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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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).
Haynes, B. F. et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N. Engl. J. Med. 366, 1275–1286 (2012).
Barouch, D. H. et al. Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys. Science 349, 320–324 (2015).
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).
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).
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).
Bradley, T. et al. Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge. Nat. Commun. 8, 15711 (2017).
Hessell, A. J. et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449, 101–104 (2007).
Bournazos, S. et al. Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell 158, 1243–1253 (2014).
Roederer, M. et al. Immunological and virological mechanisms of vaccine-mediated protection against SIV and HIV. Nature 505, 502–508 (2014).
Brown, E. P. et al. Microscale purification of antigen-specific antibodies. J. Immunol. Methods 425, 27–36 (2015).
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).
Brown, E. P. et al. Multiplexed Fc array for evaluation of antigen-specific antibody effector profiles. J. Immunol. Methods 443, 33–44 (2017).
Futosi, K., Fodor, S. & Mócsai, A. Neutrophil cell surface receptors and their intracellular signal transduction pathways. Int. Immunopharmacol. 17, 638–650 (2013).
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).
Bruhns, P. et al. Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses. Blood 113, 3716–3725 (2009).
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).
Boesch, A. W. et al. Biophysical and functional characterization of rhesus macaque IgG subclasses. Front. Immunol. 7, 589 (2016).
Jacobsen, F. W. et al. Molecular and functional characterization of cynomolgus monkey IgG subclasses. J. Immunol. 186, 341–349 (2011).
Chan, Y. N. et al. IgG binding characteristics of rhesus macaque FcγR. J. Immunol. 197, 2936–2947 (2016).
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).
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).
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).
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).
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).
Chen, G. Y. & Nuñez, G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10, 826–837 (2010).
Shi, C. & Pamer, E. G. Monocyte recruitment during infection and inflammation. Nat. Rev. Immunol. 11, 762–774 (2011).
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).
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).
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).
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).
Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).
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).
Chung, A. W. et al. Dissecting polyclonal vaccine–induced humoral immunity against HIV using systems serology. Cell 163, 988–998 (2015).
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).
Liu, J. et al. Antibody-mediated protection against SHIV challenge includes systemic clearance of distal virus. Science 353, 1045–1049 (2016).
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).
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).
Ackerman, M. E. et al. Polyfunctional HIV-specific antibody responses are associated with spontaneous HIV control. PLoS. Pathog. 12, e1005315 (2016).
Vaccari, M. et al. Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition. Nat. Med. 22, 762–770 (2016).
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).
McAndrew, E. G. et al. Determining the phagocytic activity of clinical antibody samples. J. Vis. Exp., e3588 (2011).
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).
Boesch, A. W. et al. Highly parallel characterization of IgG Fc binding interactions. Mabs 6, 915–927 (2014).
R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2013).
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).
Tibshirani, R. Regression shrinkage and selection via the Lasso. J R Stat. Soc. Series B Stat. Methodol. 58, 267–288 (1996).
Cortes, C. & Vapnik, V. Support-vector Networks. Mach. Learn. 20, 273–297 (1995).
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).
Ojala, M. & Garriga, G. C. Permutation tests for studying classifier performance. J. Mach. Learn. Res. 11, 1833–1863 (2010).
Friedman, J., Hastie, T. & Tibshirani, R. Regularization paths for generalized linear models via coordinate descent. J. Stat. Softw. 33, 1–22 (2010).
Cox, D. R. Regression models and life-tables. J R Stat. Soc. Series B Stat. Methodol. 34, 187–220 (1972).
Hastie, T., Tibshirani, R. & Friedman, J. H. The Elements of Statistical Learning: Data mining, Inference, and Prediction, 2nd ed. (Springer, New York, 2009).
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).
Therneau, T. M., & Grambsch, P. M. Modeling Survival Data: Extending the Cox Model (Springer: New York, 2000).
Guyon, I. & Elisseeff, A. An introduction to variable and feature selection. J. Mach. Learn. Res. 3, 1157–1182 (2003).
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).
Reshef, D. N. et al. Detecting novel associations in large data sets. Science 334, 1518–1524 (2011).
Lopez-Paz, D., Hennig, P. & Scholkopf, B. The randomized dependence coefficient. in 26th International Conference on Neural Information Processing Systems, Vol. 1 (2013).
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).
About this article
Current HIV/AIDS Reports (2019)