Browsing by Author "Roederer, Mario"

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Open Access
A model for harmonizing flow cytometry in clinical trials.
(Nat Immunol, 2010-11) Maecker, Holden T; McCoy, J Philip; FOCIS Human Immunophenotyping Consortium; Amos, Michael; Elliott, John; Gaigalas, Adolfas; Wang, Lili; Aranda, Richard; Banchereau, Jacques; Boshoff, Chris; Braun, Jonathan; Korin, Yael; Reed, Elaine; Cho, Judy; Hafler, David; Davis, Mark; Fathman, C Garrison; Robinson, William; Denny, Thomas; Weinhold, Kent; Desai, Bela; Diamond, Betty; Gregersen, Peter; Di Meglio, Paola; Nestle, Frank O; Peakman, Mark; Villanova, Federica; Ferbas, John; Field, Elizabeth; Kantor, Aaron; Kawabata, Thomas; Komocsar, Wendy; Lotze, Michael; Nepom, Jerry; Ochs, Hans; O'Lone, Raegan; Phippard, Deborah; Plevy, Scott; Rich, Stephen; Roederer, Mario; Rotrosen, Dan; Yeh, Jung-Hua
Complexities in sample handling, instrument setup and data analysis are barriers to the effective use of flow cytometry to monitor immunological parameters in clinical trials. The novel use of a central laboratory may help mitigate these issues.
Open Access
Establishment and maintenance of a PBMC repository for functional cellular studies in support of clinical vaccine trials.
(J Immunol Methods, 2014-07) Sambor, Anna; Garcia, Ambrosia; Berrong, Mark; Pickeral, Joy; Brown, Sara; Rountree, Wes; Sanchez, Ana; Pollara, Justin; Frahm, Nicole; Keinonen, Sarah; Kijak, Gustavo H; Roederer, Mario; Levine, Gail; D'Souza, M Patricia; Jaimes, Maria; Koup, Richard; Denny, Thomas; Cox, Josephine; Ferrari, Guido
A large repository of cryopreserved peripheral blood mononuclear cells (PBMCs) samples was created to provide laboratories testing the specimens from human immunodeficiency virus-1 (HIV-1) vaccine clinical trials the material for assay development, optimization, and validation. One hundred thirty-one PBMC samples were collected using leukapheresis procedure between 2007 and 2013 by the Comprehensive T cell Vaccine Immune Monitoring Consortium core repository. The donors included 83 human immunodeficiency virus-1 (HIV-1) seronegative and 32 HIV-1 seropositive subjects. The samples were extensively characterized for the ability of T cell subsets to respond to recall viral antigens including cytomegalovirus, Epstein-Barr virus, influenza virus, and HIV-1 using Interferon-gamma (IFN-γ) enzyme linked immunospot (ELISpot) and IFN-γ/interleukin 2 (IL-2) intracellular cytokine staining (ICS) assays. A subset of samples was evaluated over time to determine the integrity of the cryopreserved samples in relation to recovery, viability, and functionality. The principal results of our study demonstrate that viable and functional cells were consistently recovered from the cryopreserved samples. Therefore, we determined that this repository of large size cryopreserved cellular samples constitutes a unique resource for laboratories that are involved in optimization and validation of assays to evaluate T, B, and NK cellular functions in the context of clinical trials.
Open Access
Immunological and virological mechanisms of vaccine-mediated protection against SIV and HIV.
(Nature, 2014-01-23) Roederer, Mario; Keele, Brandon F; Schmidt, Stephen D; Mason, Rosemarie D; Welles, Hugh C; Fischer, Will; Labranche, Celia; Foulds, Kathryn E; Louder, Mark K; Yang, Zhi-Yong; Todd, John-Paul M; Buzby, Adam P; Mach, Linh V; Shen, Ling; Seaton, Kelly E; Ward, Brandy M; Bailer, Robert T; Gottardo, Raphael; Gu, Wenjuan; Ferrari, Guido; Alam, S Munir; Denny, Thomas N; Montefiori, David C; Tomaras, Georgia D; Korber, Bette T; Nason, Martha C; Seder, Robert A; Koup, Richard A; Letvin, Norman L; Rao, Srinivas S; Nabel, Gary J; Mascola, John R
A major challenge for the development of a highly effective AIDS vaccine is the identification of mechanisms of protective immunity. To address this question, we used a nonhuman primate challenge model with simian immunodeficiency virus (SIV). We show that antibodies to the SIV envelope are necessary and sufficient to prevent infection. Moreover, sequencing of viruses from breakthrough infections revealed selective pressure against neutralization-sensitive viruses; we identified a two-amino-acid signature that alters antigenicity and confers neutralization resistance. A similar signature confers resistance of human immunodeficiency virus (HIV)-1 to neutralization by monoclonal antibodies against variable regions 1 and 2 (V1V2), suggesting that SIV and HIV share a fundamental mechanism of immune escape from vaccine-elicited or naturally elicited antibodies. These analyses provide insight into the limited efficacy seen in HIV vaccine trials.
Open Access
Potential To Streamline Heterologous DNA Prime and NYVAC/Protein Boost HIV Vaccine Regimens in Rhesus Macaques by Employing Improved Antigens.
(J Virol, 2016-04) Asbach, Benedikt; Kliche, Alexander; Köstler, Josef; Perdiguero, Beatriz; Esteban, Mariano; Jacobs, Bertram L; Montefiori, David C; LaBranche, Celia C; Yates, Nicole L; Tomaras, Georgia D; Ferrari, Guido; Foulds, Kathryn E; Roederer, Mario; Landucci, Gary; Forthal, Donald N; Seaman, Michael S; Hawkins, Natalie; Self, Steven G; Sato, Alicia; Gottardo, Raphael; Phogat, Sanjay; Tartaglia, James; Barnett, Susan W; Burke, Brian; Cristillo, Anthony D; Weiss, Deborah E; Francis, Jesse; Galmin, Lindsey; Ding, Song; Heeney, Jonathan L; Pantaleo, Giuseppe; Wagner, Ralf
UNLABELLED: In a follow-up to the modest efficacy observed in the RV144 trial, researchers in the HIV vaccine field seek to substantiate and extend the results by evaluating other poxvirus vectors and combinations with DNA and protein vaccines. Earlier clinical trials (EuroVacc trials 01 to 03) evaluated the immunogenicity of HIV-1 clade C GagPolNef and gp120 antigens delivered via the poxviral vector NYVAC. These showed that a vaccination regimen including DNA-C priming prior to a NYVAC-C boost considerably enhanced vaccine-elicited immune responses compared to those with NYVAC-C alone. Moreover, responses were improved by using three as opposed to two DNA-C primes. In the present study, we assessed in nonhuman primates whether such vaccination regimens can be streamlined further by using fewer and accelerated immunizations and employing a novel generation of improved DNA-C and NYVAC-C vaccine candidates designed for higher expression levels and more balanced immune responses. Three different DNA-C prime/NYVAC-C+ protein boost vaccination regimens were tested in rhesus macaques. All regimens elicited vigorous and well-balanced CD8(+)and CD4(+)T cell responses that were broad and polyfunctional. Very high IgG binding titers, substantial antibody-dependent cellular cytotoxicity (ADCC), and modest antibody-dependent cell-mediated virus inhibition (ADCVI), but very low neutralization activity, were measured after the final immunizations. Overall, immune responses elicited in all three groups were very similar and of greater magnitude, breadth, and quality than those of earlier EuroVacc vaccines. In conclusion, these findings indicate that vaccination schemes can be simplified by using improved antigens and regimens. This may offer a more practical and affordable means to elicit potentially protective immune responses upon vaccination, especially in resource-constrained settings. IMPORTANCE: Within the EuroVacc clinical trials, we previously assessed the immunogenicity of HIV clade C antigens delivered in a DNA prime/NYVAC boost regimen. The trials showed that the DNA prime crucially improved the responses, and three DNA primes with a NYVAC boost appeared to be optimal. Nevertheless, T cell responses were primarily directed toward Env, and humoral responses were modest. The aim of this study was to assess improved antigens for the capacity to elicit more potent and balanced responses in rhesus macaques, even with various simpler immunization regimens. Our results showed that the novel antigens in fact elicited larger numbers of T cells with a polyfunctional profile and a good Env-GagPolNef balance, as well as high-titer and Fc-functional antibody responses. Finally, comparison of the different schedules indicates that a simpler regimen of only two DNA primes and one NYVAC boost in combination with protein may be very efficient, thus showing that the novel antigens allow for easier immunization protocols.
Open Access
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.