120 results on '"Santra, Sampa"'
Search Results
102. Augmentation and Suppression of Immune Responses to an HIV-1 DNA Vaccine by Plasmid Cytokine/Ig Administration
- Author
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Barouch, Dan H., primary, Santra, Sampa, additional, Steenbeke, Tavis D., additional, Zheng, Xin X., additional, Perry, Helen C., additional, Davies, Mary-Ellen, additional, Freed, Daniel C., additional, Craiu, Abie, additional, Strom, Terry B., additional, Shiver, John W., additional, and Letvin, Norman L., additional
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- 1998
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103. Envelope Deglycosylation Enhances Antigenicity of HIV-1 gp41 Epitopes for Both Broad Neutralizing Antibodies and Their Unmutated Ancestor Antibodies.
- Author
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Ben-Jiang Ma, Alam, S. Munir, Go, Eden P., Xiaozhi Lu, Desaire, Heather, Tomaras, Georgia D., Bowman, Cindy, Sutherland, Laura L., Scearce, Richard M., Santra, Sampa, Letvin, Norman L., Kepler, Thomas B., Hua-Xin Liao, and Haynes, Barton F.
- Subjects
GLYCOSYLATION ,ANTIGENS ,HIV ,EPITOPES ,IMMUNOGLOBULINS - Abstract
The HIV-1 gp41 envelope (Env) membrane proximal external region (MPER) is an important vaccine target that in rare subjects can elicit neutralizing antibodies. One mechanism proposed for rarity of MPER neutralizing antibody generation is lack of reverted unmutated ancestor (putative naive B cell receptor) antibody reactivity with HIV-1 envelope. We have studied the effect of partial deglycosylation under non-denaturing (native) conditions on gp140 Env antigenicity for MPER neutralizing antibodies and their reverted unmutated ancestor antibodies. We found that native deglycosylation of clade B JRFL gp140 as well as group M consensus gp140 Env CON-S selectively increased the reactivity of Env with the broad neutralizing human mAbs, 2F5 and 4E10. Whereas fully glycosylated gp140 Env either did not bind (JRFL), or weakly bound (CON-S), 2F5 and 4E10 reverted unmutated ancestors, natively deglycosylated JRFL and CON-S gp140 Envs did bind well to these putative mimics of naive B cell receptors. These data predict that partially deglycoslated Env would bind better than fully glycosylated Env to gp41-specific nai¨ve B cells with improved immunogenicity. In this regard, immunization of rhesus macaques demonstrated enhanced immunogenicity of the 2F5 MPER epitope on deglyosylated JRFL gp140 compared to glycosylated JRFL gp140. Thus, the lack of 2F5 and 4E10 reverted unmutated ancestor binding to gp140 Env may not always be due to lack of unmutated ancestor antibody reactivity with gp41 peptide epitopes, but rather, may be due to glycan interference of binding of unmutated ancestor antibodies of broad neutralizing mAb to Env gp41. [ABSTRACT FROM AUTHOR]
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- 2011
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104. Recombinant vector-induced HIV/SIV-specific CD4+ T lymphocyte responses in rhesus monkeys
- Author
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Sun, Yue, Santra, Sampa, Buzby, Adam P., Mascola, John R., Nabel, Gary J., and Letvin, Norman L.
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RECOMBINANT viruses , *T cells , *IMMUNIZATION , *GLYCOPROTEINS , *RHESUS monkeys , *HIV prevention , *VIRAL replication , *VACCINATION - Abstract
Abstract: The recently reported modest success of the RV144 Thai trial vaccine regimen in preventing HIV-1 acquisition has focused interest on the potential contribution to that protection of vaccine-elicited CD4+ T cell responses. We evaluated the induction of virus-specific CD4+ T cell responses in rhesus monkeys using a series of diverse vaccine vectors. We assessed both the magnitudes and functional profiles of the antigen-specific CD4+ T cells by measuring cytokine production, memory differentiation, and the expression of mucosal homing molecules. We found that DNA prime/recombinant MVA boost immunizations induced particularly high-frequency virus-specific CD4+ T cell responses with polyfunctional repertoires, and these responses were partially preserved following SHIV-89.6P challenge. The majority of the vaccine-elicited CD4+ T cells were CD28+ memory T cells that expressed low levels of β7. Neither the magnitudes nor the functional profiles of the virus-specific CD4+ T cells generated by vaccination were associated with a preservation of CD4+ T cells or control of viral replication following SHIV-89.6P challenge. Interestingly, monkeys primed with recombinant Ad5 immunogens showed a dramatic expansion of both the magnitude and polyfunctionality of the vaccine-elicited CD4+ T cell responses following envelope protein boost. These results demonstrate that vaccine strategies that include recombinant MVA or recombinant Ad5 vectors can elicit robust CD4+ T cell responses. [Copyright &y& Elsevier]
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- 2010
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105. Mosaic vaccines elicit CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys.
- Author
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Santra, Sampa, Hua-Xin Liao, Ruijin Zhang, Muldoon, Mark, Watson, Sydeaka, Fischer, Will, Theiler, James, Szinger, James, Balachandran, Harikrishnan, Buzby, Adam, Quinn, David, Parks, Robert J., Chun-Yen Tsao, Carville, Angela, Mansfield, Keith G., Pavlakis, George N., Felber, Barbara K., Haynes, Barton F., Korber, Bette T., and Letvin, Norman L.
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VIRAL vaccines , *HIV prevention , *IMMUNE response , *T cells , *RECOMBINANT viruses , *VIRAL proteins - Abstract
An effective HIV vaccine must elicit immune responses that recognize genetically diverse viruses. It must generate CD8+ T lymphocytes that control HIV replication and CD4+ T lymphocytes that provide help for the generation and maintenance of both cellular and humoral immune responses against the virus. Creating immunogens that can elicit cellular immune responses against the genetically varied circulating isolates of HIV presents a key challenge for creating an HIV vaccine. Polyvalent mosaic immunogens derived by in silico recombination of natural strains of HIV are designed to induce cellular immune responses that recognize genetically diverse circulating virus isolates. Here we immunized rhesus monkeys by plasmid DNA prime and recombinant vaccinia virus boost with vaccine constructs expressing either consensus or polyvalent mosaic proteins. As compared to consensus immunogens, the mosaic immunogens elicited CD8+ T lymphocyte responses to more epitopes of each viral protein than did the consensus immunogens and to more variant sequences of CD8+ T lymphocyte epitopes. This increased breadth and depth of epitope recognition may contribute both to protection against infection by genetically diverse viruses and to the control of variant viruses that emerge as they mutate away from recognition by cytotoxic T lymphocytes. [ABSTRACT FROM AUTHOR]
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- 2010
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106. Vaccine-Elicited Memory Cytotoxic T Lymphocytes Contribute to Mamu-A 01-Associated Control of Simian/Human Immunodeficiency Virus 89.6P Replication in Rhesus Monkeys.
- Author
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Seaman, Michael S., Santra, Sampa, Newberg, Michael H., Philippon, Valerie, Manson, Kelledy, Ling Xu, Gelman, Rebecca S., Panicali, Dennis, Mascola, John R., Nabel, Gary J., and Letvin, Norman L.
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T cells , *HIV , *SIMIAN viruses , *RHESUS monkeys , *VIRAL replication , *VACCINATION - Abstract
The expression of particular major histocompatibility complex (MHC) class I alleles can influence the rate of disease progression following lentiviral infections. This effect is a presumed consequence of potent cytotoxic T-lymphocyte (CTL) responses that are restricted by these MHC class I molecules. The present studies have examined the impact of the MHC class I allele Mamu-A*01 on simian/human immunodeficiency virus 89.6P (SHIV-89.6P) infection in unvaccinated and vaccinated rhesus monkeys by exploring the contribution of dominant-epitope specific CTL in this setting. Expression of Mamu-A*01 in immunologically naive monkeys was not associated with improved control of viral replication, CD4+ T-lymphocyte loss, or survival. In contrast, Mamu-A*01+ monkeys that had received heterologous prime/boost immunizations prior to challenge maintained higher CD4+ T-lymphocyte levels and better control of SHIV-89.6P replication than Mamu-A*01- monkeys. This protection was associated with the evolution of high-frequency anamnestic CTL responses specific for a dominant Mamu-A*01-restricted Gag epitope following infection. These data indicate that specific MHC class I alleles can confer protection in the setting of a pathogenic SHIV infection by their ability to elicit memory CTL following vaccination. [ABSTRACT FROM AUTHOR]
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- 2005
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107. Strong TH1-biased CD4 T cell responses are associated with diminished SIV vaccine efficacy
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Chamcha, Venkateswarlu, Reddy, Pradeep B. J., Kannanganat, Sunil, Wilkins, Courtney, Gangadhara, Sailaja, Velu, Vijayakumar, Green, Richard, Law, G. Lynn, Chang, Jean, Bowen, James R., Kozlowski, Pamela A., Lifton, Michelle, Santra, Sampa, Legere, Traci, Chea, Lynette S., Chennareddi, Lakshmi, Yu, Tianwei, Suthar, Mehul S., Silvestri, Guido, Derdeyn, Cynthia A., Gale, Michael, Villinger, Francois, Hunter, Eric, and Amara, Rama Rao
- Abstract
Vaccine-induced IFNγ+CD4 T cells migrate to and persist in mucosal tissue and negatively associate with protection against SIV.
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- 2019
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108. Cross-reactive potential of human T-lymphocyte responses in HIV-1 infection
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Giorgi, Elena E., Balachandran, Harikrishnan, Muldoon, Mark, Letvin, Norman L., Haynes, Barton F., Korber, Bette T., Santra, Sampa, Giorgi, Elena E., Balachandran, Harikrishnan, Muldoon, Mark, Letvin, Norman L., Haynes, Barton F., Korber, Bette T., and Santra, Sampa
- Abstract
An effective HIV-1 vaccine should elicit sufficient breadth of immune recognition to protect against the genetically diverse forms of the circulating virus. Evaluation of the breadth and magnitude of cellular immune responses to epitope variants is important for HIV-1 vaccine assessment. We compared HIV-1 Gag-specific T-lymphocyte responses in 20 HIV-1-infected individuals representing two different HIV-1 subtypes, B and C. By assessing T lymphocyte responses with peptides based on natural HIV-1 variants, we found evidence for limited cross-reactivity and significantly enhanced within-clade responses among clade B-infected subjects, and not among clade C-infected subjects.
109. Mosaic vaccines elicit CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys
- Author
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Santra, Sampa, Liao, Hua-Xin, Zhang, Ruijin, Muldoon, Mark, Watson, Sydeaka, Fischer, Will, Theiler, James, Szinger, James, Balachandran, Harikrishnan, Buzby, Adam, Quinn, David, Parks, Robert J., Tsao, Chun-Yen, Carville, Angela, Mansfield, Keith G., Pavlakis, George N., Felber, Barbara K., Haynes, Barton F., Korber, Bette T., Letvin, Norman L., Santra, Sampa, Liao, Hua-Xin, Zhang, Ruijin, Muldoon, Mark, Watson, Sydeaka, Fischer, Will, Theiler, James, Szinger, James, Balachandran, Harikrishnan, Buzby, Adam, Quinn, David, Parks, Robert J., Tsao, Chun-Yen, Carville, Angela, Mansfield, Keith G., Pavlakis, George N., Felber, Barbara K., Haynes, Barton F., Korber, Bette T., and Letvin, Norman L.
- Abstract
An effective HIV vaccine must elicit immune responses that recognize genetically diverse viruses. It must generate CD8+ T lymphocytes that control HIV replication and CD4+ T lymphocytes that provide help for the generation and maintenance of both cellular and humoral immune responses against the virus. Creating immunogens that can elicit cellular immune responses against the genetically varied circulating isolates of HIV presents a key challenge for creating an HIV vaccine. Polyvalent mosaic immunogens derived by in silico recombination of natural strains of HIV are designed to induce cellular immune responses that recognize genetically diverse circulating virus isolates8. Here we immunized rhesus monkeys by plasmid DNA prime and recombinant vaccinia virus boost with vaccine constructs expressing either consensus or polyvalent mosaic proteins. As compared to consensus immunogens, the mosaic immunogens elicited CD8+ T lymphocyte responses to more epitopes of each viral protein than did the consensus immunogens and to more variant sequences of CD8+ T lymphocyte epitopes. This increased breadth and depth of epitope recognition may contribute both to protection against infection by genetically diverse viruses and to the control of variant viruses that emerge as they mutate away from recognition by cytotoxic T lymphocytes.
110. Breadth of cellular and humoral immune responses elicited in rhesus monkeys by multi-valent mosaic and consensus immunogens
- Author
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Santra, Sampa, Muldoon, Mark, Watson, Sydeaka, Buzby, Adam, Balachandran, Harikrishnan, Carlson, Kevin R., Mach, Linh, Kong, Wing-Pui, McKee, Krishna, Yang, Zhi-Yong, Rao, Srinivas S., Mascola, John R., Nabel, Gary J., Korber, Bette T, Letvin, Norman L., Santra, Sampa, Muldoon, Mark, Watson, Sydeaka, Buzby, Adam, Balachandran, Harikrishnan, Carlson, Kevin R., Mach, Linh, Kong, Wing-Pui, McKee, Krishna, Yang, Zhi-Yong, Rao, Srinivas S., Mascola, John R., Nabel, Gary J., Korber, Bette T, and Letvin, Norman L.
- Abstract
To create an HIV-1 vaccine that generates sufficient breadth of immune recognition to protect against the genetically diverse forms of the circulating virus, we have been exploring vaccines based on consensus and mosaic protein designs. Increasing the valency of a mosaic immunogen cocktail increases epitope coverage but with diminishing returns, as increasingly rare epitopes are incorporated into the mosaic proteins. In this study we compared the immunogenicity of 2-valent and 3-valent HIV-1 envelope mosaic immunogens in rhesus monkeys. Immunizations with the 3-valent mosaic immunogens resulted in a modest increase in the breadth of vaccine-elicited T lymphocyte responses compared to the 2-valent mosaic immunogens. However, the 3-valent mosaic immunogens elicited significantly higher neutralizing responses to Tier 1 viruses than the 2-valent mosaic immunogens. These findings underscore the potential utility of polyvalent mosaic immunogens for eliciting both cellular and humoral immune responses to HIV-1.
111. A centralized gene-based HIV-1 vaccine elicits broad cross-clade cellular immune responses in rhesus monkeys
- Author
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Santra, Sampa, Korber, Bette T., Muldoon, Mark, Barouch, Dan H., Nabel, Gary J., Gao, Feng, Hahn, Beatrice H., Haynes, Barton F., Letvin, Norman L., Santra, Sampa, Korber, Bette T., Muldoon, Mark, Barouch, Dan H., Nabel, Gary J., Gao, Feng, Hahn, Beatrice H., Haynes, Barton F., and Letvin, Norman L.
- Abstract
One of the major challenges that must be met in developing an HIV-1 vaccine is devising a strategy to generate cellular immunity with sufficient breadth to deal with the extraordinary genetic diversity of the virus. Amino acids in the envelopes of viruses from the same clade can differ by >15%, and those from different clades can differ by >30%. It has been proposed that creating immunogens using centralized HIV-1 gene sequences might provide a practical solution to this problem. Such centralized genes can be generated by employing a number of different strategies: consensus, ancestral, or center of tree sequences. These computer-generated sequences are a shorter genetic distance from any two contemporary virus sequences than those contemporary sequences are from each other. The present study was initiated to evaluate the breadth of cellular immunity generated through immunization of rhesus monkeys with vaccine constructs expressing either an HIV-1 global consensus envelope sequence (CON-S) or a single patient isolate clade B envelope sequence (clade B). We show that vaccine immunogens expressing the single centralized gene CON-S generated cellular immune responses with significantly increased breadth compared with immunogens expressing a wild-type virus gene. In fact, CON-S immunogens elicited cellular immune responses to 3- to 4-fold more discrete epitopes of the envelope proteins from clades A, C, and G than did clade B immunogens. These findings suggest that immunization with centralized genes is a promising vaccine strategy for developing a global vaccine for HIV-1 as well as vaccines for other genetically diverse viruses.
112. Magnitude and Quality of Vaccine-Elicited T-Cell Responses in the Control of Immunodeficiency Virus Replication in Rhesus Monkeys.
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Yue Sun, Santra, Sampa, Schmitz, Jörn E., Roederer, Mario, and Letvin, Norman L.
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IMMUNOGENETICS , *VIRAL replication , *T cells , *IMMUNE response , *CELLULAR immunity - Abstract
While a diversity of immunogens that elicit qualitatively different cellular immune responses are being assessed in clinical human immunodeficiency virus vaccine trials, the consequences of those varied responses for viral control remain poorly understood. In the present study, we evaluated the induction of virus-specific T-cell responses in rhesus monkeys using a series of diverse vaccine vectors. We assessed both the magnitude and the functional profile of the virus-specific CD8+ T cells by measuring gamma interferon, interleukin-2, and tumor necrosis factor alpha production. We found that the different vectors generated virus-specific T-cell responses of different magnitudes and with different functional profiles. Heterologous prime-boost vaccine regimens induced particularly high-frequency virus-specific T-cell responses with polyfunctional repertoires. Yet, immediately after a pathogenic simian-human immunodeficiency virus (SHIV) challenge, no significant differences were observed between these cohorts of vaccinated monkeys in the magnitudes or the functional profiles of their virus-specific CD8+ T cells. This finding suggests that the high viral load shapes the functional repertoire of the cellular immune response during primary infection. Nevertheless, in all vaccination regimens, higher frequency and more polyfunctional vaccine-elicited virus-specific CD8+ T-cell responses were associated with better viral control after SHIV challenge. These observations highlight the contributions of both the quality and the magnitude of vaccine-elicited cellular immune responses in the control of immunodeficiency virus replication. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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113. Systemic Immunization with an ALVAC-HIV-1/Protein Boost Vaccine Strategy Protects Rhesus Macaques from CD4+ T-Cell Loss and Reduces both Systemic and Mucosal Simian-Human Immunodeficiency Virus SHIVKU2 RNA Levels.
- Author
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Pal, Ranajit, Venzon, David, Santra, Sampa, Kalyanaraman, Vaniambadi S., Montefiori, David C., Hocker, Lindsey, Hudacik, Lauren, Rose, Nicolas, Nacsa, Janos, Edghill-Smith, Yvette, Moniuszko, Marcin, Hel, Zden k, Belyakov, Igor M., Berzofsky, Jay A., Parks, Robyn Washington, Markham, Phillip D., Letvin, Norman I., Tartaglia, Jim, and Franchini, Genoveffa
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IMMUNODEFICIENCY , *T cells , *VACCINES , *IMMUNIZATION , *VIRUSES - Abstract
Transmission of human immunodeficiency virus type 1 (HIV-1) occurs primarily via the mucosal route, suggesting that HIV-1 vaccines may need to elicit mucosal immune responses. Here, we investigated the immunogenicity and relative efficacy of systemic immunization with two human ALVAC-HIV-1 recombinant vaccines expressing Gag, Pol, and gp120 (vCP250) or Gag, Pol, and gp160 (vCP1420) in a prime-boost protocol with their homologous vaccine native Env proteins. The relative efficacy was measured against a high-dose mucosal exposure to the pathogenic neutralization-resistant variant SHIVKU2 (simian-human immunodeficiency virus). Systemic immunization with both vaccine regimens decreased viral load levels not only in blood but unexpectedly also in mucosal sites and protected macaques from peripheral CD4+ T-cell loss. This protective effect was stronger when the gp120 antigen was included in the vaccine. Inclusion of recombinant Tat protein in the boosting phase along with the Env protein did not contribute further to the preservation of CD4+ T cells. Thus, systemic immunization with ALVAC-HIV-1 vaccine candidates elicits anti-HIV-1 immune responses able to contain virus replication also at mucosal sites in macaques. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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- View/download PDF
114. Rapid Memory CD8+ T-Lymphocyte Induction through Priming with Recombinant Mycobacterium smegmatis.
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Hovav, Avi-Hai, Cayabyab, Mark J., Panas, Michael W., Santra, Sampa, Greenland, John, Geiben, Ralf, Haynes, Barton F., Jacobs Jr., William R., and Letvin, Norman L.
- Subjects
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IMMUNOREGULATION , *VIRAL vaccines , *CELL-mediated cytotoxicity , *HIV , *MYCOBACTERIUM - Abstract
The most promising vaccine strategies for the induction of cytotoxic-T-lymphocyte responses have been heterologous prime/boost regimens employing a plasmid DNA prime and a live recombinant-vector boost. The priming immunogen in these regimens must elicit antigen-specific memory CD8+ T lymphocytes that will expand following the boosting immunization. Because plasmid DNA immunogens are expensive and their immunogenicity has proven disappointing in human clinical trials, we have been exploring novel priming immunogens that might be used in heterologous immunization regimens. Here we show that priming with a prototype recombinant Mycobacterium smegmatis strain expressing human immunodeficiency virus type 1 (HIV-1) gp120-elicited CD4+ T lymphocytes with a functional profile of helper cells as well as a CD8+ T-lymphocyte population. These CD8+ T lymphocytes rapidly differentiated to memory cells, defined on the basis of their cytokine profile and expression of CD62L and CD27. Moreover, these recombinant-mycobacterium-induced T lymphocytes rapidly expanded following boosting with a recombinant adenovirus expressing HIV-1 Env to gp120-specific CD8+ T lymphocytes. This work demonstrates a remarkable skewing of recombinant-mycobacterium-induced T lymphocytes to durable antigen-specific memory CD8+ T cells and suggests that such immunogens might be used as priming vectors in prime/boost vaccination regimens for the induction of cellular immune responses. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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115. Broadly neutralizing antibody induction by non-stabilized SARS-CoV-2 Spike mRNA vaccination in nonhuman primates.
- Author
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Malewana RD, Stalls V, May A, Lu X, Martinez DR, Schäfer A, Li D, Barr M, Sutherland LL, Lee E, Parks R, Beck WE, Newman A, Bock KW, Minai M, Nagata BM, DeMarco CT, Denny TN, Oguin TH 3rd, Rountree W, Wang Y, Mansouri K, Edwards RJ, Sempowski GD, Eaton A, Muramatsu H, Henderson R, Tam Y, Barbosa C, Tang J, Cain DW, Santra S, Moore IN, Andersen H, Lewis MG, Golding H, Seder R, Khurana S, Montefiori DC, Pardi N, Weissman D, Baric RS, Acharya P, Haynes BF, and Saunders KO
- Abstract
Immunization with mRNA or viral vectors encoding spike with diproline substitutions (S-2P) has provided protective immunity against severe COVID-19 disease. How immunization with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike elicits neutralizing antibodies (nAbs) against difficult-to-neutralize variants of concern (VOCs) remains an area of great interest. Here, we compare immunization of macaques with mRNA vaccines expressing ancestral spike either including or lacking diproline substitutions, and show the diproline substitutions were not required for protection against SARS-CoV-2 challenge or induction of broadly neutralizing B cell lineages. One group of nAbs elicited by the ancestral spike lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOCs including Omicron XBB.1.5, but lacked cross-Sarbecovirus neutralization. Structural analysis showed that the macaque broad SARS-CoV-2 VOC nAbs bound to the same epitope as a human broad SARS-CoV-2 VOC nAb, DH1193. Vaccine-induced antibodies that targeted the RBD inner face neutralized multiple Sarbecoviruses, protected mice from bat CoV RsSHC014 challenge, but lacked Omicron variant neutralization. Thus, ancestral SARS-CoV-2 spike lacking proline substitutions encoded by nucleoside-modified mRNA can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human Sarbecoviruses or recent Omicron VOCs., Competing Interests: Competing interests: DW and NP are inventors on patents regarding nucleoside modified mRNA. Ying Tam and Christopher Barbosa are employees of Acuitas Therapeutics. Rory Henderson has patents regarding engineered forms of Spike proteins. Barton Haynes, Kevin Saunders, Dapeng Li, Priyamvada Acharya, and Xiaozhi Lu have patents regarding human antibodies and their uses. N.P. served on the mRNA strategic advisory board of Sanofi Pasteur in 2022. N.P. is a member of the Scientific Advisory Board of AldexChem.
- Published
- 2023
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116. Breadth of SARS-CoV-2 Neutralization and Protection Induced by a Nanoparticle Vaccine.
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Li D, Martinez DR, Schäfer A, Chen H, Barr M, Sutherland LL, Lee E, Parks R, Mielke D, Edwards W, Newman A, Bock KW, Minai M, Nagata BM, Gagne M, Douek DC, DeMarco CT, Denny TN, Oguin TH 3rd, Brown A, Rountree W, Wang Y, Mansouri K, Edwards RJ, Ferrari G, Sempowski GD, Eaton A, Tang J, Cain DW, Santra S, Pardi N, Weissman D, Tomai MA, Fox CB, Moore IN, Andersen H, Lewis MG, Golding H, Seder R, Khurana S, Baric RS, Montefiori DC, Saunders KO, and Haynes BF
- Abstract
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.
- Published
- 2022
- Full Text
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117. Lipid nanoparticle encapsulated nucleoside-modified mRNA vaccines elicit polyfunctional HIV-1 antibodies comparable to proteins in nonhuman primates.
- Author
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Saunders KO, Pardi N, Parks R, Santra S, Mu Z, Sutherland L, Scearce R, Barr M, Eaton A, Hernandez G, Goodman D, Hogan MJ, Tombacz I, Gordon DN, Rountree RW, Wang Y, Lewis MG, Pierson TC, Barbosa C, Tam Y, Shen X, Ferrari G, Tomaras GD, Montefiori DC, Weissman D, and Haynes BF
- Abstract
Development of an effective AIDS vaccine remains a challenge. Nucleoside-modified mRNAs formulated in lipid nanoparticles (mRNA-LNP) have proved to be a potent mode of immunization against infectious diseases in preclinical studies, and are being tested for SARS-CoV-2 in humans. A critical question is how mRNA-LNP vaccine immunogenicity compares to that of traditional adjuvanted protein vaccines in primates. Here, we found that mRNA-LNP immunization compared to protein immunization elicited either the same or superior magnitude and breadth of HIV-1 Env-specific polyfunctional antibodies. Immunization with mRNA-LNP encoding Zika premembrane and envelope (prM-E) or HIV-1 Env gp160 induced durable neutralizing antibodies for at least 41 weeks. Doses of mRNA-LNP as low as 5 μg were immunogenic in macaques. Thus, mRNA-LNP can be used to rapidly generate single or multi-component vaccines, such as sequential vaccines needed to protect against HIV-1 infection. Such vaccines would be as or more immunogenic than adjuvanted recombinant protein vaccines in primates.
- Published
- 2020
- Full Text
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118. Rapid memory CD8+ T-lymphocyte induction through priming with recombinant Mycobacterium smegmatis.
- Author
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Hovav AH, Cayabyab MJ, Panas MW, Santra S, Greenland J, Geiben R, Haynes BF, Jacobs WR Jr, and Letvin NL
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, Female, Gene Products, gag immunology, HIV Envelope Protein gp120 immunology, HIV-1 immunology, Immunization, Secondary, Kinetics, Mice, Mice, Inbred BALB C, Mycobacterium smegmatis genetics, Plasmids immunology, gag Gene Products, Human Immunodeficiency Virus, AIDS Vaccines immunology, CD8-Positive T-Lymphocytes immunology, Immunologic Memory physiology, Mycobacterium smegmatis immunology
- Abstract
The most promising vaccine strategies for the induction of cytotoxic-T-lymphocyte responses have been heterologous prime/boost regimens employing a plasmid DNA prime and a live recombinant-vector boost. The priming immunogen in these regimens must elicit antigen-specific memory CD8+ T lymphocytes that will expand following the boosting immunization. Because plasmid DNA immunogens are expensive and their immunogenicity has proven disappointing in human clinical trials, we have been exploring novel priming immunogens that might be used in heterologous immunization regimens. Here we show that priming with a prototype recombinant Mycobacterium smegmatis strain expressing human immunodeficiency virus type 1 (HIV-1) gp120-elicited CD4+ T lymphocytes with a functional profile of helper cells as well as a CD8+ T-lymphocyte population. These CD8+ T lymphocytes rapidly differentiated to memory cells, defined on the basis of their cytokine profile and expression of CD62L and CD27. Moreover, these recombinant-mycobacterium-induced T lymphocytes rapidly expanded following boosting with a recombinant adenovirus expressing HIV-1 Env to gp120-specific CD8+ T lymphocytes. This work demonstrates a remarkable skewing of recombinant-mycobacterium-induced T lymphocytes to durable antigen-specific memory CD8+ T cells and suggests that such immunogens might be used as priming vectors in prime/boost vaccination regimens for the induction of cellular immune responses.
- Published
- 2007
- Full Text
- View/download PDF
119. Systemic immunization with an ALVAC-HIV-1/protein boost vaccine strategy protects rhesus macaques from CD4+ T-cell loss and reduces both systemic and mucosal simian-human immunodeficiency virus SHIVKU2 RNA levels.
- Author
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Pal R, Venzon D, Santra S, Kalyanaraman VS, Montefiori DC, Hocker L, Hudacik L, Rose N, Nacsa J, Edghill-Smith Y, Moniuszko M, Hel Z, Belyakov IM, Berzofsky JA, Parks RW, Markham PD, Letvin NL, Tartaglia J, and Franchini G
- Subjects
- Animals, HIV Antibodies blood, HIV-1 isolation & purification, Immunization, Secondary, Macaca mulatta, Research Design, Simian Immunodeficiency Virus isolation & purification, Viral Load, Viremia prevention & control, AIDS Vaccines immunology, CD4 Lymphocyte Count, HIV-1 immunology, RNA, Viral analysis, Simian Immunodeficiency Virus immunology
- Abstract
Transmission of human immunodeficiency virus type 1 (HIV-1) occurs primarily via the mucosal route, suggesting that HIV-1 vaccines may need to elicit mucosal immune responses. Here, we investigated the immunogenicity and relative efficacy of systemic immunization with two human ALVAC-HIV-1 recombinant vaccines expressing Gag, Pol, and gp120 (vCP250) or Gag, Pol, and gp160 (vCP1420) in a prime-boost protocol with their homologous vaccine native Env proteins. The relative efficacy was measured against a high-dose mucosal exposure to the pathogenic neutralization-resistant variant SHIV(KU2) (simian-human immunodeficiency virus). Systemic immunization with both vaccine regimens decreased viral load levels not only in blood but unexpectedly also in mucosal sites and protected macaques from peripheral CD4+ T-cell loss. This protective effect was stronger when the gp120 antigen was included in the vaccine. Inclusion of recombinant Tat protein in the boosting phase along with the Env protein did not contribute further to the preservation of CD4+ T cells. Thus, systemic immunization with ALVAC-HIV-1 vaccine candidates elicits anti-HIV-1 immune responses able to contain virus replication also at mucosal sites in macaques.
- Published
- 2006
- Full Text
- View/download PDF
120. Immune failure in the absence of profound CD4+ T-lymphocyte depletion in simian immunodeficiency virus-infected rapid progressor macaques.
- Author
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Hirsch VM, Santra S, Goldstein S, Plishka R, Buckler-White A, Seth A, Ourmanov I, Brown CR, Engle R, Montefiori D, Glowczwskie J, Kunstman K, Wolinsky S, and Letvin NL
- Subjects
- Animals, Antibodies, Viral blood, CD4 Lymphocyte Count, Disease Models, Animal, Disease Progression, Hepatitis A virus immunology, Lymphocyte Depletion, Macaca mulatta, T-Lymphocytes, Cytotoxic immunology, Tetanus Toxoid immunology, Time Factors, Viral Load, Virulence, CD4-Positive T-Lymphocytes immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome physiopathology, Simian Immunodeficiency Virus pathogenicity
- Abstract
A fraction of simian immunodeficiency virus (SIV)-infected macaques develop rapidly progressive disease in the apparent absence of detectable SIV-specific antibody responses. To characterize the immunopathogenesis of this syndrome, we studied viral load, CD4+ T-lymphocyte numbers as well as cellular and humoral immune responses to SIV and other exogenous antigens in four SIVsm-infected rhesus macaques that progressed to AIDS 9 to 16 weeks postinoculation. Each of these animals exhibited high levels of viremia but showed relatively preserved CD4 T lymphocytes in blood and lymphoid tissues at the time of death. Transient SIV-specific antibody responses and cytotoxic T-lymphocyte responses were observed at 2 to 4 weeks postinoculation. Two of the macaques that were immunized sequentially with tetanus toxoid and hepatitis A virus failed to develop antibody to either antigen. These studies show that the SIV-infected rapid progressor macaques initially mounted an appropriate but transient cellular and humoral immune response. The subsequent immune defect in these animals appeared to be global, affecting both cellular and humoral immunity to SIV as well as immune responses against unrelated antigens. The lack of CD4 depletion and loss of humoral and cellular immune responses suggest that their immune defect may be due to an early loss in T helper function.
- Published
- 2004
- Full Text
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