Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Antibodies, viruses and vaccines

Abstract

Neutralizing antibodies are crucial for vaccine-mediated protection against viral diseases. They probably act, in most cases, by blunting the infection, which is then resolved by cellular immunity. The protective effects of neutralizing antibodies can be achieved not only by neutralization of free virus particles, but also by several activities directed against infected cells. In certain instances, non-neutralizing antibodies contribute to protection. Several viruses, such as HIV, have evolved mechanisms to evade neutralizing-antibody responses, and these viruses present special challenges for vaccine design that are now being tackled.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The antiviral activities of antibodies.
Figure 2: Viral evasion of antibody responses.
Figure 3: Reverse vaccinology.

Similar content being viewed by others

References

  1. Oldstone, M. B. A. Viruses, Plagues and History (Oxford University Press, New York, 1998).

    Google Scholar 

  2. Whitton, J. L. & Oldstone, M. B. A. in Fields Virology (eds Knipe, D. M. & Howley, P. M.) 285–320 (Lippincott Williams, Philadelphia, 2001).

    Google Scholar 

  3. Zinkernagel, R. M. Maternal antibodies, childhood infections and autoimmune diseases. N. Engl. J. Med. 345, 1331–1335 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Zinkernagel, R. M. et al. Neutralizing antiviral antibody responses. Adv. Immunol. 79, 1–53 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Koff, W. C. & Fauci, A. S. Human trials of AIDS vaccines: current status and future directions. AIDS 3, S125–S129 (1989).

    Article  PubMed  Google Scholar 

  6. Cohen, J. AIDS research. Merck reemerges with a bold AIDS vaccine effort. Science 292, 24–25 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. McMichael, A. & Hanke, T. The quest for an AIDS vaccine: is the CD8+ T-cell approach feasible? Nature Rev. Immunol. 2, 283–291 (2002).

    Article  CAS  Google Scholar 

  8. Robinson, H. L. New hope for an AIDS vaccine. Nature Rev. Immunol. 2, 239–250 (2002).

    Article  CAS  Google Scholar 

  9. Letvin, N. L., Barouch, D. H. & Montefiori, D. C. Prospects for vaccine protection against HIV-1 infection and AIDS. Annu. Rev. Immunol. 20, 73–99 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Dimmock, N. J. Update on the neutralization of animal viruses. Rev. Med. Virol. 5, 165–179 (1995).

    Article  Google Scholar 

  11. Parren, P. W. H. I. and Burton, D. R. The anti-viral activity of antibodies in vitro and in vivo. Adv. Immunol. 77, 195–262 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Burnet, F. M., Keogh, E. V. & Lush, D. The immunological reactions of the filterable viruses. Austral. J. Exp. Biol. Med. Sci. 15, 231–368 (1937).

    CAS  Google Scholar 

  13. Spear, G. T., Hart, M., Olinger, G. G., Hashemi, F. B. & Saifuddin, M. The role of the complement system in virus infections. Curr. Top. Microbiol. Immunol. 260, 229–245 (2001).

    CAS  PubMed  Google Scholar 

  14. McCullough, K. C., Parkinson, D. & Crowther, J. R. Opsonization-enhanced phagocytosis of foot-and-mouth disease virus. Immunology 65, 187–191 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Fujinami, R. S. & Oldstone, M. B. Antiviral antibody reacting on the plasma membrane alters measles virus expression inside the cell. Nature 279, 529–530 (1979).

    Article  CAS  PubMed  Google Scholar 

  16. Levine, B. et al. Antibody-mediated clearance of alphavirus infection from neurons. Science 254, 856–860 (1991).

    Article  CAS  PubMed  Google Scholar 

  17. Gerhard, W. The role of the antibody response in influenza virus infection. Curr. Top. Microbiol. Immunol. 260, 171–190 (2001).

    CAS  PubMed  Google Scholar 

  18. Pantaleo, G. et al. Effect of anti-V3 antibodies on cell-free and cell-to-cell human immunodeficiency virus transmission. Eur. J. Immunol. 25, 226–231 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Burioni, R., Williamson, R. A., Sanna, P. P., Bloom, F. E. & Burton, D. R. Recombinant human Fab to glycoprotein D neutralizes infectivity and prevents cell-to-cell transmission of herpes simplex viruses 1 and 2 in vitro. Proc. Natl Acad. Sci. USA 91, 355–359 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hooks, J. J., Burns, W., Hayashi, K., Geis, S. & Notkins, A. L. Viral spread in the presence of neutralization antibody: mechanisms of persistence in foamy virus infection. Infect. Immun. 14, 1172–1178 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hezareh, M., Hessell, A. J., Jensen, R., van de Winkel, J. G. J. & Parren, P. W. H. I. Effector function activities of a panel of mutants of a broadly neutralizing antibody against human immunodeficiency virus type 1. J. Virol. 75, 12161–12168 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Henchal, E. A., Henchal, L. S. & Schlesinger, J. J. Synergistic interactions of anti-NS1 monoclonal antibodies protect passively immunized mice from lethal challenge with dengue 2 virus. J. Gen. Virol. 69, 2101–2107 (1988).

    Article  PubMed  Google Scholar 

  23. Manzanec, M. B., Lamm, M. E., Lyn, D., Porter, A. & Bedrud, J. G. Comparison of IgA versus IgG monoclonal antibodies for passive immunization of the murine respiratory tract. Virus. Res. 23, 1–12 (1992).

    Article  Google Scholar 

  24. Fujioka, H. et al. Immunocytochemical colocalization of specific immunoglobulin A with sendai virus protein in infected polarized epithelium. J. Exp. Med. 188, 1223–1229 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Manzanec, M. B., Coudret, C. L. & Fletcher, D. R. Intracellular neutralization of influenza virus by immunoglobulin A anti-hemagglutinin monoclonal antibodies. J. Virol. 69, 1339–1343 (1995).

    Google Scholar 

  26. Kato, H., Kato, R., Fujihashi, K. & McGhee, J. R. Role of mucosal antibodies in viral infections. Curr. Top. Microbiol. Immunol. 260, 201–228 (2001).

    CAS  PubMed  Google Scholar 

  27. Bomsel, M. et al. Intracellular neutralization of HIV transcytosis across tight epithelial barriers by anti-HIV envelope protein dlgA or IgM. Immunity 9, 277–287 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Hawkes, R. A. & Lafferty, K. J. The enhancement of virus infectivity by antibody. Virology 33, 250–261 (1967).

    Article  CAS  PubMed  Google Scholar 

  29. Halstead, S. B. Immune enhancement of viral infection. Prog. Allergy 31, 301–364 (1982).

    CAS  PubMed  Google Scholar 

  30. Morens, D. M., Halstead, S. B. & Marchette, N. J. Profiles of antibody-dependent enhancement of dengue virus type 2 infection. Microb. Pathog. 3, 231–237 (1987).

    Article  CAS  PubMed  Google Scholar 

  31. Sullivan, N., Sun, Y., Li, J., Hofmann, W. & Sodroski, J. Replicative function and neutralization sensitivity of envelope glycoproteins from primary and T-cell-line-passaged human immunodeficiency virus type 1 isolates. J. Virol. 69, 4413–4422 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Sullivan, N. J. Antibody-mediated enhancement of viral disease. Curr. Top. Microbiol. Immunol. 260, 145–169 (2001).

    CAS  PubMed  Google Scholar 

  33. Kliks, S. C., Nimmanitya, S., Nisalak, A. & Burke, D. S. Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants. Am. J. Trop. Med. Hyg. 38, 411–419 (1988).

    Article  CAS  PubMed  Google Scholar 

  34. Prince, G. A., Horswood, R. L. & Chanock, R. M. Quantitative aspects of passive immunity to respiratory syncytial virus infection in infant cotton rats. J. Virol. 55, 517–520 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Parren, P. W. H. I. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nishimura, Y. et al. Determination of a statistically valid neutralization titer in plasma that confers protection against simian–human immunodeficiency virus challenge following passive transfer of high-titered neutralizing antibodies. J. Virol. 76, 2123–2130 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wright, K. E. & Buchmeier, M. J. Antiviral antibodies attenuate T-cell-mediated immunopathology following acute lymphocytic choriomeningitis virus infection. J. Virol. 65, 3001–3006 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Parren, P. W. H. I., Geisbert, T. W., Maruyama, T., Jahrling, P. B. & Burton, D. R. Pre- and postexposure prophylaxis of ebola virus infection in an animal model by passive transfer of a neutralizing human antibody. J. Virol. 76, 6408–6412 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Schlesinger, J. J. & Chapman, S. Neutralizing F(ab′)2 fragments of protective monoclonal antibodies to yellow fever virus (YF) envelope protein fails to protect mice against lethal YF encephalitis. J. Gen. Virol. 76, 217–220 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. Chanock, R. M., Crowe, J. E. Jr, Murphy, B. R. & Burton, D. R. Human monoclonal antibody Fab fragments cloned from combinatorial libraries: potential usefulness in prevention and/or treatment of major human viral diseases. Infect. Agents Dis. 2, 118–131 (1993).

    CAS  PubMed  Google Scholar 

  41. 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).

  42. Ogra, P. L., Faden, H. & Welliver, R. C. Vaccination strategies for mucosal immune responses. Clin. Microbiol. Rev. 14, 430–445 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Burns, J. W., Siadat-Pajouh, M., Krishnaney, A. A. & Greenberg, H. G. Protective effect of rotavirus VP6-specific IgA monoclonal antibodies that lack neutralizing activity. Science 272, 104–107 (1996).

    Article  CAS  PubMed  Google Scholar 

  44. Jin, X. et al. Dramatic rise in plasma viremia after CD8+ T-cell depletion in simian immunodeficiency virus-infected macaques. J. Exp. Med. 189, 991–998 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schmitz, J. E. et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283, 857–860 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Kaech, S. M., Wherry, E. J. & Ahmed, R. Effector and memory T-cell differentiation: implications for vaccine development. Nature Rev. Immunol. 2, 251–262 (2002).

    Article  CAS  Google Scholar 

  47. McMichael, A. J. & Rowland-Jones, S. L. Cellular immune responses to HIV. Nature 410, 980–987 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Barouch, D. H. & Letvin, N. L. CD8+ cytotoxic T-lymphocyte responses to lentiviruses and herpesviruses. Curr. Opin. Immunol. 13, 479–482 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Alexander-Miller, M. A., Leggatt, G. R. & Berzofsky, J. A. Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy. Proc. Natl Acad. Sci. USA 93, 4102–4107 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Slifka, M. K. & Whitton, J. L. Functional avidity maturation of CD8+ T cells without selection of higher affinity TCR. Nature Immunol. 2, 711–717 (2001).

    Article  CAS  Google Scholar 

  51. Picker, L. J. & Maino, V. C. The CD4+ T-cell response to HIV-1. Curr. Opin. Immunol. 12, 381–386 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Kalams, S. A. & Walker, B. D. The critical need for CD4 help in maintaining effective cytotoxic T-lymphocyte responses. J. Exp. Med. 188, 2199–2204 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hasenkrug, K. J. & Chesebro, B. Immunity to retroviral infection: the Friend virus model. Proc. Natl Acad. Sci. USA 94, 7811–7816 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Dittmer, U., Brooks, D. M. & Hasenkrug, K. J. Requirement for multiple lymphocyte subsets in protection by a live-attenuated vaccine against retroviral infection. Nature Med. 5, 189–193 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Dittmer, U. & Hasenkrug, K. J. Different immunological requirements for protection against acute versus persistent friend retrovirus infections. Virology 272, 177–182 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Slifka, M. K. & Ahmed, R. Long-term humoral immunity against viruses: revisiting the issue of plasma-cell longevity. Trends Microbiol. 4, 394–400 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Slifka, M. K. & Ahmed, R. Long-lived plasma cells: a mechanism for maintaining persistent antibody production. Curr. Opin. Immunol. 10, 252–258 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Ochsenbein, A. F. et al. Protective long-term antibody memory by antigen-driven and T-help-dependent differentiation of long-lived memory B cells to short-lived plasma cells independent of secondary lymphoid organs. Proc. Natl Acad. Sci. USA 97, 13263–13268 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Janeway, C. A. Use of concentrated human serum γ-globulin in the prevention and attenuation of measles. NY Acad. Med. 21, 202 (1945).

    CAS  Google Scholar 

  60. Krugman, S. The clinical use of γ-globulin. N. Engl. J. Med. 269, 195–201 (1963).

    Article  CAS  PubMed  Google Scholar 

  61. Copelovici, Y., Strulovici, D., Cristea, A. L., Tudor, V. & Armasu, V. Data on the efficiency of specific antimumps immunoglobulins in the prevention of mumps and of its complications. Virologie 30, 171–177 (1979).

    CAS  PubMed  Google Scholar 

  62. Martin du Pan, R., Koechli, B. & Douath, A. Protection of nonimmune volunteers against rubella by intravenous administration of normal human γ-globulin. J. Infect. Dis. 126, 341–344 (1972).

    Article  CAS  PubMed  Google Scholar 

  63. Balfour, H. H. Jr et al. Prevention or modification of varicella using zoster-immune plasma. Am. J. Dis. Child. 131, 693–696 (1977).

    PubMed  Google Scholar 

  64. Kreil, T. R., Maier, E., Fraiss, S. & Eibl, M. M. Neutralizing antibodies protect against lethal flavivirus challenge but allow for the development of active humoral immunity to a nonstructural virus protein. J. Virol. 72, 3076–3081 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Good, R. A. & Zak, S. Z. Disturbance in γ-globulin synthesis as 'experiments of nature'. Pediatrics 18, 109–149 (1956).

    CAS  PubMed  Google Scholar 

  66. Sanna, P. P. & Burton, D. R. Role of antibodies in controlling viral disease: lessons from experiments of nature and gene knockouts. J. Virol. 74, 9813–9817 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Klavinskis, S., Oldstone, M. B. A. & Whitton, J. L. in Vaccines 89. Modern Approaches to New Vaccines Including Prevention of AIDS (eds Brown, F., Chanock, R., Ginsberg, H. & Lerner, R.) 485–489 (Cold Spring Harbor Laboratory Press, 1989).

    Google Scholar 

  68. Ulmer, J. B. et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 259, 1745–1749 (1993).

    Article  CAS  PubMed  Google Scholar 

  69. Kulkarni, A. B. et al. Cytotoxic T cells specific for a single peptide on the M2 protein of respiratory syncytial virus are the sole mediators of resistance induced by immunization with M2 encoded by a recombinant vaccinia virus. J. Virol. 69, 1261–1264 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Hislop, A. D. et al. Vaccine-induced cytotoxic T lymphocytes protect against retroviral challenge. Nature Med. 4, 1193–1196 (1998).

    Article  CAS  PubMed  Google Scholar 

  71. Mateo, L., Gardner, J. & Suhrbier, A. Delayed emergence of bovine leukemia virus after vaccination with a protective cytotoxic T-cell-based vaccine. AIDS Res. Hum. Retroviruses 17, 1447–1453 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Shiver, J. W. et al. Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 415, 331–335 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Allen, T. M. et al. Tat-vaccinated macaques do not control simian immunodeficiency virus SIVmac239 replication. J. Virol. 76, 4108–4112 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bachmann, M. F. & Zinkernagel, R. M. The influence of virus structure on antibody responses and virus serotype formation. Immunol. Today 17, 553–558 (1996).

    Article  CAS  PubMed  Google Scholar 

  75. Bachmann, M. F. & Zinkernagel, R. M. Neutralizing antiviral B-cell responses. Annu. Rev. Immunol. 15, 235–270 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Roben, P. et al. Recognition properties of a panel of human recombinant Fab fragments to the CD4 binding site of gp120 that show differing abilities to neutralize human immunodeficiency virus type 1. J. Virol. 68, 4821–4828 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Sattentau, Q. J. & Moore, J. P. Human immunodeficiency virus type 1 neutralization is determined by epitope exposure on the gp120 oligomer. J. Exp. Med. 182, 185–196 (1995).

    Article  CAS  PubMed  Google Scholar 

  78. Sakurai, H. et al. Human antibody responses to mature and immature forms of viral envelope in respiratory syncytial virus infection: significance for subunit vaccines. J. Virol. 73, 2956–2962 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Moore, J. P. & Ho, D. D. HIV-1 neutralization: the consequences of viral adaptation to growth on transformed T cells. AIDS 9, S117–S136 (1995).

    PubMed  Google Scholar 

  80. Parren, P. W. H. I., Sattentau, Q. J. & Burton, D. R. HIV-1 antibody – debris or virion? Nature Med. 3, 366–367 (1997).

    Article  CAS  PubMed  Google Scholar 

  81. Burton, D. R. & Parren, P. W. H. I. Vaccines and the induction of functional antibodies: time to look beyond the molecules of natural infection? Nature Med. 6, 123–125 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Francis, T. Jr. Influenza: the newe acquayantance. Ann. Int. Med. 39, 203–221 (1953).

    Article  PubMed  Google Scholar 

  83. Davenport, F. M. & Hennessy, A. V. Predetermination by infection and by vaccination of antibody response to influenza virus vaccines. J. Exp. Med. 106, 835–850 (1957).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Fazekas de St. Groth, S. & Webster, R. G. Disquisitions on original antigenic sin. I. Evidence in man. J. Exp. Med. 124, 331–345 (1966).

    Article  CAS  PubMed  Google Scholar 

  85. East, I. J., Todd, P. E. & Leach, S. J. Original antigenic sin: experiments with a defined antigen. Mol. Immunol. 17, 1539–1544 (1980).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I would like to thank K. Hasenkrug, P. Parren, P. Poignard, D. Watkins, L. Whitton, R. Zinkernagel and M. Zwick for critical reading of the manuscript, and many colleagues at the Scripps Research Institute for enlightening discussions. I thank the National Institutes of Health and the International AIDS Vaccine Initiative for financial support.

Author information

Authors and Affiliations

Authors

Related links

Related links

DATABASES

Entrez

BLV

Dengue virus

Ebola virus

EBV

FMDV

FMLV

hepatitis A

hepatitis B

HIV-1

measles

mumps

polio

rabies virus

RSV

rubella

SHIV

SIV

TBEV

varicella zoster

vesicular stomatitis virus

yellow fever virus

LocusLink

CD46

PIGR

Glossary

AGAMMAGLOBULINAEMIC

A person who has an inherited disorder that is characterized by very low levels of immunoglobulins.

DNA-SHUFFLED ENVELOPE LIBRARIES

Libraries of envelope molecules that are produced by in vitro homologous recombination of random fragments of envelope genes generated from pools of parental envelope genes.

HUMANIZED ANTIBODY

An antibody in which protein engineering is used to reduce the amount of 'foreign' protein sequence by swapping rodent antibody constant regions and the variable-domain framework regions with sequences that are found in human antibodies.

ORIGINAL ANTIGENIC SIN

A phenomenon in which the antibody response that is elicted in an individual after secondary viral infection reacts more strongly to the viral variant that originally infected the individual. Can also be shown for closely related antigens of non-viral origin.

SUBUNIT VACCINES

Vaccines that contain only a small part of the pathogen, such as the protein that forms the coat surrounding the nucleic acid of a virus. Usually produced by genetic engineering.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burton, D. Antibodies, viruses and vaccines. Nat Rev Immunol 2, 706–713 (2002). https://doi.org/10.1038/nri891

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri891

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing