Browsing by Author "Schäfer, Alexandra"

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    Breadth of SARS-CoV-2 Neutralization and Protection Induced by a Nanoparticle Vaccine
    Li, Dapeng; Martinez, David R; Martinez, David R; Schäfer, Alexandra; Chen, Haiyan; Barr, Maggie; Sutherland, Laura L; Lee, Esther; Parks, Robert; Mielke, Dieter; Edwards, Whitney; Newman, Amanda; Bock, Kevin W; Minai, Mahnaz; Nagata, Bianca M; Gagne, Matthew; Douek, Daniel C; DeMarco, C Todd; Denny, Thomas N; Oguin, Thomas H; Brown, Alecia; Rountree, Wes; Wang, Yunfei; Mansouri, Katayoun; Edwards, Robert J; Ferrari, Guido; Sempowski, Gregory D; Eaton, Amanda; Tang, Juanjie; Cain, Derek W; Santra, Sampa; Pardi, Norbert; Weissman, Drew; Tomai, Mark A; Fox, Christopher B; Moore, Ian N; Andersen, Hanne; Lewis, Mark G; Golding, Hana; Seder, Robert; Khurana, Surender; Baric, Ralph S; Montefiori, David C; Saunders, Kevin O; Haynes, Barton F
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    Breadth of SARS-CoV-2 Neutralization and Protection Induced by a Nanoparticle Vaccine.
    (bioRxiv, 2022-02-14) Li, Dapeng; Martinez, David R; Schäfer, Alexandra; Chen, Haiyan; Barr, Maggie; Sutherland, Laura L; Lee, Esther; Parks, Robert; Mielke, Dieter; Edwards, Whitney; Newman, Amanda; Bock, Kevin W; Minai, Mahnaz; Nagata, Bianca M; Gagne, Matthew; Douek, Daniel C; DeMarco, C Todd; Denny, Thomas N; Oguin, Thomas H; Brown, Alecia; Rountree, Wes; Wang, Yunfei; Mansouri, Katayoun; Edwards, Robert J; Ferrari, Guido; Sempowski, Gregory D; Eaton, Amanda; Tang, Juanjie; Cain, Derek W; Santra, Sampa; Pardi, Norbert; Weissman, Drew; Tomai, Mark A; Fox, Christopher B; Moore, Ian N; Andersen, Hanne; Lewis, Mark G; Golding, Hana; Seder, Robert; Khurana, Surender; Baric, Ralph S; Montefiori, David C; Saunders, Kevin O; Haynes, Barton F
    Coronavirus vaccines that are highly effective against SARS-CoV-2 variants are needed to control the current pandemic. We previously reported a receptor-binding domain (RBD) sortase A-conjugated ferritin nanoparticle (RBD-scNP) vaccine that induced neutralizing antibodies against SARS-CoV-2 and pre-emergent sarbecoviruses and protected monkeys from SARS-CoV-2 WA-1 infection. Here, we demonstrate SARS-CoV-2 RBD-scNP immunization induces potent neutralizing antibodies in non-human primates (NHPs) against all eight SARS-CoV-2 variants tested including the Beta, Delta, and Omicron variants. The Omicron variant was neutralized by RBD-scNP-induced serum antibodies with a mean of 10.6-fold reduction of ID50 titers compared to SARS-CoV-2 D614G. Immunization with RBD-scNPs protected NHPs from SARS-CoV-2 WA-1, Beta, and Delta variant challenge, and protected mice from challenges of SARS-CoV-2 Beta variant and two other heterologous sarbecoviruses. These results demonstrate the ability of RBD-scNPs to induce broad neutralization of SARS-CoV-2 variants and to protect NHPs and mice from multiple different SARS-related viruses. Such a vaccine could provide the needed immunity to slow the spread of and reduce disease caused by SARS-CoV-2 variants such as Delta and Omicron.
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    Host range, transmissibility and antigenicity of a pangolin coronavirus.
    (Nature microbiology, 2023-10) Hou, Yixuan J; Chiba, Shiho; Leist, Sarah R; Meganck, Rita M; Martinez, David R; Schäfer, Alexandra; Catanzaro, Nicholas J; Sontake, Vishwaraj; West, Ande; Edwards, Catlin E; Yount, Boyd; Lee, Rhianna E; Gallant, Samuel C; Zost, Seth J; Powers, John; Adams, Lily; Kong, Edgar F; Mattocks, Melissa; Tata, Aleksandra; Randell, Scott H; Tata, Purushothama R; Halfmann, Peter; Crowe, James E; Kawaoka, Yoshihiro; Baric, Ralph S
    The pathogenic and cross-species transmission potential of SARS-CoV-2-related coronaviruses (CoVs) remain poorly characterized. Here we recovered a wild-type pangolin (Pg) CoV GD strain including derivatives encoding reporter genes using reverse genetics. In primary human cells, PgCoV replicated efficiently but with reduced fitness and showed less efficient transmission via airborne route compared with SARS-CoV-2 in hamsters. PgCoV was potently inhibited by US Food and Drug Administration approved drugs, and neutralized by COVID-19 patient sera and SARS-CoV-2 therapeutic antibodies in vitro. A pan-Sarbecovirus antibody and SARS-CoV-2 S2P recombinant protein vaccine protected BALB/c mice from PgCoV infection. In K18-hACE2 mice, PgCoV infection caused severe clinical disease, but mice were protected by a SARS-CoV-2 human antibody. Efficient PgCoV replication in primary human cells and hACE2 mice, coupled with a capacity for airborne spread, highlights an emergence potential. However, low competitive fitness, pre-immune humans and the benefit of COVID-19 countermeasures should impede its ability to spread globally in human populations.
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    In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies
    (Cell, 2021) Li, Dapeng; Edwards, Robert J; Manne, Kartik; Martinez, David R; Schäfer, Alexandra; Alam, S Munir; Wiehe, Kevin; Lu, Xiaozhi; Parks, Robert; Sutherland, Laura L; others
    SARS-CoV-2-neutralizing antibodies (NAbs) protect against COVID-19. A concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated NAbs against the receptor-binding domain (RBD) or the N-terminal domain (NTD) of SARS-CoV-2 spike from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infection in vitro, while five non-neutralizing NTD antibodies mediated FcγR-independent in vitro infection enhancement. However, both types of infection-enhancing antibodies protected from SARS-CoV-2 replication in monkeys and mice. Three of 46 monkeys infused with enhancing antibodies had higher lung inflammation scores compared to controls. One monkey had alveolar edema and elevated bronchoalveolar lavage inflammatory cytokines. Thus, while in vitro antibody-enhanced infection does not necessarily herald enhanced infection in vivo, increased lung inflammation can rarely occur in SARS-CoV-2 antibody-infused macaques.
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    The functions of SARS-CoV-2 neutralizing and infection-enhancing antibodies in vitro and in mice and nonhuman primates.
    (bioRxiv, 2021-02-18) Li, Dapeng; Edwards, Robert J; Manne, Kartik; Martinez, David R; Schäfer, Alexandra; Alam, S Munir; Wiehe, Kevin; Lu, Xiaozhi; Parks, Robert; Sutherland, Laura L; Oguin, Thomas H; McDanal, Charlene; Perez, Lautaro G; Mansouri, Katayoun; Gobeil, Sophie MC; Janowska, Katarzyna; Stalls, Victoria; Kopp, Megan; Cai, Fangping; Lee, Esther; Foulger, Andrew; Hernandez, Giovanna E; Sanzone, Aja; Tilahun, Kedamawit; Jiang, Chuancang; Tse, Longping V; Bock, Kevin W; Minai, Mahnaz; Nagata, Bianca M; Cronin, Kenneth; Gee-Lai, Victoria; Deyton, Margaret; Barr, Maggie; Holle, Tarra Von; Macintyre, Andrew N; Stover, Erica; Feldman, Jared; Hauser, Blake M; Caradonna, Timothy M; Scobey, Trevor D; Rountree, Wes; Wang, Yunfei; Moody, M Anthony; Cain, Derek W; DeMarco, C Todd; Denny, ThomasN; Woods, Christopher W; Petzold, Elizabeth W; Schmidt, Aaron G; Teng, I-Ting; Zhou, Tongqing; Kwong, Peter D; Mascola, John R; Graham, Barney S; Moore, Ian N; Seder, Robert; Andersen, Hanne; Lewis, Mark G; Montefiori, David C; Sempowski, Gregory D; Baric, Ralph S; Acharya, Priyamvada; Haynes, Barton F; Saunders, Kevin O
    SARS-CoV-2 neutralizing antibodies (NAbs) protect against COVID-19. A concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated NAbs against the receptor-binding domain (RBD) and the N-terminal domain (NTD) of SARS-CoV-2 spike from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV-1 infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infection in vitro , while five non-neutralizing NTD antibodies mediated FcγR-independent in vitro infection enhancement. However, both types of infection-enhancing antibodies protected from SARS-CoV-2 replication in monkeys and mice. Nonetheless, three of 31 monkeys infused with enhancing antibodies had higher lung inflammation scores compared to controls. One monkey had alveolar edema and elevated bronchoalveolar lavage inflammatory cytokines. Thus, while in vitro antibody-enhanced infection does not necessarily herald enhanced infection in vivo , increased lung inflammation can occur in SARS-CoV-2 antibody-infused macaques.