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Santra, Sampa

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Santra

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Sampa

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Santra, Sampa

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2015 - 20187

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Author's Publications: search.filters.isAuthorOfPublication.765d3a2c-21e4-4a21-9744-d7115dee1c9f

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Now showing 1 - 7 of 7
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    Zika virus protection by a single low dose nucleoside modified mRNA vaccination
    (2017) Pardi, Norbert; Hogan, Michael J.; Pelc, Rebecca S.; Muramatsu, Hiromi; Andersen, Hanne; DeMaso, Christina R.; Dowd, Kimberly A.; Sutherland, Laura L.; Scearce, Richard M.; Parks, Robert; Wagner, Wendeline; Granados, Alex; Greenhouse, Jack; Walker, Michelle; Willis, Elinor; Yu, Jae-Sung; McGee, Charles E.; Sempowski, Gregory D.; Mui, Barbara L.; Tam, Ying K.; Huang, Yan-Jang; Vanlandingham, Dana; Holmes, Veronica M.; Balachandran, Harikrishnan; Sahu, Sujata; Lifton, Michelle; Higgs, Stephen; Hensley, Scott E.; Madden, Thomas D.; Hope, Michael J.; Karikó, Katalin; Santra, Sampa; Graham, Barney S.; Lewis, Mark G.; Pierson, Theodore C.; Haynes, Barton F.; Weissman, Drew
    Zika virus (ZIKV) has recently emerged as an explosive pandemic associated with severe neuropathology in newborns and adults1. There are no ZIKV-specific treatments or preventatives; thus, development of a safe and effective vaccine is a high priority. Messenger RNA (mRNA) has emerged as a versatile and highly effective platform to deliver vaccine antigens and therapeutic proteins2,3. Here, we demonstrate that a single low-dose intradermal immunization with lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP) encoding the pre-membrane and envelope (prM-E) glycoproteins of a 2013 ZIKV outbreak strain elicited potent and durable neutralizing antibody responses in mice and non-human primates. Immunization with 30 μg of nucleoside-modified ZIKV mRNA-LNPs protected mice from ZIKV challenges at 2 weeks or 5 months post-vaccination, and a single dose of 50 μg was sufficient to protect non-human primates from a challenge at 5 weeks post-vaccination. These data demonstrate that nucleoside-modified mRNA-LNPs elicit rapid and durable protective immunity and thus represent a new and promising vaccine candidate for the global fight against ZIKV.
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    A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge
    (Nature Publishing Group UK, 2018) Madani, Navid; Princiotto, Amy M.; Mach, Linh; Ding, Shilei; Prevost, Jérémie; Richard, Jonathan; Hora, Bhavna; Sutherland, Laura; Zhao, Connie A.; Conn, Brandon P.; Bradley, Todd; Moody, M. Anthony; Melillo, Bruno; Finzi, Andrés; Haynes, Barton F.; Smith III, Amos B.; Santra, Sampa; Sodroski, Joseph
    The envelope glycoprotein (Env) trimer ((gp120/gp41)3) mediates human immunodeficiency virus (HIV-1) entry into cells. The “closed,” antibody-resistant Env trimer is driven to more open conformations by binding the host receptor, CD4. Broadly neutralizing antibodies that recognize conserved elements of the closed Env are potentially protective, but are elicited inefficiently. HIV-1 has evolved multiple mechanisms to evade readily elicited antibodies against more open Env conformations. Small-molecule CD4-mimetic compounds (CD4mc) bind the HIV-1 gp120 Env and promote conformational changes similar to those induced by CD4, exposing conserved Env elements to antibodies. Here, we show that a CD4mc synergizes with antibodies elicited by monomeric HIV-1 gp120 to protect monkeys from multiple high-dose intrarectal challenges with a heterologous simian-human immunodeficiency virus (SHIV). The protective immune response persists for at least six months after vaccination. CD4mc should increase the protective efficacy of any HIV-1 Env vaccine that elicits antibodies against CD4-induced conformations of Env.
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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
    (Public Library of Science, 2015) 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 Engelbert; Moody, M. A.; 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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    Amino Acid Changes in the HIV-1 gp41 Membrane Proximal Region Control Virus Neutralization Sensitivity
    (Elsevier, 2016) Bradley, Todd; Trama, Ashley; Tumba, Nancy; Gray, Elin; Lu, Xiaozhi; Madani, Navid; Jahanbakhsh, Fatemeh; Eaton, Amanda; Xia, Shi-Mao; Parks, Robert; Lloyd, Krissey E.; Sutherland, Laura L.; Scearce, Richard M.; Bowman, Cindy M.; Barnett, Susan; Abdool-Karim, Salim S.; Boyd, Scott D.; Melillo, Bruno; Smith, Amos B.; Sodroski, Joseph; Kepler, Thomas B.; Alam, S.Munir; Gao, Feng; Bonsignori, Mattia; Liao, Hua-Xin; Moody, M. Anthony; Montefiori, David; Santra, Sampa; Morris, Lynn; Haynes, Barton F.
    Most HIV-1 vaccines elicit neutralizing antibodies that are active against highly sensitive (tier-1) viruses or rare cases of vaccine-matched neutralization-resistant (tier-2) viruses, but no vaccine has induced antibodies that can broadly neutralize heterologous tier-2 viruses. In this study, we isolated antibodies from an HIV-1-infected individual that targeted the gp41 membrane-proximal external region (MPER) that may have selected single-residue changes in viral variants in the MPER that resulted in neutralization sensitivity to antibodies targeting distal epitopes on the HIV-1 Env. Similarly, a single change in the MPER in a second virus from another infected-individual also conferred enhanced neutralization sensitivity. These gp41 single-residue changes thus transformed tier-2 viruses into tier-1 viruses that were sensitive to vaccine-elicited tier-1 neutralizing antibodies. These data demonstrate that Env amino acid changes within the MPER bnAb epitope of naturally-selected escape viruses can increase neutralization sensitivity to multiple types of neutralizing antibodies, and underscore the critical importance of the MPER for maintaining the integrity of the tier-2 HIV-1 trimer.
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    Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge
    (Nature Publishing Group, 2017) Bradley, Todd; Pollara, Justin; Santra, Sampa; Vandergrift, Nathan; Pittala, Srivamshi; Bailey-Kellogg, Chris; Shen, Xiaoying; Parks, Robert; Goodman, Derrick; Eaton, Amanda; Balachandran, Harikrishnan; Mach, Linh V.; Saunders, Kevin O.; Weiner, Joshua A.; Scearce, Richard; Sutherland, Laura L.; Phogat, Sanjay; Tartaglia, Jim; Reed, Steven G.; Hu, Shiu-Lok; Theis, James F.; Pinter, Abraham; Montefiori, David C.; Kepler, Thomas B.; Peachman, Kristina K.; Rao, Mangala; Michael, Nelson L.; Suscovich, Todd J.; Alter, Galit; Ackerman, Margaret E.; Moody, M. Anthony; Liao, Hua-Xin; Tomaras, Georgia; Ferrari, Guido; Korber, Bette T.; Haynes, Barton F.
    The RV144 Thai trial HIV-1 vaccine of recombinant poxvirus (ALVAC) and recombinant HIV-1 gp120 subtype B/subtype E (B/E) proteins demonstrated 31% vaccine efficacy. Here we design an ALVAC/Pentavalent B/E/E/E/E vaccine to increase the diversity of gp120 motifs in the immunogen to elicit a broader antibody response and enhance protection. We find that immunization of rhesus macaques with the pentavalent vaccine results in protection of 55% of pentavalent-vaccine-immunized macaques from simian–human immunodeficiency virus (SHIV) challenge. Systems serology of the antibody responses identifies plasma antibody binding to HIV-infected cells, peak ADCC antibody titres, NK cell-mediated ADCC and antibody-mediated activation of MIP-1β in NK cells as the four immunological parameters that best predict decreased infection risk that are improved by the pentavalent vaccine. Thus inclusion of additional gp120 immunogens to a pox-prime/protein boost regimen can augment antibody responses and enhance protection from a SHIV challenge in rhesus macaques.
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    Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations
    (Nature Publishing Group UK, 2017) Williams, Wilton B.; Zhang, Jinsong; Jiang, Chuancang; Nicely, Nathan I.; Fera, Daniela; Luo, Kan; Moody, M. Anthony; Liao, Hua-Xin; Alam, S. Munir; Kepler, Thomas B.; Ramesh, Akshaya; Wiehe, Kevin; Holland, James A.; Bradley, Todd; Vandergrift, Nathan; Saunders, Kevin O.; Parks, Robert; Foulger, Andrew; Xia, Shi-Mao; Bonsignori, Mattia; Montefiori, David C.; Louder, Mark; Eaton, Amanda; Santra, Sampa; Scearce, Richard; Sutherland, Laura; Newman, Amanda; Bouton-Verville, Hilary; Bowman, Cindy; Bomze, Howard; Gao, Feng; Marshall, Dawn J.; Whitesides, John F.; Nie, Xiaoyan; Kelsoe, Garnett; Reed, Steven G.; Fox, Christopher B.; Clary, Kim; Koutsoukos, Marguerite; Franco, David; Mascola, John R.; Harrison, Stephen; Haynes, Barton F.; Verkoczy, Laurent
    A strategy for HIV-1 vaccine development is to define envelope (Env) evolution of broadly neutralizing antibodies (bnAbs) in infection and to recreate those events by vaccination. Here, we report host tolerance mechanisms that limit the development of CD4-binding site (CD4bs), HCDR3-binder bnAbs via sequential HIV-1 Env vaccination. Vaccine-induced macaque CD4bs antibodies neutralize 7% of HIV-1 strains, recognize open Env trimers, and accumulate relatively modest somatic mutations. In naive CD4bs, unmutated common ancestor knock-in mice Env+B cell clones develop anergy and partial deletion at the transitional to mature B cell stage, but become Env− upon receptor editing. In comparison with repetitive Env immunizations, sequential Env administration rescue anergic Env+ (non-edited) precursor B cells. Thus, stepwise immunization initiates CD4bs-bnAb responses, but immune tolerance mechanisms restrict their development, suggesting that sequential immunogen-based vaccine regimens will likely need to incorporate strategies to expand bnAb precursor pools.
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    Strong, but Age-Dependent, Protection Elicited by a Deoxyribonucleic Acid/Modified Vaccinia Ankara Simian Immunodeficiency Virus Vaccine
    (Oxford University Press, 2016) Chamcha, Venkateswarlu; Kannanganat, Sunil; Gangadhara, Sailaja; Nabi, Rafiq; Kozlowski, Pamela A.; Montefiori, David C.; LaBranche, Celia C.; Wrammert, Jens; Keele, Brandon F.; Balachandran, Harikrishnan; Sahu, Sujata; Lifton, Michelle; Santra, Sampa; Basu, Rahul; Moss, Bernard; Robinson, Harriet L.; Amara, Rama Rao
    Background. In this study, we analyzed the protective efficacy of a simian immunodeficiency virus (SIV) macaque 239 (SIVmac239) analogue of the clinically tested GOVX-B11 deoxyribonucleic acid (DNA)/modified vaccinia Ankara (MVA) human immunodeficiency virus vaccine. Methods. The tested vaccine used a DNA immunogen mutated to mimic the human vaccine and a regimen with DNA deliveries at weeks 0 and 8 and MVA deliveries at weeks 16 and 32. Twelve weekly rectal challenges with 0.3 animal infectious doses of SIV sootey mangabey E660 (SIVsmE660) were administered starting at 6 months after the last immunization. Results. Over the first 6 rectal exposures to SIVsmE660, <10-year-old tripartite motif-containing protein 5 (TRIM5)α-permissive rhesus macaques showed an 80% reduction in per-exposure risk of infection as opposed to a 46% reduction in animals over 10 years old; and, over the 12 challenges, they showed a 72% as opposed to a 10% reduction. Analyses of elicited immune responses suggested that higher antibody responses in the younger animals had played a role in protection. Conclusions. The simian analogue of the GOVX-B11 HIV provided strong protection against repeated rectal challenges in young adult macaques.