28 results on '"Silacci, Chiara"'
Search Results
2. Protection of calves by a prefusion-stabilized bovine RSV F vaccine
- Author
-
Zhang, Baoshan, Chen, Lei, Silacci, Chiara, Thom, Michelle, Boyington, Jeffrey C., Druz, Aliaksandr, Joyce, M. Gordon, Guzman, Efrain, Kong, Wing- Pui, Lai, Yen-Ting, Stewart-Jones, Guillaume B. E., Tsybovsky, Yaroslav, Yang, Yongping, Zhou, Tongqing, Baxa, Ulrich, Mascola, John R., Corti, Davide, Lanzavecchia, Antonio, Taylor, Geraldine, and Kwong, Peter D.
- Published
- 2017
- Full Text
- View/download PDF
3. EBOLA VIRUS: Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody
- Author
-
Corti, Davide, Misasi, John, Mulangu, Sabue, Stanley, Daphne A., Kanekiyo, Masaru, Wollen, Suzanne, Ploquin, Aurélie, Doria-Rose, Nicole A., Staupe, Ryan P., Bailey, Michael, Shi, Wei, Choe, Misook, Marcus, Hadar, Thompson, Emily A., Cagigi, Alberto, Silacci, Chiara, Fernandez-Rodriguez, Blanca, Perez, Laurent, Sallusto, Federica, Vanzetta, Fabrizia, Agatic, Gloria, Cameroni, Elisabetta, Kisalu, Neville, Gordon, Ingelise, Ledgerwood, Julie E., Mascola, John R., Graham, Barney S., Muyembe-Tamfun, Jean-Jacques, Trefry, John C., Lanzavecchia, Antonio, and Sullivan, Nancy J.
- Published
- 2016
- Full Text
- View/download PDF
4. Cross-neutralization of four paramyxoviruses by a human monoclonal antibody
- Author
-
Corti, Davide, Bianchi, Siro, Vanzetta, Fabrizia, Minola, Andrea, Perez, Laurent, Agatic, Gloria, Guarino, Barbara, Silacci, Chiara, Marcandalli, Jessica, Marsland, Benjamin J., Piralla, Antonio, Percivalle, Elena, Sallusto, Federica, Baldanti, Fausto, and Lanzavecchia, Antonio
- Subjects
Paramyxoviruses -- Control ,Monoclonal antibodies -- Usage -- Health aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
A human monoclonal antibody has been identified which can cross-neutralize both human respiratory syncytial virus (HRSV) and human metapneumovirus (HMPV), demonstrating that a single monoclonal antibody can target different viruses, a discovery that may lead to the creation of new therapeutics and vaccines. A broadly active anti-paramyxovirus antibody Human respiratory syncytial virus (HRSV) is a major cause of morbidity and mortality in young children and the elderly, with no effective therapy or vaccine. Corti et al. describe a human monoclonal antibody, named MPE8, with prophylactic and therapeutic potential. The antibody potently cross-neutralizes HRSV and human metapneumovirus, as well as two animal viruses. It is specific for the pre-fusion F protein, suggesting that a vaccine based on a stabilized pre-fusion F protein might be able to selectively elicit neutralizing antibodies. Broadly neutralizing antibodies reactive against most and even all variants of the same viral species have been described for influenza and HIV-1 (ref. 1). However, whether a neutralizing antibody could have the breadth of range to target different viral species was unknown. Human respiratory syncytial virus (HRSV) and human metapneumovirus (HMPV) are common pathogens that cause severe disease in premature newborns, hospitalized children.sup.2,3 and immune-compromised patients.sup.2,4,5, and play a role in asthma exacerbations.sup.6. Although antisera generated against either HRSV or HMPV are not cross-neutralizing.sup.7, we speculated that, because of the repeated exposure to these viruses, cross-neutralizing antibodies may be selected in some individuals. Here we describe a human monoclonal antibody (MPE8) that potently cross-neutralizes HRSV and HMPV as well as two animal paramyxoviruses: bovine RSV (BRSV) and pneumonia virus of mice (PVM). In its germline configuration, MPE8 is HRSV-specific and its breadth is achieved by somatic mutations in the light chain variable region. MPE8 did not result in the selection of viral escape mutants that evaded antibody targeting and showed potent prophylactic efficacy in animal models of HRSV and HMPV infection, as well as prophylactic and therapeutic efficacy in the more relevant model of lethal PVM infection. The core epitope of MPE8 was mapped on two highly conserved anti-parallel [beta]-strands on the pre-fusion viral F protein, which are rearranged in the post-fusion F protein conformation. Twenty-six out of the thirty HRSV-specific neutralizing antibodies isolated were also found to be specific for the pre-fusion F protein. Taken together, these results indicate that MPE8 might be used for the prophylaxis and therapy of severe HRSV and HMPV infections and identify the pre-fusion F protein as a candidate HRSV vaccine., Author(s): Davide Corti [sup.1] [sup.2] , Siro Bianchi [sup.1] , Fabrizia Vanzetta [sup.1] , Andrea Minola [sup.2] , Laurent Perez [sup.2] , Gloria Agatic [sup.1] , Barbara Guarino [sup.1] , [...]
- Published
- 2013
- Full Text
- View/download PDF
5. Rapid development of broadly influenza neutralizing antibodies through redundant mutations
- Author
-
Pappas, Leontios, Foglierini, Mathilde, Piccoli, Luca, Kallewaard, Nicole L., Turrini, Filippo, Silacci, Chiara, Fernandez-Rodriguez, Blanca, Agatic, Gloria, Giacchetto-Sasselli, Isabella, Pellicciotta, Gabriele, Sallusto, Federica, Zhu, Qing, Vicenzi, Elisa, Corti, Davide, and Lanzavecchia, Antonio
- Published
- 2014
- Full Text
- View/download PDF
6. Structure and function analysis of an antibody recognizing all influenza A subtypes
- Author
-
Kallewaard, Nicole L., Corti, Davide, Collins, Patrick J., Neu, Ursula, McAuliffe, Josephine M., Benjamin, Ebony, Wachter-Rosati, Leslie, Palmer-Hill, Frances J., Yuan, Andy Q., Walker, Philip A., Vorlaender, Matthias K., Bianchi, Siro, Guarino, Barbara, De Marco, Anna, Vanzetta, Fabrizia, Agatic, Gloria, Foglierini, Mathilde, Pinna, Debora, Fernandez-Rodriguez, Blanca, Fruehwirth, Alexander, Silacci, Chiara, Ogrodowicz, Roksana W., Martin, Stephen R., Sallusto, Federica, Suzich, JoAnn A., Lanzavecchia, Antonio, Zhu, Qing, Gamblin, Steven J., Skehel, John J., Kallewaard, Nicole L., Corti, Davide, Collins, Patrick J., Neu, Ursula, McAuliffe, Josephine M., Benjamin, Ebony, Wachter-Rosati, Leslie, Palmer-Hill, Frances J., Yuan, Andy Q., Walker, Philip A., Vorlaender, Matthias K., Bianchi, Siro, Guarino, Barbara, De Marco, Anna, Vanzetta, Fabrizia, Agatic, Gloria, Foglierini, Mathilde, Pinna, Debora, Fernandez-Rodriguez, Blanca, Fruehwirth, Alexander, Silacci, Chiara, Ogrodowicz, Roksana W., Martin, Stephen R., Sallusto, Federica, Suzich, JoAnn A., Lanzavecchia, Antonio, Zhu, Qing, Gamblin, Steven J., and Skehel, John J.
- Abstract
Influenza virus remains a threat because of its ability to evade vaccine-induced immune responses due to antigenic drift. Here, we describe the isolation, evolution, and structure of a broad-spectrum human monoclonal antibody (mAb), MEDI8852, effectively reacting with all influenza A hemagglutinin (HA) subtypes. MEDI8852 uses the heavy-chain VH6-1 gene and has higher potency and breadth when compared to other anti-stem antibodies. MEDI8852 is effective in mice and ferrets with a therapeutic window superior to that of oseltamivir. Crystallographic analysis of Fab alone or in complex with H5 or H7 HA proteins reveals that MEDI8852 binds through a coordinated movement of CDRs to a highly conserved epitope encompassing a hydrophobic groove in the fusion domain and a large portion of the fusion peptide, distinguishing it from other structurally characterized cross- reactive antibodies. The unprecedented breadth and potency of neutralization by MEDI8852 support its development as immunotherapy for influenza virus-infected humans.
- Published
- 2021
7. Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine
- Author
-
Corti, Davide, Suguitan, Jr., Amorsolo L., Pinna, Debora, Silacci, Chiara, Fernandez-Rodriguez, Blanca M., Vanzetta, Fabrizia, Santos, Celia, Luke, Catherine J., Torres-Velez, Fernando J., Temperton, Nigel J., Weiss, Robin A., Sallusto, Federica, Subbarao, Kanta, and Lanzavecchia, Antonio
- Subjects
Immunization -- Research -- Health aspects ,Viral antibodies -- Properties -- Health aspects -- Research ,Influenza vaccines -- Health aspects -- Research ,Genetic variation -- Identification and classification -- Research -- Health aspects ,Antibodies -- Properties -- Health aspects -- Research ,Health care industry - Abstract
The target of neutralizing antibodies that protect against influenza virus infection is the viral protein HA. Genetic and antigenic variation in HA has been used to classify influenza viruses into subtypes (H1-H16). The neutralizing antibody response to influenza virus is thought to be specific for a few antigenically related isolates within a given subtype. However, while heterosubtypic antibodies capable of neutralizing multiple influenza virus subtypes have been recently isolated from phage display libraries, it is not known whether such antibodies are produced in the course of an immune response to influenza virus infection or vaccine. Here we report that, following vaccination with seasonal influenza vaccine containing H1 and H3 influenza virus subtypes, some individuals produce antibodies that cross-react with H5 HA. By immortalizing IgG-expressing B cells from 4 individuals, we isolated 20 heterosubtypic mAbs that bound and neutralized viruses belonging to several HA subtypes (H1, H2, H5, H6, and H9), including the pandemic A/California/07/09 H1N1 isolate. The mAbs used different VH genes and carried a high frequency of somatic mutations. With the exception of a mAb that bound to the HA globular head, all heterosubtypic mAbs bound to acid-sensitive epitopes in the HA stem region. Four mAbs were evaluated in vivo and protected mice from challenge with influenza viruses representative of different subtypes. These findings reveal that seasonal influenza vaccination can induce polyclonal heterosubtypic neutralizing antibodies that cross-react with the swine-origin pandemic H1N1 influenza virus and with the highly pathogenic H5N1 virus., Introduction The HA is the major glycoprotein of influenza virus that mediates binding to cell surface sialic acid through the globular head domain (HA1) and the subsequent pH-dependent entry through [...]
- Published
- 2010
- Full Text
- View/download PDF
8. Structural Basis for Broad HIV-1 Neutralization by the MPER-Specific Human Broadly Neutralizing Antibody LN01
- Author
-
Pinto, Dora, primary, Fenwick, Craig, additional, Caillat, Christophe, additional, Silacci, Chiara, additional, Guseva, Serafima, additional, Dehez, François, additional, Chipot, Christophe, additional, Barbieri, Sonia, additional, Minola, Andrea, additional, Jarrossay, David, additional, Tomaras, Georgia D., additional, Shen, Xiaoying, additional, Riva, Agostino, additional, Tarkowski, Maciej, additional, Schwartz, Olivier, additional, Bruel, Timothée, additional, Dufloo, Jérémy, additional, Seaman, Michael S., additional, Montefiori, David C., additional, Lanzavecchia, Antonio, additional, Corti, Davide, additional, Pantaleo, Giuseppe, additional, and Weissenhorn, Winfried, additional
- Published
- 2019
- Full Text
- View/download PDF
9. Crystal structure and size-dependent neutralization properties of HK20, a human monoclonal antibody binding to the highly conserved heptad repeat 1 of gp41
- Author
-
Sabin, Charles, Corti, Davide, Buzon, Victor, Seaman, Mike S., Hulsik, David Lutje, Hinz, Andreas, Vanzetta, Fabrizia, Agatic, Gloria, Silacci, Chiara, Mainetti, Lara, Scarlatti, Gabriella, Sallusto, Federica, Weiss, Robin, Lanzavecchia, Antonio, Weissenhorn, Winfried, Sabin, Charles, Corti, Davide, Buzon, Victor, Seaman, Mike S., Hulsik, David Lutje, Hinz, Andreas, Vanzetta, Fabrizia, Agatic, Gloria, Silacci, Chiara, Mainetti, Lara, Scarlatti, Gabriella, Sallusto, Federica, Weiss, Robin, Lanzavecchia, Antonio, and Weissenhorn, Winfried
- Abstract
The human monoclonal antibody (mAb) HK20 neutralizes a broad spectrum of primary HIV-1 isolates by targeting the highly conserved heptad repeat 1 (HR1) of gp41, which is transiently exposed during HIV-1 entry. Here we present the crystal structure of the HK20 Fab in complex with a gp41 mimetic 5-Helix at 2.3 A° resolution. HK20 employs its heavy chain CDR H2 and H3 loops to bind into a conserved hydrophobic HR1 pocket that is occupied by HR2 residues in the gp41 post fusion conformation. Compared to the previously described HR1-specific mAb D5, HK20 approaches its epitope with a different angle which might favor epitope access and thus contribute to its higher neutralization breadth and potency. Comparison of the neutralization activities of HK20 IgG, Fab and scFv employing both single cycle and multiple cycle neutralization assays revealed much higher potencies for the smaller Fab and scFv over IgG, implying that the target site is difficult to access for complete antibodies. Nevertheless, two thirds of sera from HIV-1 infected individuals contain significant titers of HK20-inhibiting antibodies. The breadth of neutralization of primary isolates across all clades, the higher potencies for Cclade viruses and the targeting of a distinct site as compared to the fusion inhibitor T-20 demonstrate the potential of HK20 scFv as a therapeutic tool.
- Published
- 2019
10. Protection of calves by a prefusion-stabilized bovine RSV F vaccine
- Author
-
Zhang, Baoshan, Chen, Lei, Silacci, Chiara, Thom, Michelle, Boyington, Jeffrey C., Druz, Aliaksandr, Joyce, M. Gordon, Guzman, Efrain, Kong, Wing-Pui, Lai, Yen-Ting, Stewart-Jones, Guillaume B. E., Tsybovsky, Yaroslav, Yang, Yongping, Zhou, Tongqing, Baxa, Ulrich, Mascola, John R., Corti, Davide, Lanzavecchia, Antonio, Taylor, Geraldine, Kwong, Peter D., Zhang, Baoshan, Chen, Lei, Silacci, Chiara, Thom, Michelle, Boyington, Jeffrey C., Druz, Aliaksandr, Joyce, M. Gordon, Guzman, Efrain, Kong, Wing-Pui, Lai, Yen-Ting, Stewart-Jones, Guillaume B. E., Tsybovsky, Yaroslav, Yang, Yongping, Zhou, Tongqing, Baxa, Ulrich, Mascola, John R., Corti, Davide, Lanzavecchia, Antonio, Taylor, Geraldine, and Kwong, Peter D.
- Abstract
Bovine respiratory syncytial virus, a major cause of respiratory disease in calves, is closely related to human RSV, a leading cause of respiratory disease in infants. Recently, promising human RSV-vaccine candidates have been engineered that stabilize the metastable fusion (F) glycoprotein in its prefusion state; however, the absence of a relevant animal model for human RSV has complicated assessment of these vaccine candidates. Here, we use a combination of structure-based design, antigenic characterization, and X-ray crystallography to translate human RSV F stabilization into the bovine context. A “DS2” version of bovine respiratory syncytial virus F with subunits covalently fused, fusion peptide removed, and pre-fusion conformation stabilized by cavity-filling mutations and intra- and inter-protomer disulfides was recognized by pre-fusion- specific antibodies, AM14, D25, and MPE8, and elicited bovine respiratory syncytial virus- neutralizing titers in calves >100-fold higher than those elicited by post-fusion F. When challenged with a heterologous bovine respiratory syncytial virus, virus was not detected in nasal secretions nor in respiratory tract samples of DS2-immunized calves; by contrast bovine respiratory syncytial virus was detected in all post-fusion- and placebo-immunized calves. Our results demonstrate proof-of-concept that DS2-stabilized RSV F immunogens can induce highly protective immunity from RSV in a native host with implications for the efficacy of prefusion- stabilized F vaccines in humans and for the prevention of bovine respiratory syncytial virus in calves.
- Published
- 2019
11. Adjuvants and the vaccine response to the DS-Cav1-stabilized fusion glycoprotein of respiratory syncytial virus
- Author
-
Sastry, Mallika, Zhang, Baoshan, Chen, Man, Joyce, M. Gordon, Kong, Wing-Pui, Chuang, Gwo-Yu, Ko, Kiyoon, Kumar, Azad, Silacci, Chiara, Thom, Michelle, Salazar, Andres M., Corti, Davide, Lanzavecchia, Antonio, Taylor, Geraldine, Mascola, John R., Graham, Barney S., Kwong, Peter D., Sastry, Mallika, Zhang, Baoshan, Chen, Man, Joyce, M. Gordon, Kong, Wing-Pui, Chuang, Gwo-Yu, Ko, Kiyoon, Kumar, Azad, Silacci, Chiara, Thom, Michelle, Salazar, Andres M., Corti, Davide, Lanzavecchia, Antonio, Taylor, Geraldine, Mascola, John R., Graham, Barney S., and Kwong, Peter D.
- Abstract
Appropriate adjuvant selection may be essential to optimize the potency and to tailor the immune response of subunit vaccines. To induce protective responses against respiratory syncytial virus (RSV)—a highly prevalent childhood pathogen without a licensed vaccine—we previously engineered a pre-fusion-stabilized trimeric RSV F (pre-F) “DS-Cav1” immunogen, which induced high titer RSV-neutralizing antibodies, in mice and non-human primates, when formulated with adjuvants Poly (I:C) and Poly (IC:LC), respectively. To assess the impact of different adjuvants, here we formulated RSV F DS-Cav1 with multiple adjuvants and assessed immune responses. Very high RSV-neutralizing antibody responses (19,006 EC50) were observed in naïve mice immunized with 2 doses of DS-Cav1 adjuvanted with Sigma adjuvant system (SAS), an oil-in-water adjuvant, plus Carbopol; high responses (3658–7108) were observed with DS-Cav1 adjuvanted with Alum, SAS alone, Adjuplex, Poly (I:C) and Poly (IC:LC); and moderate responses (1251–2129) were observed with DS-Cav1 adjuvanted with the TLR4 agonist MPLA, Alum plus MPLA or AddaVax. In contrast, DS-Cav1 without adjuvant induced low-level responses (6). A balanced IgG1 and IgG2a (Th2/Th1) immune response was elicited in most of the high to very high response groups (all but Alum and Adjuplex). We also tested the immune response induced by DS-Cav1 in elderly mice with pre-existing DS-Cav1 immunity; we observed that DS-Cav1 adjuvanted with SAS plus Carbopol boosted the response 2-3-fold, whereas DS-Cav1 adjuvanted with alum boosted the response 5-fold. Finally, we tested whether a mixture of ISA 71 VG and Carbopol would enhanced the antibody response in DS-Cav1 immunized calves. While pre-F-stabilized bovine RSV F induced very high titers in mice when adjuvanted with SAS plus Carbopol, the addition of Carbopol to ISA 71 VG did not enhance immune responses in calves. The vaccine response to pre-F-stabilized RSV F is augmented by adjuvant, but the degree of
- Published
- 2019
12. Structural basis for broad HIV-1 neutralization by the MPER-specific human broadly neutralizing antibody LN01
- Author
-
Pinto, Dora, Fenwick, Craig, Caillat, Christophe, Silacci, Chiara, Guseva, Serafima, Dehez, François, Chipot, Christophe, Barbieri, Sonia, Minola, Andrea, Jarrossay, David, Tomaras, Georgia D., Shen, Xiaoying, Riva, Agostino, Tarkowski, Maciej, Schwartz, Olivier, Bruel, Timothée, Dufloo, Jérémy, Seaman, Michael S., Montefiori, David C., Lanzavecchia, Antonio, Corti, Davide, Pantaleo, Giuseppe, Weissenhorn, Winfried, Pinto, Dora, Fenwick, Craig, Caillat, Christophe, Silacci, Chiara, Guseva, Serafima, Dehez, François, Chipot, Christophe, Barbieri, Sonia, Minola, Andrea, Jarrossay, David, Tomaras, Georgia D., Shen, Xiaoying, Riva, Agostino, Tarkowski, Maciej, Schwartz, Olivier, Bruel, Timothée, Dufloo, Jérémy, Seaman, Michael S., Montefiori, David C., Lanzavecchia, Antonio, Corti, Davide, Pantaleo, Giuseppe, and Weissenhorn, Winfried
- Abstract
Potent and broadly neutralizing antibodies (bnAbs) are the hallmark of HIV-1 protection by vaccination. The membrane-proximal external region (MPER) of the HIV-1 gp41 fusion protein is targeted by the most broadly reactive HIV-1 neutralizing antibodies. Here, we examine the structural and molecular mechansims of neutralization by anti-MPER bnAb, LN01, which was isolated from lymph-node-derived germinal center B cells of an elite controller and exhibits broad neutralization breadth. LN01 engages both MPER and the transmembrane (TM) region, which together form a continuous helix in complex with LN01. The tilted TM orientation allows LN01 to interact simultaneously with the peptidic component of the MPER epitope and membrane via two specific lipid binding sites of the antibody paratope. Although LN01 carries a high load of somatic mutations, most key residues interacting with the MPER epitope and lipids are germline encoded, lending support for the LN01 epitope as a candidate for lineage-based vaccine development.
- Published
- 2019
13. Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine
- Author
-
Corti, Davide, Suguitan Jr., Amorsolo, Pinna, Debora, Silacci, Chiara, Fernandez-Rodriguez, Blanca M., Vanzetta, Fabrizia, Santos, Celia, Luke, Catherine J., Torres-Velez, Fernando J., Temperton, Nigel J., Weiss, Robin A., Sallusto, Federica, Subbarao, Kanta, Lanzavecchia, Antonio, Corti, Davide, Suguitan Jr., Amorsolo, Pinna, Debora, Silacci, Chiara, Fernandez-Rodriguez, Blanca M., Vanzetta, Fabrizia, Santos, Celia, Luke, Catherine J., Torres-Velez, Fernando J., Temperton, Nigel J., Weiss, Robin A., Sallusto, Federica, Subbarao, Kanta, and Lanzavecchia, Antonio
- Abstract
The target of neutralizing antibodies that protect against influenza virus infection is the viral protein HA. Genetic and antigenic variation in HA has been used to classify influenza viruses into subtypes (H1–H16). The neutralizing antibody response to influenza virus is thought to be specific for a few antigenically related isolates within a given subtype. However, while heterosubtypic antibodies capable of neutralizing multiple influenza virus subtypes have been recently isolated from phage display libraries, it is not known whether such antibodies are produced in the course of an immune response to influenza virus infection or vaccine. Here we report that, following vaccination with seasonal influenza vaccine containing H1 and H3 influenza virus subtypes, some individuals produce antibodies that cross-react with H5 HA. By immortalizing IgG-expressing B cells from 4 individuals, we isolated 20 heterosubtypic mAbs that bound and neutralized viruses belonging to several HA subtypes (H1, H2, H5, H6, and H9), including the pandemic A/California/07/09 H1N1 isolate. The mAbs used different VH genes and carried a high frequency of somatic mutations. With the exception of a mAb that bound to the HA globular head, all heterosubtypic mAbs bound to acid- sensitive epitopes in the HA stem region. Four mAbs were evaluated in vivo and protected mice from challenge with influenza viruses representative of different subtypes. These findings reveal that seasonal influenza vaccination can induce polyclonal heterosubtypic neutralizing antibodies that cross-react with the swine-origin pandemic H1N1 influenza virus and with the highly pathogenic H5N1 virus.
- Published
- 2019
14. Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals
- Author
-
Corti, Davide, Langedijk, Johannes P. M., Hinz, Andreas, Seaman, Michael S., Vanzetta, Fabrizia, Fernandez-Rodriguez, Blanca M., Silacci, Chiara, Pinna, Debora, Jarrossay, David, Balla-Jhagjhoorsingh, Sunita, Willems, Betty, Zekveld, Maria J., Dreja, O’Sullivan, Eithne, Pade, Corinna, Orkin, Chloe, Jeffs, Simon A., Montefiori, David C., David, Davis, Weissenhorn, Winfried, McKnight, Aine, Heeney, Jonathan L., Sallusto, Federica, Sattentau, Quentin J., Weiss, robin A., Lanzavecchia, Antonio, Corti, Davide, Langedijk, Johannes P. M., Hinz, Andreas, Seaman, Michael S., Vanzetta, Fabrizia, Fernandez-Rodriguez, Blanca M., Silacci, Chiara, Pinna, Debora, Jarrossay, David, Balla-Jhagjhoorsingh, Sunita, Willems, Betty, Zekveld, Maria J., Dreja, O’Sullivan, Eithne, Pade, Corinna, Orkin, Chloe, Jeffs, Simon A., Montefiori, David C., David, Davis, Weissenhorn, Winfried, McKnight, Aine, Heeney, Jonathan L., Sallusto, Federica, Sattentau, Quentin J., Weiss, robin A., and Lanzavecchia, Antonio
- Abstract
Background The isolation of human monoclonal antibodies (mAbs) that neutralize a broad spectrum of primary HIV-1 isolates and the characterization of the human neutralizing antibody B cell response to HIV-1 infection are important goals that are central to the design of an effective antibody-based vaccine. Methods and Findings We immortalized IgG+ memory B cells from individuals infected with diverse clades of HIV-1 and selected on the basis of plasma neutralization profiles that were cross-clade and relatively potent. Culture supernatants were screened using various recombinant forms of the envelope glycoproteins (Env) in multiple parallel assays. We isolated 58 mAbs that were mapped to different Env surfaces, most of which showed neutralizing activity. One mAb in particular (HJ16) specific for a novel epitope proximal to the CD4 binding site on gp120 selectively neutralized a multi-clade panel of Tier-2 HIV-1 pseudoviruses, and demonstrated reactivity that was comparable in breadth, but distinct in neutralization specificity, to that of the other CD4 binding site-specific neutralizing mAb b12. A second mAb (HGN194) bound a conserved epitope in the V3 crown and neutralized all Tier-1 and a proportion of Tier-2 pseudoviruses tested, irrespective of clade. A third mAb (HK20) with broad neutralizing activity, particularly as a Fab fragment, recognized a highly conserved epitope in the HR-1 region of gp41, but showed striking assay-dependent selectivity in its activity. Conclusions This study reveals that by using appropriate screening methods, a large proportion of memory B cells can be isolated that produce mAbs with HIV-1 neutralizing activity. Three of these mAbs show unusual breadth of neutralization and therefore add to the current panel of HIV-1 neutralizing antibodies with potential for passive protection and template-based vaccine design.
- Published
- 2019
15. Structural Basis for Broad HIV-1 Neutralization by a Novel MPER-Specific Human Broadly Neutralizing Antibody
- Author
-
Pinto, Dora, primary, Fenwick, Craig, additional, Caillat, Christophe, additional, Silacci, Chiara, additional, Guseva, Serafima, additional, Dehez, François, additional, Chipot, Christophe, additional, Barbieri, Sonia, additional, Minola, Andrea, additional, Jarrossay, David, additional, Tomaras, Georgia D., additional, Shen, Xiaoying, additional, Riva, Agostino, additional, Tarkowski, Maciej, additional, Schwartz, Olivier, additional, Bruel, Timothée, additional, Dufloo, Jérémy, additional, Seaman, Michael S., additional, Montefiori, David C., additional, Lanzavecchia, Antonio, additional, Corti, Davide, additional, Pantaleo, Giuseppe, additional, and Weissenhorn, Winfried, additional
- Published
- 2019
- Full Text
- View/download PDF
16. Adjuvants and the vaccine response to the DS-Cav1-stabilized fusion glycoprotein of respiratory syncytial virus
- Author
-
Sastry, Mallika, primary, Zhang, Baoshan, additional, Chen, Man, additional, Joyce, M. Gordon, additional, Kong, Wing-Pui, additional, Chuang, Gwo-Yu, additional, Ko, Kiyoon, additional, Kumar, Azad, additional, Silacci, Chiara, additional, Thom, Michelle, additional, Salazar, Andres M., additional, Corti, Davide, additional, Lanzavecchia, Antonio, additional, Taylor, Geraldine, additional, Mascola, John R., additional, Graham, Barney S., additional, and Kwong, Peter D., additional
- Published
- 2017
- Full Text
- View/download PDF
17. Structure and Function Analysis of an Antibody Recognizing All Influenza A Subtypes
- Author
-
Kallewaard, Nicole L., primary, Corti, Davide, additional, Collins, Patrick J., additional, Neu, Ursula, additional, McAuliffe, Josephine M., additional, Benjamin, Ebony, additional, Wachter-Rosati, Leslie, additional, Palmer-Hill, Frances J., additional, Yuan, Andy Q., additional, Walker, Philip A., additional, Vorlaender, Matthias K., additional, Bianchi, Siro, additional, Guarino, Barbara, additional, De Marco, Anna, additional, Vanzetta, Fabrizia, additional, Agatic, Gloria, additional, Foglierini, Mathilde, additional, Pinna, Debora, additional, Fernandez-Rodriguez, Blanca, additional, Fruehwirth, Alexander, additional, Silacci, Chiara, additional, Ogrodowicz, Roksana W., additional, Martin, Stephen R., additional, Sallusto, Federica, additional, Suzich, JoAnn A., additional, Lanzavecchia, Antonio, additional, Zhu, Qing, additional, Gamblin, Steven J., additional, and Skehel, John J., additional
- Published
- 2016
- Full Text
- View/download PDF
18. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins
- Author
-
Corti, Davide, Voss, Jarrod, Gamblin, Steven J., Codoni, Giosiana, Macagno, Annalisa, Jarrossay, David, Vachieri, Sebastien G., Pinna, Debora, Minola, Andrea, Vanzetta, Fabrizia, Silacci, Chiara, Fernandez-Rodriguez, Blanca M., Agatic, Gloria, Bianchi, Siro, Giacchetto-Sasselli, Isabella, Calder, Lesley, Sallusto, Federica, Collins, Patrick, Haire, Lesley F., Temperton, Nigel J., Langedijk, Johannes P. M., Skehel, John J., Lanzavecchia, Antonio, Corti, Davide, Voss, Jarrod, Gamblin, Steven J., Codoni, Giosiana, Macagno, Annalisa, Jarrossay, David, Vachieri, Sebastien G., Pinna, Debora, Minola, Andrea, Vanzetta, Fabrizia, Silacci, Chiara, Fernandez-Rodriguez, Blanca M., Agatic, Gloria, Bianchi, Siro, Giacchetto-Sasselli, Isabella, Calder, Lesley, Sallusto, Federica, Collins, Patrick, Haire, Lesley F., Temperton, Nigel J., Langedijk, Johannes P. M., Skehel, John J., and Lanzavecchia, Antonio
- Abstract
The isolation of broadly neutralizing antibodies against influenza A viruses has been a long-sought goal for therapeutic approaches and vaccine design. Using a single-cell culture method for screening large numbers of human plasma cells, we isolated a neutralizing monoclonal antibody that recognized the hemagglutinin (HA) glycoprotein of all 16 subtypes and neutralized both group 1 and group 2 influenza A viruses. Passive transfer of this antibody conferred protection to mice and ferrets. Complexes with HAs from the group 1 H1 and the group 2 H3 subtypes analyzed by x-ray crystallography showed that the antibody bound to a conserved epitope in the F subdomain. This antibody may be used for passive protection and to inform vaccine design because of its broad specificity and neutralization potency.
- Published
- 2011
19. A Neutralizing Antibody Selected from Plasma Cells That Binds to Group 1 and Group 2 Influenza A Hemagglutinins
- Author
-
Corti, Davide, primary, Voss, Jarrod, additional, Gamblin, Steven J., additional, Codoni, Giosiana, additional, Macagno, Annalisa, additional, Jarrossay, David, additional, Vachieri, Sebastien G., additional, Pinna, Debora, additional, Minola, Andrea, additional, Vanzetta, Fabrizia, additional, Silacci, Chiara, additional, Fernandez-Rodriguez, Blanca M., additional, Agatic, Gloria, additional, Bianchi, Siro, additional, Giacchetto-Sasselli, Isabella, additional, Calder, Lesley, additional, Sallusto, Federica, additional, Collins, Patrick, additional, Haire, Lesley F., additional, Temperton, Nigel, additional, Langedijk, Johannes P. M., additional, Skehel, John J., additional, and Lanzavecchia, Antonio, additional
- Published
- 2011
- Full Text
- View/download PDF
20. Crystal Structure and Size-Dependent Neutralization Properties of HK20, a Human Monoclonal Antibody Binding to the Highly Conserved Heptad Repeat 1 of gp41
- Author
-
Sabin, Charles, primary, Corti, Davide, additional, Buzon, Victor, additional, Seaman, Mike S., additional, Lutje Hulsik, David, additional, Hinz, Andreas, additional, Vanzetta, Fabrizia, additional, Agatic, Gloria, additional, Silacci, Chiara, additional, Mainetti, Lara, additional, Scarlatti, Gabriella, additional, Sallusto, Federica, additional, Weiss, Robin, additional, Lanzavecchia, Antonio, additional, and Weissenhorn, Winfried, additional
- Published
- 2010
- Full Text
- View/download PDF
21. Analysis of Memory B Cell Responses and Isolation of Novel Monoclonal Antibodies with Neutralizing Breadth from HIV-1-Infected Individuals
- Author
-
Corti, Davide, primary, Langedijk, Johannes P. M., additional, Hinz, Andreas, additional, Seaman, Michael S., additional, Vanzetta, Fabrizia, additional, Fernandez-Rodriguez, Blanca M., additional, Silacci, Chiara, additional, Pinna, Debora, additional, Jarrossay, David, additional, Balla-Jhagjhoorsingh, Sunita, additional, Willems, Betty, additional, Zekveld, Maria J., additional, Dreja, Hanna, additional, O'Sullivan, Eithne, additional, Pade, Corinna, additional, Orkin, Chloe, additional, Jeffs, Simon A., additional, Montefiori, David C., additional, Davis, David, additional, Weissenhorn, Winfried, additional, McKnight, Áine, additional, Heeney, Jonathan L., additional, Sallusto, Federica, additional, Sattentau, Quentin J., additional, Weiss, Robin A., additional, and Lanzavecchia, Antonio, additional
- Published
- 2010
- Full Text
- View/download PDF
22. Structure and function analysis of an antibody recognizing all influenza A subtypes
- Author
-
Kallewaard, Nicole L., Corti, Davide, Collins, Patrick J., Neu, Ursula, McAuliffe, Josephine M., Benjamin, Ebony, Wachter-Rosati, Leslie, Palmer-Hill, Frances J., Yuan, Andy Q., Walker, Philip A., Vorlaender, Matthias K., Bianchi, Siro, Guarino, Barbara, De Marco, Anna, Vanzetta, Fabrizia, Agatic, Gloria, Foglierini, Mathilde, Pinna, Debora, Fernandez-Rodriguez, Blanca, Fruehwirth, Alexander, Silacci, Chiara, Ogrodowicz, Roksana W., Martin, Stephen R., Sallusto, Federica, Suzich, JoAnn A., Lanzavecchia, Antonio, Zhu, Qing, Gamblin, Steven J., Skehel, John J., Kallewaard, Nicole L., Corti, Davide, Collins, Patrick J., Neu, Ursula, McAuliffe, Josephine M., Benjamin, Ebony, Wachter-Rosati, Leslie, Palmer-Hill, Frances J., Yuan, Andy Q., Walker, Philip A., Vorlaender, Matthias K., Bianchi, Siro, Guarino, Barbara, De Marco, Anna, Vanzetta, Fabrizia, Agatic, Gloria, Foglierini, Mathilde, Pinna, Debora, Fernandez-Rodriguez, Blanca, Fruehwirth, Alexander, Silacci, Chiara, Ogrodowicz, Roksana W., Martin, Stephen R., Sallusto, Federica, Suzich, JoAnn A., Lanzavecchia, Antonio, Zhu, Qing, Gamblin, Steven J., and Skehel, John J.
- Abstract
Influenza virus remains a threat because of its ability to evade vaccine-induced immune responses due to antigenic drift. Here, we describe the isolation, evolution, and structure of a broad-spectrum human monoclonal antibody (mAb), MEDI8852, effectively reacting with all influenza A hemagglutinin (HA) subtypes. MEDI8852 uses the heavy-chain VH6-1 gene and has higher potency and breadth when compared to other anti-stem antibodies. MEDI8852 is effective in mice and ferrets with a therapeutic window superior to that of oseltamivir. Crystallographic analysis of Fab alone or in complex with H5 or H7 HA proteins reveals that MEDI8852 binds through a coordinated movement of CDRs to a highly conserved epitope encompassing a hydrophobic groove in the fusion domain and a large portion of the fusion peptide, distinguishing it from other structurally characterized cross- reactive antibodies. The unprecedented breadth and potency of neutralization by MEDI8852 support its development as immunotherapy for influenza virus-infected humans.
23. Structural basis for broad HIV-1 neutralization by the MPER-specific human broadly neutralizing antibody LN01
- Author
-
Pinto, Dora, Fenwick, Craig, Caillat, Christophe, Silacci, Chiara, Guseva, Serafima, Dehez, François, Chipot, Christophe, Barbieri, Sonia, Minola, Andrea, Jarrossay, David, Tomaras, Georgia D., Shen, Xiaoying, Riva, Agostino, Tarkowski, Maciej, Schwartz, Olivier, Bruel, Timothée, Dufloo, Jérémy, Seaman, Michael S., Montefiori, David C., Lanzavecchia, Antonio, Corti, Davide, Pantaleo, Giuseppe, Weissenhorn, Winfried, Pinto, Dora, Fenwick, Craig, Caillat, Christophe, Silacci, Chiara, Guseva, Serafima, Dehez, François, Chipot, Christophe, Barbieri, Sonia, Minola, Andrea, Jarrossay, David, Tomaras, Georgia D., Shen, Xiaoying, Riva, Agostino, Tarkowski, Maciej, Schwartz, Olivier, Bruel, Timothée, Dufloo, Jérémy, Seaman, Michael S., Montefiori, David C., Lanzavecchia, Antonio, Corti, Davide, Pantaleo, Giuseppe, and Weissenhorn, Winfried
- Abstract
Potent and broadly neutralizing antibodies (bnAbs) are the hallmark of HIV-1 protection by vaccination. The membrane-proximal external region (MPER) of the HIV-1 gp41 fusion protein is targeted by the most broadly reactive HIV-1 neutralizing antibodies. Here, we examine the structural and molecular mechansims of neutralization by anti-MPER bnAb, LN01, which was isolated from lymph-node-derived germinal center B cells of an elite controller and exhibits broad neutralization breadth. LN01 engages both MPER and the transmembrane (TM) region, which together form a continuous helix in complex with LN01. The tilted TM orientation allows LN01 to interact simultaneously with the peptidic component of the MPER epitope and membrane via two specific lipid binding sites of the antibody paratope. Although LN01 carries a high load of somatic mutations, most key residues interacting with the MPER epitope and lipids are germline encoded, lending support for the LN01 epitope as a candidate for lineage-based vaccine development.
24. Crystal structure and size-dependent neutralization properties of HK20, a human monoclonal antibody binding to the highly conserved heptad repeat 1 of gp41
- Author
-
Sabin, Charles, Corti, Davide, Buzon, Victor, Seaman, Mike S., Hulsik, David Lutje, Hinz, Andreas, Vanzetta, Fabrizia, Agatic, Gloria, Silacci, Chiara, Mainetti, Lara, Scarlatti, Gabriella, Sallusto, Federica, Weiss, Robin, Lanzavecchia, Antonio, Weissenhorn, Winfried, Sabin, Charles, Corti, Davide, Buzon, Victor, Seaman, Mike S., Hulsik, David Lutje, Hinz, Andreas, Vanzetta, Fabrizia, Agatic, Gloria, Silacci, Chiara, Mainetti, Lara, Scarlatti, Gabriella, Sallusto, Federica, Weiss, Robin, Lanzavecchia, Antonio, and Weissenhorn, Winfried
- Abstract
The human monoclonal antibody (mAb) HK20 neutralizes a broad spectrum of primary HIV-1 isolates by targeting the highly conserved heptad repeat 1 (HR1) of gp41, which is transiently exposed during HIV-1 entry. Here we present the crystal structure of the HK20 Fab in complex with a gp41 mimetic 5-Helix at 2.3 A° resolution. HK20 employs its heavy chain CDR H2 and H3 loops to bind into a conserved hydrophobic HR1 pocket that is occupied by HR2 residues in the gp41 post fusion conformation. Compared to the previously described HR1-specific mAb D5, HK20 approaches its epitope with a different angle which might favor epitope access and thus contribute to its higher neutralization breadth and potency. Comparison of the neutralization activities of HK20 IgG, Fab and scFv employing both single cycle and multiple cycle neutralization assays revealed much higher potencies for the smaller Fab and scFv over IgG, implying that the target site is difficult to access for complete antibodies. Nevertheless, two thirds of sera from HIV-1 infected individuals contain significant titers of HK20-inhibiting antibodies. The breadth of neutralization of primary isolates across all clades, the higher potencies for Cclade viruses and the targeting of a distinct site as compared to the fusion inhibitor T-20 demonstrate the potential of HK20 scFv as a therapeutic tool.
25. Protection of calves by a prefusion-stabilized bovine RSV F vaccine
- Author
-
Zhang, Baoshan, Chen, Lei, Silacci, Chiara, Thom, Michelle, Boyington, Jeffrey C., Druz, Aliaksandr, Joyce, M. Gordon, Guzman, Efrain, Kong, Wing-Pui, Lai, Yen-Ting, Stewart-Jones, Guillaume B. E., Tsybovsky, Yaroslav, Yang, Yongping, Zhou, Tongqing, Baxa, Ulrich, Mascola, John R., Corti, Davide, Lanzavecchia, Antonio, Taylor, Geraldine, Kwong, Peter D., Zhang, Baoshan, Chen, Lei, Silacci, Chiara, Thom, Michelle, Boyington, Jeffrey C., Druz, Aliaksandr, Joyce, M. Gordon, Guzman, Efrain, Kong, Wing-Pui, Lai, Yen-Ting, Stewart-Jones, Guillaume B. E., Tsybovsky, Yaroslav, Yang, Yongping, Zhou, Tongqing, Baxa, Ulrich, Mascola, John R., Corti, Davide, Lanzavecchia, Antonio, Taylor, Geraldine, and Kwong, Peter D.
- Abstract
Bovine respiratory syncytial virus, a major cause of respiratory disease in calves, is closely related to human RSV, a leading cause of respiratory disease in infants. Recently, promising human RSV-vaccine candidates have been engineered that stabilize the metastable fusion (F) glycoprotein in its prefusion state; however, the absence of a relevant animal model for human RSV has complicated assessment of these vaccine candidates. Here, we use a combination of structure-based design, antigenic characterization, and X-ray crystallography to translate human RSV F stabilization into the bovine context. A “DS2” version of bovine respiratory syncytial virus F with subunits covalently fused, fusion peptide removed, and pre-fusion conformation stabilized by cavity-filling mutations and intra- and inter-protomer disulfides was recognized by pre-fusion- specific antibodies, AM14, D25, and MPE8, and elicited bovine respiratory syncytial virus- neutralizing titers in calves >100-fold higher than those elicited by post-fusion F. When challenged with a heterologous bovine respiratory syncytial virus, virus was not detected in nasal secretions nor in respiratory tract samples of DS2-immunized calves; by contrast bovine respiratory syncytial virus was detected in all post-fusion- and placebo-immunized calves. Our results demonstrate proof-of-concept that DS2-stabilized RSV F immunogens can induce highly protective immunity from RSV in a native host with implications for the efficacy of prefusion- stabilized F vaccines in humans and for the prevention of bovine respiratory syncytial virus in calves.
26. Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals
- Author
-
Corti, Davide, Langedijk, Johannes P. M., Hinz, Andreas, Seaman, Michael S., Vanzetta, Fabrizia, Fernandez-Rodriguez, Blanca M., Silacci, Chiara, Pinna, Debora, Jarrossay, David, Balla-Jhagjhoorsingh, Sunita, Willems, Betty, Zekveld, Maria J., Dreja, O’Sullivan, Eithne, Pade, Corinna, Orkin, Chloe, Jeffs, Simon A., Montefiori, David C., David, Davis, Weissenhorn, Winfried, McKnight, Aine, Heeney, Jonathan L., Sallusto, Federica, Sattentau, Quentin J., Weiss, robin A., Lanzavecchia, Antonio, Corti, Davide, Langedijk, Johannes P. M., Hinz, Andreas, Seaman, Michael S., Vanzetta, Fabrizia, Fernandez-Rodriguez, Blanca M., Silacci, Chiara, Pinna, Debora, Jarrossay, David, Balla-Jhagjhoorsingh, Sunita, Willems, Betty, Zekveld, Maria J., Dreja, O’Sullivan, Eithne, Pade, Corinna, Orkin, Chloe, Jeffs, Simon A., Montefiori, David C., David, Davis, Weissenhorn, Winfried, McKnight, Aine, Heeney, Jonathan L., Sallusto, Federica, Sattentau, Quentin J., Weiss, robin A., and Lanzavecchia, Antonio
- Abstract
Background The isolation of human monoclonal antibodies (mAbs) that neutralize a broad spectrum of primary HIV-1 isolates and the characterization of the human neutralizing antibody B cell response to HIV-1 infection are important goals that are central to the design of an effective antibody-based vaccine. Methods and Findings We immortalized IgG+ memory B cells from individuals infected with diverse clades of HIV-1 and selected on the basis of plasma neutralization profiles that were cross-clade and relatively potent. Culture supernatants were screened using various recombinant forms of the envelope glycoproteins (Env) in multiple parallel assays. We isolated 58 mAbs that were mapped to different Env surfaces, most of which showed neutralizing activity. One mAb in particular (HJ16) specific for a novel epitope proximal to the CD4 binding site on gp120 selectively neutralized a multi-clade panel of Tier-2 HIV-1 pseudoviruses, and demonstrated reactivity that was comparable in breadth, but distinct in neutralization specificity, to that of the other CD4 binding site-specific neutralizing mAb b12. A second mAb (HGN194) bound a conserved epitope in the V3 crown and neutralized all Tier-1 and a proportion of Tier-2 pseudoviruses tested, irrespective of clade. A third mAb (HK20) with broad neutralizing activity, particularly as a Fab fragment, recognized a highly conserved epitope in the HR-1 region of gp41, but showed striking assay-dependent selectivity in its activity. Conclusions This study reveals that by using appropriate screening methods, a large proportion of memory B cells can be isolated that produce mAbs with HIV-1 neutralizing activity. Three of these mAbs show unusual breadth of neutralization and therefore add to the current panel of HIV-1 neutralizing antibodies with potential for passive protection and template-based vaccine design.
27. Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine
- Author
-
Corti, Davide, Suguitan Jr., Amorsolo, Pinna, Debora, Silacci, Chiara, Fernandez-Rodriguez, Blanca M., Vanzetta, Fabrizia, Santos, Celia, Luke, Catherine J., Torres-Velez, Fernando J., Temperton, Nigel J., Weiss, Robin A., Sallusto, Federica, Subbarao, Kanta, Lanzavecchia, Antonio, Corti, Davide, Suguitan Jr., Amorsolo, Pinna, Debora, Silacci, Chiara, Fernandez-Rodriguez, Blanca M., Vanzetta, Fabrizia, Santos, Celia, Luke, Catherine J., Torres-Velez, Fernando J., Temperton, Nigel J., Weiss, Robin A., Sallusto, Federica, Subbarao, Kanta, and Lanzavecchia, Antonio
- Abstract
The target of neutralizing antibodies that protect against influenza virus infection is the viral protein HA. Genetic and antigenic variation in HA has been used to classify influenza viruses into subtypes (H1–H16). The neutralizing antibody response to influenza virus is thought to be specific for a few antigenically related isolates within a given subtype. However, while heterosubtypic antibodies capable of neutralizing multiple influenza virus subtypes have been recently isolated from phage display libraries, it is not known whether such antibodies are produced in the course of an immune response to influenza virus infection or vaccine. Here we report that, following vaccination with seasonal influenza vaccine containing H1 and H3 influenza virus subtypes, some individuals produce antibodies that cross-react with H5 HA. By immortalizing IgG-expressing B cells from 4 individuals, we isolated 20 heterosubtypic mAbs that bound and neutralized viruses belonging to several HA subtypes (H1, H2, H5, H6, and H9), including the pandemic A/California/07/09 H1N1 isolate. The mAbs used different VH genes and carried a high frequency of somatic mutations. With the exception of a mAb that bound to the HA globular head, all heterosubtypic mAbs bound to acid- sensitive epitopes in the HA stem region. Four mAbs were evaluated in vivo and protected mice from challenge with influenza viruses representative of different subtypes. These findings reveal that seasonal influenza vaccination can induce polyclonal heterosubtypic neutralizing antibodies that cross-react with the swine-origin pandemic H1N1 influenza virus and with the highly pathogenic H5N1 virus.
28. Adjuvants and the vaccine response to the DS-Cav1-stabilized fusion glycoprotein of respiratory syncytial virus
- Author
-
Sastry, Mallika, Zhang, Baoshan, Chen, Man, Joyce, M. Gordon, Kong, Wing-Pui, Chuang, Gwo-Yu, Ko, Kiyoon, Kumar, Azad, Silacci, Chiara, Thom, Michelle, Salazar, Andres M., Corti, Davide, Lanzavecchia, Antonio, Taylor, Geraldine, Mascola, John R., Graham, Barney S., Kwong, Peter D., Sastry, Mallika, Zhang, Baoshan, Chen, Man, Joyce, M. Gordon, Kong, Wing-Pui, Chuang, Gwo-Yu, Ko, Kiyoon, Kumar, Azad, Silacci, Chiara, Thom, Michelle, Salazar, Andres M., Corti, Davide, Lanzavecchia, Antonio, Taylor, Geraldine, Mascola, John R., Graham, Barney S., and Kwong, Peter D.
- Abstract
Appropriate adjuvant selection may be essential to optimize the potency and to tailor the immune response of subunit vaccines. To induce protective responses against respiratory syncytial virus (RSV)—a highly prevalent childhood pathogen without a licensed vaccine—we previously engineered a pre-fusion-stabilized trimeric RSV F (pre-F) “DS-Cav1” immunogen, which induced high titer RSV-neutralizing antibodies, in mice and non-human primates, when formulated with adjuvants Poly (I:C) and Poly (IC:LC), respectively. To assess the impact of different adjuvants, here we formulated RSV F DS-Cav1 with multiple adjuvants and assessed immune responses. Very high RSV-neutralizing antibody responses (19,006 EC50) were observed in naïve mice immunized with 2 doses of DS-Cav1 adjuvanted with Sigma adjuvant system (SAS), an oil-in-water adjuvant, plus Carbopol; high responses (3658–7108) were observed with DS-Cav1 adjuvanted with Alum, SAS alone, Adjuplex, Poly (I:C) and Poly (IC:LC); and moderate responses (1251–2129) were observed with DS-Cav1 adjuvanted with the TLR4 agonist MPLA, Alum plus MPLA or AddaVax. In contrast, DS-Cav1 without adjuvant induced low-level responses (6). A balanced IgG1 and IgG2a (Th2/Th1) immune response was elicited in most of the high to very high response groups (all but Alum and Adjuplex). We also tested the immune response induced by DS-Cav1 in elderly mice with pre-existing DS-Cav1 immunity; we observed that DS-Cav1 adjuvanted with SAS plus Carbopol boosted the response 2-3-fold, whereas DS-Cav1 adjuvanted with alum boosted the response 5-fold. Finally, we tested whether a mixture of ISA 71 VG and Carbopol would enhanced the antibody response in DS-Cav1 immunized calves. While pre-F-stabilized bovine RSV F induced very high titers in mice when adjuvanted with SAS plus Carbopol, the addition of Carbopol to ISA 71 VG did not enhance immune responses in calves. The vaccine response to pre-F-stabilized RSV F is augmented by adjuvant, but the degree of
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.