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.

Route of immunization defines multiple mechanisms of vaccine-mediated protection against SIV

Abstract

Antibodies are the primary correlate of protection for most licensed vaccines; however, their mechanisms of protection may vary, ranging from physical blockade to clearance via the recruitment of innate immunity. Here, we uncover striking functional diversity in vaccine-induced antibodies that is driven by immunization site and is associated with reduced risk of SIV infection in nonhuman primates. While equivalent levels of protection were observed following intramuscular (IM) and aerosol (AE) immunization with an otherwise identical DNA prime–Ad5 boost regimen, reduced risk of infection was associated with IgG-driven antibody-dependent monocyte-mediated phagocytosis in the IM vaccinees, but with vaccine-elicited IgA-driven neutrophil-mediated phagocytosis in AE-immunized animals. Thus, although route-independent correlates indicate a critical role for phagocytic Fc-effector activity in protection from SIV, the site of immunization may drive this Fc activity via distinct innate effector cells and antibody isotypes. Moreover, the same correlates predicted protection from SHIV infection in a second nonhuman primate vaccine trial using a disparate IM canarypox prime–protein boost strategy, analogous to that used in the first moderately protective human HIV vaccine trial. These data identify orthogonal functional humoral mechanisms, initiated by distinct vaccination routes and immunization strategies, pointing to multiple, potentially complementary correlates of immunity that may support the rational design of a protective vaccine against HIV.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: There is equivalent protection from SIV acquisition in SIVmac239-immunized animals despite striking Fc-profile differences induced via distinct routes of immunization.
Fig. 2: Fc-biophysical antibody binding profiles accurately predict protection across immunogens and routes of administration.
Fig. 3: Phagocytic vaccine–specific functional antibodies predict protection from infection.
Fig. 4: Dissecting mechanisms of arm-specific protection.
Fig. 5: DNA–rAd5 minimal biomarkers of vaccine response also predict protection in ALVAC/protein-immunized NHPs.

References

  1. Rerks-Ngarm, S. et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N. Engl. J. Med. 361, 2209–2220 (2009).

    CAS  Article  PubMed  Google Scholar 

  2. Haynes, B. F. et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N. Engl. J. Med. 366, 1275–1286 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Barouch, D. H. et al. Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys. Science 349, 320–324 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Barouch, D. H. et al. Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys. Cell 155, 531–539 (2013).

    CAS  Article  PubMed  Google Scholar 

  5. Alpert, M. D. et al. ADCC develops over time during persistent infection with live-attenuated SIV and is associated with complete protection against SIVmac251 challenge. PLoS. Pathog. 8, e1002890 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Fouts, T. R. et al. Balance of cellular and humoral immunity determines the level of protection by HIV vaccines in rhesus macaque models of HIV infection. Proc. Natl Acad. Sci. USA 112, E992–E999 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Bradley, T. et al. Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge. Nat. Commun. 8, 15711 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Hessell, A. J. et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449, 101–104 (2007).

    CAS  Article  PubMed  Google Scholar 

  9. Bournazos, S. et al. Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell 158, 1243–1253 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Roederer, M. et al. Immunological and virological mechanisms of vaccine-mediated protection against SIV and HIV. Nature 505, 502–508 (2014).

    CAS  Article  PubMed  Google Scholar 

  11. Brown, E. P. et al. Microscale purification of antigen-specific antibodies. J. Immunol. Methods 425, 27–36 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Mahan, A. E. et al. A method for high-throughput, sensitive analysis of IgG Fc and Fab glycosylation by capillary electrophoresis. J. Immunol. Methods 417, 34–44 (2015).

    CAS  Article  PubMed  Google Scholar 

  13. Brown, E. P. et al. Multiplexed Fc array for evaluation of antigen-specific antibody effector profiles. J. Immunol. Methods 443, 33–44 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Futosi, K., Fodor, S. & Mócsai, A. Neutrophil cell surface receptors and their intracellular signal transduction pathways. Int. Immunopharmacol. 17, 638–650 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Umaña, P., Jean-Mairet, J., Moudry, R., Amstutz, H. & Bailey, J. E. Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat. Biotechnol. 17, 176–180 (1999).

    Article  PubMed  Google Scholar 

  16. Bruhns, P. et al. Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses. Blood 113, 3716–3725 (2009).

    CAS  Article  PubMed  Google Scholar 

  17. Watkins, J. D. et al. Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission. AIDS 27, F13–F20 (2013).

    CAS  Article  PubMed  Google Scholar 

  18. Boesch, A. W. et al. Biophysical and functional characterization of rhesus macaque IgG subclasses. Front. Immunol. 7, 589 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jacobsen, F. W. et al. Molecular and functional characterization of cynomolgus monkey IgG subclasses. J. Immunol. 186, 341–349 (2011).

    CAS  Article  PubMed  Google Scholar 

  20. Chan, Y. N. et al. IgG binding characteristics of rhesus macaque FcγR. J. Immunol. 197, 2936–2947 (2016).

    CAS  Article  PubMed  Google Scholar 

  21. Trist, H. M. et al. Polymorphisms and interspecies differences of the activating and inhibitory FcγRII of Macaca nemestrina influence the binding of human IgG subclasses. J. Immunol. 192, 792–803 (2014).

    CAS  Article  PubMed  Google Scholar 

  22. Warncke, M. et al. Different adaptations of IgG effector function in human and nonhuman primates and implications for therapeutic antibody treatment. J. Immunol. 188, 4405–4411 (2012).

    CAS  Article  PubMed  Google Scholar 

  23. Yates, N. L. et al. Vaccine-induced Env V1-V2 IgG3 correlates with lower HIV-1 infection risk and declines soon after vaccination. Sci. Transl. Med. 6, 228ra39 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chung, A. W. et al. Polyfunctional Fc-effector profiles mediated by IgG subclass selection distinguish RV144 and VAX003 vaccines. Sci. Transl. Med. 6, 228ra38 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Sips, M. et al. Fc receptor-mediated phagocytosis in tissues as a potent mechanism for preventive and therapeutic HIV vaccine strategies. Mucosal Immunol. 9, 1584–1595 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Chen, G. Y. & Nuñez, G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10, 826–837 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Shi, C. & Pamer, E. G. Monocyte recruitment during infection and inflammation. Nat. Rev. Immunol. 11, 762–774 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Bolton, D. L., Song, K., Tomaras, G. D., Rao, S. & Roederer, M. Unique cellular and humoral immunogenicity profiles generated by aerosol, intranasal, or parenteral vaccination in rhesus macaques. Vaccine 35, 639–646 (2017).

    CAS  Article  PubMed  Google Scholar 

  29. Johansson, E. L., Wassén, L., Holmgren, J., Jertborn, M. & Rudin, A. Nasal and vaginal vaccinations have differential effects on antibody responses in vaginal and cervical secretions in humans. Infect. Immun. 69, 7481–7486 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Kozlowski, P. A., Cu-Uvin, S., Neutra, M. R. & Flanigan, T. P. Comparison of the oral, rectal, and vaginal immunization routes for induction of antibodies in rectal and genital tract secretions of women. Infect. Immun. 65, 1387–1394 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Nardelli-Haefliger, D. et al. Specific antibody levels at the cervix during the menstrual cycle of women vaccinated with human papillomavirus 16 virus–like particles. J. Natl Cancer. Inst. 95, 1128–1137 (2003).

    Article  PubMed  Google Scholar 

  32. Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).

    CAS  Article  PubMed  Google Scholar 

  33. Tomaras, G. D. et al. Vaccine-induced plasma IgA specific for the C1 region of the HIV-1 envelope blocks binding and effector function of IgG. Proc. Natl Acad. Sci. USA 110, 9019–9024 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Chung, A. W. et al. Dissecting polyclonal vaccine–induced humoral immunity against HIV using systems serology. Cell 163, 988–998 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Sholukh, A. M. et al. Defense-in-depth by mucosally administered anti-HIV dimeric IgA2 and systemic IgG1 mAbs: complete protection of rhesus monkeys from mucosal SHIV challenge. Vaccine 33, 2086–2095 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Liu, J. et al. Antibody-mediated protection against SHIV challenge includes systemic clearance of distal virus. Science 353, 1045–1049 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Fischer, W. et al. Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants. Nat. Med. 13, 100–106 (2007).

    CAS  Article  PubMed  Google Scholar 

  38. Letvin, N. L. et al. Immune and genetic correlates of vaccine protection against mucosal infection by SIV in monkeys. Sci. Transl. Med. 3, 81ra36 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ackerman, M. E. et al. Polyfunctional HIV-specific antibody responses are associated with spontaneous HIV control. PLoS. Pathog. 12, e1005315 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Vaccari, M. et al. Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition. Nat. Med. 22, 762–770 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Ackerman, M. E. et al. A robust, high-throughput assay to determine the phagocytic activity of clinical antibody samples. J. Immunol. Methods 366, 8–19 (2011).

    CAS  Article  PubMed  Google Scholar 

  42. McAndrew, E. G. et al. Determining the phagocytic activity of clinical antibody samples. J. Vis. Exp., e3588 (2011).

  43. Gómez-Román, V. R. et al. A simplified method for the rapid fluorometric assessment of antibody-dependent cell-mediated cytotoxicity. J. Immunol. Methods 308, 53–67 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Boesch, A. W. et al. Highly parallel characterization of IgG Fc binding interactions. Mabs 6, 915–927 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  45. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2013).

  46. Smoot, M. E., Ono, K., Ruscheinski, J., Wang, P. L. & Ideker, T. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics 27, 431–432 (2011).

    CAS  Article  PubMed  Google Scholar 

  47. Tibshirani, R. Regression shrinkage and selection via the Lasso. J R Stat. Soc. Series B Stat. Methodol. 58, 267–288 (1996).

    Google Scholar 

  48. Cortes, C. & Vapnik, V. Support-vector Networks. Mach. Learn. 20, 273–297 (1995).

    Google Scholar 

  49. Lau, K. S. et al. In vivo systems analysis identifies spatial and temporal aspects of the modulation of TNF-α-induced apoptosis and proliferation by MAPKs. Sci. Signal. 4, ra16 (2011).

    PubMed  PubMed Central  Google Scholar 

  50. Ojala, M. & Garriga, G. C. Permutation tests for studying classifier performance. J. Mach. Learn. Res. 11, 1833–1863 (2010).

    Google Scholar 

  51. Friedman, J., Hastie, T. & Tibshirani, R. Regularization paths for generalized linear models via coordinate descent. J. Stat. Softw. 33, 1–22 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Cox, D. R. Regression models and life-tables. J R Stat. Soc. Series B Stat. Methodol. 34, 187–220 (1972).

    Google Scholar 

  53. Hastie, T., Tibshirani, R. & Friedman, J. H. The Elements of Statistical Learning: Data mining, Inference, and Prediction, 2nd ed. (Springer, New York, 2009).

  54. Drasgow, F. Polychoric and Polyserial Correlations. in Encyclopedia of Statistical Sciences, 2nd edn. (eds Kotz, S., Read, C. B., Balakrishnan, N., Vidakovic, B. & Johnson, N. L.) (John Wiley and Sons, Inc., Hoboken, NJ, USA, 2006).

  55. Therneau, T. M., & Grambsch, P. M. Modeling Survival Data: Extending the Cox Model (Springer: New York, 2000).

  56. Guyon, I. & Elisseeff, A. An introduction to variable and feature selection. J. Mach. Learn. Res. 3, 1157–1182 (2003).

    Google Scholar 

  57. Harrell, F. E. Jr, Lee, K. L. & Mark, D. B. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat. Med. 15, 361–387 (1996).

    Article  PubMed  Google Scholar 

  58. Reshef, D. N. et al. Detecting novel associations in large data sets. Science 334, 1518–1524 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Lopez-Paz, D., Hennig, P. & Scholkopf, B. The randomized dependence coefficient. in 26th International Conference on Neural Information Processing Systems, Vol. 1 (2013).

Download references

Acknowledgements

We would like to thank W. E. Johnson (Boston University) for his help with statistical review. These studies were supported by the Bill and Melinda Gates Foundation (OPP1032817 and OPP1114729) and the National Institutes of Health (R37 AI080289, R01 AI102291, P01 AI120756, R01 AI131975, and R01 AI102660).

Author information

Authors and Affiliations

Authors

Contributions

M.E.A., M.R. and G.A. conceived of and designed the study. M.E.A., G.D.T., B.F.H., D.A.L., C.B.-K., M.R. and G.A. supervised experimental and statistical analysis. J.D. and S.P. performed data analysis. T. Broge, C.L., E.P.B., T. Bradley, H.N., S.L., J.K.S., S.O.K., N.M., D.G., and M.S. performed assays. T.J.S. and J.A.W. aggregated data. M.E.A., J.D., S.P. and G.A. wrote the manuscript.

Corresponding authors

Correspondence to Margaret E. Ackerman or Galit Alter.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 and Supplementary Tables 12

Reporting Summary

Source Data 1

Source Data

Source Data 2

Source Data

Code File 1

Supplementary Code File

Code File 2

Supplementary Code File

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ackerman, M.E., Das, J., Pittala, S. et al. Route of immunization defines multiple mechanisms of vaccine-mediated protection against SIV. Nat Med 24, 1590–1598 (2018). https://doi.org/10.1038/s41591-018-0161-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41591-018-0161-0

Further reading

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