 dosing interval impacts the kinetics, quality, and magnitude of immune responses in mice

Author

Garcia-Dominguez, Dario, primary, Henry, Carole, additional, Ma, LingZhi, additional, Jani, Hardik, additional, Amato, Nicholas J., additional, Manning, Taylor, additional, Freyn, Alec, additional, Davis, Heather, additional, Hsiao, Chiaowen Joyce, additional, Li, Mengying, additional, Koch, Hillary, additional, Elbashir, Sayda, additional, DiPiazza, Anthony, additional, Carfi, Andrea, additional, Edwards, Darin, additional, and Bahl, Kapil, additional

Published
2022
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7. T cell immunity to SARS-CoV-2 following natural infection and vaccination

Author

DiPiazza, Anthony T., Graham, Barney S., and Ruckwardt, Tracy J.

Subjects
0301 basic medicine, Cellular immunity, COVID-19 Vaccines, T-Lymphocytes, viruses, Population, T cells, Biophysics, Disease, medicine.disease_cause, Biochemistry, Article, 03 medical and health sciences, 0302 clinical medicine, Immunity, Humans, Medicine, education, Molecular Biology, Coronavirus, education.field_of_study, SARS-CoV-2, business.industry, Vaccination, COVID-19, Cell Biology, 030104 developmental biology, Respiratory failure, 030220 oncology & carcinogenesis, Immunology, Respiratory virus, Infection, business
Abstract

SARS-CoV-2 first emerged in the human population in late 2019 in Wuhan, China, and in a matter of months, spread across the globe resulting in the Coronavirus Disease 19 (COVID-19) pandemic and substantial economic fallout. SARS-CoV-2 is transmitted between humans via respiratory particles, with infection presenting a spectrum of clinical manifestations ranging from asymptomatic to respiratory failure with multiorgan dysfunction and death in severe cases. Prior experiences with human pathogenic coronaviruses and respiratory virus diseases in general have revealed an important role for cellular immunity in limiting disease severity. Here, we review some of the key mechanisms underlying cell-mediated immunity to respiratory viruses and summarize our current understanding of the functional capacity and role of SARS-CoV-2-specific T cells following natural infection and vaccination.

Published
2021

8. Chimeric Fusion (F) and Attachment (G) Glycoprotein Antigen Delivery by mRNA as a Candidate Nipah Vaccine

Author

Loomis, Rebecca J., primary, DiPiazza, Anthony T., additional, Falcone, Samantha, additional, Ruckwardt, Tracy J., additional, Morabito, Kaitlyn M., additional, Abiona, Olubukola M., additional, Chang, Lauren A., additional, Caringal, Ria T., additional, Presnyak, Vladimir, additional, Narayanan, Elisabeth, additional, Tsybovsky, Yaroslav, additional, Nair, Deepika, additional, Hutchinson, Geoffrey B., additional, Stewart-Jones, Guillaume B. E., additional, Kueltzo, Lisa A., additional, Himansu, Sunny, additional, Mascola, John R., additional, Carfi, Andrea, additional, and Graham, Barney S., additional

Published
2021
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9. Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants

Author

Wang, Lingshu, primary, Zhou, Tongqing, additional, Zhang, Yi, additional, Yang, Eun Sung, additional, Schramm, Chaim A., additional, Shi, Wei, additional, Pegu, Amarendra, additional, Oloniniyi, Olamide K., additional, Henry, Amy R., additional, Darko, Samuel, additional, Narpala, Sandeep R., additional, Hatcher, Christian, additional, Martinez, David R., additional, Tsybovsky, Yaroslav, additional, Phung, Emily, additional, Abiona, Olubukola M., additional, Antia, Avan, additional, Cale, Evan M., additional, Chang, Lauren A., additional, Choe, Misook, additional, Corbett, Kizzmekia S., additional, Davis, Rachel L., additional, DiPiazza, Anthony T., additional, Gordon, Ingelise J., additional, Hait, Sabrina Helmold, additional, Hermanus, Tandile, additional, Kgagudi, Prudence, additional, Laboune, Farida, additional, Leung, Kwanyee, additional, Liu, Tracy, additional, Mason, Rosemarie D., additional, Nazzari, Alexandra F., additional, Novik, Laura, additional, O’Connell, Sarah, additional, O’Dell, Sijy, additional, Olia, Adam S., additional, Schmidt, Stephen D., additional, Stephens, Tyler, additional, Stringham, Christopher D., additional, Talana, Chloe Adrienna, additional, Teng, I-Ting, additional, Wagner, Danielle A., additional, Widge, Alicia T., additional, Zhang, Baoshan, additional, Roederer, Mario, additional, Ledgerwood, Julie E., additional, Ruckwardt, Tracy J., additional, Gaudinski, Martin R., additional, Moore, Penny L., additional, Doria-Rose, Nicole A., additional, Baric, Ralph S., additional, Graham, Barney S., additional, McDermott, Adrian B., additional, Douek, Daniel C., additional, Kwong, Peter D., additional, Mascola, John R., additional, Sullivan, Nancy J., additional, and Misasi, John, additional

Published
2021
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10. COVID-19 vaccine mRNA-1273 elicits a protective immune profile in mice that is not associated with vaccine-enhanced disease upon SARS-CoV-2 challenge

Author

DiPiazza, Anthony T., primary, Leist, Sarah R., additional, Abiona, Olubukola M., additional, Moliva, Juan I., additional, Werner, Anne, additional, Minai, Mahnaz, additional, Nagata, Bianca M., additional, Bock, Kevin W., additional, Phung, Emily, additional, Schäfer, Alexandra, additional, Dinnon, Kenneth H., additional, Chang, Lauren A., additional, Loomis, Rebecca J., additional, Boyoglu-Barnum, Seyhan, additional, Alvarado, Gabriela S., additional, Sullivan, Nancy J., additional, Edwards, Darin K., additional, Morabito, Kaitlyn M., additional, Mascola, John R., additional, Carfi, Andrea, additional, Corbett, Kizzmekia S., additional, Moore, Ian N., additional, Baric, Ralph S., additional, Graham, Barney S., additional, and Ruckwardt, Tracy J., additional

Published
2021
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11. Antibodies with potent and broad neutralizing activity against antigenically diverse and highly transmissible SARS-CoV-2 variants

Author

Wang, Lingshu, primary, Zhou, Tongqing, additional, Zhang, Yi, additional, Yang, Eun Sung, additional, Schramm, Chaim A., additional, Shi, Wei, additional, Pegu, Amarendra, additional, Oloninyi, Olamide K., additional, Ransier, Amy, additional, Darko, Samuel, additional, Narpala, Sandeep R., additional, Hatcher, Christian, additional, Martinez, David R., additional, Tsybovsky, Yaroslav, additional, Phung, Emily, additional, Abiona, Olubukola M., additional, Cale, Evan M., additional, Chang, Lauren A., additional, Corbett, Kizzmekia S., additional, DiPiazza, Anthony T., additional, Gordon, Ingelise J., additional, Leung, Kwanyee, additional, Liu, Tracy, additional, Mason, Rosemarie D., additional, Nazzari, Alexandra, additional, Novik, Laura, additional, Olia, Adam S., additional, Doria-Rose, Nicole A., additional, Stephens, Tyler, additional, Stringham, Christopher D., additional, Talana, Chloe Adrienna, additional, Teng, I-Ting, additional, Wagner, Danielle, additional, Widge, Alicia T., additional, Zhang, Baoshan, additional, Roederer, Mario, additional, Ledgerwood, Julie E., additional, Ruckwardt, Tracy J., additional, Gaudinski, Martin R., additional, Baric, Ralph S., additional, Graham, Barney S., additional, McDermott, Adrian B., additional, Douek, Daniel C., additional, Kwong, Peter D., additional, Mascola, John R, additional, Sullivan, Nancy J., additional, and Misasi, John, additional

Published
2021
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12. Structure-Based Design with Tag-Based Purification and In-Process Biotinylation Enable Streamlined Development of SARS-CoV-2 Spike Molecular Probes

Author

Zhou, Tongqing, primary, Teng, I-Ting, additional, Olia, Adam S., additional, Cerutti, Gabriele, additional, Gorman, Jason, additional, Nazzari, Alexandra, additional, Shi, Wei, additional, Tsybovsky, Yaroslav, additional, Wang, Lingshu, additional, Wang, Shuishu, additional, Zhang, Baoshan, additional, Zhang, Yi, additional, Katsamba, Phinikoula S., additional, Petrova, Yuliya, additional, Banach, Bailey B., additional, Fahad, Ahmed S., additional, Liu, Lihong, additional, Lopez Acevedo, Sheila N., additional, Madan, Bharat, additional, Oliveira de Souza, Matheus, additional, Pan, Xiaoli, additional, Wang, Pengfei, additional, Wolfe, Jacy R., additional, Yin, Michael, additional, Ho, David D., additional, Phung, Emily, additional, DiPiazza, Anthony, additional, Chang, Lauren A., additional, Abiona, Olubukola M., additional, Corbett, Kizzmekia S., additional, DeKosky, Brandon J., additional, Graham, Barney S., additional, Mascola, John R., additional, Misasi, John, additional, Ruckwardt, Tracy, additional, Sullivan, Nancy J., additional, Shapiro, Lawrence, additional, and Kwong, Peter D., additional

Published
2020
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13. SARS-CoV-2 mRNA Vaccine Development Enabled by Prototype Pathogen Preparedness

Author

Corbett, Kizzmekia S., primary, Edwards, Darin, additional, Leist, Sarah R., additional, Abiona, Olubukola M., additional, Boyoglu-Barnum, Seyhan, additional, Gillespie, Rebecca A., additional, Himansu, Sunny, additional, Schäfer, Alexandra, additional, Ziwawo, Cynthia T., additional, DiPiazza, Anthony T., additional, Dinnon, Kenneth H., additional, Elbashir, Sayda M., additional, Shaw, Christine A., additional, Woods, Angela, additional, Fritch, Ethan J., additional, Martinez, David R., additional, Bock, Kevin W., additional, Minai, Mahnaz, additional, Nagata, Bianca M., additional, Hutchinson, Geoffrey B., additional, Bahl, Kapil, additional, Garcia-Dominguez, Dario, additional, Ma, LingZhi, additional, Renzi, Isabella, additional, Kong, Wing-Pui, additional, Schmidt, Stephen D., additional, Wang, Lingshu, additional, Zhang, Yi, additional, Stevens, Laura J., additional, Phung, Emily, additional, Chang, Lauren A., additional, Loomis, Rebecca J., additional, Altaras, Nedim Emil, additional, Narayanan, Elisabeth, additional, Metkar, Mihir, additional, Presnyak, Vlad, additional, Liu, Catherine, additional, Louder, Mark K., additional, Shi, Wei, additional, Leung, Kwanyee, additional, Yang, Eun Sung, additional, West, Ande, additional, Gully, Kendra L., additional, Wang, Nianshuang, additional, Wrapp, Daniel, additional, Doria-Rose, Nicole A., additional, Stewart-Jones, Guillaume, additional, Bennett, Hamilton, additional, Nason, Martha C., additional, Ruckwardt, Tracy J., additional, McLellan, Jason S., additional, Denison, Mark R., additional, Chappell, James D., additional, Moore, Ian N., additional, Morabito, Kaitlyn M., additional, Mascola, John R., additional, Baric, Ralph S., additional, Carfi, Andrea, additional, and Graham, Barney S., additional

Published
2020
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14. Insights into CD4 T Cell-Mediated Immunity to Influenza Viruses

Author

DiPiazza, Anthony Thomas, Sant, Andrea J., DiPiazza, Anthony Thomas, and Sant, Andrea J.

Abstract

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Microbiology and Immunology, 2018., Influenza A viruses continue to pose a threat to human health worldwide and virusspecific CD4 T cells are key to protective immunity. The goal of the experiments within this thesis was to provide novel insight into elements within CD4 T cell responses that influence CD4 T cell specificity and function. Using a combination of novel reporter viruses, intravascular labeling in vivo, multi-parameter flow cytometry, and cytokine ELISpot procedures in two mammalian models, this work examined various stages of the developing immune response and the relationship between antigen acquisition, CD4 T cell fate choice, trafficking and compartmentalization within the inflamed lung, antigen specificity, and cytokine functionality. We found that pandemic 2009 H1N1 virus infection resulted in a broad pattern of viral antigen acquisition in the lung. Complex subpopulations of MHC class II-positive cells from both the hematopoietic and non-hematopoietic lineages were identified, with dynamic shifts over time. Our results demonstrated that antigen access occurs by uptake of exogenous antigen as well as infection. Finally, our results confirmed that many different cell types displayed peptide:MHC class II complexes in situ and possessed the capacity to stimulate influenza-specific CD4 T cells. These results correlated with differences in infection status, cell lineage, and MHC class II expression. These data suggest that there are many different types of antigen presenting cells in the lung that may impose additional checkpoints of CD4 T cell functionality and regulation. At the peak of the immune response, we found that lung CD4 T cells compartmentalized to vasculature and tissue. Antigen-experienced CD4 T cells were enriched in the tissue and expressed higher levels of molecules involved in trafficking to sites of pulmonary infection, damage, and repair. Surprisingly, we found similar representation in the fine specificity, immunodominance hierarchy, and polyfunctional potential of ef

Published
2019

15. A novel vaccine strategy to overcome poor immunogenicity of avian influenza vaccines through mobilization of memory CD4 T cells established by seasonal influenza

Author

National Institutes of Health (US), Japan Agency for Medical Research and Development, National Institute of Allergy and Infectious Diseases (US), Centers of Excellence for Influenza Research and Surveillance (US), DiPiazza, Anthony T., Fan, Shufang, Rattan, Ajitanuj, DeDiego, Marta L., Chaves, F. Javier, Neumann, Gabriele, Kawaoka, Yoshihiro, Sant, Andrea J., National Institutes of Health (US), Japan Agency for Medical Research and Development, National Institute of Allergy and Infectious Diseases (US), Centers of Excellence for Influenza Research and Surveillance (US), DiPiazza, Anthony T., Fan, Shufang, Rattan, Ajitanuj, DeDiego, Marta L., Chaves, F. Javier, Neumann, Gabriele, Kawaoka, Yoshihiro, and Sant, Andrea J.

Abstract

Avian influenza vaccines exhibit poor immunogenicity in humans. We hypothesized that one factor underlying weak B cell responses was sequence divergence between avian and seasonal influenza hemagglutinin proteins, thus limiting the availability of adequate CD4 T cell help. To test this, a novel chimeric hemagglutinin protein (cH7/3) was derived, comprised of the stem domain from seasonal H3 hemagglutinin and the head domain from avian H7. Immunological memory to seasonal influenza was established in mice, through strategies that included seasonal inactivated vaccines, Flumist, and synthetic peptides derived from the H3 stalk domain. After establishment of memory, mice were vaccinated with H7 or cH7/3 protein. The cH7/3 Ag was able to recall H3-specific CD4 T cells, and this potentiated CD4 T cell response was associated with enhanced early germinal center response and rapid elicitation of Abs to H7, including Abs specific for the H7 head domain. These results suggest that in pandemic situations, inclusion of CD4 T cell epitopes from seasonal viruses have the potential to overcome the poor immunogenicity of avian vaccines by helping B cells and conferring greater subtype-specific Ab response to viral HA.

Published
2019

23. A proof of concept for structure-based vaccine design targeting RSV in humans.

Author

Crank, Michelle C., Ruckwardt, Tracy J., Chen, Man, Morabito, Kaitlyn M., Phung, Emily, Costner, Pamela J., Holman, LaSonji A., Hickman, Somia P., Berkowitz, Nina M., Gordon, Ingelise J., Yamshchikov, Galina V., Gaudinski, Martin R., Kumar, Azad, Chang, Lauren A., Moin, Syed M., Hill, Juliane P., DiPiazza, Anthony T., Schwartz, Richard M., Kueltzo, Lisa, and Cooper, Jonathan W.

Published
2019
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27. Characterization of humoral and cellular immunologic responses to an mRNA-based human cytomegalovirus vaccine from a phase 1 trial of healthy adults.

Author

Kai Wu, Yixuan Jacob Hou, Makrinos, Dan, Runxia Liu, Zhu, Alex, Koch, Matthew, Wen-Han Yu, Paila, Yamuna D., Chandramouli, Sumana, Panther, Lori, Henry, Carole, DiPiazza, Anthony, and Carfi, Andrea

Subjects
*T cells, *T helper cells, *MESSENGER RNA, *HUMAN cytomegalovirus, *IMMUNOLOGIC memory, *ADULTS, *CYTOMEGALOVIRUS diseases, *CYTOMEGALOVIRUSES, *VACCINE approval
Abstract

mRNA-1647 is an investigational mRNA-based vaccine against cytomegalovirus (CMV) that contains sequences encoding the CMV proteins glycoprotein B and pentamer. Humoral and cellular immune responses were evaluated in blood samples collected from healthy CMV-seropositive and CMV-seronegative adults who participated in a phase 1 trial of a three-dose series of mRNA-1647 (NCT03382405). Neutralizing antibody (nAb) titers against fibroblast and epithelial cell infection in sera from CMV-seronegative mRNA-1647 recipients were higher than those in sera from control CMV-seropositive samples and remained elevated up to 12 months after dose 3. nAb responses elicited by mRNA-1647 were comparable across 14 human CMV (HCMV) strains. Frequencies of antigen-specific memory B cells increased in CMV-seropositive and CMV-seronegative participants after each mRNA-1647 dose and remained elevated for up to 6 months after dose 3. mRNA-1647 elicited robust increases in frequencies and polyfunctionality of CD4+ T helper type 1 and effector CD8+ T cells in samples from CMV-seronegative and CMV-seropositive participants after stimulation with HCMV-specific peptides. The administration of three doses of mRNA-1647 to healthy adults elicited high nAb titers with wide-breadth, long-lasting memory B cells, and strong polyfunctional T-cell responses. These findings support further clinical development of the mRNA-1647 vaccine against CMV. IMPORTANCE Cytomegalovirus (CMV), a common virus that can infect people of all ages, may lead to serious health problems in unborn babies and those with a weakened immune system. Currently, there is no approved vaccine available to prevent CMV infection; however, the investigational messenger RNA (mRNA)-based CMV vaccine, mRNA-1647, is undergoing evaluation in clinical trials. The current analysis examined samples from a phase 1 trial of mRNA-1647 in healthy adults to better understand how the immune system reacts to vaccination. Three doses of mRNA-1647 produced a long-lasting immune response, thus supporting further investigation of the vaccine in the prevention of CMV infection. [ABSTRACT FROM AUTHOR]

Published
2024
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28. Avian and Human Seasonal Influenza Hemagglutinin Proteins Elicit CD4 T Cell Responses That Are Comparable in Epitope Abundance and Diversity

Author

DiPiazza, Anthony, Richards, Katherine, Poulton, Nicholas, and Sant, Andrea J.

Abstract

ABSTRACTAvian influenza viruses remain a significant concern due to their pandemic potential. Vaccine trials have suggested that humans respond poorly to avian influenza vaccines relative to seasonal vaccines. It is important to understand, first, if there is a general deficiency in the ability of avian hemagglutinin (HA) proteins to generate immune responses and, if so, what underlies this defect. This question is of particular interest because it has been suggested that in humans, the poor immunogenicity of H7 vaccines may be due to a paucity of CD4 T cell epitopes. Because of the generally high levels of cross-reactive CD4 T cells in humans, it is not possible to compare the inherent immunogenicities of avian and seasonal HA proteins in an unbiased manner. Here, we empirically examine the epitope diversity and abundance of CD4 T cells elicited by seasonal and avian HA proteins. HLA-DR1 and HLA-DR4 transgenic mice were vaccinated with purified HA proteins, and CD4 T cells to specific epitopes were identified and quantified. These studies revealed that the diversity and abundance of CD4 T cells specific for HA do not segregate on the basis of whether the HA was derived from human seasonal or avian influenza viruses. Therefore, we conclude that failure in responses to avian vaccines in humans is likely due to a lack of cross-reactive CD4 T cell memory perhaps coupled with competition with or suppression of naive, HA-specific CD4 T cells by memory CD4 T cells specific for more highly conserved proteins.

Published
2016
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29. Characterization of humoral and cellular immunologic responses to an mRNA-based human cytomegalovirus vaccine from a phase 1 trial of healthy adults.

Author

Wu K, Hou YJ, Makrinos D, Liu R, Zhu A, Koch M, Yu W-H, Paila YD, Chandramouli S, Panther L, Henry C, DiPiazza A, and Carfi A

Subjects
Adult, Humans, Antibodies, Viral, CD8-Positive T-Lymphocytes, Cytomegalovirus physiology, RNA, Messenger genetics, Cytomegalovirus Infections immunology, Cytomegalovirus Vaccines administration & dosage, Cytomegalovirus Vaccines immunology
Abstract

mRNA-1647 is an investigational mRNA-based vaccine against cytomegalovirus (CMV) that contains sequences encoding the CMV proteins glycoprotein B and pentamer. Humoral and cellular immune responses were evaluated in blood samples collected from healthy CMV-seropositive and CMV-seronegative adults who participated in a phase 1 trial of a three-dose series of mRNA-1647 (NCT03382405). Neutralizing antibody (nAb) titers against fibroblast and epithelial cell infection in sera from CMV-seronegative mRNA-1647 recipients were higher than those in sera from control CMV-seropositive samples and remained elevated up to 12 months after dose 3. nAb responses elicited by mRNA-1647 were comparable across 14 human CMV (HCMV) strains. Frequencies of antigen-specific memory B cells increased in CMV-seropositive and CMV-seronegative participants after each mRNA-1647 dose and remained elevated for up to 6 months after dose 3. mRNA-1647 elicited robust increases in frequencies and polyfunctionality of CD4 + T helper type 1 and effector CD8 + T cells in samples from CMV-seronegative and CMV-seropositive participants after stimulation with HCMV-specific peptides. The administration of three doses of mRNA-1647 to healthy adults elicited high nAb titers with wide-breadth, long-lasting memory B cells, and strong polyfunctional T-cell responses. These findings support further clinical development of the mRNA-1647 vaccine against CMV.IMPORTANCECytomegalovirus (CMV), a common virus that can infect people of all ages, may lead to serious health problems in unborn babies and those with a weakened immune system. Currently, there is no approved vaccine available to prevent CMV infection; however, the investigational messenger RNA (mRNA)-based CMV vaccine, mRNA-1647, is undergoing evaluation in clinical trials. The current analysis examined samples from a phase 1 trial of mRNA-1647 in healthy adults to better understand how the immune system reacts to vaccination. Three doses of mRNA-1647 produced a long-lasting immune response, thus supporting further investigation of the vaccine in the prevention of CMV infection.CLINICAL TRIALSRegistered at ClinicalTrials.gov (NCT03382405)., Competing Interests: All authors are employees of Moderna, Inc., and may hold stock/stock options in the company.

Published
2024
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30. Antibodies with potent and broad neutralizing activity against antigenically diverse and highly transmissible SARS-CoV-2 variants.

Author

Wang L, Zhou T, Zhang Y, Yang ES, Schramm CA, Shi W, Pegu A, Oloninyi OK, Ransier A, Darko S, Narpala SR, Hatcher C, Martinez DR, Tsybovsky Y, Phung E, Abiona OM, Cale EM, Chang LA, Corbett KS, DiPiazza AT, Gordon IJ, Leung K, Liu T, Mason RD, Nazzari A, Novik L, Olia AS, Doria-Rose NA, Stephens T, Stringham CD, Talana CA, Teng IT, Wagner D, Widge AT, Zhang B, Roederer M, Ledgerwood JE, Ruckwardt TJ, Gaudinski MR, Baric RS, Graham BS, McDermott AB, Douek DC, Kwong PD, Mascola JR, Sullivan NJ, and Misasi J

Abstract

The emergence of highly transmissible SARS-CoV-2 variants of concern (VOC) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identify four receptor-binding domain targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 12 variants including the B.1.1.7 and B.1.351 VOCs. Two of them are ultrapotent, with sub-nanomolar neutralization titers (IC50 <0.0006 to 0.0102 μ g/mL; IC80 < 0.0006 to 0.0251 μ g/mL). We define the structural and functional determinants of binding for all four VOC-targeting antibodies, and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting potential means to mitigate resistance development. These results define the basis of therapeutic cocktails against VOCs and suggest that targeted boosting of existing immunity may increase vaccine breadth against VOCs.

Published
2021
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31. Structure-Based Design with Tag-Based Purification and In-Process Biotinylation Enable Streamlined Development of SARS-CoV-2 Spike Molecular Probes.

Author

Zhou T, Teng IT, Olia AS, Cerutti G, Gorman J, Nazzari A, Shi W, Tsybovsky Y, Wang L, Wang S, Zhang B, Zhang Y, Katsamba PS, Petrova Y, Banach BB, Fahad AS, Liu L, Acevedo SNL, Madan B, de Souza MO, Pan X, Wang P, Wolfe JR, Yin M, Ho DD, Phung E, DiPiazza A, Chang L, Abiona O, Corbett KS, DeKosky BJ, Graham BS, Mascola JR, Misasi J, Ruckwardt T, Sullivan NJ, Shapiro L, and Kwong PD

Abstract

Biotin-labeled molecular probes, comprising specific regions of the SARS-CoV-2 spike, would be helpful in the isolation and characterization of antibodies targeting this recently emerged pathogen. To develop such probes, we designed constructs incorporating an N-terminal purification tag, a site-specific protease-cleavage site, the probe region of interest, and a C-terminal sequence targeted by biotin ligase. Probe regions included full-length spike ectodomain as well as various subregions, and we also designed mutants to eliminate recognition of the ACE2 receptor. Yields of biotin-labeled probes from transient transfection ranged from ~0.5 mg/L for the complete ectodomain to &gt;5 mg/L for several subregions. Probes were characterized for antigenicity and ACE2 recognition, and the structure of the spike ectodomain probe was determined by cryo-electron microscopy. We also characterized antibody-binding specificities and cell-sorting capabilities of the biotinylated probes. Altogether, structure-based design coupled to efficient purification and biotinylation processes can thus enable streamlined development of SARS-CoV-2 spike-ectodomain probes. Funding: Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID). Support for this work was also provided by COVID-19 Fast Grants, the Jack Ma Foundation, the Self Graduate Fellowship Program, and NIH grants DP5OD023118, R21AI143407, and R21AI144408. Some of this work was performed at the Columbia University Cryo-EM Center at the Zuckerman Institute, and some at the Simons Electron Microscopy Center (SEMC) and National Center for Cryo-EM Access and Training (NCCAT) located at the New York Structural Biology Center, supported by grants from the Simons Foundation (SF349247), NYSTAR, and the NIH National Institute of General Medical Sciences (GM103310). Conflict of Interest: The authors declare that they have no conflict of interest. Ethical Approval: Peripheral blood mononuclear cells (PBMCs) for B cell sorting were obtained from a convalescent SARS-CoV-2 patient (collected 75 days post symptom onset under an IRB approved clinical trial protocol, VRC 200 - ClinicalTrials.gov Identifier: NCT00067054) and a healthy control donor from the NIH blood bank pre-SARS-CoV-2 pandemic.

Published
2020
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32. SARS-CoV-2 mRNA Vaccine Development Enabled by Prototype Pathogen Preparedness.

Author

Corbett KS, Edwards D, Leist SR, Abiona OM, Boyoglu-Barnum S, Gillespie RA, Himansu S, Schäfer A, Ziwawo CT, DiPiazza AT, Dinnon KH, Elbashir SM, Shaw CA, Woods A, Fritch EJ, Martinez DR, Bock KW, Minai M, Nagata BM, Hutchinson GB, Bahl K, Garcia-Dominguez D, Ma L, Renzi I, Kong WP, Schmidt SD, Wang L, Zhang Y, Stevens LJ, Phung E, Chang LA, Loomis RJ, Altaras NE, Narayanan E, Metkar M, Presnyak V, Liu C, Louder MK, Shi W, Leung K, Yang ES, West A, Gully KL, Wang N, Wrapp D, Doria-Rose NA, Stewart-Jones G, Bennett H, Nason MC, Ruckwardt TJ, McLellan JS, Denison MR, Chappell JD, Moore IN, Morabito KM, Mascola JR, Baric RS, Carfi A, and Graham BS

Abstract

A SARS-CoV-2 vaccine is needed to control the global COVID-19 public health crisis. Atomic-level structures directed the application of prefusion-stabilizing mutations that improved expression and immunogenicity of betacoronavirus spike proteins. Using this established immunogen design, the release of SARS-CoV-2 sequences triggered immediate rapid manufacturing of an mRNA vaccine expressing the prefusion-stabilized SARS-CoV-2 spike trimer (mRNA-1273). Here, we show that mRNA-1273 induces both potent neutralizing antibody and CD8 T cell responses and protects against SARS-CoV-2 infection in lungs and noses of mice without evidence of immunopathology. mRNA-1273 is currently in a Phase 2 clinical trial with a trajectory towards Phase 3 efficacy evaluation., Competing Interests: Competing Interest Declaration K.S.C., N.W., J.S.M., and B.S.G. are inventors on International Patent Application No. WO/2018/081318 entitled “Prefusion Coronavirus Spike Proteins and Their Use.” K.S.C., O.M.A., G.B.H., N.W., D.W., J.S.M, and B.S.G. are inventors on US Patent Application No. 62/972,886 entitled “2019-nCoV Vaccine”. R.S.B. filed an invention report for the SARS-CoV-2 MA virus (UNC ref. #18752).

Published
2020
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33. Analyses of Cellular Immune Responses in Ferrets Following Influenza Virus Infection.

Author

DiPiazza AT, Richards KA, Liu WC, Albrecht RA, and Sant AJ

Subjects
Animals, Cytokines metabolism, Enzyme-Linked Immunospot Assay, Ferrets, Flow Cytometry, Humans, Influenza, Human immunology, Influenza, Human virology, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Lymphocyte Depletion, Orthomyxoviridae Infections metabolism, Host-Pathogen Interactions, Immunity, Cellular, Orthomyxoviridae immunology, Orthomyxoviridae Infections immunology, Orthomyxoviridae Infections virology
Abstract

Ferrets are an ideal animal model in which to study the transmission of respiratory viruses as well as disease progression and vaccine efficacy because of their close anatomical and physiological resemblances to humans. However, a paucity of reagents and standardized procedures has hampered research progress, especially for studying cell-mediated immunity. The approaches described here-leukocyte isolation from whole blood and secondary lymphoid tissues-are generalizable, highly reproducible, and deliver single cell suspensions with excellent cell viability. Importantly, we have now developed assays to quantify key cellular components and antigen-specific T cell responses at the single cell level from multiple tissue compartments following influenza infection in ferrets. Collectively, these methods were instrumental in flow cytometry studies that revealed alterations in immune cell composition and distribution across lymphoid tissues following viral infection. Furthermore, sorting of T cell populations and peptide restimulation ex vivo in cytokine ELISpot assays has provided novel insight into the influenza-specific CD4 and CD8 T cell repertoire. The detailed procedures for these techniques are described in this chapter and can likely be adapted for the analyses of responses to many respiratory pathogens.

Published
2018
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