Journal articles: 'Broadly reactive antibody'

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Parker, Tracy Dewese, Noritoshi Kitamoto, Tomoyuki Tanaka, Anne M. Hutson, and Mary K. Estes. "Identification of Genogroup I and Genogroup II Broadly Reactive Epitopes on the Norovirus Capsid." Journal of Virology 79, no. 12 (June 15, 2005): 7402–9. http://dx.doi.org/10.1128/jvi.79.12.7402-7409.2005.

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ABSTRACT Norwalk virus, a member of the family Caliciviridae, is an important cause of acute epidemic nonbacterial gastroenteritis. Norwalk and related viruses are classified in a separate genus of Caliciviridae called Norovirus, which is comprised of at least three genogroups based on sequence differences. Many of the currently available immunologic reagents used to study these viruses are type specific, which limits the identification of antigenically distinct viruses in detection assays. Identification of type-specific and cross-reactive epitopes is essential for designing broadly cross-reactive diagnostic assays and dissecting the immune response to calicivirus infection. To address this, we have mapped the epitopes on the norovirus capsid protein for both a genogroup I-cross-reactive monoclonal antibody and a genogroup II-cross-reactive monoclonal antibody by use of norovirus deletion and point mutants. The epitopes for both monoclonal antibodies mapped to the C-terminal P1 subdomain of the capsid protein. Although the genogroup I-cross-reactive monoclonal antibody was previously believed to recognize a linear epitope, our results indicate that a conformational component of the epitope explains the monoclonal antibody's genogroup specificity. Identification of the epitopes for these monoclonal antibodies is of significance, as they are components in a commercially available norovirus-diagnostic enzyme-linked immunosorbent assay.

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Leon, Paul E., Wenqian He, Caitlin E. Mullarkey, Mark J. Bailey, Matthew S. Miller, Florian Krammer, Peter Palese, and Gene S. Tan. "Optimal activation of Fc-mediated effector functions by influenza virus hemagglutinin antibodies requires two points of contact." Proceedings of the National Academy of Sciences 113, no. 40 (September 19, 2016): E5944—E5951. http://dx.doi.org/10.1073/pnas.1613225113.

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Influenza virus strain-specific monoclonal antibodies (mAbs) provide protection independent of Fc gamma receptor (FcγR) engagement. In contrast, optimal in vivo protection achieved by broadly reactive mAbs requires Fc–FcγR engagement. Most strain-specific mAbs target the head domain of the viral hemagglutinin (HA), whereas broadly reactive mAbs typically recognize epitopes within the HA stalk. This observation has led to questions regarding the mechanism regulating the activation of Fc-dependent effector functions by broadly reactive antibodies. To dissect the molecular mechanism responsible for this dichotomy, we inserted the FLAG epitope into discrete locations on HAs. By characterizing the interactions of several FLAG-tagged HAs with a FLAG-specific antibody, we show that in addition to Fc–FcγR engagement mediated by the FLAG-specific antibody, a second intermolecular bridge between the receptor-binding region of the HA and sialic acid on effector cells is required for optimal activation. Inhibition of this second molecular bridge, through the use of an F(ab′)2or the mutation of the sialic acid-binding site, renders the Fc–FcγR interaction unable to optimally activate effector cells. Our findings indicate that broadly reactive mAbs require two molecular contacts to possibly stabilize the immunologic synapse and potently induce antibody-dependent cell-mediated antiviral responses: (i) the interaction between the Fc of a mAb bound to HA with the FcγR of the effector cell and (ii) the interaction between the HA and its sialic acid receptor on the effector cell. This concept might be broadly applicable for protective antibody responses to viral pathogens that have suitable receptors on effector cells.

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West, Anthony P., Rachel P. Galimidi, Christopher P. Foglesong, Priyanthi N. P. Gnanapragasam, Joshua S. Klein, and Pamela J. Bjorkman. "Evaluation of CD4-CD4i Antibody Architectures Yields Potent, Broadly Cross-Reactive Anti-Human Immunodeficiency Virus Reagents." Journal of Virology 84, no. 1 (October 28, 2009): 261–69. http://dx.doi.org/10.1128/jvi.01528-09.

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ABSTRACT The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) has several adaptations that allow the virus to evade antibody neutralization. Nevertheless, a few broadly cross-reactive neutralizing antibodies as well as reagents containing portions of CD4, the HIV receptor, have demonstrated partial efficacy in suppressing viral replication. One type of reagent designed for improved HIV neutralization fuses the CD4 D1-D2 domains to the variable regions of an antibody recognizing the CD4-induced (CD4i) coreceptor binding site on the gp120 portion of the HIV envelope spike. We designed, expressed, purified, and tested the neutralization potencies of CD4-CD4i antibody reagents with different architectures, antibody combining sites, and linkers. We found that fusing CD4 to the heavy chain of the CD4i antibody E51 yields a bivalent reagent including an antibody Fc region that expresses well, is expected to have a long serum half-life, and has comparable or greater neutralization activity than well-known broadly neutralizing anti-HIV antibodies. A CD4 fusion with the anti-HIV carbohydrate antibody 2G12 also results in a potent neutralizing reagent with more broadly neutralizing activity than 2G12 alone.

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Kubickova, Barbara, Jörg A. Schenk, Franziska Ramm, Kornelija Markuškienė, Jochen Reetz, Paul Dremsek, Paulius Lukas Tamosiunas, et al. "A broadly cross-reactive monoclonal antibody against hepatitis E virus capsid antigen." Applied Microbiology and Biotechnology 105, no. 12 (June 2021): 4957–73. http://dx.doi.org/10.1007/s00253-021-11342-7.

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Abstract To generate a hepatitis E virus (HEV) genotype 3 (HEV-3)–specific monoclonal antibody (mAb), the Escherichia coli–expressed carboxy-terminal part of its capsid protein was used to immunise BALB/c mice. The immunisation resulted in the induction of HEV-specific antibodies of high titre. The mAb G117-AA4 of IgG1 isotype was obtained showing a strong reactivity with the homologous E. coli, but also yeast-expressed capsid protein of HEV-3. The mAb strongly cross-reacted with ratHEV capsid protein derivatives produced in both expression systems and weaker with an E. coli–expressed batHEV capsid protein fragment. In addition, the mAb reacted with capsid protein derivatives of genotypes HEV-2 and HEV-4 and common vole hepatitis E virus (cvHEV), produced by the cell-free synthesis in Chinese hamster ovary (CHO) and Spodoptera frugiperda (Sf21) cell lysates. Western blot and line blot reactivity of the mAb with capsid protein derivatives of HEV-1 to HEV-4, cvHEV, ratHEV and batHEV suggested a linear epitope. Use of truncated derivatives of ratHEV capsid protein in ELISA, Western blot, and a Pepscan analysis allowed to map the epitope within a partially surface-exposed region with the amino acid sequence LYTSV. The mAb was also shown to bind to human patient–derived HEV-3 from infected cell culture and to hare HEV-3 and camel HEV-7 capsid proteins from transfected cells by immunofluorescence assay. The novel mAb may serve as a useful tool for further investigations on the pathogenesis of HEV infections and might be used for diagnostic purposes. Key points • The antibody showed cross-reactivity with capsid proteins of different hepeviruses. • The linear epitope of the antibody was mapped in a partially surface-exposed region. • The antibody detected native HEV-3 antigen in infected mammalian cells.

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Duval, Mark, Marshall R. Posner, and Lisa A. Cavacini. "A Bispecific Antibody Composed of a Nonneutralizing Antibody to the gp41 Immunodominant Region and an Anti-CD89 Antibody Directs Broad Human Immunodeficiency Virus Destruction by Neutrophils." Journal of Virology 82, no. 9 (February 13, 2008): 4671–74. http://dx.doi.org/10.1128/jvi.02499-07.

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ABSTRACT In addition to the direct neutralization of virus, there is a broader potential for antibody-mediated inhibition of human immunodeficiency virus (HIV) by targeting HIV to effector cells. We demonstrate here that a bispecific antibody incorporating a broadly reactive anti-gp41 antibody, F240, and an anti-IgA receptor (CD89) antibody is effective at directing neutrophils to destroy HIV. Not only are neutrophils the predominant type of white blood cells and very efficient at mediating cell cytotoxicity, they are relatively resistant to infection with HIV. Therefore, they represent a significant weapon against infection if they can be directed and armed to destroy HIV and infected cells.

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Haynes, Barton F., and David C. Montefiori. "Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates." Expert Review of Vaccines 5, no. 3 (June 2006): 347–63. http://dx.doi.org/10.1586/14760584.5.3.347.

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Haynes, Barton F., and David C. Montefiori. "Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates." Expert Review of Vaccines 5, no. 4 (August 2006): 579–95. http://dx.doi.org/10.1586/14760584.5.4.579.

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Krammer, Florian, Åsne Jul-Larsen, Irina Margine, Ariana Hirsh, Haakon Sjursen, Maria Zambon, and Rebecca J. Cox. "An H7N1 Influenza Virus Vaccine Induces Broadly Reactive Antibody Responses against H7N9 in Humans." Clinical and Vaccine Immunology 21, no. 8 (June 18, 2014): 1153–63. http://dx.doi.org/10.1128/cvi.00272-14.

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ABSTRACTEmerging H7N9 influenza virus infections in Asia have once more spurred the development of effective prepandemic H7 vaccines. However, many vaccines based on avian influenza viruses—including H7—are poorly immunogenic, as measured by traditional correlates of protection. Here we reevaluated sera from an H7N1 human vaccine trial performed in 2006. We examined cross-reactive antibody responses to divergent H7 strains, including H7N9, dissected the antibody response into head- and stalk-reactive antibodies, and tested thein vivopotency of these human sera in a passive-transfer H7N9 challenge experiment with mice. Although only a low percentage of vaccinees induced neutralizing antibody responses against the homologous vaccine strain and also H7N9, we detected strong cross-reactivity to divergent H7 hemagglutinins (HAs) in a large proportion of the cohort with a quantitative enzyme-linked immunosorbent assay. Furthermore, H7N1 vaccination induced antibodies to both the head and stalk domains of the HA, which is in sharp contrast to seasonal inactivated vaccines. Finally, we were able to show that both neutralizing and nonneutralizing antibodies improvedin vivovirus clearance in a passive-transfer H7N9 challenge mouse model.

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Reyes, Raphael, Louise Turner, Isaac Ssewanyana, John Rek, Bryan Greenhouse, Sebastiaan Bol, Thomas Lavstsen, and Evelien M. Bunnik. "91074 Identification of monoclonal antibodies with broad reactivity against the malaria parasite variant surface antigen responsible for severe malaria." Journal of Clinical and Translational Science 5, s1 (March 2021): 18–19. http://dx.doi.org/10.1017/cts.2021.451.

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ABSTRACT IMPACT: This study aims to provide insight into naturally acquired immunity against severe malaria, thereby laying the foundation for the design of novel vaccine candidates to prevent severe disease as well as monoclonal antibody therapies to treat severe malaria. OBJECTIVES/GOALS: Severe malaria is caused by parasite surface antigens that contain high sequence diversity. Nevertheless, P. falciparum-exposed individuals develop antibody responses against these antigens. Our goal is to isolate antibodies with broad reactivity to understand how disease protection is acquired. METHODS/STUDY POPULATION: Our study cohort consists of Ugandan adults living in a malaria-endemic region with high transmission intensity, who are protected against severe malaria. Using fluorescently labeled probes of parasite surface antigens, we have isolated antigen-specific B cells from these donors. We then expressed the corresponding monoclonal antibodies in vitro. These antibodies were screened against a library of variant surface antigens to determine antibody breadth and potential to inhibit interaction of the parasite surface antigen with host receptors, a critical step in pathogenesis. Additionally, using a panel of variant surface antigen mutants, we have predicted the epitopes targeted by the broadest monoclonal antibodies. RESULTS/ANTICIPATED RESULTS: We have identified three monoclonal antibodies with exceptionally broad reactivity and inhibitory activity against our panel of severe disease-inducing variant surface antigens. We have identified two major sites targeted by these broadly reactive antibodies. The first site was associated with the largest breadth, but limited inhibitory potential, while the second site showed high-affinity antibody binding and inhibition of receptor binding. Interestingly, two of these three antibodies were very similar in structure, even though they were isolated from different donors. Isolation of antigen-specific B cells from additional donors will enable us to identify how common such broadly reactive antibodies are and allow the identification of additional epitopes DISCUSSION/SIGNIFICANCE OF FINDINGS: This study is the first to isolate broadly reactive antibodies that are likely to protect against severe malaria in naturally immune individuals. Further characterization of antibody-antigen interactions will inform the development of this surface antigen as a vaccine candidate for malaria.

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Zheng, Qingbing, Lin Xia, Wai Lan Wu, Zhenhua Zheng, Yongting Huo, Jun Wu, Yanning Liu, et al. "Properties and Therapeutic Efficacy of Broadly Reactive Chimeric and Humanized H5-Specific Monoclonal Antibodies against H5N1 Influenza Viruses." Antimicrobial Agents and Chemotherapy 55, no. 4 (January 18, 2011): 1349–57. http://dx.doi.org/10.1128/aac.01436-10.

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ABSTRACTHighly pathogenic H5N1 virus infection causes severe disease and a high rate of fatality in humans. Development of humanized monoclonal antibodies may provide an efficient therapeutic regime for H5N1 virus infection. In the present study, broadly cross-reactive monoclonal antibodies (MAbs) derived from mice were humanized to minimize immunogenicity. One chimeric antibody (cAb) and seven humanized antibodies (hAbs) were constructed. These antibodies retained broad-spectrum reactivity to H5N1 viruses, binding to recombinant H5-subtype HA1 molecules expressed in CHO cells in a dose-dependent manner and exhibiting similar reactivities against antigenically distinct H5N1 viruses in hemagglutination inhibition (HI) assays. One humanized antibody, 37 hAb, showed HI and neutralization activities comparable to that of the parental murine antibody, 13D4 MAb, while the other six antibodies were less reactive to H5N1 viruses. Analysis of amino acid sequences in the variable region frameworks of the seven humanized antibodies found that Q5 and Y27 in the VH region are highly conserved murine residues. Comparison of the three-dimensional structures derived from the variable regions of MAbs 37 hAb, H1202-34, and 13D4 revealed that residue substitutions at sites 70 and 46 may be the major cause for the observed differences in binding affinity. Examination of the chimeric antibody and one of the humanized antibodies, 37 hAb, showed that both antibodies offered postinfection protection against lethal challenge with antigenically diverse H5N1 viruses in the mouse model. Chimeric and humanized antibodies which retain the broadly reactive and protective properties of murine H5-specific monoclonal antibodies have great potential for use in the treatment of human H5N1 infection.

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Thibodeaux, Brett A., Nathan M. Liss, Amanda N. Panella, and John T. Roehrig. "Development of a Human-Murine Chimeric Immunoglobulin M for Use in the Serological Detection of Human Alphavirus Antibodies." Clinical and Vaccine Immunology 18, no. 12 (October 5, 2011): 2181–82. http://dx.doi.org/10.1128/cvi.05269-11.

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ABSTRACTDiagnosis of human alphaviral infections relies on serological techniques, such as the immunoglobulin M antibody capture–enzyme-linked immunosorbent assay (MAC-ELISA). We have humanized the alphavirus broadly cross-reactive murine monoclonal antibody 1A4B-6 to create a reagent capable of replacing human positive sera in the MAC-ELISA for diagnosis of human alphaviral infections.

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Marasco, W. A., J. Bagley, C. Zani, M. Posner, L. Cavacini, W. A. Haseltine, and J. Sodroski. "Characterization of the cDNA of a broadly reactive neutralizing human anti-gp120 monoclonal antibody." Journal of Clinical Investigation 90, no. 4 (October 1, 1992): 1467–78. http://dx.doi.org/10.1172/jci116014.

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Wei, Lili, Zhongliang Shen, Xue Zhao, Yanxin Wu, Wei Liu, Junqi Zhang, Youhua Xie, and Jing Liu. "A broadly reactive monoclonal antibody detects multiple genotypes of hepatitis B virus X protein." Archives of Virology 159, no. 10 (May 17, 2014): 2731–35. http://dx.doi.org/10.1007/s00705-014-2111-6.

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Costa, Matthew R., Justin Pollara, Regina Whitney Edwards, Michael S. Seaman, Miroslaw K. Gorny, David C. Montefiori, Hua-Xin Liao, Guido Ferrari, Shan Lu, and Shixia Wang. "Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001." Journal of Virology 90, no. 22 (September 14, 2016): 10362–78. http://dx.doi.org/10.1128/jvi.01458-16.

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ABSTRACTHIV-1 is able to elicit broadly potent neutralizing antibodies in a very small subset of individuals only after several years of infection, and therefore, vaccines that elicit these types of antibodies have been difficult to design. The RV144 trial showed that moderate protection is possible and that this protection may correlate with antibody-dependent cellular cytotoxicity (ADCC) activity. Our previous studies demonstrated that in an HIV vaccine phase I trial, the DP6-001 trial, a polyvalent Env DNA prime-protein boost formulation could elicit potent and broadly reactive, gp120-specific antibodies with positive neutralization activities. Here we report on the production and analysis of HIV-1 Env-specific human monoclonal antibodies (hMAbs) isolated from vaccinees in the DP6-001 trial. For this initial report, 13 hMAbs from four vaccinees in the DP6-001 trial showed broad binding to gp120 proteins of diverse subtypes both autologous and heterologous to vaccine immunogens. Equally cross-reactive Fc receptor-mediated functional activities, including ADCC and antibody-dependent cellular phagocytosis (ADCP) activities, were present with both immune sera and isolated MAbs, confirming the induction of nonneutralizing functional hMAbs by the DNA prime-protein boost vaccination. Elicitation of broadly reactive hMAbs by vaccination in healthy human volunteers confirms the value of the polyvalent formulation in this HIV vaccine design.IMPORTANCEThe roles of Fc receptor-mediated protective antibody responses are gaining more attention due to their potential contribution to the low-level protection against HIV-1 infection that they provided in the RV144 trial. At the same time, information about hMabs from other human HIV vaccine studies is very limited. In the current study, both immune sera and monoclonal antibodies from vaccinated humans showed not only high-level ADCC and ADCP activities but also cross-subtype ADCC and ADCP activities when a polyvalent DNA prime-protein boost vaccine formulation was used.

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Ko, Yi-An, Yueh-Hsiang Yu, Yen-Fei Wu, Yung-Chieh Tseng, Chia-Lin Chen, King-Siang Goh, Hsin-Yu Liao, et al. "A non-neutralizing antibody broadly protects against influenza virus infection by engaging effector cells." PLOS Pathogens 17, no. 8 (August 5, 2021): e1009724. http://dx.doi.org/10.1371/journal.ppat.1009724.

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Hemagglutinin (HA) is the immunodominant protein of the influenza virus. We previously showed that mice injected with a monoglycosylated influenza A HA (HAmg) produced cross-strain-reactive antibodies and were better protected than mice injected with a fully glycosylated HA (HAfg) during lethal dose challenge. We employed a single B-cell screening platform to isolate the cross-protective monoclonal antibody (mAb) 651 from mice immunized with the HAmg of A/Brisbane/59/2007 (H1N1) influenza virus (Bris/07). The mAb 651 recognized the head domain of a broad spectrum of HAs from groups 1 and 2 influenza A viruses and offered prophylactic and therapeutic efficacy against A/California/07/2009 (H1N1) (Cal/09) and Bris/07 infections in mice. The antibody did not possess neutralizing activity; however, antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis mediated by natural killer cells and alveolar macrophages were important in the protective efficacy of mAb 651. Together, this study highlighted the significance of effector functions for non-neutralizing antibodies to exhibit protection against influenza virus infection.

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Sei, Clara J., Mangala Rao, Richard F. Schuman, Luke T. Daum, Gary R. Matyas, Nimisha Rikhi, Kevin Muema, et al. "Conserved Influenza Hemagglutinin, Neuraminidase and Matrix Peptides Adjuvanted with ALFQ Induce Broadly Neutralizing Antibodies." Vaccines 9, no. 7 (June 25, 2021): 698. http://dx.doi.org/10.3390/vaccines9070698.

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A universal influenza candidate vaccine that targets multiple conserved influenza virus epitopes from hemagglutinin (HA), neuraminidase (NA) and matrix (M2e) proteins was combined with the potent Army liposomal adjuvant (ALFQ) to promote induction of broad immunity to seasonal and pandemic influenza strains. The unconjugated and CRM-conjugated composite peptides formulated with ALFQ were highly immunogenic and induced both humoral and cellular immune responses in mice. Broadly reactive serum antibodies were induced across various IgG isotypes. Mice immunized with the unconjugated composite peptide developed antibody responses earlier than mice immunized with conjugated peptides, and the IgG antibodies were broadly reactive and neutralizing across Groups 1 and 2 influenza viruses. Multi-epitope unconjugated influenza composite peptides formulated with ALFQ provide a novel strategy for the development of a universal influenza vaccine. These synthetic peptide vaccines avoid the pitfalls of egg-produced influenza vaccines and production can be scaled up rapidly and economically.

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Ferguson, M., D. M. A. Evans, D. I. Magrath, P. D. Minor, J. W. Almond, and G. C. Schild. "Induction by synthetic peptides of broadly reactive, type-specific neutralizing antibody to poliovirus type 3." Virology 143, no. 2 (June 1985): 505–15. http://dx.doi.org/10.1016/0042-6822(85)90389-7.

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Huang, Junqiong, Shannon P. Hilchey, Jiong Wang, Jessica Gerigan, and Martin S. Zand. "IL-15 enhances cross-reactive antibody recall responses to seasonal H3 influenza viruses in vitro." F1000Research 6 (November 15, 2017): 2015. http://dx.doi.org/10.12688/f1000research.12999.1.

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Background:Recently, several human monoclonal antibodies that target conserved epitopes on the stalk region of influenza hemagglutinin (HA) have shown broad reactivity to influenza A subtypes. Also, vaccination with recombinant chimeric HA or stem fragments from H3 influenza viruses induce broad immune protection in mice and humans. However, it is unclear whether stalk-binding antibodies can be induced in human memory B cells by seasonal H3N2 viruses.Methods: In this study, we recruited 13 donors previously exposed to H3 viruses, the majority (12 of 13) of which had been immunized with seasonal influenza vaccines. We evaluated plasma baseline strain-specific and stalk-reactive anti-HA antibodies and B cell recall responses to inactivated H3N2 A/Victoria/361/2011 virusin vitrousing a high throughput multiplex (mPlex-Flu) assay.Results:Stalk-reactive IgG was detected in the plasma of 7 of the subjects. Inactivated H3 viral particles rapidly induced clade cross-reactive antibodies in B cell cultures derived from all 13 donors. In addition, H3 stalk-reactive antibodies were detected in culture supernatants from 7 of the 13 donors (53.8%). H3 stalk-reactive antibodies were also induced by H1 and H7 subtypes. Interestingly, broadly cross-reactive antibody recall responses to H3 strains were also enhanced by stimulating B cellsin vitrowith CpG2006ODN in the presence of IL-15. H3 stalk-reactive antibodies were detected in CpG2006ODN + IL-15 stimulated B cell cultures derived from 12 of the 13 donors (92.3%), with high levels detected in cultures from 7 of the 13 donors.Conclusions:Our results demonstrate that stalk-reactive antibody recall responses induced by seasonal H3 viruses and CpG2006ODN can be enhanced by IL-15.

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KOUP, RICHARD A., CHERYL A. PIKORA, GAIL MAZZARA, DENNIS PANICALI, and JOHN L. SULLIVAN. "Broadly Reactive Antibody-Dependent Cellular Cytotoxic Response to HIV-1 Envelope Glycoproteins Precedes Broad Neutralizing Response in Human Infection." Viral Immunology 4, no. 4 (January 1991): 215–23. http://dx.doi.org/10.1089/vim.1991.4.215.

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Carter, Donald M., Christopher A. Darby, Bradford C. Lefoley, Corey J. Crevar, Timothy Alefantis, Raymond Oomen, Stephen F. Anderson, et al. "Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses." Journal of Virology 90, no. 9 (February 24, 2016): 4720–34. http://dx.doi.org/10.1128/jvi.03152-15.

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ABSTRACTOne of the challenges of developing influenza A vaccines is the diversity of antigenically distinct isolates. Previously, a novel hemagglutinin (HA) for H5N1 influenza was derived from a methodology termed computationally optimized broadly reactive antigen (COBRA). This COBRA HA elicited a broad antibody response against H5N1 isolates from different clades. We now report the development and characterization of a COBRA-based vaccine for both seasonal and pandemic H1N1 influenza virus isolates. Nine prototype H1N1 COBRA HA proteins were developed and tested in mice using a virus-like particle (VLP) format for the elicitation of broadly reactive, functional antibody responses and protection against viral challenge. These candidates were designed to recognize H1N1 viruses isolated within the last 30 years. In addition, several COBRA candidates were designed based on sequences of H1N1 viruses spanning the past 100 years, including modern pandemic H1N1 isolates. Four of the 9 H1N1 COBRA HA proteins (X1, X3, X6, and P1) had the broadest hemagglutination inhibition (HAI) activity against a panel of 17 H1N1 viruses. These vaccines were used in cocktails or prime-boost combinations. The most effective regimens that both elicited the broadest HAI response and protected mice against a pandemic H1N1 challenge were vaccines that contained the P1 COBRA VLP and either the X3 or X6 COBRA VLP vaccine. These mice had little or no detectable viral replication, comparable to that observed with a matched licensed vaccine. This is the first report describing a COBRA-based HA vaccine strategy that elicits a universal, broadly reactive, protective response against seasonal and pandemic H1N1 isolates.IMPORTANCEUniversal influenza vaccine approaches have the potential to be paradigm shifting for the influenza vaccine field, with the goal of replacing the current standard of care with broadly cross-protective vaccines. We have used COBRA technology to develop an HA head-based strategy that elicits antibodies against many H1 strains that have undergone genetic drift and has potential as a “subtype universal” vaccine. Nine HA COBRA candidates were developed, and these vaccines were used alone, in cocktails or in prime-boost combinations. The most effective regimens elicited the broadest hemagglutination inhibition (HAI) response against a panel of H1N1 viruses isolated over the past 100 years. This is the first report describing a COBRA-based HA vaccine strategy that elicits a broadly reactive response against seasonal and pandemic H1N1 isolates.

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Kong, Rui, Mark K. Louder, Kshitij Wagh, Robert T. Bailer, Allan deCamp, Kelli Greene, Hongmei Gao, et al. "Improving Neutralization Potency and Breadth by Combining Broadly Reactive HIV-1 Antibodies Targeting Major Neutralization Epitopes." Journal of Virology 89, no. 5 (December 17, 2014): 2659–71. http://dx.doi.org/10.1128/jvi.03136-14.

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ABSTRACTThe isolation of broadly neutralizing HIV-1 monoclonal antibodies (MAbs) to distinct epitopes on the viral envelope glycoprotein (Env) provides the potential to use combinations of MAbs for prevention and treatment of HIV-1 infection. Since many of these MAbs have been isolated in the last few years, the potency and breadth of MAb combinations have not been well characterized. In two parallel experiments, we examined thein vitroneutralizing activities of double-, triple-, and quadruple-MAb combinations targeting four distinct epitopes, including the CD4-binding site, the V1V2-glycan region, the V3-glycan supersite, and the gp41 membrane-proximal external region (MPER), using a panel of 125 Env-pseudotyped viruses. All MAb combinations showed substantially improved neutralization breadth compared to the corresponding single MAbs, while the neutralization potency of individual MAbs was maintained. At a 50% inhibitory concentration (IC50) cutoff of 1 μg/ml per antibody, double-MAb combinations neutralized 89 to 98% of viruses, and triple combinations neutralized 98 to 100%. Overall, the improvement of neutralization breadth was closely predicted by an additive-effect model and explained by complementary neutralization profiles of antibodies recognizing distinct epitopes. Subtle but consistent favorable interactions were observed in some MAb combinations, whereas less favorable interactions were observed on a small subset of viruses that are highly sensitive to V3-glycan MAbs. These data demonstrate favorablein vitrocombinations of broadly neutralizing HIV-1 MAbs and suggest that such combinations could have utility for HIV-1 prevention and treatment.IMPORTANCEOver the last 5 years, numerous broadly reactive HIV-1-neutralizing MAbs have been isolated from B cells of HIV-1-infected donors. Each of these MAbs binds to one of the major vulnerable sites (epitopes) on the surface of the viral envelope glycoprotein. Since antibodies to distinct viral epitopes could theoretically act together to provide greater potency and breadth of virus neutralization, we tested physical mixtures of double, triple, and quadruple combinations of neutralizing MAbs targeting four major epitopes on HIV-1 Env. When tested together, antibody combinations showed substantially improved neutralization breadth compared to single MAbs. This improvement could be explained by the complementary neutralization profiles of individual MAbs. We further demonstrated that each antibody maintained its full neutralization potency when used in combination with other MAbs. These data provide a rationale for clinical use of antibody-based combinations for HIV-1 prevention and therapy.

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Portnoff, Alyse D., Nita Patel, Michael J. Massare, Haixia Zhou, Jing-Hui Tian, Bin Zhou, Vivek Shinde, Gregory M. Glenn, and Gale Smith. "Influenza Hemagglutinin Nanoparticle Vaccine Elicits Broadly Neutralizing Antibodies against Structurally Distinct Domains of H3N2 HA." Vaccines 8, no. 1 (February 22, 2020): 99. http://dx.doi.org/10.3390/vaccines8010099.

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Influenza vaccine effectiveness varies annually due to the fast evolving seasonal influenza A(H3N2) strain and egg-derived mutations—both of which can cause a mismatch between the vaccine and circulating strains. To address these limitations, we have developed a hemagglutinin (HA)-based protein-detergent nanoparticle influenza vaccine (NIV) with a saponin-based Matrix-M™ adjuvant. In a phase 1 clinical trial of older adults, the vaccine demonstrated broadly cross-reactive A(H3N2) HA antibody responses. Two broadly neutralizing monoclonal antibodies derived from NIV-immunized mice were characterized by transmission electron microscopy (TEM), antibody competition assays, fluorescence-activated cell sorting (FACS) analysis, and protein–protein docking. These antibodies recognize two conserved regions of the head domain, namely the receptor binding site and the vestigial esterase subdomain, thus demonstrating the potential for an HA subunit vaccine to elicit antibodies targeting structurally and antigenically distinct but conserved sites. Antibody competition studies with sera from the phase 1 trial in older adults confirmed that humans also make antibodies to these two head domains and against the highly conserved stem domain. This data supports the potential of an adjuvanted recombinant HA nanoparticle vaccine to induce broadly protective immunity and improved vaccine efficacy.

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Sangster, Mark Y., Phuong Q. T. Nguyen, and David J. Topham. "Role of Memory B Cells in Hemagglutinin-Specific Antibody Production Following Human Influenza A Virus Infection." Pathogens 8, no. 4 (September 28, 2019): 167. http://dx.doi.org/10.3390/pathogens8040167.

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When influenza A virus infects an immune individual, preexisting memory B cell (MBC) activation and rapid anamnestic antibody production plays a key role in viral clearance. The most effective neutralizing antibodies target the antigenically variable head of the viral hemagglutinin (HA); antibodies against the conserved HA stalk provide broader but less potent protection. In this review, we provide a comprehensive picture of an adult’s HA-specific antibody response to influenza virus infection. The process is followed from preexisting HA-specific MBC activation and rapid production of anti-HA antibodies, through to germinal center seeding and adaptation of the response to novel features of the HA. A major focus of the review is the role of competition between preexisting MBCs in determining the character of the HA-reactive antibody response. HA novelty modifies this competition and can shift the response from the immunodominant head to the stalk. We suggest that antibodies resulting from preexisting MBC activation are important regulators of anti-HA antibody production and play a role in positive selection of germinal center B cells reactive to novel HA epitopes. Our review also considers the role of MBCs in the effects of early-life imprinting on HA head- and stalk-specific antibody responses to influenza infection. An understanding of the processes described in this review will guide development of vaccination strategies that provide broadly effective protection.

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Malonis, Ryan J., James T. Earnest, Arthur S. Kim, Matthew Angeliadis, Frederick W. Holtsberg, M. Javad Aman, Rohit K. Jangra, et al. "Near-germline human monoclonal antibodies neutralize and protect against multiple arthritogenic alphaviruses." Proceedings of the National Academy of Sciences 118, no. 37 (September 10, 2021): e2100104118. http://dx.doi.org/10.1073/pnas.2100104118.

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Arthritogenic alphaviruses are globally distributed, mosquito-transmitted viruses that cause rheumatological disease in humans and include Chikungunya virus (CHIKV), Mayaro virus (MAYV), and others. Although serological evidence suggests that some antibody-mediated heterologous immunity may be afforded by alphavirus infection, the extent to which broadly neutralizing antibodies that protect against multiple arthritogenic alphaviruses are elicited during natural infection remains unknown. Here, we describe the isolation and characterization of MAYV-reactive alphavirus monoclonal antibodies (mAbs) from a CHIKV-convalescent donor. We characterized 33 human mAbs that cross-reacted with CHIKV and MAYV and engaged multiple epitopes on the E1 and E2 glycoproteins. We identified five mAbs that target distinct regions of the B domain of E2 and potently neutralize multiple alphaviruses with differential breadth of inhibition. These broadly neutralizing mAbs (bNAbs) contain few somatic mutations and inferred germline–revertants retained neutralizing capacity. Two bNAbs, DC2.M16 and DC2.M357, protected against both CHIKV- and MAYV-induced musculoskeletal disease in mice. These findings enhance our understanding of the cross-reactive and cross-protective antibody response to human alphavirus infections.

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Shen, Xiaoying, Robert J. Parks, David C. Montefiori, Jennifer L. Kirchherr, Brandon F. Keele, Julie M. Decker, William A. Blattner, et al. "In Vivo gp41 Antibodies Targeting the 2F5 Monoclonal Antibody Epitope Mediate Human Immunodeficiency Virus Type 1 Neutralization Breadth." Journal of Virology 83, no. 8 (February 4, 2009): 3617–25. http://dx.doi.org/10.1128/jvi.02631-08.

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ABSTRACT The broadly neutralizing human monoclonal antibodies (MAbs) 2F5 and 4E10, both targeting the highly conserved human immunodeficiency virus type 1 (HIV-1) envelope membrane proximal external region (MPER), are among the MAbs with the broadest heterologous neutralizing activity and are of considerable interest for HIV-1 vaccine development. We have identified serum antibodies from an HIV-infected subject that both were broadly neutralizing and specifically targeted MPER epitopes that overlap the 2F5 epitope. These MPER-specific antibodies were made 15 to 20 months following transmission and concomitantly with the development of autoantibodies. Our findings suggest that multiple events (i.e., genetic predisposition and HIV-1 immune dysregulation) may be required for induction of broadly reactive gp41 MPER antibodies in natural infection.

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Hooper, Jay W., David M. Custer, Jeffrey Smith, and Victoria Wahl-Jensen. "Hantaan/Andes virus DNA vaccine elicits a broadly cross-reactive neutralizing antibody response in nonhuman primates." Virology 347, no. 1 (March 2006): 208–16. http://dx.doi.org/10.1016/j.virol.2005.11.035.

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Verkoczy, L., M. Diaz, T. M. Holl, Y. B. Ouyang, H. Bouton-Verville, S. M. Alam, H. X. Liao, G. Kelsoe, and B. F. Haynes. "Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance." Proceedings of the National Academy of Sciences 107, no. 1 (December 14, 2009): 181–86. http://dx.doi.org/10.1073/pnas.0912914107.

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Torresi, Joseph, Owen M. Stock, Alexandra E. Fischer, Lara Grollo, Heidi Drummer, Irene Boo, Weiguang Zeng, Linda Earnest-Silveira, and David C. Jackson. "A self-adjuvanting multiepitope immunogen that induces a broadly cross-reactive antibody to hepatitis C virus." Hepatology 45, no. 4 (2007): 911–20. http://dx.doi.org/10.1002/hep.21538.

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Martin, Cameron, Suryakant D. Waghela, Shehnaz Lokhandwala, Andy Ambrus, Jocelyn Bray, Christina Vuong, Vanitha Vinodkumar, et al. "Characterization of a Broadly Reactive Anti-CD40 Agonistic Monoclonal Antibody for Potential Use as an Adjuvant." PLOS ONE 12, no. 1 (January 20, 2017): e0170504. http://dx.doi.org/10.1371/journal.pone.0170504.

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Yamayoshi, Seiya, Ryuta Uraki, Mutsumi Ito, Maki Kiso, Sumiho Nakatsu, Atsuhiro Yasuhara, Kohei Oishi, Tadahiro Sasaki, Kazuyoshi Ikuta, and Yoshihiro Kawaoka. "A Broadly Reactive Human Anti-hemagglutinin Stem Monoclonal Antibody That Inhibits Influenza A Virus Particle Release." EBioMedicine 17 (March 2017): 182–91. http://dx.doi.org/10.1016/j.ebiom.2017.03.007.

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Avnir, Yuval, Kristina L. Prachanronarong, Zhen Zhang, Shurong Hou, Eric C. Peterson, Jianhua Sui, Hatem Zayed, et al. "Structural Determination of the Broadly Reactive Anti-IGHV1-69 Anti-idiotypic Antibody G6 and Its Idiotope." Cell Reports 21, no. 11 (December 2017): 3243–55. http://dx.doi.org/10.1016/j.celrep.2017.11.056.

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Wrammert, Jens, Dimitrios Koutsonanos, Gui-Mei Li, Srilatha Edupuganti, Jianhua Sui, Michael Morrissey, Megan McCausland, et al. "Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection." Journal of Experimental Medicine 208, no. 1 (January 10, 2011): 181–93. http://dx.doi.org/10.1084/jem.20101352.

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The 2009 pandemic H1N1 influenza pandemic demonstrated the global health threat of reassortant influenza strains. Herein, we report a detailed analysis of plasmablast and monoclonal antibody responses induced by pandemic H1N1 infection in humans. Unlike antibodies elicited by annual influenza vaccinations, most neutralizing antibodies induced by pandemic H1N1 infection were broadly cross-reactive against epitopes in the hemagglutinin (HA) stalk and head domain of multiple influenza strains. The antibodies were from cells that had undergone extensive affinity maturation. Based on these observations, we postulate that the plasmablasts producing these broadly neutralizing antibodies were predominantly derived from activated memory B cells specific for epitopes conserved in several influenza strains. Consequently, most neutralizing antibodies were broadly reactive against divergent H1N1 and H5N1 influenza strains. This suggests that a pan-influenza vaccine may be possible, given the right immunogen. Antibodies generated potently protected and rescued mice from lethal challenge with pandemic H1N1 or antigenically distinct influenza strains, making them excellent therapeutic candidates.

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Shiota, Tomoyuki, Michio Okame, Sayaka Takanashi, Pattara Khamrin, Makiko Takagi, Kenji Satou, Yuichi Masuoka, et al. "Characterization of a Broadly Reactive Monoclonal Antibody against Norovirus Genogroups I and II: Recognition of a Novel Conformational Epitope." Journal of Virology 81, no. 22 (September 12, 2007): 12298–306. http://dx.doi.org/10.1128/jvi.00891-07.

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ABSTRACT Norovirus, which belongs to the family Caliciviridae, is one of the major causes of nonbacterial acute gastroenteritis in the world. The main human noroviruses are of genogroup I (GI) and genogroup II (GII), which were subdivided further into at least 15 and 18 genotypes (GI/1 to GI/15 and GII/1 to GII/18), respectively. The development of immunological diagnosis for norovirus had been hindered by the antigen specificity of the polyclonal antibody. Therefore, several laboratories have produced broadly reactive monoclonal antibodies, which recognize the linear GI and GII cross-reactive epitopes or the conformational GI-specific epitope. In this study, we characterized the novel monoclonal antibody 14-1 (MAb14-1) for further development of the rapid immunochromatography test. Our results demonstrated that MAb14-1 could recognize 15 recombinant virus-like particles (GI/1, 4, 8, and 11 and GII/1 to 7 and 12 to 15) and showed weak affinity to the virus-like particle of GI/3. This recognition range is the broadest of the existing monoclonal antibodies. The epitope for MAb14-1 was identified by fragment, sequence, structural, and mutational analyses. Both terminal antigenic regions (amino acid positions 418 to 426 and 526 to 534) on the C-terminal P1 domain formed the conformational epitope and were in the proximity of the insertion region (positions 427 to 525). These regions contained six amino acids responsible for antigenicity that were conserved among genogroup(s), genus, and Caliciviridae. This epitope mapping explained the broad reactivity and different titers among GI and GII. To our knowledge, we are the first group to identify the GI and GII cross-reactive monoclonal antibody, which recognizes the novel conformational epitope. From these data, MAb14-1 could be used further to develop immunochromatography.

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Crill, Wayne D., Nicole B. Trainor, and Gwong-Jen J. Chang. "A detailed mutagenesis study of flavivirus cross-reactive epitopes using West Nile virus-like particles." Journal of General Virology 88, no. 4 (April 1, 2007): 1169–74. http://dx.doi.org/10.1099/vir.0.82640-0.

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Human flavivirus infections elicit virus species-specific and cross-reactive immune responses. The flavivirus envelope (E) glycoprotein is the primary antigen inducing protective immunity; however, the presence of cross-reactive antibodies in human sera creates problems for serodiagnosis. Using a West Nile virus-like particle system, we performed mutagenesis across all three E protein functional domains to identify epitope determinants for a panel of monoclonal antibodies (mAbs) raised against different flaviviruses and exhibiting diverse patterns of cross-reactivity. Residues within the highly conserved fusion peptide were the only epitope determinants identified and were important not only for broadly cross-reactive mAbs recognizing all of the medically important flavivirus serocomplexes, but also for less-broad, complex-reactive mAbs. Moreover, different substitutions at specific fusion peptide residues produced highly variable effects on antibody reactivity and virus-like particle secretion. These results support and extend the conclusion that the fusion peptide region constitutes an immunodominant epitope stimulating antibodies with diverse patterns of cross-reactivity.

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Kraft, Zane, Nina R. Derby, Ruth A. McCaffrey, Rachel Niec, Wendy M. Blay, Nancy L. Haigwood, Eirini Moysi, et al. "Macaques Infected with a CCR5-Tropic Simian/Human Immunodeficiency Virus (SHIV) Develop Broadly Reactive Anti-HIV Neutralizing Antibodies." Journal of Virology 81, no. 12 (March 28, 2007): 6402–11. http://dx.doi.org/10.1128/jvi.00424-07.

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ABSTRACT The development of anti-human immunodeficiency virus (anti-HIV) neutralizing antibodies and the evolution of the viral envelope glycoprotein were monitored in rhesus macaques infected with a CCR5-tropic simian/human immunodeficiency virus (SHIV), SHIVSF162P4. Homologous neutralizing antibodies developed within the first month of infection in the majority of animals, and their titers were independent of the extent and duration of viral replication during chronic infection. The appearance of homologous neutralizing antibody responses was preceded by the appearance of amino acid changes in specific variable and conserved regions of gp120. Amino acid changes first appeared in the V1, V2, C2, and V3 regions and subsequently in the C3, V4, and V5 regions. Heterologous neutralizing antibody responses developed over time only in animals with sustained plasma viremia. Within 2 years postinfection the breadth of these responses was as broad as that observed in certain patients infected with HIV type 1 (HIV-1) for over a decade. Despite the development of broad anti-HIV-1 neutralizing antibody responses, viral replication persisted in these animals due to viral escape. Our studies indicate that cross-reactive neutralizing antibodies are elicited in a subset of SHIVSF162P4 infected macaques and that their development requires continuous viral replication for extended periods of time. More importantly, their late appearance does not prevent progression to disease. The availability of an animal model where cross-reactive anti-HIV neutralizing antibodies are developed may facilitate the identification of virologic and immunologic factors conducive to the development of such antibodies.

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Gambhira, Ratish, Balasubramanyam Karanam, Subhashini Jagu, Jeffrey N. Roberts, Christopher B. Buck, Ioannis Bossis, Hannah Alphs, Timothy Culp, Neil D. Christensen, and Richard B. S. Roden. "A Protective and Broadly Cross-Neutralizing Epitope of Human Papillomavirus L2." Journal of Virology 81, no. 24 (October 10, 2007): 13927–31. http://dx.doi.org/10.1128/jvi.00936-07.

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ABSTRACT We generated a monoclonal antibody, RG-1, that binds to highly conserved L2 residues 17 to 36 and neutralizes human papillomavirus 16 (HPV16) and HPV18. Passive immunotherapy with RG-1 was protective in mice. Antiserum to the HPV16 L2 peptide comprising residues 17 to 36 (peptide 17-36) neutralized pseudoviruses HPV5, HPV6, HPV16, HPV 18, HPV31, HPV 45, HPV 52, HPV 58, bovine papillomavirus 1, and HPV11 native virions. Depletion of HPV16 L2 peptide 17-36-reactive antibodies from cross-neutralizing rabbit and human L2-specific sera abolished cross-neutralization and drastically reduced neutralization of the cognate type. This cross-neutralization of diverse HPVs associated with cervical cancer, genital warts, and epidermodysplasia verruciformis suggests the possibility of a broadly protective, peptide-based vaccine.

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Keck, Zhen-yong, Christine Girard-Blanc, Wenyan Wang, Patrick Lau, Adam Zuiani, Felix A. Rey, Thomas Krey, Michael S. Diamond, and Steven K. H. Foung. "Antibody Response to Hypervariable Region 1 Interferes with Broadly Neutralizing Antibodies to Hepatitis C Virus." Journal of Virology 90, no. 6 (January 6, 2016): 3112–22. http://dx.doi.org/10.1128/jvi.02458-15.

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ABSTRACTHypervariable region 1 (HVR1) (amino acids [aa] 384 to 410) on the E2 glycoprotein of hepatitis C virus contributes to persistent infection by evolving escape mutations that attenuate binding of inhibitory antibodies and by blocking access of broadly neutralizing antibodies to their epitopes. A third proposed mechanism of immune antagonism is that poorly neutralizing antibodies binding to HVR1 interfere with binding of other superior neutralizing antibodies. Epitope mapping of human monoclonal antibodies (HMAbs) that bind to an adjacent, conserved domain on E2 encompassing aa 412 to 423 revealed two subsets, designated HC33 HMAbs. While both subsets have contact residues within aa 412 to 423, alanine-scanning mutagenesis suggested that one subset, which includes HC33.8, has an additional contact residue within HVR1. To test for interference of anti-HVR1 antibodies with binding of antibodies to aa 412 to 423 and other E2 determinants recognized by broadly neutralizing HMAbs, two murine MAbs against HVR1 (H77.16) and aa 412 to 423 (H77.39) were studied. As expected, H77.39 inhibited the binding of all HC33 HMAbs. Unexpectedly, H77.16 also inhibited the binding of both subsets of HC33 HMAbs. This inhibition also was observed against other broadly neutralizing HMAbs to epitopes outside aa 412 to 423. Combination antibody neutralization studies by the median-effect analysis method with H77.16 and broadly reactive HMAbs revealed antagonism between these antibodies. Structural studies demonstrated conformational flexibility in this antigenic region, which supports the possibility of anti-HVR1 antibodies hindering the binding of broadly neutralizing MAbs. These findings support the hypothesis that anti-HVR1 antibodies can interfere with a protective humoral response against HCV infection.IMPORTANCEHVR1 contributes to persistent infection by evolving mutations that escape from neutralizing antibodies to HVR1 and by shielding broadly neutralizing antibodies from their epitopes. This study provides insight into a new immune antagonism mechanism by which the binding of antibodies to HVR1 blocks the binding and activity of broadly neutralizing antibodies to HCV. Immunization strategies that avoid the induction of HVR1 antibodies should increase the inhibitory activity of broadly neutralizing anti-HCV antibodies elicited by candidate vaccines.

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Hoa, Le Nguyen Minh, Le Quynh Mai, Juliet E. Bryant, Pham Quang Thai, Nguyen Le Khanh Hang, Nguyen Thi Thu Yen, Tran Nhu Duong, et al. "Association between Hemagglutinin Stem-Reactive Antibodies and Influenza A/H1N1 Virus Infection during the 2009 Pandemic." Journal of Virology 90, no. 14 (May 11, 2016): 6549–56. http://dx.doi.org/10.1128/jvi.00093-16.

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ABSTRACTThe discovery of influenza virus broadly neutralizing (BrN) antibodies prompted efforts to develop universal vaccines. Influenza virus stem-reactive (SR) broadly neutralizing antibodies have been detected by screening antibody phage display libraries. However, studies of SR BrN antibodies in human serum, and their association with natural infection, are limited. To address this, pre- and postpandemic sera from a prospective community cohort study in Vietnam were assessed for antibodies that inhibit SR BrN monoclonal antibody (MAb) (C179) binding to H1N1 pandemic 2009 virus (H1N1pdm09). Of 270 households, 33 with at least one confirmed H1N1pdm09 illness or at least two seroconverters were included. The included households comprised 71 infected and 41 noninfected participants. Sera were tested as 2-fold dilutions between 1:5 and 1:40. Fifty percent C179 inhibition (IC50) titers did not exceed 10, although both IC50titers and percent C179 inhibition by sera diluted 1:5 or 1:10 correlated with hemagglutination inhibition (HI) and microneutralization (MN) titers (allP< 0.001). Thirteen (12%) participants had detectable prepandemic IC50titers, but only one reached a titer of 10. This proportion increased to 44% after the pandemic, when 39 participants had a titer of 10, and 67% of infected compared to 44% of noninfected had detectable IC50titers (P< 0.001). The low levels of SR antibodies in prepandemic sera were not associated with subsequent H1N1pdm09 infection (P= 0.241), and the higher levels induced by H1N1pdm09 infection returned to prepandemic levels within 2 years. The findings indicate that natural infection induces only low titers of SR antibodies that are not sustained.IMPORTANCEUniversal influenza vaccines could have substantial health and economic benefits. The focus of universal vaccine research has been to induce antibodies that prevent infection by diverse influenza virus strains. These so-called broadly neutralizing antibodies are readily detected in mice and ferrets after infection with a series of distinct influenza virus strains. The 2009 H1N1 pandemic provided an opportunity to investigate whether infection with a novel strain induced broadly neutralizing antibodies in humans. We found that broadly neutralizing antibodies were induced, but levels were low and poorly maintained. This could represent an obstacle for universal vaccine development and warrants further investigation.

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Matsushita, Shuzo, Soichiro Takahama, Junji Shibata, Tetsuya Kimura, Koichi Shiozaki, Yasuyuki Eda, Atsushi Koito, Toshio Murakami, and Kazuhisa Yoshimura. "Ex vivo neutralization of HIV-1 quasi-species by a broadly reactive humanized monoclonal antibody KD-247." Human Antibodies 14, no. 3-4 (May 9, 2006): 81–88. http://dx.doi.org/10.3233/hab-2005-143-405.

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Quinnan, Gerald V., Peng Fei Zhang, Da Wei Fu, Ming Dong, and Harvey J. Alter. "Expression and Characterization of HIV Type 1 Envelope Protein Associated with a Broadly Reactive Neutralizing Antibody Response." AIDS Research and Human Retroviruses 15, no. 6 (April 10, 1999): 561–70. http://dx.doi.org/10.1089/088922299311088.

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Shang, Dazhuang, Wenwu Zhai, and Jean-Pierre Allain. "Broadly Cross-Reactive, High-Affinity Antibody to Hypervariable Region 1 of the Hepatitis C Virus in Rabbits." Virology 258, no. 2 (June 1999): 396–405. http://dx.doi.org/10.1006/viro.1999.9730.

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von Gegerfelt, Agneta, Charlotta Nilsson, Per Putkonen, and Kristina Broliden. "Broadly reactive HIV-2 and SIVmac specific antibody-dependent cellular cytotoxicity in immunized and infected cynomolgus monkeys." Vaccine 12, no. 13 (January 1994): 1203–8. http://dx.doi.org/10.1016/0264-410x(94)90244-5.

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Thibodeaux, Brett A., and John T. Roehrig. "Development of a Human-Murine Chimeric Immunoglobulin M Antibody for Use in the Serological Detection of Human Flavivirus Antibodies." Clinical and Vaccine Immunology 16, no. 5 (March 18, 2009): 679–85. http://dx.doi.org/10.1128/cvi.00354-08.

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ABSTRACT Current diagnosis of human flaviviral infections relies heavily on serological techniques such as the immunoglobulin M (IgM) antibody capture enzyme-linked immunosorbent assay (MAC-ELISA). Broad application of this assay is hindered by a lack of standardized human positive-control sera that react with the wide variety of flaviviruses that can cause human disease, e.g., dengue virus (DENV), West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and St. Louis encephalitis virus (SLEV). We have created a human-murine chimeric antibody combining the variable regions of the broadly flavivirus cross-reactive murine monoclonal antibody (MAb) 6B6C-1 and the constant region of human IgM to produce a standardized reagent capable of replacing human positive-control sera in a MAC-ELISA for the diagnosis of all human flaviviral infections. The human-murine chimeric IgM antibody secreted from plasmid-transformed Sp2/0-Ag14 cells had a level of serological activity identical to that of 6B6C-1 as measured by ELISA, immunoblotting, and MAC-ELISA for multiple members of the flavivirus genus, including WNV, SLEV, YFV, DENV, and JEV.

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Dhillon, Amandeep K., Helen Donners, Ralph Pantophlet, Welkin E. Johnson, Julie M. Decker, George M. Shaw, Fang-Hua Lee, et al. "Dissecting the Neutralizing Antibody Specificities of Broadly Neutralizing Sera from Human Immunodeficiency Virus Type 1-Infected Donors." Journal of Virology 81, no. 12 (April 4, 2007): 6548–62. http://dx.doi.org/10.1128/jvi.02749-06.

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ABSTRACT Attempts to elicit broadly neutralizing antibody responses by human immunodeficiency virus type 1 (HIV-1) vaccine antigens have been met with limited success. To better understand the requirements for cross-neutralization of HIV-1, we have characterized the neutralizing antibody specificities present in the sera of three asymptomatic individuals exhibiting broad neutralization. Two individuals were infected with clade B viruses and the third with a clade A virus. The broadly neutralizing activity could be exclusively assigned to the protein A-reactive immunoglobulin G (IgG) fraction of all three donor sera. Neutralization inhibition assays performed with a panel of linear peptides corresponding to the third hypervariable (V3) loop of gp120 failed to inhibit serum neutralization of a panel of HIV-1 viruses. The sera also failed to neutralize chimeric simian immunodeficiency virus (SIV) and HIV-2 viruses displaying highly conserved gp41-neutralizing epitopes, suggesting that antibodies directed against these epitopes likely do not account for the broad neutralizing activity observed. Polyclonal IgG was fractionated on recombinant monomeric clade B gp120, and the neutralization capacities of the gp120-depleted samples were compared to that of the original polyclonal IgG. We found that the gp120-binding antibody population mediated neutralization of some isolates, but not all. Overall, the data suggest that broad neutralization results from more than one specificity in the sera but that the number of these specificities is likely small. The most likely epitope recognized by the monomeric gp120 binding neutralizing fraction is the CD4 binding site, although other epitopes, such as the glycan shield, cannot be excluded.

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Elledge, Susanna K., Hai L. Tran, Alec H. Christian, Veronica Steri, Byron Hann, F. Dean Toste, Christopher J. Chang, and James A. Wells. "Systematic identification of engineered methionines and oxaziridines for efficient, stable, and site-specific antibody bioconjugation." Proceedings of the National Academy of Sciences 117, no. 11 (March 2, 2020): 5733–40. http://dx.doi.org/10.1073/pnas.1920561117.

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The field of chemical modification of proteins has been dominated by random modification of lysines or more site-specific labeling of cysteines, each with attendant challenges. Recently, we have developed oxaziridine chemistry for highly selective modification of methionine called redox-activated chemical tagging (ReACT) but have not broadly tested the molecular parameters for efficient and stable protein modification. Here we systematically scanned methionines throughout one of the most popular antibody scaffolds, trastuzumab, used for antibody engineering and drug conjugation. We tested the expression, reactivities, and stabilities of 123 single engineered methionines distributed over the surface of the antibody when reacted with oxaziridine. We found uniformly high expression for these mutants and excellent reaction efficiencies with a panel of oxaziridines. Remarkably, the stability to hydrolysis of the sulfimide varied more than 10-fold depending on temperature and the site of the engineered methionine. Interestingly, the most stable and reactive sites were those that were partially buried, presumably because of their reduced access to water. There was also a 10-fold variation in stability depending on the nature of the oxaziridine, which was determined to be inversely correlated with the electrophilic nature of the sulfimide. Importantly, the stabilities of the best analogs were sufficient to support their use as antibody drug conjugates and potent in a breast cancer mouse xenograft model over a month. These studies provide key parameters for broad application of ReACT for efficient, stable, and site-specific antibody and protein bioconjugation to native or engineered methionines.

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Brade, Lore, Holger Heine, Satish Raina, Gracjana Klein, Franco di Padova, Helmut Brade, and Sven Müller-Loennies. "Immunization with an anti-idiotypic antibody against the broadly lipopolysaccharide-reactive antibody WN1 222-5 inducesEscherichia coliR3-core-type specific antibodies in rabbits." Innate Immunity 18, no. 2 (August 15, 2011): 279–93. http://dx.doi.org/10.1177/1753425911401055.

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Sei, Clara J., Nimisha Rikhi, Rachmat Hidajat, Richard F. Schuman, Kevin Muema, Jasmine M. Mutunga, Luke T. Daum, and Gerald W. Fischer. "2752. Peptide Vaccines Utilizing Conserved Hemagglutinin, Neuraminidase, and Matrix Ectodomain Influenza Epitopes Demonstrate Functional Activity Against Group 1 and 2 Influenza Strains." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S969—S970. http://dx.doi.org/10.1093/ofid/ofz360.2429.

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Abstract Background Globally, prevention and control of seasonal influenza has faced many challenges in the selection of a vaccine composition that antigenically matches circulating viruses. A universal influenza vaccine approach that targets small conserved influenza virus epitopes/peptides such as the extracellular domain of Matrix 2 (M2e) and induces broadly reactive antibodies may be helpful for both seasonal influenza outbreaks and pandemics. Here we report the ability of two composite peptide vaccines, individually and in combination, to induce broadly reactive antibodies that have binding and functional activity across several contemporary influenza strains in Group 1 and 2. Methods Mice were immunized with peptide composite vaccines against Hemagglutinin (HA), Neuraminidase (NA) and M2e, individually and in combination. Peptide composite vaccines, conjugated to CRM were administered subcutaneously with adjuvant and at least two booster doses. Serum antibody titers were analyzed using an anti-influenza ELISA for binding activity to peptides and live influenza viruses (H3N2 and H1N1) and functional activity was evaluated in vitro using Microneutralization, Hemagglutination Inhibition (HAI), and Antibody-Dependent Cellular Cytotoxicity (ADCC) assays. Results Mice given the peptide composite conjugate vaccines, individually and in combination, had strong humoral responses producing high serum anti-influenza titers post-booster immunization. Anti-influenza serum antibodies demonstrated functional activity against influenza A (H3N2 and H1N1) contemporary strains showing neutralization, HAI and ADCC activity. Conclusion Peptide conjugate vaccines were highly immunogenic in mice. Broadly reactive serum antibodies against the peptides and live influenza viruses were detected. These vaccines individually or in combination, induced antibodies that demonstrated functional activity against contemporary influenza strains in Group 1 and 2 and induced functional anti-influenza monoclonal antibodies. A vaccine that targets one or more HA, NA and M2e influenza epitopes may more closely approach the goal for a true universal influenza vaccine. In vivo protection studies are currently being designed. Disclosures All authors: No reported disclosures.

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Ellebedy, A. H., F. Krammer, G. M. Li, M. S. Miller, C. Chiu, J. Wrammert, C. Y. Chang, et al. "Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans." Proceedings of the National Academy of Sciences 111, no. 36 (August 25, 2014): 13133–38. http://dx.doi.org/10.1073/pnas.1414070111.

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Wilkinson, Royce A., Chayne Piscitelli, Martin Teintze, Lisa A. Cavacini, Marshall R. Posner, and C. Martin Lawrence. "Structure of the Fab Fragment of F105, a Broadly Reactive Anti-Human Immunodeficiency Virus (HIV) Antibody That Recognizes the CD4 Binding Site of HIV Type 1 gp120." Journal of Virology 79, no. 20 (October 15, 2005): 13060–69. http://dx.doi.org/10.1128/jvi.79.20.13060-13069.2005.

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ABSTRACT We have determined the crystal structure of the Fab fragment from F105, a broadly reactive human antibody with limited potency that recognizes the CD4 binding site of gp120. The structure reveals an extended CDR H3 loop with a phenylalanine residue at the apex and shows a striking pattern of serine and tyrosine residues. Modeling the interaction between gp120 and F105 suggests that the phenylalanine may recognize the binding pocket of gp120 used by Phe43 of CD4 and that numerous tyrosine and serine residues form hydrogen bonds with the main chain atoms of gp120. A comparison of the F105 structure to that of immunoglobulin G1 b12, a much more potent and broadly neutralizing antibody with an overlapping epitope, suggests similarities that contribute to the broad recognition of human immunodeficiency virus by both antibodies. While the putative epitope for F105 shows significant overlap with that predicted for b12, it appears to differ from the b12 epitope in extending across the interface between the inner and outer domains of gp120. In contrast, the CDR loops of b12 appear to interact predominantly with the outer domain of gp120. The difference between the predicted epitopes for b12 and F105 suggests that the unique potency of b12 may arise from its ability to avoid the interface between the inner and outer domains of gp120.

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Doria-Rose, Nicole A., Jinal N. Bhiman, Ryan S. Roark, Chaim A. Schramm, Jason Gorman, Gwo-Yu Chuang, Marie Pancera, et al. "New Member of the V1V2-Directed CAP256-VRC26 Lineage That Shows Increased Breadth and Exceptional Potency." Journal of Virology 90, no. 1 (October 14, 2015): 76–91. http://dx.doi.org/10.1128/jvi.01791-15.

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ABSTRACT The epitopes defined by HIV-1 broadly neutralizing antibodies (bNAbs) are valuable templates for vaccine design, and studies of the immunological development of these antibodies are providing insights for vaccination strategies. In addition, the most potent and broadly reactive of these bNAbs have potential for clinical use. We previously described a family of 12 V1V2-directed neutralizing antibodies, CAP256-VRC26, isolated from an HIV-1 clade C-infected donor at years 1, 2, and 4 of infection (N. A. Doria-Rose et al., Nature 509:55–62, 2014, http://dx.doi.org/10.1038/nature13036 ). Here, we report on the isolation and characterization of new members of the family mostly obtained at time points of peak serum neutralization breadth and potency. Thirteen antibodies were isolated from B cell culture, and eight were isolated using trimeric envelope probes for differential single B cell sorting. One of the new antibodies displayed a 10-fold greater neutralization potency than previously published lineage members. This antibody, CAP256-VRC26.25, neutralized 57% of diverse clade viral isolates and 70% of clade C isolates with remarkable potency. Among the viruses neutralized, the median 50% inhibitory concentration was 0.001 μg/ml. All 33 lineage members targeted a quaternary epitope focused on V2. While all known bNAbs targeting the V1V2 region interact with the N160 glycan, the CAP256-VRC26 antibodies showed an inverse correlation of neutralization potency with dependence on this glycan. Overall, our results highlight the ongoing evolution within a single antibody lineage and describe more potent and broadly neutralizing members with potential clinical utility, particularly in areas where clade C is prevalent. IMPORTANCE Studies of HIV-1 broadly neutralizing antibodies (bNAbs) provide valuable information for vaccine design, and the most potent and broadly reactive of these bNAbs have potential for clinical use. We previously described a family of V1V2-directed neutralizing antibodies from an HIV-1 clade C-infected donor. Here, we report on the isolation and characterization of new members of the family mostly obtained at time points of peak serum neutralization breadth and potency. One of the new antibodies, CAP256-VRC26.25, displayed a 10-fold greater neutralization potency than previously described lineage members. It neutralized 57% of diverse clade viral isolates and 70% of clade C isolates with remarkable potency: the median 50% inhibitory concentration was 0.001 μg/ml. Our results highlight the ongoing evolution within a single antibody lineage and describe more potent and broadly neutralizing members with potential clinical utility, particularly in areas where clade C is prevalent.

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Journal articles on the topic 'Broadly reactive antibody'

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