Browsing by Author "Douek, Daniel C"

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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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    Determinants of protection among HIV‐exposed seronegative persons: an overview.
    (J Infect Dis, 2010-11-01) Lederman, Michael M; Alter, Galit; Daskalakis, Demetre C; Rodriguez, Benigno; Sieg, Scott F; Hardy, Gareth; Cho, Michael; Anthony, Donald; Harding, Clifford; Weinberg, Aaron; Silverman, Robert H; Douek, Daniel C; Margolis, Leonid; Goldstein, David B; Carrington, Mary; Goedert, James J
    Both clinical experience and a growing medical literature indicate that some persons who have been exposed to human immunodeficiency virus (HIV) infection remain uninfected. Although in some instances this may represent good fortune, cohorts of uninfected persons have been reported who are considered at high risk for infection. In these cohorts a variety of characteristics have been proposed as mediating protection, but to date only the 32–base pair deletion in the chemokine (C‐C motif) receptor 5 gene, which results in complete failure of cell surface expression of this coreceptor, has been associated with high‐level protection from HIV infection. With this in mind, there are probably many other factors that may individually or in combination provide some level of protection from acquisition of HIV infection. Because some of these factors are probably incompletely protective or inconsistently active, identifying them with confidence will be difficult. Nonetheless, clarifying the determinants of protection against HIV infection is a high priority that will require careful selection of high‐risk uninfected cohorts, who should undergo targeted studies of plausible mediators and broad screening for unexpected determinants of protection.
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    High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men.
    (PLoS pathogens, 2010) Li, H; Bar, KJ; Wang, S; Decker, JM; Chen, Y; Sun, C; Salazar Gonzalez, JF; Salazar, MG; Learn, GH; Morgan, CJ; Schumacher, JE; Hraber, P; Giorgi, EE; Bhattacharya, T; Korber, BT; Perelson, AS; Eron, JJ; Cohen, MS; Hicks, CB; Haynes, BF; Markowitz, M; Keele, BF; Hahn, BH; Shaw, GM
    Elucidating virus-host interactions responsible for HIV-1 transmission is important for advancing HIV-1 prevention strategies. To this end, single genome amplification (SGA) and sequencing of HIV-1 within the context of a model of random virus evolution has made possible for the first time an unambiguous identification of transmitted/founder viruses and a precise estimation of their numbers. Here, we applied this approach to HIV-1 env analyses in a cohort of acutely infected men who have sex with men (MSM) and found that a high proportion (10 of 28; 36%) had been productively infected by more than one virus. In subjects with multivariant transmission, the minimum number of transmitted viruses ranged from 2 to 10 with viral recombination leading to rapid and extensive genetic shuffling among virus lineages. A combined analysis of these results, together with recently published findings based on identical SGA methods in largely heterosexual (HSX) cohorts, revealed a significantly higher frequency of multivariant transmission in MSM than in HSX [19 of 50 subjects (38%) versus 34 of 175 subjects (19%); Fisher's exact p = 0.008]. To further evaluate the SGA strategy for identifying transmitted/founder viruses, we analyzed 239 overlapping 5' and 3' half genome or env-only sequences from plasma viral RNA (vRNA) and blood mononuclear cell DNA in an MSM subject who had a particularly well-documented virus exposure history 3-6 days before symptom onset and 14-17 days before peak plasma viremia (47,600,000 vRNA molecules/ml). All 239 sequences coalesced to a single transmitted/founder virus genome in a time frame consistent with the clinical history, and a molecular clone of this genome encoded replication competent virus in accord with model predictions. Higher multiplicity of HIV-1 infection in MSM compared with HSX is consistent with the demonstrably higher epidemiological risk of virus acquisition in MSM and could indicate a greater challenge for HIV-1 vaccines than previously recognized.
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    Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques.
    (PLoS Pathog, 2015-08) Santra, Sampa; Tomaras, Georgia D; Warrier, Ranjit; Nicely, Nathan I; Liao, Hua-Xin; Pollara, Justin; Liu, Pinghuang; Alam, S Munir; Zhang, Ruijun; Cocklin, Sarah L; Shen, Xiaoying; Duffy, Ryan; Xia, Shi-Mao; Schutte, Robert J; Pemble Iv, Charles W; Dennison, S Moses; Li, Hui; Chao, Andrew; Vidnovic, Kora; Evans, Abbey; Klein, Katja; Kumar, Amit; Robinson, James; Landucci, Gary; Forthal, Donald N; Montefiori, David C; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Pitisuttithum, Punnee; Rerks-Ngarm, Supachai; Robb, Merlin L; Michael, Nelson L; Kim, Jerome H; Soderberg, Kelly A; Giorgi, Elena E; Blair, Lily; Korber, Bette T; Moog, Christiane; Shattock, Robin J; Letvin, Norman L; Schmitz, Joern E; Moody, MA; Gao, Feng; Ferrari, Guido; Shaw, George M; Haynes, Barton F
    HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.
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    KIR polymorphisms modulate peptide-dependent binding to an MHC class I ligand with a Bw6 motif.
    (PLoS pathogens, 2011-03) Colantonio, Arnaud D; Bimber, Benjamin N; Neidermyer, William J; Reeves, R Keith; Alter, Galit; Altfeld, Marcus; Johnson, R Paul; Carrington, Mary; O'Connor, David H; Evans, David T
    Molecular interactions between killer immunoglobulin-like receptors (KIRs) and their MHC class I ligands play a central role in the regulation of natural killer (NK) cell responses to viral pathogens and tumors. Here we identify Mamu-A1*00201 (Mamu-A*02), a common MHC class I molecule in the rhesus macaque with a canonical Bw6 motif, as a ligand for Mamu-KIR3DL05. Mamu-A1*00201 tetramers folded with certain SIV peptides, but not others, directly stained primary NK cells and Jurkat cells expressing multiple allotypes of Mamu-KIR3DL05. Differences in binding avidity were associated with polymorphisms in the D0 and D1 domains of Mamu-KIR3DL05, whereas differences in peptide-selectivity mapped to the D1 domain. The reciprocal exchange of the third predicted MHC class I-contact loop of the D1 domain switched the specificity of two Mamu-KIR3DL05 allotypes for different Mamu-A1*00201-peptide complexes. Consistent with the function of an inhibitory KIR, incubation of lymphocytes from Mamu-KIR3DL05(+) macaques with target cells expressing Mamu-A1*00201 suppressed the degranulation of tetramer-positive NK cells. These observations reveal a previously unappreciated role for D1 polymorphisms in determining the selectivity of KIRs for MHC class I-bound peptides, and identify the first functional KIR-MHC class I interaction in the rhesus macaque. The modulation of KIR-MHC class I interactions by viral peptides has important implications to pathogenesis, since it suggests that the immunodeficiency viruses, and potentially other types of viruses and tumors, may acquire changes in epitopes that increase the affinity of certain MHC class I ligands for inhibitory KIRs to prevent the activation of specific NK cell subsets.
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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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    Recapitulation of HIV-1 Env-antibody coevolution in macaques leading to neutralization breadth.
    (Science (New York, N.Y.), 2020-11-19) Roark, Ryan S; Li, Hui; Williams, Wilton B; Chug, Hema; Mason, Rosemarie D; Gorman, Jason; Wang, Shuyi; Lee, Fang-Hua; Rando, Juliette; Bonsignori, Mattia; Hwang, Kwan-Ki; Saunders, Kevin O; Wiehe, Kevin; Moody, M Anthony; Hraber, Peter T; Wagh, Kshitij; Giorgi, Elena E; Russell, Ronnie M; Bibollet-Ruche, Frederic; Liu, Weimin; Connell, Jesse; Smith, Andrew G; DeVoto, Julia; Murphy, Alexander I; Smith, Jessica; Ding, Wenge; Zhao, Chengyan; Chohan, Neha; Okumura, Maho; Rosario, Christina; Ding, Yu; Lindemuth, Emily; Bauer, Anya M; Bar, Katharine J; Ambrozak, David; Chao, Cara W; Chuang, Gwo-Yu; Geng, Hui; Lin, Bob C; Louder, Mark K; Nguyen, Richard; Zhang, Baoshan; Lewis, Mark G; Raymond, Donald D; Doria-Rose, Nicole A; Schramm, Chaim A; Douek, Daniel C; Roederer, Mario; Kepler, Thomas B; Kelsoe, Garnett; Mascola, John R; Kwong, Peter D; Korber, Bette T; Harrison, Stephen C; Haynes, Barton F; Hahn, Beatrice H; Shaw, George M
    Neutralizing antibodies elicited by HIV-1 coevolve with viral envelope proteins (Env) in distinctive patterns, in some cases acquiring substantial breadth. We report that primary HIV-1 envelope proteins-when expressed by simian-human immunodeficiency viruses in rhesus macaques-elicited patterns of Env-antibody coevolution strikingly similar to those in humans. This included conserved immunogenetic, structural and chemical solutions to epitope recognition and precise Env-am ino acid substitutions, insertions and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2-apex mode of recognition like that of human bNAbs PGT145/PCT64-35S. Another rhesus antibody bound the CD4-binding site by CD4 mimicry mirroring human bNAbs 8ANC131/CH235/VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.
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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.