Browsing by Author "Barr, Maggie"

Now showing 1 - 7 of 7
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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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    Immune checkpoint modulation enhances HIV-1 antibody induction.
    (Nature communications, 2020-02-19) Bradley, Todd; Kuraoka, Masayuki; Yeh, Chen-Hao; Tian, Ming; Chen, Huan; Cain, Derek W; Chen, Xuejun; Cheng, Cheng; Ellebedy, Ali H; Parks, Robert; Barr, Maggie; Sutherland, Laura L; Scearce, Richard M; Bowman, Cindy M; Bouton-Verville, Hilary; Santra, Sampa; Wiehe, Kevin; Lewis, Mark G; Ogbe, Ane; Borrow, Persephone; Montefiori, David; Bonsignori, Mattia; Anthony Moody, M; Verkoczy, Laurent; Saunders, Kevin O; Ahmed, Rafi; Mascola, John R; Kelsoe, Garnett; Alt, Frederick W; Haynes, Barton F
    Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX40 along with HIV envelope (Env) vaccines to rhesus macaques and bnAb immunoglobulin knock-in (KI) mice expressing diverse precursors of CD4 binding site HIV-1 bnAbs. CTLA-4 blockade augments HIV-1 Env antibody responses in macaques, and in a bnAb-precursor mouse model, CTLA-4 blocking or OX40 agonist antibodies increase germinal center B and T follicular helper cells and plasma neutralizing antibodies. Thus, modulation of CTLA-4 or OX40 immune checkpoints during vaccination can promote germinal center activity and enhance HIV-1 Env antibody responses.
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    Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses.
    (Nature, 2021-06) Saunders, Kevin O; Lee, Esther; Parks, Robert; Martinez, David R; Li, Dapeng; Chen, Haiyan; Edwards, Robert J; Gobeil, Sophie; Barr, Maggie; Mansouri, Katayoun; Alam, S Munir; Sutherland, Laura L; Cai, Fangping; Sanzone, Aja M; Berry, Madison; Manne, Kartik; Bock, Kevin W; Minai, Mahnaz; Nagata, Bianca M; Kapingidza, Anyway B; Azoitei, Mihai; Tse, Longping V; Scobey, Trevor D; Spreng, Rachel L; Rountree, R Wes; DeMarco, C Todd; Denny, Thomas N; Woods, Christopher W; Petzold, Elizabeth W; Tang, Juanjie; Oguin, Thomas H; Sempowski, Gregory D; Gagne, Matthew; Douek, Daniel C; Tomai, Mark A; Fox, Christopher B; Seder, Robert; Wiehe, Kevin; Weissman, Drew; Pardi, Norbert; Golding, Hana; Khurana, Surender; Acharya, Priyamvada; Andersen, Hanne; Lewis, Mark G; Moore, Ian N; Montefiori, David C; Baric, Ralph S; Haynes, Barton F
    Betacoronaviruses caused the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome, as well as the current pandemic of SARS coronavirus 2 (SARS-CoV-2)1-4. Vaccines that elicit protective immunity against SARS-CoV-2 and betacoronaviruses that circulate in animals have the potential to prevent future pandemics. Here we show that the immunization of macaques with nanoparticles conjugated with the receptor-binding domain of SARS-CoV-2, and adjuvanted with 3M-052 and alum, elicits cross-neutralizing antibody responses against bat coronaviruses, SARS-CoV and SARS-CoV-2 (including the B.1.1.7, P.1 and B.1.351 variants). Vaccination of macaques with these nanoparticles resulted in a 50% inhibitory reciprocal serum dilution (ID50) neutralization titre of 47,216 (geometric mean) for SARS-CoV-2, as well as in protection against SARS-CoV-2 in the upper and lower respiratory tracts. Nucleoside-modified mRNAs that encode a stabilized transmembrane spike or monomeric receptor-binding domain also induced cross-neutralizing antibody responses against SARS-CoV and bat coronaviruses, albeit at lower titres than achieved with the nanoparticles. These results demonstrate that current mRNA-based vaccines may provide some protection from future outbreaks of zoonotic betacoronaviruses, and provide a multimeric protein platform for the further development of vaccines against multiple (or all) betacoronaviruses.
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    SARS-CoV-2 vaccination induces neutralizing antibodies against pandemic and pre-emergent SARS-related coronaviruses in monkeys.
    (bioRxiv, 2021-02-17) Saunders, Kevin O; Lee, Esther; Parks, Robert; Martinez, David R; Li, Dapeng; Chen, Haiyan; Edwards, Robert J; Gobeil, Sophie; Barr, Maggie; Mansouri, Katayoun; Alam, S Munir; Sutherland, Laura L; Cai, Fangping; Sanzone, Aja M; Berry, Madison; Manne, Kartik; Kapingidza, Anyway B; Azoitei, Mihai; Tse, Longping V; Scobey, Trevor D; Spreng, Rachel L; Rountree, R Wes; DeMarco, C Todd; Denny, Thomas N; Woods, Christopher W; Petzold, Elizabeth W; Oguin, Thomas H; Sempowski, Gregory D; Gagne, Matthew; Douek, Daniel C; Tomai, Mark A; Fox, Christopher B; Seder, Robert; Wiehe, Kevin; Weissman, Drew; Pardi, Norbert; Acharya, Priyamvada; Andersen, Hanne; Lewis, Mark G; Moore, Ian N; Montefiori, David C; Baric, Ralph S; Haynes, Barton F
    Betacoronaviruses (betaCoVs) caused the severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, and now the SARS-CoV-2 pandemic. Vaccines that elicit protective immune responses against SARS-CoV-2 and betaCoVs circulating in animals have the potential to prevent future betaCoV pandemics. Here, we show that immunization of macaques with a multimeric SARS-CoV-2 receptor binding domain (RBD) nanoparticle adjuvanted with 3M-052-Alum elicited cross-neutralizing antibody responses against SARS-CoV-1, SARS-CoV-2, batCoVs and the UK B.1.1.7 SARS-CoV-2 mutant virus. Nanoparticle vaccination resulted in a SARS-CoV-2 reciprocal geometric mean neutralization titer of 47,216, and robust protection against SARS-CoV-2 in macaque upper and lower respiratory tracts. Importantly, nucleoside-modified mRNA encoding a stabilized transmembrane spike or monomeric RBD protein also induced SARS-CoV-1 and batCoV cross-neutralizing antibodies, albeit at lower titers. These results demonstrate current mRNA vaccines may provide some protection from future zoonotic betaCoV outbreaks, and provide a platform for further development of pan-betaCoV nanoparticle vaccines.
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    Stabilized HIV-1 envelope immunization induces neutralizing antibodies to the CD4bs and protects macaques against mucosal infection.
    (Science translational medicine, 2022-09) Saunders, Kevin O; Edwards, Robert J; Tilahun, Kedamawit; Manne, Kartik; Lu, Xiaozhi; Cain, Derek W; Wiehe, Kevin; Williams, Wilton B; Mansouri, Katayoun; Hernandez, Giovanna E; Sutherland, Laura; Scearce, Richard; Parks, Robert; Barr, Maggie; DeMarco, Todd; Eater, Chloe M; Eaton, Amanda; Morton, Georgeanna; Mildenberg, Benjamin; Wang, Yunfei; Rountree, R Wes; Tomai, Mark A; Fox, Christopher B; Moody, M Anthony; Alam, S Munir; Santra, Sampa; Lewis, Mark G; Denny, Thomas N; Shaw, George M; Montefiori, David C; Acharya, Priyamvada; Haynes, Barton F
    A successful HIV-1 vaccine will require induction of a polyclonal neutralizing antibody (nAb) response, yet vaccine-mediated induction of such a response in primates remains a challenge. We found that a stabilized HIV-1 CH505 envelope (Env) trimer formulated with a Toll-like receptor 7/8 agonist induced potent HIV-1 polyclonal nAbs that correlated with protection from homologous simian-human immunodeficiency virus (SHIV) infection. The serum dilution that neutralized 50% of virus replication (ID50 titer) required to protect 90% of macaques was 1:364 against the challenge virus grown in primary rhesus CD4+ T cells. Structural analyses of vaccine-induced nAbs demonstrated targeting of the Env CD4 binding site or the N156 glycan and the third variable loop base. Autologous nAb specificities similar to those elicited in macaques by vaccination were isolated from the human living with HIV from which the CH505 Env immunogen was derived. CH505 viral isolates were isolated that mutated the V1 to escape both the infection-induced and vaccine-induced antibodies. These results define the specificities of a vaccine-induced nAb response and the protective titers of HIV-1 vaccine-induced nAbs required to protect nonhuman primates from low-dose mucosal challenge by SHIVs bearing a primary transmitted/founder Env.
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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.