Review Article | Published:

Passive immunotherapy of viral infections: 'super-antibodies' enter the fray

Nature Reviews Immunology volume 18, pages 297308 (2018) | Download Citation


Antibodies have been used for more than 100 years in the therapy of infectious diseases, but a new generation of highly potent and/or broadly cross-reactive human monoclonal antibodies (sometimes referred to as 'super-antibodies') offers new opportunities for intervention. The isolation of these antibodies, most of which are rarely induced in human infections, has primarily been achieved by large-scale screening for suitable donors and new single B cell approaches to human monoclonal antibody generation. Engineering the antibodies to improve half-life and effector functions has further augmented their in vivo activity in some cases. Super-antibodies offer promise for the prophylaxis and therapy of infections with a range of viruses, including those that are highly antigenically variable and those that are newly emerging or that have pandemic potential. The next few years will be decisive in the realization of the promise of super-antibodies.

Key points

  • Antibodies have been used for over a century prophylactically and, less often, therapeutically against viruses.

  • 'Super-antibodies' — a new generation of highly potent and/or broadly cross-reactive human monoclonal antibodies — offer new opportunities for prophylaxis and therapy of viral infections.

  • Super-antibodies are typically generated infrequently and/or in a limited number of individuals during natural infections.

  • Isolation of these antibodies has primarily been achieved by large-scale screening for suitable donors and new single B cell approaches to human monoclonal antibody generation.

  • Super-antibodies may offer the possibility of treating multiple viruses of a given family with a single reagent. They are also valuable templates for rational vaccine design.

  • The great potency of super-antibodies has many advantages for practical development as therapeutic reagents. These advantages can be enhanced by a variety of antibody engineering technologies.

  • Subscribe to Nature Reviews Immunology for full access:



Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.


  1. 1.

    History and practice: antibodies in infectious diseases. Microbiol. Spectr. (2015).

  2. 2.

    & History of passive antibody administration for prevention and treatment of infectious diseases. Curr. Opin. HIV AIDS 10, 129–134 (2015). This article is an excellent account of the history of passive antibody administration.

  3. 3.

    , , & Therapeutic antibodies for infectious diseases. Bull. World Health Organ. 95, 235–237 (2017).

  4. 4.

    & Antibodies in infectious diseases: polyclonals, monoclonals and niche biotechnology. N. Biotechnol. 28, 489–501 (2011).

  5. 5.

    , & Monoclonal antibody-based therapies for microbial diseases. Vaccine 27 (Suppl. 6), G38–G46 (2009).

  6. 6.

    & Tools to therapeutically harness the human antibody response. Nat. Rev. Immunol. 12, 709–719 (2012).

  7. 7.

    What are the most powerful immunogen design vaccine strategies? Reverse vaccinology 2.0 shows great promise. Cold Spring Harb. Perspect. Biol. 9, a030262 (2017).

  8. 8.

    et al. Cross-neutralizing human anti-poliovirus antibodies bind the recognition site for cellular receptor. Proc. Natl Acad. Sci. USA 110, 20242–20247 (2013).

  9. 9.

    et al. Isolation and characterization of broad and ultrapotent human monoclonal antibodies with therapeutic activity against Chikungunya virus. Cell Host Microbe 18, 86–95 (2015).

  10. 10.

    et al. Functional and structural characterization of neutralizing epitopes of measles virus hemagglutinin protein. J. Virol. 87, 666–675 (2013).

  11. 11.

    et al. Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors. Sci. Immunol. 1, eaaj1879 (2016).

  12. 12.

    et al. Cross-neutralization of four paramyxoviruses by a human monoclonal antibody. Nature 501, 439–443 (2013). This paper is one of the first descriptions of an mAb with pan-virus-type neutralizing ability.

  13. 13.

    et al. Isolation of human monoclonal antibodies that potently neutralize human cytomegalovirus infection by targeting different epitopes on the gH/gL/UL128-131A complex. J. Virol. 84, 1005–1013 (2010).

  14. 14.

    et al. Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection. Science 353, 823–826 (2016).

  15. 15.

    et al. Arenavirus glycan shield promotes neutralizing antibody evasion and protracted infection. PLoS Pathog. 11, e1005276 (2015).

  16. 16.

    et al. Factors associated with the development of cross-reactive neutralizing antibodies during human immunodeficiency virus type 1 infection. J. Virol. 83, 757–769 (2009).

  17. 17.

    et al. The neutralization breadth of HIV-1 develops incrementally over four years and is associated with CD4+ T cell decline and high viral load during acute infection. J. Virol. 85, 4828–4840 (2011).

  18. 18.

    et al. Breadth of human immunodeficiency virus-specific neutralizing activity in sera: clustering analysis and association with clinical variables. J. Virol. 84, 1631–1636 (2010).

  19. 19.

    et al. Human immunodeficiency virus type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm. J. Virol. 83, 7337–7348 (2009). This study describes the assembly and use of a large cohort of HIV-infected individuals with broad neutralizing sera as the starting point for super-antibody generation.

  20. 20.

    , , & Endemic Lassa fever in Liberia. IV. Selection of optimally effective plasma for treatment by passive immunization. Trans. R. Soc. Trop. Med. Hyg. 79, 380–384 (1985).

  21. 21.

    et al. Immune history profoundly affects broadly protective B cell responses to influenza. Sci. Transl Med. 7, 316ra192 (2015).

  22. 22.

    & Human antibodies that neutralize HIV-1: identification, structures, and B cell ontogenies. Immunity 37, 412–425 (2012).

  23. 23.

    & Antibody responses to envelope glycoproteins in HIV-1 infection. Nat. Immunol. 16, 571–576 (2015).

  24. 24.

    , & Broadly neutralizing antibodies and the search for an HIV-1 vaccine: the end of the beginning. Nat. Rev. Immunol. 13, 693–701 (2013).

  25. 25.

    & Broadly neutralizing antibodies to HIV and their role in vaccine design. Annu. Rev. Immunol. 34, 635–659 (2016).

  26. 26.

    et al. Structural insights on the role of antibodies in HIV-1 vaccine and therapy. Cell 156, 633–648 (2014).

  27. 27.

    & Broadly neutralizing antiviral antibodies. Annu. Rev. Immunol. 31, 705–742 (2013). This article is a comprehensive review of bnAbs against multiple viruses.

  28. 28.

    et al. Immune history shapes specificity of pandemic H1N1 influenza antibody responses. J. Exp. Med. 210, 1493–1500 (2013).

  29. 29.

    et al. Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells. Proc. Natl Acad. Sci. USA 109, 9047–9052 (2012).

  30. 30.

    et al. Vaccine-induced antibodies that neutralize group 1 and group 2 influenza A viruses. Cell 166, 609–623 (2016).

  31. 31.

    et al. Preferential induction of cross-group influenza A hemagglutinin stem-specific memory B cells after H7N9 immunization in humans. Sci. Immunol. 2, eaan2676 (2017).

  32. 32.

    et al. Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor. Nature 454, 177–182 (2008).

  33. 33.

    , , & Broadly neutralizing antibodies present new prospects to counter highly antigenically diverse viruses. Science 337, 183–186 (2012).

  34. 34.

    A vaccine for HIV type 1: the antibody perspective. Proc. Natl Acad. Sci. USA 94, 10018–10023 (1997).

  35. 35.

    et al. Broad HIV-1 neutralization mediated by CD4-binding site antibodies. Nat. Med. 13, 1032–1034 (2007).

  36. 36.

    et al. Broadly cross-neutralizing antibodies in HIV-1 patients with undetectable viremia. J. Virol. 85, 5804–5813 (2011).

  37. 37.

    et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326, 285–289 (2009). This article presents the isolation of the first of a new generation of HIV bnAbs and one of the first super-antibodies.

  38. 38.

    et al. PGV04, an HIV-1 gp120 CD4 binding site antibody, is broad and potent in neutralization but does not induce conformational changes characteristic of CD4. J. Virol. 86, 4394–4403 (2012).

  39. 39.

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

  40. 40.

    et al. Recombinant HIV envelope trimer selects for quaternary-dependent antibodies targeting the trimer apex. Proc. Natl Acad. Sci. USA 111, 17624–17629 (2014).

  41. 41.

    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).

  42. 42.

    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). This article describes a very broad influenza virus-specific super-antibody of the type that indicates that a universal flu vaccine may be possible.

  43. 43.

    et al. Development of broad-spectrum human monoclonal antibodies for rabies post-exposure prophylaxis. EMBO Mol. Med. 8, 407–421 (2016).

  44. 44.

    et al. Recurrent potent human neutralizing antibodies to Zika virus in Brazil and Mexico. Cell 169, 597–609.e11 (2017).

  45. 45.

    & Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).

  46. 46.

    et al. Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope-specific broadly neutralizing antibodies and their inferred unmutated common ancestors. J. Virol. 85, 9998–10009 (2011).

  47. 47.

    et al. Identification of a CD4-binding-site antibody to HIV that evolved near-pan neutralization breadth. Immunity 45, 1108–1121 (2016).

  48. 48.

    et al. Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies. Nature 509, 55–62 (2014).

  49. 49.

    et al. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming. Nat. Med. 16, 123–128 (2010).

  50. 50.

    et al. Most neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits. Nat. Commun. 7, 11544 (2016).

  51. 51.

    et al. Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody. Science 340, 1113–1117 (2013).

  52. 52.

    et al. Cross-neutralizing and protective human antibody specificities to poxvirus infections. Cell 167, 684–694.e9 (2016).

  53. 53.

    et al. Prophylactic and postexposure efficacy of a potent human monoclonal antibody against MERS coronavirus. Proc. Natl Acad. Sci. USA 112, 10473–10478 (2015).

  54. 54.

    et al. Cross-reactive and potent neutralizing antibody responses in human survivors of natural ebolavirus infection. Cell 164, 392–405 (2016).

  55. 55.

    et al. Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody. Science 351, 1339–1342 (2016).

  56. 56.

    et al. Structural and molecular basis for Ebola virus neutralization by protective human antibodies. Science 351, 1343–1346 (2016).

  57. 57.

    , , , & A novel strategy for generating monoclonal antibodies from single, isolated lymphocytes producing antibodies of defined specificities. Proc. Natl Acad. Sci. USA 93, 7843–7848 (1996). This article provides the first description of single B cell technology for the isolation of multiple mAbs.

  58. 58.

    et al. Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J. Immunol. Methods 329, 112–124 (2008). This article describes the application of single B cell technology to the isolation of human mAbs.

  59. 59.

    et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

  60. 60.

    et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329, 856–861 (2010). This article presents the isolation of the prototype broadly neutralizing super-antibody to the CD4 binding site, VRC01.

  61. 61.

    et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 329, 811–817 (2010).

  62. 62.

    et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 333, 1633–1637 (2011).

  63. 63.

    et al. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science 333, 1593–1602 (2011).

  64. 64.

    et al. Isolation of potent neutralizing antibodies from a survivor of the 2014 Ebola virus outbreak. Science 351, 1078–1083 (2016). This article describes the isolation of large numbers of mAbs from an Ebola virus survivor immediately following the outbreak and rapid identification of super-antibodies.

  65. 65.

    et al. Characteristics of memory B cells elicited by a highly efficacious HPV vaccine in subjects with no pre-existing immunity. PLoS Pathog. 10, e1004461 (2014).

  66. 66.

    et al. Antibodies from a human survivor define sites of vulnerability for broad protection against ebolaviruses. Cell 169, 878–890.e15 (2017).

  67. 67.

    et al. Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows. Nature 548, 108–111 (2017). This article describes the reliable generation of broadly neutralizing HIV antibodies by simple immunization in cows, suggesting that this animal has special value in super-antibody generation.

  68. 68.

    et al. Immunization-elicited broadly protective antibody reveals ebolavirus fusion loop as a site of vulnerability. Cell 169, 891–904.e15 (2017).

  69. 69.

    , , & Characterization of a circulating subpopulation of spontaneous antitetanus toxoid antibody producing B cells following in vivo booster immunization. J. Immunol. 122, 2498–2504 (1979).

  70. 70.

    et al. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature 453, 667–671 (2008). This article provides a description of a plasmablast approach to super-antibody generation.

  71. 71.

    et al. B Cell responses during secondary Dengue virus infection are dominated by highly cross-reactive, memory-derived plasmablasts. J. Virol. 90, 5574–5585 (2016).

  72. 72.

    et al. A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus. Nat. Immunol. 16, 170–177 (2015).

  73. 73.

    et al. VP4- and VP7-specific antibodies mediate heterotypic immunity to rotavirus in humans. Sci. Transl Med. 9, eaam5434 (2017).

  74. 74.

    et al. Vaccine-induced plasmablast responses in rhesus macaques: phenotypic characterization and a source for generating antigen-specific monoclonal antibodies. J. Immunol. Methods 416, 69–83 (2015).

  75. 75.

    et al. Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J. Exp. Med. 208, 181–193 (2011).

  76. 76.

    et al. Zika virus activates de novo and cross-reactive memory B cell responses in dengue-experienced donors. Sci. Immunol. 2, eaan6809 (2017).

  77. 77.

    et al. Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection. Proc. Natl Acad. Sci. USA 112, 8738–8743 (2015).

  78. 78.

    et al. Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo. Sci. Transl Med. 8, 326ra21 (2016).

  79. 79.

    et al. DNA vaccine-derived human IgG produced in transchromosomal bovines protect in lethal models of hantavirus pulmonary syndrome. Sci. Transl Med. 6, 264ra162 (2014).

  80. 80.

    et al. Antibody preparations from human transchromosomic cows exhibit prophylactic and therapeutic efficacy against Venezuelan equine encephalitis virus. J. Virol. 91, e00226-17 (2017).

  81. 81.

    et al. Production of potent fully human polyclonal antibodies against Ebola Zaire virus in transchromosomal cattle. Sci. Rep. 6, 24897 (2016).

  82. 82.

    et al. Neutralizing human antibodies prevent Zika virus replication and fetal disease in mice. Nature 540, 443–447 (2016).

  83. 83.

    et al. Molecular determinants of human neutralizing antibodies isolated from a patient infected with Zika virus. Sci. Transl Med. 8, 369ra179 (2016).

  84. 84.

    et al. Human antibody responses after dengue virus infection are highly cross-reactive to Zika virus. Proc. Natl Acad. Sci. USA 113, 7852–7857 (2016).

  85. 85.

    et al. Structural basis of potent Zika-dengue virus antibody cross-neutralization. Nature 536, 48–53 (2016).

  86. 86.

    et al. The human immune response to Dengue virus is dominated by highly cross-reactive antibodies endowed with neutralizing and enhancing activity. Cell Host Microbe 8, 271–283 (2010).

  87. 87.

    et al. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature 503, 277–280 (2013).

  88. 88.

    et al. Combination therapy using chimeric monoclonal antibodies protects mice from lethal H5N1 infection and prevents formation of escape mutants. PLoS ONE 4, e5672 (2009).

  89. 89.

    et al. Human-monoclonal-antibody therapy protects nonhuman primates against advanced Lassa fever. Nat. Med. 23, 1146–1149 (2017). This study is the first demonstration in nonhuman primates that mAbs can protect against advanced Lassa fever.

  90. 90.

    et al. Neutralizing human monoclonal antibodies prevent Zika virus infection in macaques. Sci. Transl Med. 9, eaan8184 (2017).

  91. 91.

    et al. Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques. Science 358, 85–90 (2017). This study provides a novel design of antibodies to cope with HIV diversity by incorporating three specificities into a single antibody-like molecule.

  92. 92.

    et al. Protection against a mixed SHIV challenge by a broadly neutralizing antibody cocktail. Sci. Transl Med. 9, eaao4235 (2017).

  93. 93.

    et al. A human bi-specific antibody against Zika virus with high therapeutic potential. Cell 171, 229–241.e15 (2017).

  94. 94.

    [No authors listed.] Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact-RSV Study Group. Pediatrics 102, 531–537 (1998).

  95. 95.

    et al. A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants. Sci. Transl Med. 9, eaaj1928 (2017). This article is a description of an RSV-specific super-antibody that shows about ten times greater in vivo efficacy than palivizumab in cotton rats.

  96. 96.

    et al. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat. Struct. Mol. Biol. 16, 265–273 (2009).

  97. 97.

    et al. Ebola GP-specific monoclonal antibodies protect mice and guinea pigs from lethal Ebola virus infection. PLoS Negl. Trop. Dis. 6, e1575 (2012).

  98. 98.

    et al. Epitopes involved in antibody-mediated protection from Ebola virus. Science 287, 1664–1666 (2000).

  99. 99.

    et al. Protection of Macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies. J. Virol. 73, 4009–4018 (1999).

  100. 100.

    et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat. Med. 6, 207–210 (2000).

  101. 101.

    et al. Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro. J. Virol. 75, 8340–8347 (2001).

  102. 102.

    et al. The hemagglutinin A stem antibody MEDI8852 prevents and controls disease and limits transmission of pandemic influenza viruses. J. Infect. Dis. 216, 356–365 (2017).

  103. 103.

    et al. Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques. Nat. Med. 15, 951–954 (2009).

  104. 104.

    et al. Broadly neutralizing human anti-HIV antibody 2G12 is effective in protection against mucosal SHIV challenge even at low serum neutralizing titers. PLoS Pathog. 5, e1000433 (2009).

  105. 105.

    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).

  106. 106.

    et al. Broadly neutralizing antibodies targeting the HIV-1 envelope V2 apex confer protection against a clade C SHIV challenge. Sci. Transl Med. 9, eaal1321 (2017).

  107. 107.

    & Vectored antibody gene delivery for the prevention or treatment of HIV infection. Curr. Opin. HIV AIDS 10, 190–197 (2015).

  108. 108.

    et al. Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys. Nat. Med. 15, 901–906 (2009). This article is the initial report of vectored prophylaxis applied in macaques.

  109. 109.

    et al. AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature 519, 87–91 (2015). The article describes the extreme breadth for an engineered antibody molecule incorporating novel features.

  110. 110.

    et al. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature 481, 81–84 (2011). This is a study developing vectored immunoprophylaxis for HIV.

  111. 111.

    et al. Sustained delivery of a broadly neutralizing antibody in nonhuman primates confers long-term protection against simian/human immunodeficiency virus infection. J. Virol. 89, 5895–5903 (2015).

  112. 112.

    et al. Protection against dengue disease by synthetic nucleic acid antibody prophylaxis/immunotherapy. Sci. Rep. 5, 12616 (2015).

  113. 113.

    et al. Optimized and enhanced DNA plasmid vector based in vivo construction of a neutralizing anti-HIV-1 envelope glycoprotein Fab. Hum. Vaccines Immunother. 9, 2253–2262 (2013).

  114. 114.

    et al. Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge. Nat. Commun. 8, 14630 (2017).

  115. 115.

    et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat. Genet. 47, 1187–1193 (2015).

  116. 116.

    et al. Erythropoietin gene therapy leads to autoimmune anemia in macaques. Blood 103, 3300–3302 (2004).

  117. 117.

    et al. Monoclonal antibodies produced by muscle after plasmid injection and electroporation. Mol. Ther. 9, 328–336 (2004).

  118. 118.

    & Treatment of respiratory syncytial virus with palivizumab: a systematic review. World J. Pediatr. 6, 296–300 (2010).

  119. 119.

    et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503, 224–228 (2013). This study describes a surprisingly effective monotherapy for SHIV infection in macaques.

  120. 120.

    et al. HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc. Natl Acad. Sci. USA 110, 16538–16543 (2013).

  121. 121.

    et al. Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo. Immunity 10, 431–438 (1999).

  122. 122.

    et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522, 487–491 (2015). This article describes the first use of a super-antibody in HIV infection in humans.

  123. 123.

    et al. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature 535, 556–560 (2016).

  124. 124.

    et al. Antibody 10–1074 suppresses viremia in HIV-1-infected individuals. Nat. Med. 23, 185–191 (2017).

  125. 125.

    et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci. Transl Med. 7, 319ra206 (2015).

  126. 126.

    et al. Effect of HIV antibody VRC01 on viral rebound after treatment interruption. N. Engl. J. Med. 375, 2037–2050 (2016).

  127. 127.

    et al. HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1. Science 352, 997–1001 (2016). This article describes how super-antibody HIV therapy appears to enhance host immune responses in general.

  128. 128.

    et al. Monoclonal antibody therapy for Junin virus infection. Proc. Natl Acad. Sci. USA 113, 4458–4463 (2016).

  129. 129.

    et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature 514, 47–53 (2014). This study is the first demonstration of successful antibody therapy against established Ebola virus disease in nonhuman primates.

  130. 130.

    et al. Nanobodies® as inhaled biotherapeutics for lung diseases. Pharmacol. Ther. 169, 47–56 (2017).

  131. 131.

    et al. Nanobodies® specific for respiratory syncytial virus fusion protein protect against infection by inhibition of fusion. J. Infect. Dis. 204, 1692–1701 (2011).

  132. 132.

    et al. Generation and characterization of ALX-0171, a potent novel therapeutic nanobody for the treatment of respiratory syncytial virus infection. Antimicrob. Agents Chemother. 60, 6–13 (2015).

  133. 133.

    et al. Potent single-domain antibodies that arrest respiratory syncytial virus fusion protein in its prefusion state. Nat. Commun. 8, 14158 (2017). This article describes the use of a single-domain antibody against RSV.

  134. 134.

    et al. Engineered human IgG antibodies with longer serum half-lives in primates. J. Biol. Chem. 279, 6213–6216 (2004).

  135. 135.

    , & Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J. Biol. Chem. 281, 23514–23524 (2006).

  136. 136.

    et al. Enhanced antibody half-life improves in vivo activity. Nat. Biotechnol. 28, 157–159 (2010).

  137. 137.

    et al. Safety, tolerability, and pharmacokinetics of MEDI4893, an investigational, extended-half-life, anti-Staphylococcus aureus alpha-toxin human monoclonal antibody, in healthy adults. Antimicrob. Agents Chemother. 61, e01020-16 (2017).

  138. 138.

    et al. Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. Nature 514, 642–645 (2014).

  139. 139.

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

  140. 140.

    et al. Engineered antibody Fc variants with enhanced effector function. Proc. Natl Acad. Sci. USA 103, 4005–4010 (2006).

  141. 141.

    Molecular engineering and design of therapeutic antibodies. Curr. Opin. Immunol. 20, 460–470 (2008). This is a review of strategies for enhancing antibody effector function.

  142. 142.

    et al. Coupling mammalian cell surface display with somatic hypermutation for the discovery and maturation of human antibodies. Proc. Natl Acad. Sci. USA 108, 20455–20460 (2011).

  143. 143.

    & Yeast surface display for screening combinatorial polypeptide libraries. Nat. Biotechnol. 15, 553–557 (1997).

  144. 144.

    , , & Phage antibodies: filamentous phage displaying antibody variable domains. Nature 348, 552–554 (1990).

  145. 145.

    et al. Generation of a large combinatorial library of the immunoglobulin repertoire in phage lambda. Science 246, 1275–1281 (1989).

  146. 146.

    et al. Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery. Nat. Biotechnol. 32, 356–363 (2014).

  147. 147.

    et al. Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice. Proc. Natl Acad. Sci. USA 111, 5153–5158 (2014).

  148. 148.

    et al. A method for identification of HIV gp140 binding memory B cells in human blood. J. Immunol. Methods 343, 65–67 (2009).

  149. 149.

    , & Human monoclonal antibodies by immortalization of memory B cells. Curr. Opin. Biotechnol. 18, 523–528 (2007).

  150. 150.

    et al. Isolation of human monoclonal antibodies from peripheral blood B cells. Nat. Protoc. 8, 1907–1915 (2013).

  151. 151.

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

  152. 152.

    & Identification and specificity of broadly neutralizing antibodies against HIV. Immunol. Rev. 275, 11–20 (2017).

  153. 153.

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

  154. 154.

    et al. Tackling influenza with broadly neutralizing antibodies. Curr. Opin. Virol. 24, 60–69 (2017).

  155. 155.

    & Perspective on the structural and functional constraints for immune evasion: insights from influenza virus. J. Mol. Biol. 429, 2694–2709 (2017).

  156. 156.

    et al. Structural basis for antibody cross-neutralization of respiratory syncytial virus and human metapneumovirus. Nat. Microbiol. 2, 16272 (2017).

Download references


The authors thank J. Mascola, D. Sok and M. Vasquez for comments on the manuscript. The authors also thank L. Hangartner and C. Corbaci for assistance with figure preparation. D.R.B. acknowledges the financial support from the US National Institute of Allergy and Infectious Disease, the International AIDS Vaccine Initiative, the Bill and Melinda Gates Foundation and the Ragon Institute.

Author information


  1. Adimab LLC, Lebanon, New Hampshire 03766, USA.

    • Laura M. Walker
  2. Department of Immunology and Microbiology, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.

    • Dennis R. Burton
  3. International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA.

    • Dennis R. Burton
  4. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02139, USA.

    • Dennis R. Burton


  1. Search for Laura M. Walker in:

  2. Search for Dennis R. Burton in:


Both authors contributed to research and discussion of the content of the article and to writing, reviewing and editing of the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Laura M. Walker or Dennis R. Burton.


Humanized mouse antibodies

Genetically engineered mouse antibodies in which the protein sequence has been modified to increase its similarity to human antibodies, thereby decreasing its potential immunogenicity.

Transchromosomal cows

Cows that have been genetically modified to incorporate human chromosomes so that upon immunization they generate human antibodies.

Antibody-dependent cellular cytotoxicity

(ADCC). A mechanism by which Fc receptor-bearing effector cells such as natural killer (NK) cells recognize and kill antibody-coated target cells, such as virus-infected cells. The Fc portions of the coating antibodies interact with an Fc receptor (for example, FcγRIII; which is expressed by NK cells), thereby initiating a signalling cascade that results in the release of cytotoxic granules (containing perforin and granzyme B) from the effector cell, which lead to cell death of the antibody-coated cell.

Complement-dependent cytotoxicity

A mechanism of antibody-mediated immunity whereby the association of an antibody on a target cell surface leads to binding of the complement component C1q and triggering of the classical complement cascade. The cascade leads to elimination of target cells by a number of mechanisms, including the formation of the membrane attack complex, the cytolytic end product of the complement cascade.

Hyperimmune globulins

Antibody preparations generated from plasma of donors with high titres of an antibody against a specific pathogen or antigen. Hyperimmune globulins are available against rabies virus, hepatitis B virus and varicella zoster virus, among other viruses.

About this article

Publication history



Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.