Search
Close this search box.

Triple tandem trimer immunogens for HIV-1 and influenza nucleic acid-based vaccines – npj Vaccines

  • Kwong, P. D. & Mascola, J. R. HIV-1 vaccines based on antibody identification, B cell ontogeny, and epitope structure. Immunity 48, 855–871 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • McCoy, L. E. The expanding array of HIV broadly neutralizing antibodies. Retrovirology 15, 70 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sok, D. & Burton, D. R. Recent progress in broadly neutralizing antibodies to HIV. Nat. Immunol. 19, 1179–1188 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Del Moral-Sánchez, I. & Sliepen, K. Strategies for inducing effective neutralizing antibody responses against HIV-1. Expert Rev. Vaccines 18, 1127–1143 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Williams, W. B., Wiehe, K., Saunders, K. O. & Haynes, B. F. Strategies for induction of HIV-1 envelope-reactive broadly neutralizing antibodies. J. Int. AIDS Soc. 24, e25831 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Derking, R. & Sanders, R. W. Structure-guided envelope trimer design in HIV-1 vaccine development: a narrative review. J. Int. AIDS Soc. 24, e25797 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Moldt, B. et al. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc. Natl. Acad. Sci. USA 109, 18921–18925 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shingai, M. et al. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques. J. Exp. Med. 211, 2061–2074 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gautam, R. et al. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533, 105–109 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Feng, Y., Broder, C. C., Kennedy, P. E. & Berger, E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272, 872–877 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Maddon, P. J. et al. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell 47, 333–348 (1986).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sanders, R. W. & Moore, J. P. HIV: a stamp on the envelope. Nature 514, 437–438 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McDougal, J. S. et al. Binding of HTLV-III/LAV to T4+ T cells by a complex of the 110K viral protein and the T4 molecule. Science 231, 382–385 (1986).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Moore, J. P., Trkola, A. & Dragic, T. Co-receptors for HIV-1 entry. Curr. Opin. Immunol. 9, 551–562 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • McCune, J. M. et al. Endoproteolytic cleavage of gp160 is required for the activation of human immunodeficiency virus. Cell 53, 55–67 (1988).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Moulard, M. & Decroly, E. Maturation of HIV envelope glycoprotein precursors by cellular endoproteases. Biochim. Biophys. Acta 1469, 121–132 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Poignard, P., Saphire, E. O., Parren, P. W. & Burton, D. R. gp120: biologic aspects of structural features. Annu. Rev. Immunol. 19, 253–274 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Willey, R. L., Bonifacino, J. S., Potts, B. J., Martin, M. A. & Klausner, R. D. Biosynthesis, cleavage, and degradation of the human immunodeficiency virus 1 envelope glycoprotein gp160. Proc. Natl. Acad. Sci. USA 85, 9580–9584 (1988).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Moore, J. P., McKeating, J. A., Weiss, R. A. & Sattentau, Q. J. Dissociation of gp120 from HIV-1 virions induced by soluble CD4. Science 250, 1139–1142 (1990).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chakrabarti, B. K. et al. HIV type 1 Env precursor cleavage state affects recognition by both neutralizing and nonneutralizing gp41 antibodies. AIDS Res. Hum. Retroviruses 27, 877–887 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sliepen, K. & Sanders, R. W. HIV-1 envelope glycoprotein immunogens to induce broadly neutralizing antibodies. Expert Rev. Vaccines 15, 349–365 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sanders, R. W. et al. HIV-1 VACCINES. HIV-1 neutralizing antibodies induced by native-like envelope trimers. Science 349, aac4223 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kovacs, J. M. et al. HIV-1 envelope trimer elicits more potent neutralizing antibody responses than monomeric gp120. Proc. Natl. Acad. Sci. USA 109, 12111–12116 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Julien, J.-P. et al. Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9. Proc. Natl. Acad. Sci. USA 110, 4351–4356 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hoffenberg, S. et al. Identification of an HIV-1 clade A envelope that exhibits broad antigenicity and neutralization sensitivity and elicits antibodies targeting three distinct epitopes. J. Virol. 87, 5372–5383 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Davenport, T. M. et al. Binding interactions between soluble HIV envelope glycoproteins and quaternary-structure-specific monoclonal antibodies PG9 and PG16. J. Virol. 85, 7095–7107 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Binley, J. M. et al. A recombinant human immunodeficiency virus type 1 envelope glycoprotein complex stabilized by an intermolecular disulfide bond between the gp120 and gp41 subunits is an antigenic mimic of the trimeric virion-associated structure. J. Virol. 74, 627–643 (2000).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Binley, J. M. et al. Enhancing the proteolytic maturation of human immunodeficiency virus type 1 envelope glycoproteins. J. Virol. 76, 2606–2616 (2002).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sanders, R. W. et al. Stabilization of the soluble, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1. J. Virol. 76, 8875–8889 (2002).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sanders, R. W. et al. A next-generation cleaved, soluble HIV-1 Env trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies. PLoS Pathog. 9, e1003618 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sanders, R. W. & Moore, J. P. Virus vaccines: proteins prefer prolines. Cell Host Microbe 29, 327–333 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ringe, R. P. et al. Cleavage strongly influences whether soluble HIV-1 envelope glycoprotein trimers adopt a native-like conformation. Proc. Natl. Acad. Sci. USA 110, 18256–18261 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Julien, J.-P. et al. Crystal structure of a soluble cleaved HIV-1 envelope trimer. Science 342, 1477–1483 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lyumkis, D. et al. Cryo-EM structure of a fully glycosylated soluble cleaved HIV-1 envelope trimer. Science 342, 1484–1490 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Georgiev, I. S. et al. Single-chain soluble BG505.SOSIP gp140 trimers as structural and antigenic mimics of mature closed HIV-1 Env. J. Virol. 89, 5318–5329 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sharma, S. K. et al. Cleavage-independent HIV-1 Env trimers engineered as soluble native spike mimetics for vaccine design. Cell Rep. 11, 539–550 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kong, L. et al. Uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability. Nat. Commun. 7, 12040 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sarkar, A. et al. Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer. Nat. Commun. 9, 1956 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, J. H. & Crotty, S. HIV vaccinology: 2021 update. Semin. Immunol. 51, 101470 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, M. A. A comparison of plasmid DNA and mRNA as vaccine technologies. Vaccines 7, 37 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines—a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pardi, N., Hogan, M. J. & Weissman, D. Recent advances in mRNA vaccine technology. Curr. Opin. Immunol. 65, 14–20 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pilkington, E. H. et al. From influenza to COVID-19: Lipid nanoparticle mRNA vaccines at the frontiers of infectious diseases. Acta Biomater. 131, 16–40 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pardi, N. et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J. Exp. Med. 215, 1571–1588 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Blasi, M. et al. IDLV-HIV-1 Env vaccination in non-human primates induces affinity maturation of antigen-specific memory B cells. Commun Biol 1, 134 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bloom, K., van den Berg, F. & Arbuthnot, P. Self-amplifying RNA vaccines for infectious diseases. Gene Ther. 28, 117–129 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lundstrom, K. Self-replicating RNA viruses for vaccine development against infectious diseases and cancer. Vaccines 9, 1187 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Negri, D. R. et al. Integrase-defective lentiviral-vector-based vaccine: a new vector for induction of T cell immunity. Expert Opin. Biol. Ther. 11, 739–750 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gallinaro, A. et al. Integrase defective lentiviral vector as a vaccine platform for delivering influenza antigens. Front. Immunol. 9, 171 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Folegatti, P. M. et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 396, 467–478 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Harbury, P. B., Kim, P. S. & Alber, T. Crystal structure of an isoleucine-zipper trimer. Nature 371, 80–83 (1994).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Harbury, P. B., Zhang, T., Kim, P. S. & Alber, T. A switch between two-, three-, and four-stranded coiled coils in GCN4 leucine zipper mutants. Science 262, 1401–1407 (1993).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Landschulz, W. H., Johnson, P. F. & McKnight, S. L. The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science 240, 1759–1764 (1988).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Güthe, S. et al. Very fast folding and association of a trimerization domain from bacteriophage T4 fibritin. J. Mol. Biol. 337, 905–915 (2004).

    Article 
    PubMed 

    Google Scholar
     

  • Tao, Y., Strelkov, S. V., Mesyanzhinov, V. V. & Rossmann, M. G. Structure of bacteriophage T4 fibritin: a segmented coiled coil and the role of the C-terminal domain. Structure 5, 789–798 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Du, S. X. et al. Effect of trimerization motifs on quaternary structure, antigenicity, and immunogenicity of a noncleavable HIV-1 gp140 envelope glycoprotein. Virology 395, 33–44 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kovacs, J. M. et al. Stable, uncleaved HIV-1 envelope glycoprotein gp140 forms a tightly folded trimer with a native-like structure. Proc. Natl. Acad. Sci. USA 111, 18542–18547 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chakrabarti, B. K. et al. Robust neutralizing antibodies elicited by HIV-1 JRFL envelope glycoprotein trimers in nonhuman primates. J. Virol. 87, 13239–13251 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sliepen, K., van Montfort, T., Melchers, M., Isik, G. & Sanders, R. W. Immunosilencing a highly immunogenic protein trimerization domain. J. Biol. Chem. 290, 7436–7442 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Weldon, W. C. et al. Enhanced immunogenicity of stabilized trimeric soluble influenza hemagglutinin. PLoS ONE 5, e12466 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bosch, B. J. et al. Recombinant soluble, multimeric HA and NA exhibit distinctive types of protection against pandemic swine-origin 2009 A(H1N1) influenza virus infection in ferrets. J. Virol. 84, 10366–10374 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Du, L. et al. A recombinant vaccine of H5N1 HA1 fused with foldon and human IgG Fc induced complete cross-clade protection against divergent H5N1 viruses. PLoS ONE 6, e16555 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ringe, R. P. et al. Influences on the design and purification of soluble, recombinant native-like HIV-1 envelope glycoprotein trimers. J. Virol. 89, 12189–12210 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • de Taeye, S. W. et al. Immunogenicity of stabilized HIV-1 envelope trimers with reduced exposure of non-neutralizing epitopes. Cell 163, 1702–1715 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Steichen, J. M. et al. HIV vaccine design to target germline precursors of glycan-dependent broadly neutralizing antibodies. Immunity 45, 483–496 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Walker, L. M. et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477, 466–470 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Doria-Rose, N. A. et al. New member of the V1V2-directed CAP256-VRC26 lineage that shows increased breadth and exceptional potency. J. Virol. 90, 76–91 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Falkowska, E. et al. Broadly neutralizing HIV antibodies define a glycan-dependent epitope on the prefusion conformation of gp41 on cleaved envelope trimers. Immunity 40, 657–668 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, J. H. et al. A broadly neutralizing antibody targets the dynamic HIV envelope trimer apex via a long, rigidified, and anionic β-hairpin structure. Immunity 46, 690–702 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Del Moral-Sánchez, I. et al. High thermostability improves neutralizing antibody responses induced by native-like HIV-1 envelope trimers. NPJ Vaccines 7, 27 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Seabright, G. E., Doores, K. J., Burton, D. R. & Crispin, M. Protein and glycan mimicry in HIV vaccine design. J. Mol. Biol. 431, 2223–2247 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Derking, R. et al. Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike. Cell Rep. 35, 108933 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sliepen, K. et al. Structure and immunogenicity of a stabilized HIV-1 envelope trimer based on a group-M consensus sequence. Nat. Commun. 10, 2355 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dicks, M. D. J. et al. A novel chimpanzee adenovirus vector with low human seroprevalence: improved systems for vector derivation and comparative immunogenicity. PLoS ONE 7, e40385 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kaynarcalidan, O., Moreno Mascaraque, S. & Drexler, I. Vaccinia virus: from crude smallpox vaccines to elaborate viral vector vaccine design. Biomedicines 9, 1780 (2021).

  • Volz, A. & Sutter, G. Modified vaccinia virus Ankara: history, value in basic research, and current perspectives for vaccine development. Adv. Virus Res. 97, 187–243 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Morris, S. J., Sebastian, S., Spencer, A. J. & Gilbert, S. C. Simian adenoviruses as vaccine vectors. Future Virol. 11, 649–659 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • García-Arriaza, J., Esteban, M. & López, D. Modified vaccinia virus ankara as a viral vector for vaccine candidates against chikungunya virus. Biomedicines 9, 1780 (2021).

    Article 

    Google Scholar
     

  • Volkmann, A. et al. The Brighton Collaboration standardized template for collection of key information for risk/benefit assessment of a Modified Vaccinia Ankara (MVA) vaccine platform. Vaccine 39, 3067–3080 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Capucci, S. et al. HIV-1-neutralizing antibody induced by simian adenovirus- and poxvirus MVA-vectored BG505 native-like envelope trimers. PLoS ONE 12, e0181886 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wee, E. G. et al. Effect of epitope variant co-delivery on the depth of CD8 T cell responses induced by HIV-1 conserved mosaic vaccines. Mol. Ther. Methods Clin. Dev. 21, 741–753 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mohamed, Y. S. et al. Specificity of CD8 T-cell responses following vaccination with conserved regions of HIV-1 in Nairobi, Kenya. Vaccines 8, 260 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hanke, T. Aiming for protective T-cell responses: a focus on the first generation conserved-region HIVconsv vaccines in preventive and therapeutic clinical trials. Expert Rev. Vaccines 18, 1029–1041 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Brouwer, P. J. M. et al. Enhancing and shaping the immunogenicity of native-like HIV-1 envelope trimers with a two-component protein nanoparticle. Nat. Commun. 10, 4272 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brouwer, P. J. M. et al. Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles. NPJ Vaccines 6, 24 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hu, J. K. et al. Murine antibody responses to cleaved soluble HIV-1 envelope trimers are highly restricted in specificity. J. Virol. 89, 10383–10398 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bianchi, M. et al. Electron-microscopy-based epitope mapping defines specificities of polyclonal antibodies elicited during HIV-1 BG505 envelope trimer immunization. Immunity 49, 288–300.e8 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nogal, B. et al. Mapping polyclonal antibody responses in non-human primates vaccinated with HIV Env trimer subunit vaccines. Cell Rep. 30, 3755–3765.e7 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McCoy, L. E. et al. Holes in the glycan shield of the native HIV envelope are a target of trimer-elicited neutralizing antibodies. Cell Rep. 16, 2327–2338 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Klasse, P. J. et al. Epitopes for neutralizing antibodies induced by HIV-1 envelope glycoprotein BG505 SOSIP trimers in rabbits and macaques. PLOS Pathogens 14, e1006913 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, Y. R. et al. Autologous antibody responses to an HIV envelope glycan hole are not easily broadened in rabbits. Journal of Virology 94, e01861–19 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cottrell, C. A. et al. Mapping the immunogenic landscape of near-native HIV-1 envelope trimers in non-human primates. PLoS Pathog. 16, e1008753 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rey, F. A. & Lok, S.-M. Common features of enveloped viruses and implications for immunogen design for next-generation vaccines. Cell 172, 1319–1334 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dreyfus, C. et al. Highly conserved protective epitopes on influenza B viruses. Science 337, 1343–1348 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ekiert, D. C. et al. Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature 489, 526–532 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bangaru, S. et al. A site of vulnerability on the influenza virus hemagglutinin head domain trimer interface. Cell 177, 1136–1152.e18 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ekiert, D. C. et al. A highly conserved neutralizing epitope on group 2 influenza A Viruses. Science 333, 843–850 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Corti, D. et al. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science 333, 850–856 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • An, Y., McCullers, J. A., Alymova, I., Parsons, L. M. & Cipollo, J. F. Glycosylation analysis of engineered H3N2 influenza A virus hemagglutinins with sequentially added historically relevant glycosylation sites. J. Proteome Res. 14, 3957–3969 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lee, C.-C. D. et al. A cross-neutralizing antibody between HIV-1 and influenza virus. PLoS Pathog. 17, e1009407 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sellhorn, G. et al. Engineering, expression, purification, and characterization of stable clade A/B recombinant soluble heterotrimeric gp140 proteins. J. Virol. 86, 128–142 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • de la Peña, A. T. et al. Improving the immunogenicity of native-like HIV-1 envelope trimers by hyperstabilization. Cell Rep. 20, 1805–1817 (2017).

    Article 

    Google Scholar
     

  • Schorcht, A. et al. Neutralizing antibody responses induced by HIV-1 envelope glycoprotein SOSIP trimers derived from elite neutralizers. J. Virol. 94, e01214–e01220 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nogal, B. et al. HIV envelope trimer-elicited autologous neutralizing antibodies bind a region overlapping the N332 glycan supersite. Sci. Adv. 6, eaba0512 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Reiss, E. I. M. M. et al. Fine-mapping the immunodominant antibody epitopes on consensus sequence-based HIV-1 envelope trimer vaccine candidates. NPJ Vaccines 7, 152 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McMahon, M. et al. Assessment of a quadrivalent nucleoside-modified mRNA vaccine that protects against group 2 influenza viruses. Proc. Natl. Acad. Sci. USA 119, e2206333119 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Boyoglu-Barnum, S. et al. Quadrivalent influenza nanoparticle vaccines induce broad protection. Nature 592, 623–628 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Isakova-Sivak, I. et al. Influenza vaccine: progress in a vaccine that elicits a broad immune response. Expert Rev. Vaccines 20, 1097–1112 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Khalil, N. & Bernstein, D. I. Influenza vaccines: where we are, where we are going. Curr. Opin. Pediatr. 34, 119–125 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Krammer, F., Pica, N., Hai, R., Margine, I. & Palese, P. Chimeric hemagglutinin influenza virus vaccine constructs elicit broadly protective stalk-specific antibodies. J. Virol. 87, 6542–6550 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Throsby, M. et al. Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells. PLoS ONE 3, e3942 (2008).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Krause, J. C. et al. A broadly neutralizing human monoclonal antibody that recognizes a conserved, novel epitope on the globular head of the influenza H1N1 virus hemagglutinin. J. Virol. 85, 10905–10908 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Behrens, A.-J. et al. Molecular architecture of the cleavage-dependent mannose patch on a soluble HIV-1 envelope glycoprotein trimer. J. Virol. 91, e01894–16 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhu, X. et al. Influenza chimeric hemagglutinin structures in complex with broadly protective antibodies to the stem and trimer interface. Proc. Natl Acad. Sci. USA 119, e220082111 (2022).

    Article 

    Google Scholar
     

  • Guthmiller, J. J. et al. Broadly neutralizing antibodies target a haemagglutinin anchor epitope. Nature 602, 314–320 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wijesundara, D. K. et al. Rapid response subunit vaccine design in the absence of structural information. Front. Immunol. 11, 592370 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chappell, K. J. et al. Safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Infect. Dis. 21, 1383–1394 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Létourneau, S. et al. Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS ONE 2, e984 (2007).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sliepen, K. et al. Engineering and characterization of a fluorescent native-like HIV-1 envelope glycoprotein trimer. Biomolecules 5, 2919–2934 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • June, C. H., O’Connor, R. S., Kawalekar, O. U., Ghassemi, S. & Milone, M. C. CAR T cell immunotherapy for human cancer. Science 359, 1361–1365 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Slaymaker, I. M. & Gaudelli, N. M. Engineering Cas9 for human genome editing. Curr. Opin. Struct. Biol. 69, 86–98 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ahmad, Z. A. et al. scFv antibody: principles and clinical application. Clin. Dev. Immunol. 2012, 980250 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Permana, D., Putra, H. E. & Djaenudin, D. Designed protein multimerization and polymerization for functionalization of proteins. Biotechnol. Lett. 44, 341–365 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pollock, K. M. et al. Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial. EClinicalMedicine 44, 101262 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Markham, A. Brolucizumab: first approval. Drugs 79, 1997–2000 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Dhillon, S. Tebentafusp: first approval. Drugs 82, 703–710 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ringe, R. P. et al. Closing and opening holes in the glycan shield of HIV-1 envelope glycoprotein SOSIP trimers can redirect the neutralizing antibody response to the newly unmasked epitopes. J. Virol. 93, e01656–18 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Medina-Ramírez, M. et al. Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo. J. Exp. Med. 214, 2573–2590 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Escolano, A. et al. Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques. Nature 570, 468–473 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xu, K. et al. Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1. Nat. Med. 24, 857–867 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Crooks, E. T. et al. Engineering well-expressed, V2-immunofocusing HIV-1 envelope glycoprotein membrane trimers for use in heterologous prime-boost vaccine regimens. PLoS Pathog. 17, e1009807 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Klasse, P. J. et al. Sequential and simultaneous immunization of rabbits with HIV-1 envelope glycoprotein SOSIP.664 trimers from clades A, B and C. PLoS Pathog. 12, e1005864 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • de la Peña, A. T. et al. Immunogenicity in rabbits of HIV-1 SOSIP trimers from clades A, B, and C, given individually, sequentially, or in combination. J. Virol. 92, e01957–17 (2018).


    Google Scholar
     

  • Escolano, A. et al. Sequential immunization elicits broadly neutralizing anti-HIV-1 antibodies in Ig knockin mice. Cell 166, 1445–1458.e12 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Haynes, B. F., Kelsoe, G., Harrison, S. C. & Kepler, T. B. B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study. Nat. Biotechnol. 30, 423–433 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aldon, Y. et al. Rational design of DNA-expressed stabilized native-like HIV-1 envelope trimers. Cell Rep. 24, 3324–3338.e5 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, P. et al. A multiclade env–gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques. Nat. Med. 27, 2234–2245 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Melzi, E. et al. Membrane-bound mRNA immunogens lower the threshold to activate HIV Env V2 apex-directed broadly neutralizing B cell precursors in humanized mice. Immunity 55, 2168–2186.e6 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guenaga, J. et al. Structure-guided redesign increases the propensity of HIV Env to generate highly stable soluble trimers. J. Virol. 90, 2806–2817 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • van Gils, M. J. et al. An HIV-1 antibody from an elite neutralizer implicates the fusion peptide as a site of vulnerability. Nat Microbiol 2, 16199 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Whittle, J. R. R. et al. Flow cytometry reveals that H5N1 vaccination elicits cross-reactive stem-directed antibodies from multiple Ig heavy-chain lineages. J. Virol. 88, 4047–4057 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xiong, X. et al. Enhanced human receptor binding by H5 haemagglutinins. Virology 456–457, 179–187 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Park, M.-S., Steel, J., García-Sastre, A., Swayne, D. & Palese, P. Engineered viral vaccine constructs with dual specificity: avian influenza and Newcastle disease. Proc. Natl. Acad. Sci. USA 103, 8203–8208 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pandey, A. et al. Impact of preexisting adenovirus vector immunity on immunogenicity and protection conferred with an adenovirus-based H5N1 influenza vaccine. PLoS ONE 7, e33428 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pettersen, E. F. et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci. 30, 70–82 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pritchard, L. K. et al. Structural constraints determine the glycosylation of HIV-1 envelope trimers. Cell Rep. 11, 1604–1613 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Suloway, C. et al. Automated molecular microscopy: the new Leginon system. J. Struct. Biol. 151, 41–60 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lander, G. C. et al. Appion: an integrated, database-driven pipeline to facilitate EM image processing. J. Struct. Biol. 166, 95–102 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Scheres, S. H. W. RELION: implementation of a Bayesian approach to cryo-EM structure determination. J. Struct. Biol. 180, 519–530 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kabat, E. A., Te Wu, T., Perry, H. M., Gottesman, K. S. & Foeller, C. Sequences of Proteins of Immunological Interest 5th edition (National Institutes of Health, 1991).

  • Ondondo, B. et al. Novel conserved-region T-cell mosaic vaccine with high global HIV-1 coverage is recognized by protective responses in untreated infection. Mol. Ther. 24, 832–842 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ott, G. et al. MF59. Design and evaluation of a safe and potent adjuvant for human vaccines. Pharm. Biotechnol. 6, 277–296 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Calabro, S. et al. The adjuvant effect of MF59 is due to the oil-in-water emulsion formulation, none of the individual components induce a comparable adjuvant effect. Vaccine 31, 3363–3369 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Montefiori, D. C. Measuring HIV neutralization in a luciferase reporter gene assay. Methods Mol. Biol. 485, 395–405 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wei, X. et al. Antibody neutralization and escape by HIV-1. Nature 422, 307–312 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar