Fc-Mediated Antibody Effector Functions During Respiratory Syncytial Virus Infection and Disease

Elisabeth A van Erp, Willem Luytjes, Gerben Ferwerda, Puck B van Kasteren, Elisabeth A van Erp, Willem Luytjes, Gerben Ferwerda, Puck B van Kasteren

Abstract

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections and hospitalization in infants under 1 year of age and there is currently no market-approved vaccine available. For protection against infection, young children mainly depend on their innate immune system and maternal antibodies. Traditionally, antibody-mediated protection against viral infections is thought to be mediated by direct binding of antibodies to viral particles, resulting in virus neutralization. However, in the case of RSV, virus neutralization titers do not provide an adequate correlate of protection. The current lack of understanding of the mechanisms by which antibodies can protect against RSV infection and disease or, alternatively, contribute to disease severity, hampers the design of safe and effective vaccines against this virus. Importantly, neutralization is only one of many mechanisms by which antibodies can interfere with viral infection. Antibodies consist of two structural regions: a variable fragment (Fab) that mediates antigen binding and a constant fragment (Fc) that mediates downstream effector functions via its interaction with Fc-receptors on (innate) immune cells or with C1q, the recognition molecule of the complement system. The interaction with Fc-receptors can lead to killing of virus-infected cells through a variety of immune effector mechanisms, including antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Antibody-mediated complement activation may lead to complement-dependent cytotoxicity (CDC). In addition, both Fc-receptor interactions and complement activation can exert a broad range of immunomodulatory functions. Recent studies have emphasized the importance of Fc-mediated antibody effector functions in both protection and pathogenesis for various infectious agents. In this review article, we aim to provide a comprehensive overview of the current knowledge on Fc-mediated antibody effector functions in the context of RSV infection, discuss their potential role in establishing the balance between protection and pathogenesis, and point out important gaps in our understanding of these processes. Furthermore, we elaborate on the regulation of these effector functions on both the cellular and humoral side. Finally, we discuss the implications of Fc-mediated antibody effector functions for the rational design of safe and effective vaccines and monoclonal antibody therapies against RSV.

Keywords: ADCC; ADCP; Fc gamma receptor; Fc-mediated effector functions; RSV; antibody; antibody functionality; vaccine.

Figures

Figure 1
Figure 1
Fc-mediated antibody effector functions. Antibodies elicit a wide range of effector functions during viral infections. These include but are not necessarily limited to the functions depicted in this figure. DC, dendritic cell; FcγR, Fc gamma receptor; MAC, membrane attack complex; NK cell, natural killer cell.
Figure 2
Figure 2
Antibody-dependent cell-mediated cytotoxicity (ADCC). Fc gamma receptors present on for example natural killer (NK) cells engage antibody-bound infected cells and induce target cell death through the release of cytotoxic granules. FcγRIIIA, Fc gamma receptor IIIA; NK cell, natural killer cell; RSV, respiratory syncytial virus.
Figure 3
Figure 3
Antibody-dependent cellular phagocytosis (ADCP). Phagocytes can clear virus-infected cells and immune complexes that are engaged by Fc gamma receptors through phagocytosis. Uptake of viral particles or proteins leads to antigen presentation, which induces the adaptive immune system. FcγR, Fc gamma receptor; MHC, major histocompatibility complex; RSV, respiratory syncytial virus.
Figure 4
Figure 4
Antibody-mediated complement activation. Binding of C1q to antibody-bound virus-infected cells leads to activation of the classical complement pathway. C3 convertase (C4bC2a) is formed and cleaves C3 into C3a and C3b. Active C4b can be cleaved into the enzymatically inactive form C4d, which serves as a marker for complement activation. Further downstream in the classical complement pathway, C5 is cleaved into C5a and C5b. C3a and C5a are anaphylatoxins that stimulate a pro-inflammatory environment, although they act in different ways: C3a induces C3aR signaling, whereas C5a inhibits C3aR expression. C3b binds to pathogens and infected cells, leading to phagocytosis through complement receptors found on immune cells. The terminal complement components will assemble into the membrane attack complex (MAC), resulting in direct lysis of the infected cell. C3aR, C3a Receptor; MAC, membrane attack complex; RSV, respiratory syncytial virus.
Figure 5
Figure 5
Antibody-mediated immunomodulation. Immune complexes can skew immune cell maturation and activation of granulocytes, dendritic cells, T cells, B cells, and phagocytes. This immunomodulation can lead to (A) degranulation, (B) skewing of T cell responses, (C) regulation of B cell antibody responses, and (D) phagocytosis-induced secretion of immunomodulatory mediators. ROS, reactive oxygen species.
Figure 6
Figure 6
Antibody-dependent enhancement (ADE) of infection. ADE of infection has been shown in vitro for multiple viruses, including RSV. High antibody titers neutralize the virus completely. Sub-neutralizing antibody titers form immune complexes that can interact with both the virus receptor and Fc gamma receptors, leading to enhanced infection levels compared to infection in the absence of antibodies.
Figure 7
Figure 7
Antibody-dependent enhancement (ADE) of disease. ADE of disease refers to a process in which the presence of pathogen-specific antibodies contributes to disease severity. Highly neutralizing antibodies result in sterile immunity, preventing infection and disease (left panel). The presence of low levels of protective antibodies allows for viral replication and leads to an Fc-mediated immune response that can either contribute to protection (second panel) or potentially lead to more severe disease (third panel) compared to infection in the absence of antibodies (right panel). It is currently unknown whether Fc-mediated effector functions can lead to severe disease and which immunological mechanisms determine the difference between protective or enhancing Fc-mediated responses.
Figure 8
Figure 8
Antibody glycosylation. Each IgG molecule contains a glycosylation site that can harbor a variety of glycans, consisting of varying combinations of mannose, (bisecting) N-acetylglycosamine, fucose, galactose, and sialic acid. Antibody effector activity is substantially impaired in absence of this glycan. Fab, antigen-binding fragment; Fc, crystallizable fragment; GlcNAc, N-acetylglycosamine.
Figure 9
Figure 9
The balance between Fc-mediated protection and enhanced disease. Antibody effector functions, regulated by differences in antibody characteristics, are suspected to play a role in disease outcome upon RSV infection. Immune activation by Fc-mediated effector functions is likely needed for efficient viral clearance. However, excessive activation may lead to inflammation and tissue damage. A balanced and contained immune response is most likely the key to protection upon infection. Ab, antibody; ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; ADE, antibody-dependent enhancement.

References

    1. Shi T, McAllister DA, O'Brien KL, Simoes EAF, Madhi SA, Gessner BD, et al. . Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet. (2017) 390:946–58. 10.1016/S0140-6736(17)30938-8
    1. Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA, et al. . The burden of respiratory syncytial virus infection in young children. N Engl J Med. (2009) 360:588–98. 10.1056/NEJMoa0804877
    1. Geoghegan S, Erviti A, Caballero MT, Vallone F, Zanone SM, Losada JV, et al. . Mortality due to respiratory syncytial virus. Burden and Risk Factors. Am J Respir Crit Care Med. (2017) 195:96–103. 10.1164/rccm.201603-0658OC
    1. Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child. (1986) 140:543–6. 10.1001/archpedi.1986.02140200053026
    1. Eick A, Karron R, Shaw J, Thumar B, Reid R, Santosham M, et al. . The role of neutralizing antibodies in protection of American Indian infants against respiratory syncytial virus disease. Pediatr Infect Dis J. (2008) 27:207–12. 10.1097/INF.0b013e31815ac585
    1. Chu HY, Steinhoff MC, Magaret A, Zaman K, Roy E, Langdon G, et al. . Respiratory syncytial virus transplacental antibody transfer and kinetics in mother-infant pairs in Bangladesh. J Infect Dis. (2014) 210:1582–9. 10.1093/infdis/jiu316
    1. Vieira SE, Gilio AE, Durigon EL, Ejzenberg B. Lower respiratory tract infection caused by respiratory syncytial virus in infants: the role played by specific antibodies. Clinics. (2007) 62:709–16. 10.1590/S1807-59322007000600009
    1. Stensballe LG, Ravn H, Kristensen K, Agerskov K, Meakins T, Aaby P, et al. . Respiratory syncytial virus neutralizing antibodies in cord blood, respiratory syncytial virus hospitalization, and recurrent wheeze. J Allergy Clin Immunol. (2009) 123:398–403. 10.1016/j.jaci.2008.10.043
    1. Nyiro JU, Sande CJ, Mutunga M, Kiyuka PK, Munywoki PK, Scott JA, et al. . Absence of association between cord specific antibody levels and severe Respiratory Syncytial Virus (RSV) disease in early infants: a case control study from Coastal Kenya. PLoS ONE. (2016) 11:e0166706. 10.1371/journal.pone.0166706
    1. Chu HY, Tielsch J, Katz J, Magaret AS, Khatry S, LeClerq SC, et al. . Transplacental transfer of maternal respiratory syncytial virus (RSV) antibody and protection against RSV disease in infants in rural Nepal. J Clin Virol. (2017) 95:90–5. 10.1016/j.jcv.2017.08.017
    1. Jans J, Wicht O, Widjaja I, Ahout IM, de Groot R, Guichelaar T, et al. . Characteristics of RSV-specific maternal antibodies in plasma of hospitalized, acute RSV patients under three months of age. PLoS ONE. (2017) 12:e0170877. 10.1371/journal.pone.0170877
    1. Plotkin SA, Gilbert P. (2018). Correlates of protection. In: Plotkin SA, editor. Plotkin's Vaccines. 7th ed. Philadelphia, PA: Elsevier; 35–40. 10.1016/B978-0-323-35761-6.00003-1
    1. DiLillo DJ, Tan GS, Palese P, Ravetch JV. Broadly neutralizing hemagglutinin stalk-specific antibodies require FcγR interactions for protection against influenza virus in vivo. Nat Med. (2014) 20:143–51. 10.1038/nm.3443
    1. Henry Dunand CJ, Leon PE, Huang M, Choi A, Chromikova V, Ho IY, et al. . Both neutralizing and non-neutralizing human H7N9 influenza vaccine-induced monoclonal antibodies confer protection. Cell Host Microbe. (2016) 19:800–13. 10.1016/j.chom.2016.05.014
    1. Vanderven HA, Liu L, Ana-Sosa-Batiz F, Nguyen TH, Wan Y, Wines B, et al. . Fc functional antibodies in humans with severe H7N9 and seasonal influenza. JCI Insight. (2017) 2:92750. 10.1172/jci.insight.92750
    1. Hessell AJ, Hangartner L, Hunter M, Havenith CE, Beurskens FJ, Bakker JM, et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature. (2007) 449:101–4. 10.1038/nature06106
    1. Bournazos S, Klein F, Pietzsch J, Seaman MS, Nussenzweig MC, Ravetch JV. Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell. (2014) 158:1243–53. 10.1016/j.cell.2014.08.023
    1. Gunn BM, Yu WH, Karim MM, Brannan JM, Herbert AS, Wec AZ, et al. . A role for Fc function in therapeutic monoclonal antibody-mediated protection against ebola virus. Cell Host Microbe. (2018) 24:221–233.e225. 10.1016/j.chom.2018.07.009
    1. Saphire EO, Schendel SL, Fusco ML, Gangavarapu K, Gunn BM, Wec AZ, et al. . Systematic analysis of monoclonal antibodies against ebola virus GP defines features that contribute to protection. Cell. (2018) 174:938–52 e913. 10.1016/j.cell.2018.07.033
    1. Acosta EG, Bartenschlager R. Paradoxical role of antibodies in dengue virus infections: considerations for prophylactic vaccine development. Expert Rev Vacc. (2016) 15:467–82. 10.1586/14760584.2016.1121814
    1. Wang TT, Sewatanon J, Memoli MJ, Wrammert J, Bournazos S, Bhaumik SK, et al. . IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity. Science. (2017) 355:395–8. 10.1126/science.aai8128
    1. Polack FP, Teng MN, Collins PL, Prince GA, Exner M, Regele H, et al. . A role for immune complexes in enhanced respiratory syncytial virus disease. J Exp Med. (2002) 196:859–65. 10.1084/jem.20020781
    1. Openshaw PJ, Tregoning JS. Immune responses and disease enhancement during respiratory syncytial virus infection. Clin Microbiol Rev. (2005) 18:541–55. 10.1128/CMR.18.3.541-555.2005
    1. Delgado MF, Coviello S, Monsalvo AC, Melendi GA, Hernandez JZ, Batalle JP, et al. . Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease. Nat Med. (2009) 15:34–41. 10.1038/nm.1894
    1. Smyth MJ, Cretney E, Kelly JM, Westwood JA, Street SE, Yagita H, et al. . Activation of NK cell cytotoxicity. Mol Immunol. (2005) 42:501–10. 10.1016/j.molimm.2004.07.034
    1. Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. (2012) 12:278–87. 10.1038/nrc3236
    1. Bonsignori M, Pollara J, Moody MA, Alpert MD, Chen X, Hwang KK, et al. . Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial target multiple epitopes and preferentially use the VH1 gene family. J Virol. (2012) 86:11521–32. 10.1128/JVI.01023-12
    1. Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras GD, Alam SM, et al. . Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med. (2012) 366:1275–86. 10.1056/NEJMoa1113425
    1. Corey L, Gilbert PB, Tomaras GD, Haynes BF, Pantaleo G, Fauci AS. Immune correlates of vaccine protection against HIV-1 acquisition. Sci Transl Med. (2015) 7:310rv317. 10.1126/scitranslmed.aac7732
    1. Baum LL, Cassutt KJ, Knigge K, Khattri R, Margolick J, Rinaldo C, et al. . HIV-1 gp120-specific antibody-dependent cell-mediated cytotoxicity correlates with rate of disease progression. J Immunol. (1996) 157:2168–73.
    1. Lambotte O, Ferrari G, Moog C, Yates NL, Liao HX, Parks RJ, et al. . Heterogeneous neutralizing antibody and antibody-dependent cell cytotoxicity responses in HIV-1 elite controllers. AIDS. (2009) 23:897–906. 10.1097/QAD.0b013e328329f97d
    1. Wren LH, Chung AW, Isitman G, Kelleher AD, Parsons MS, Amin J, et al. . Specific antibody-dependent cellular cytotoxicity responses associated with slow progression of HIV infection. Immunology. (2013) 138:116–23. 10.1111/imm.12016
    1. Ackerman ME, Mikhailova A, Brown EP, Dowell KG, Walker BD, Bailey-Kellogg C, et al. . Polyfunctional HIV-Specific Antibody Responses Are Associated with Spontaneous HIV Control. PLoS Pathog. (2016) 12:e1005315. 10.1371/journal.ppat.1005315
    1. Jegaskanda S, Luke C, Hickman HD, Sangster MY, Wieland-Alter WF, McBride JM, et al. . Generation and protective ability of influenza virus-specific antibody-dependent cellular cytotoxicity in humans elicited by vaccination, natural infection, and experimental challenge. J Infect Dis. (2016) 214:945–52. 10.1093/infdis/jiw262
    1. Vanderven HA, Jegaskanda S, Wheatley AK, Kent SJ. Antibody-dependent cellular cytotoxicity and influenza virus. Curr Opin Virol. (2017) 22:89–96. 10.1016/j.coviro.2016.12.002
    1. Huber VC, Lynch JM, Bucher DJ, Le J, Metzger DW. Fc receptor-mediated phagocytosis makes a significant contribution to clearance of influenza virus infections. J Immunol. (2001) 166:7381–8. 10.4049/jimmunol.166.12.7381
    1. Khurana S, Loving CL, Manischewitz J, King LR, Gauger PC, Henningson J, et al. . Vaccine-induced anti-HA2 antibodies promote virus fusion and enhance influenza virus respiratory disease. Sci Transl Med. (2013) 5:200ra114. 10.1126/scitranslmed.3006366
    1. Co MD, Terajima M, Thomas SJ, Jarman RG, Rungrojcharoenkit K, Fernandez S, et al. . Relationship of preexisting influenza hemagglutination inhibition, complement-dependent lytic, and antibody-dependent cellular cytotoxicity antibodies to the development of clinical illness in a prospective study of A(H1N1)pdm09 Influenza in children. Viral Immunol. (2014) 27:375–82. 10.1089/vim.2014.0061
    1. Ye ZW, Yuan S, Poon KM, Wen L, Yang D, Sun Z, et al. . Antibody-dependent cell-mediated cytotoxicity epitopes on the hemagglutinin head region of pandemic H1N1 influenza virus play detrimental roles in H1N1-infected mice. Front Immunol. (2017) 8:317. 10.3389/fimmu.2017.00317
    1. Garcia G, Arango M, Perez AB, Fonte L, Sierra B, Rodriguez-Roche R, et al. . Antibodies from patients with dengue viral infection mediate cellular cytotoxicity. J Clin Virol. (2006) 37:53–7. 10.1016/j.jcv.2006.04.010
    1. Laoprasopwattana K, Libraty DH, Endy TP, Nisalak A, Chunsuttiwat S, Ennis FA, et al. . Antibody-dependent cellular cytotoxicity mediated by plasma obtained before secondary dengue virus infections: potential involvement in early control of viral replication. J Infect Dis. (2007) 195:1108–16. 10.1086/512860
    1. Liu Q, Fan C, Li Q, Zhou S, Huang W, Wang L, et al. . Antibody-dependent-cellular-cytotoxicity-inducing antibodies significantly affect the post-exposure treatment of Ebola virus infection. Sci Rep. (2017) 7:45552. 10.1038/srep45552
    1. Hussell T, Openshaw PJ. Intracellular IFN-gamma expression in natural killer cells precedes lung CD8+ T cell recruitment during respiratory syncytial virus infection. J Gen Virol. (1998) 79(Pt 11):2593–601. 10.1099/0022-1317-79-11-2593
    1. Li F, Zhu H, Sun R, Wei H, Tian Z. Natural killer cells are involved in acute lung immune injury caused by respiratory syncytial virus infection. J Virol. (2012) 86:2251–8. 10.1128/JVI.06209-11
    1. Long X, Xie J, Zhao K, Li W, Tang W, Chen S, et al. . NK cells contribute to persistent airway inflammation and AHR during the later stage of RSV infection in mice. Med Microbiol Immunol. (2016) 205:459–70. 10.1007/s00430-016-0459-9
    1. Welliver TP, Garofalo RP, Hosakote Y, Hintz KH, Avendano L, Sanchez K, et al. . Severe human lower respiratory tract illness caused by respiratory syncytial virus and influenza virus is characterized by the absence of pulmonary cytotoxic lymphocyte responses. J Infect Dis. (2007) 195:1126–36. 10.1086/512615
    1. Larranaga CL, Ampuero SL, Luchsinger VF, Carrion FA, Aguilar NV, Morales PR, et al. . Impaired immune response in severe human lower tract respiratory infection by respiratory syncytial virus. Pediatr Infect Dis J. (2009) 28:867–73. 10.1097/INF.0b013e3181a3ea71
    1. Brand HK, Ferwerda G, Preijers F, de Groot R, Neeleman C, Staal FJ, et al. . CD4+ T-cell counts and interleukin-8 and CCL-5 plasma concentrations discriminate disease severity in children with RSV infection. Pediatr Res. (2013) 73:187–93. 10.1038/pr.2012.163
    1. Leahy TR, McManus R, Doherty DG, Grealy R, Coulter T, Smyth P, et al. . Interleukin-15 is associated with disease severity in viral bronchiolitis. Eur Respir J. (2016) 47:212–22. 10.1183/13993003.00642-2015
    1. Tripp RA, Moore D, Barskey A, IV, Jones L, Moscatiello C, Keyserling H, et al. . Peripheral blood mononuclear cells from infants hospitalized because of respiratory syncytial virus infection express T helper-1 and T helper-2 cytokines and CC chemokine messenger RNA. J Infect Dis. (2002) 185:1388–94. 10.1086/340505
    1. Kerrin A, Fitch P, Errington C, Kerr D, Waxman L, Riding K, et al. . Differential lower airway dendritic cell patterns may reveal distinct endotypes of RSV bronchiolitis. Thorax. (2017) 72:620–7. 10.1136/thoraxjnl-2015-207358
    1. Scott R, de Landazuri MO, Gardner PS, Owen JJ. Human antibody-dependent cell-mediated cytotoxicity against target cells infected with respiratory syncytial virus. Clin Exp Immunol. (1977) 28:19–26.
    1. Meguro H, Kervina M, Wright PF. Antibody-dependent cell-mediated cytotoxicity against cells infected with respiratory syncytial virus: characterization of in vitro and in vivo properties. J Immunol. (1979) 122:2521–6.
    1. McLellan JS, Chen M, Leung S, Graepel KW, Du X, Yang Y, et al. . Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody. Science. (2013) 340:1113–7. 10.1126/science.1234914
    1. Gupta N, LeGoff J, Chamat S, Mercier-Delarue S, Touzelet O, Power UF, et al. . Affinity-purified respiratory syncytial virus antibodies from intravenous immunoglobulin exert potent antibody-dependent cellular cytotoxicity. PLoS ONE. (2013) 8:e69390. 10.1371/journal.pone.0069390
    1. Cortjens B, Yasuda E, Yu X, Wagner K, Claassen YB, Bakker AQ, et al. ls. J Virol. (2017) 91:e02357–16. 10.1128/JVI.02357-16
    1. Haynes LM, Caidi H, Radu GU, Miao C, Harcourt JL, Tripp RA, et al. . Therapeutic monoclonal antibody treatment targeting respiratory syncytial virus (RSV) G protein mediates viral clearance and reduces the pathogenesis of RSV infection in BALB/c mice. J Infect Dis. (2009) 200:439–47. 10.1086/600108
    1. Miao C, Radu GU, Caidi H, Tripp RA, Anderson LJ, Haynes LM. Treatment with respiratory syncytial virus G glycoprotein monoclonal antibody or F(ab')2 components mediates reduced pulmonary inflammation in mice. J Gen Virol. (2009) 90(Pt 5):1119–23. 10.1099/vir.0.009308-0
    1. Kaul TN, Welliver RC, Ogra PL. Development of antibody-dependent cell-mediated cytotoxicity in the respiratory tract after natural infection with respiratory syncytial virus. Infect Immun. (1982) 37:492–8.
    1. Corbeil S, Seguin C, Trudel M. Involvement of the complement system in the protection of mice from challenge with respiratory syncytial virus Long strain following passive immunization with monoclonal antibody 18A2B2. Vaccine. (1996) 14:521–5. 10.1016/0264-410X(95)00222-M
    1. Mekseepralard C, Toms GL, Routledge EG. Protection of mice against Human respiratory syncytial virus by wild-type and aglycosyl mouse-human chimaeric IgG antibodies to subgroup-conserved epitopes on the G glycoprotein. J Gen Virol. (2006) 87(Pt 5):1267–73. 10.1099/vir.0.81660-0
    1. He W, Chen CJ, Mullarkey CE, Hamilton JR, Wong CK, Leon PE, et al. . Alveolar macrophages are critical for broadly-reactive antibody-mediated protection against influenza A virus in mice. Nat Commun. (2017) 8:846. 10.1038/s41467-017-00928-3
    1. Ana-Sosa-Batiz F, Vanderven H, Jegaskanda S, Johnston A, Rockman S, Laurie K, et al. . Influenza-specific antibody-dependent phagocytosis. PLoS ONE. (2016) 11:e0154461. 10.1371/journal.pone.0154461
    1. Baraniak I, Kropff B, Ambrose L, McIntosh M, McLean GR, Pichon S, et al. Protection from cytomegalovirus viremia following glycoprotein B vaccination is not dependent on neutralizing antibodies. Proc Natl Acad Sci USA. (2018) 115:6273–8. 10.1073/pnas.1800224115
    1. Nelson CS, Huffman T, Jenks JA, Cisneros de la Rosa E, Xie G, Vandergrift N, et al. . HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions. Proc Natl Acad Sci USA. (2018) 115:6267–72. 10.1073/pnas.1800177115
    1. Barouch DH, Stephenson KE, Borducchi EN, Smith K, Stanley K, McNally AG, et al. . Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys. Cell. (2013) 155:531–9. 10.1016/j.cell.2013.09.061
    1. Barouch DH, Alter G, Broge T, Linde C, Ackerman ME, Brown EP, et al. . Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys. Science. (2015) 349:320–4. 10.1126/science.aab3886
    1. Zaiss AK, Vilaysane A, Cotter MJ, Clark SA, Meijndert HC, Colarusso P, et al. . Antiviral antibodies target adenovirus to phagolysosomes and amplify the innate immune response. J Immunol. (2009) 182:7058–68. 10.4049/jimmunol.0804269
    1. Vogt MR, Dowd KA, Engle M, Tesh RB, Johnson S, Pierson TC, et al. . Poorly neutralizing cross-reactive antibodies against the fusion loop of West Nile virus envelope protein protect in vivo via Fcgamma receptor and complement-dependent effector mechanisms. J Virol. (2011) 85:11567–80. 10.1128/JVI.05859-11
    1. McCullough KC, Parkinson D, Crowther JR. Opsonization-enhanced phagocytosis of foot-and-mouth disease virus. Immunology. (1988) 65:187–91.
    1. Quattrocchi V, Langellotti C, Pappalardo JS, Olivera V, Di Giacomo S, van Rooijen N, et al. . Role of macrophages in early protective immune responses induced by two vaccines against foot and mouth disease. Antiviral Res. (2011) 92:262–70. 10.1016/j.antiviral.2011.08.007
    1. Faden H, Kaul TN, Ogra PL. Activation of oxidative and arachidonic acid metabolism in neutrophils by respiratory syncytial virus antibody complexes: possible role in disease. J Infect Dis. (1983) 148:110–6. 10.1093/infdis/148.1.110
    1. Arnold R, Werner F, Humbert B, Werchau H, Konig W. Effect of respiratory syncytial virus-antibody complexes on cytokine (IL-8, IL-6, TNF-alpha) release and respiratory burst in human granulocytes. Immunology. (1994) 82:184–91.
    1. Kimpen JL, Garofalo R, Welliver RC, Fujihara K, Ogra PL. An ultrastructural study of the interaction of human eosinophils with respiratory syncytial virus. Pediatr Allergy Immunol. (1996) 7:48–53. 10.1111/j.1399-3038.1996.tb00105.x
    1. Bukreyev A, Yang L, Collins PL. The secreted G protein of human respiratory syncytial virus antagonizes antibody-mediated restriction of replication involving macrophages and complement. J Virol. (2012) 86:10880–4. 10.1128/JVI.01162-12
    1. Borsos T, Rapp HJ. Complement fixation on cell surfaces by 19S and 7S antibodies. Science. (1965) 150:505–6. 10.1126/science.150.3695.505
    1. Diebolder CA, Beurskens FJ, de Jong RN, Koning RI, Strumane K, Lindorfer MA, et al. . Complement is activated by IgG hexamers assembled at the cell surface. Science. (2014) 343:1260–3. 10.1126/science.1248943
    1. Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT. Complement system part I - molecular mechanisms of activation and regulation. Front Immunol. (2015) 6:262. 10.3389/fimmu.2015.00262
    1. Merle NS, Noe R, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina LT. Complement system part II: role in immunity. Front Immunol. (2015) 6:257. 10.3389/fimmu.2015.00257
    1. Hebell T, Ahearn JM, Fearon DT. Suppression of the immune response by a soluble complement receptor of B lymphocytes. Science. (1991) 254:102–5. 10.1126/science.1718035
    1. Gonzalez SF, Lukacs-Kornek V, Kuligowski MP, Pitcher LA, Degn SE, Turley SJ, et al. . Complement-dependent transport of antigen into B cell follicles. J Immunol. (2010) 185:2659–64. 10.4049/jimmunol.1000522
    1. Mehlhop E, Nelson S, Jost CA, Gorlatov S, Johnson S, Fremont DH, et al. . Complement protein C1q reduces the stoichiometric threshold for antibody-mediated neutralization of West Nile virus. Cell Host Microbe. (2009) 6:381–91. 10.1016/j.chom.2009.09.003
    1. Wu Y, Cho M, Shore D, Song M, Choi J, Jiang T, et al. . A potent broad-spectrum protective human monoclonal antibody crosslinking two haemagglutinin monomers of influenza A virus. Nat Commun. (2015) 6:7708. 10.1038/ncomms8708
    1. Benhnia MR, McCausland MM, Laudenslager J, Granger SW, Rickert S, Koriazova L, et al. . Heavily isotype-dependent protective activities of human antibodies against vaccinia virus extracellular virion antigen B5. J Virol. (2009) 83:12355–67. 10.1128/JVI.01593-09
    1. Li F, Freed DC, Tang A, Rustandi RR, Troutman MC, Espeseth AS, et al. . Complement enhances in vitro neutralizing potency of antibodies to human cytomegalovirus glycoprotein B (gB) and immune sera induced by gB/MF59 vaccination. NPJ Vacc. (2017) 2:36. 10.1038/s41541-017-0038-0
    1. Churdboonchart V, Bhamarapravati N, Futrakul P. Crossed immunoelectrophoresis for the detection of split products of the third complement in dengue hemorrhagic fever. I. Observations in patients' plasma. Am J Trop Med Hyg. (1983) 32:569–76. 10.4269/ajtmh.1983.32.569
    1. Nascimento EJ, Silva AM, Cordeiro MT, Brito CA, Gil LH, Braga-Neto U, et al. . Alternative complement pathway deregulation is correlated with dengue severity. PLoS ONE. (2009) 4:e6782. 10.1371/journal.pone.0006782
    1. Senaldi G, Peakman M, McManus T, Davies ET, Tee DE, Vergani D. Activation of the complement system in human immunodeficiency virus infection: relevance of the classical pathway to pathogenesis and disease severity. J Infect Dis. (1990) 162:1227–32. 10.1093/infdis/162.6.1227
    1. Fust G, Toth FD, Kiss J, Ujhelyi E, Nagy I, Banhegyi D. Neutralizing and enhancing antibodies measured in complement-restored serum samples from HIV-1-infected individuals correlate with immunosuppression and disease. AIDS. (1994) 8:603–9. 10.1097/00002030-199405000-00005
    1. Kaul TN, Welliver RC, Ogra PL. Appearance of complement components and immunoglobulins on nasopharyngeal epithelial cells following naturally acquired infection with respiratory syncytial virus. J Med Virol. (1982) 9:149–58. 10.1002/jmv.1890090210
    1. Kaul TN, Welliver RC, Ogra PL. Comparison of fluorescent-antibody, neutralizing-antibody, and complement-enhanced neutralizing-antibody assays for detection of serum antibody to respiratory syncytial virus. J Clin Microbiol. (1981) 13:957–62.
    1. Kruijsen D, Bakkers MJ, van Uden NO, Viveen MC, van der Sluis TC, Kimpen JL, et al. . Serum antibodies critically affect virus-specific CD4+/CD8+ T cell balance during respiratory syncytial virus infections. J Immunol. (2010) 185:6489–98. 10.4049/jimmunol.1002645
    1. Melendi GA, Hoffman SJ, Karron RA, Irusta PM, Laham FR, Humbles A, et al. . C5 modulates airway hyperreactivity and pulmonary eosinophilia during enhanced respiratory syncytial virus disease by decreasing C3a receptor expression. J Virol. (2007) 81:991–9. 10.1128/JVI.01783-06
    1. Bera MM, Lu B, Martin TR, Cui S, Rhein LM, Gerard C, et al. . Th17 cytokines are critical for respiratory syncytial virus-associated airway hyperreponsiveness through regulation by complement C3a and tachykinins. J Immunol. (2011) 187:4245–55. 10.4049/jimmunol.1101789
    1. Hu X, Li X, Hu C, Qin L, He R, Luo L, et al. . Respiratory Syncytial Virus Exacerbates OVA-mediated asthma in mice through C5a-C5aR regulating CD4(+)T cells Immune Responses. Sci Rep. (2017) 7:15207. 10.1038/s41598-017-15471-w
    1. Bradley T, Pollara J, Santra S, Vandergrift N, Pittala S, Bailey-Kellogg C, et al. . Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge. Nat Commun. (2017) 8:15711. 10.1038/ncomms15711
    1. Nimmerjahn F, Ravetch JV. Fcgamma receptors: old friends and new family members. Immunity. (2006) 24:19–28. 10.1016/j.immuni.2005.11.010
    1. Nimmerjahn F, Ravetch JV. Anti-inflammatory actions of intravenous immunoglobulin. Annu Rev Immunol. (2008) 26:513–33. 10.1146/annurev.immunol.26.021607.090232
    1. Pearse RN, Kawabe T, Bolland S, Guinamard R, Kurosaki T, Ravetch JV. SHIP recruitment attenuates Fc gamma RIIB-induced B cell apoptosis. Immunity. (1999) 10:753–60. 10.1016/S1074-7613(00)80074-6
    1. Bolland S, Ravetch JV. Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity. (2000) 13:277–85. 10.1016/S1074-7613(00)00027-3
    1. Wang TT, Maamary J, Tan GS, Bournazos S, Davis CW, Krammer F, et al. . Anti-HA glycoforms drive B cell affinity selection and determine influenza vaccine efficacy. Cell. (2015) 162:160–9. 10.1016/j.cell.2015.06.026
    1. Amigorena S, Salamero J, Davoust J, Fridman WH, Bonnerot C. Tyrosine-containing motif that transduces cell activation signals also determines internalization and antigen presentation via type III receptors for IgG. Nature. (1992) 358:337–41. 10.1038/358337a0
    1. Boruchov AM, Heller G, Veri MC, Bonvini E, Ravetch JV, Young JW. Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. J Clin Invest. (2005) 115:2914–23. 10.1172/JCI24772
    1. Dhodapkar KM, Kaufman JL, Ehlers M, Banerjee DK, Bonvini E, Koenig S, et al. . Selective blockade of inhibitory Fcgamma receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells. Proc Natl Acad Sci USA. (2005) 102:2910–5. 10.1073/pnas.0500014102
    1. Dhodapkar KM, Banerjee D, Connolly J, Kukreja A, Matayeva E, Veri MC, et al. . Selective blockade of the inhibitory Fcgamma receptor (FcgammaRIIB) in human dendritic cells and monocytes induces a type I interferon response program. J Exp Med. (2007) 204:1359–69. 10.1084/jem.20062545
    1. Anderson CF, Mosser DM. Cutting edge: biasing immune responses by directing antigen to macrophage Fc gamma receptors. J Immunol. (2002) 168:3697–701. 10.4049/jimmunol.168.8.3697
    1. Kaul TN, Faden H, Ogra PL. Effect of respiratory syncytial virus and virus-antibody complexes on the oxidative metabolism of human neutrophils. Infect Immun. (1981) 32:649–54.
    1. Everard ML, Swarbrick A, Wrightham M, McIntyre J, Dunkley C, James PD, et al. . Analysis of cells obtained by bronchial lavage of infants with respiratory syncytial virus infection. Arch Dis Child. (1994) 71:428–32. 10.1136/adc.71.5.428
    1. Bataki EL, Evans GS, Everard ML. Respiratory syncytial virus and neutrophil activation. Clin Exp Immunol. (2005) 140:470–7. 10.1111/j.1365-2249.2005.02780.x
    1. Gomez RS, Ramirez BA, Cespedes PF, Cautivo KM, Riquelme SA, Prado CE, et al. . Contribution of Fcγ receptors to human respiratory syncytial virus pathogenesis and the impairment of T cell activation by dendritic cells. Immunology. (2015) 147:55–72. 10.1111/imm.12541
    1. Schijf MA, Lukens MV, Kruijsen D, van Uden NO, Garssen J, Coenjaerts FE, et al. . Respiratory syncytial virus induced type I IFN production by pDC is regulated by RSV-infected airway epithelial cells, RSV-exposed monocytes and virus specific antibodies. PLoS ONE. (2013) 8:e81695. 10.1371/journal.pone.0081695
    1. Vissers M, Schreurs I, Jans J, Heldens J, de Groot R, de Jonge MI, et al. . Antibodies enhance CXCL10 production during RSV infection of infant and adult immune cells. Cytokine. (2015) 76:458–64. 10.1016/j.cyto.2015.07.024
    1. Ichikawa A, Kuba K, Morita M, Chida S, Tezuka H, Hara H, et al. . CXCL10-CXCR3 enhances the development of neutrophil-mediated fulminant lung injury of viral and nonviral origin. Am J Respir Crit Care Med. (2013) 187:65–77. 10.1164/rccm.201203-0508OC
    1. Halstead SB, Mahalingam S, Marovich MA, Ubol S, Mosser DM. Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet Infect Dis. (2010) 10:712–22. 10.1016/S1473-3099(10)70166-3
    1. Taylor A, Foo SS, Bruzzone R, Vu Dinh L, King NJ, Mahalingam S. Fc receptors in antibody-dependent enhancement of viral infections. Immunol Rev. (2015) 268:340–64. 10.1111/imr.12367
    1. Krilov LR, Anderson LJ, Marcoux L, Bonagura VR, Wedgwood JF. Antibody-mediated enhancement of respiratory syncytial virus infection in two monocyte/macrophage cell lines. J Infect Dis. (1989) 160:777–82. 10.1093/infdis/160.5.777
    1. Osiowy C, Horne D, Anderson R. Antibody-dependent enhancement of respiratory syncytial virus infection by sera from young infants. Clin Diagn Lab Immunol. (1994) 1:670–77.
    1. Gimenez HB, Chisholm S, Dornan J, Cash P. Neutralizing and enhancing activities of human respiratory syncytial virus-specific antibodies. Clin Diagn Lab Immunol. (1996) 3:280–6.
    1. van Erp EA, van Kasteren PB, Guichelaar T, Ahout IML, de Haan CAM, Luytjes W, et al. In vitro enhancement of respiratory syncytial virus infection by maternal antibodies does not explain disease severity in infants. J Virol. (2017) 91:e00851–17. 10.1128/JVI.00851-17
    1. van Erp EA, Feyaerts D, Duijst M, Mulder HL, Wicht O, Luytjes W, et al. Respiratory syncytial virus (RSV) infects primary neonatal and adult natural killer cells and affects their antiviral effector function. J Infect Dis. (2018) 219:723–33. 10.1093/infdis/jiy566
    1. Mascola JR, Mathieson BJ, Zack PM, Walker MC, Halstead SB, Burke DS. Summary report: workshop on the potential risks of antibody-dependent enhancement in human HIV vaccine trials. AIDS Res Hum Retroviruses. (1993) 9:1175–84. 10.1089/aid.1993.9.1175
    1. Polack FP. Atypical measles and enhanced respiratory syncytial virus disease (ERD) made simple. Pediatr Res. (2007) 62:111–5. 10.1203/PDR.0b013e3180686ce0
    1. Skowronski DM, De Serres G, Crowcroft NS, Janjua NZ, Boulianne N, Hottes TS, et al. . Association between the 2008-09 seasonal influenza vaccine and pandemic H1N1 illness during Spring-Summer 2009: four observational studies from Canada. PLoS Med. (2010) 7:e1000258. 10.1371/journal.pmed.1000258
    1. Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A, et al. . Antibody-dependent enhancement of severe dengue disease in humans. Science. (2017) 358:929–32. 10.1126/science.aan6836
    1. Murphy BR, Sotnikov AV, Lawrence LA, Banks SM, Prince GA. Enhanced pulmonary histopathology is observed in cotton rats immunized with formalin-inactivated respiratory syncytial virus (RSV) or purified F glycoprotein and challenged with RSV 3-6 months after immunization. Vaccine. (1990) 8:497–502.
    1. Murphy BR, Sotnikov A, Paradiso PR, Hildreth SW, Jenson AB, Baggs RB, et al. . Immunization of cotton rats with the fusion (F) and large (G) glycoproteins of respiratory syncytial virus (RSV) protects against RSV challenge without potentiating RSV disease. Vaccine. (1989) 7:533–40.
    1. Schneider-Ohrum K, Cayatte C, Bennett AS, Rajani GM, McTamney P, Nacel K, et al. . Immunization with low doses of recombinant postfusion or prefusion respiratory syncytial virus F primes for vaccine-enhanced disease in the cotton rat model independently of the presence of a Th1-Biasing (GLA-SE) or Th2-biasing (alum) adjuvant. J Virol. (2017) 91:e02180–16. 10.1128/jvi.02180-16
    1. Aleyd E, Heineke MH, van Egmond M. The era of the immunoglobulin A Fc receptor FcαRI; its function and potential as target in disease. Immunol Rev. (2015) 268:123–38. 10.1111/imr.12337
    1. Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol. (2014) 5:520. 10.3389/fimmu.2014.00520
    1. Bruhns P, Iannascoli B, England P, Mancardi DA, Fernandez N, Jorieux S, et al. . Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood. (2009) 113:3716–25. 10.1182/blood-2008-09-179754
    1. Jennewein MF, Alter G. The immunoregulatory roles of antibody glycosylation. Trends Immunol. (2017) 38:358–72. 10.1016/j.it.2017.02.004
    1. Pone EJ, Zhang J, Mai T, White CA, Li G, Sakakura JK, et al. . BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-kappaB pathway. Nat Commun. (2012) 3:767. 10.1038/ncomms1769
    1. Wagner DK, Graham BS, Wright PF, Walsh EE, Kim HW, Reimer CB, et al. . Serum immunoglobulin G antibody subclass responses to respiratory syncytial virus F and G glycoproteins after primary infection. J Clin Microbiol. (1986) 24:304–6.
    1. Watt PJ, Zardis M, Lambden PR. Age related IgG subclass response to respiratory syncytial virus fusion protein in infected infants. Clin Exp Immunol. (1986) 64:503–9.
    1. Ferrante A, Beard LJ, Feldman RG. IgG subclass distribution of antibodies to bacterial and viral antigens. Pediatr Infect Dis J. (1990) 9(8 Suppl.):S16–24. 10.1097/00006454-199008001-00004
    1. Bruggemann M, Williams GT, Bindon CI, Clark MR, Walker MR, Jefferis R, et al. . Comparison of the effector functions of human immunoglobulins using a matched set of chimeric antibodies. J Exp Med. (1987) 166:1351–61. 10.1084/jem.166.5.1351
    1. Tay MZ, Liu P, Williams LD, McRaven MD, Sawant S, Gurley TC, et al. . Antibody-mediated internalization of infectious HIV-1 virions differs among antibody isotypes and subclasses. PLoS Pathog. (2016) 12:e1005817. 10.1371/journal.ppat.1005817
    1. Stapleton NM, Andersen JT, Stemerding AM, Bjarnarson SP, Verheul RC, Gerritsen J, et al. . Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential. Nat Commun. (2011) 2:599. 10.1038/ncomms1608
    1. Bournazos S, Ravetch JV. Fcγ receptor function and the design of vaccination strategies. Immunity. (2017) 47:224–33. 10.1016/j.immuni.2017.07.009
    1. Chung AW, Ghebremichael M, Robinson H, Brown E, Choi I, Lane S, et al. . Polyfunctional Fc-effector profiles mediated by IgG subclass selection distinguish RV144 and VAX003 vaccines. Sci Transl Med. (2014) 6:228ra238. 10.1126/scitranslmed.3007736
    1. Habibi MS, Jozwik A, Makris S, Dunning J, Paras A, DeVincenzo JP, et al. . Impaired Antibody-mediated protection and defective IgA B-cell memory in experimental infection of adults with respiratory syncytial virus. Am J Respir Crit Care Med. (2015) 191:1040–9. 10.1164/rccm.201412-2256OC
    1. Walsh EE, Falsey AR. Humoral and mucosal immunity in protection from natural respiratory syncytial virus infection in adults. J Infect Dis. (2004) 190:373–8. 10.1086/421524
    1. Leschinskaya NP, Pokrovskaya EE, Kantorovitch EA, Grigorjeva SK, Shvartsman Ya S. Ontogenesis of the formation of secretory antibodies to respiratory syncytial (RS) virus. Epidemiol Infect. (1988) 101:565–75.
    1. Jacobino SR, Nederend M, Reijneveld JF, Augustijn D, Jansen JHM, Meeldijk J, et al. . Reformatting palivizumab and motavizumab from IgG to human IgA impairs their efficacy against RSV infection in vitro and in vivo. MAbs. (2018) 10:453–62. 10.1080/19420862.2018.1433974
    1. Welliver RC, Wong DT, Sun M, Middleton E, Jr, Vaughan RS, et al. . The development of respiratory syncytial virus-specific IgE and the release of histamine in nasopharyngeal secretions after infection. N Engl J Med. (1981) 305:841–6. 10.1056/NEJM198110083051501
    1. Russi JC, Delfraro A, Borthagaray MD, Velazquez B, Garcia-Barreno B, Hortal M. Evaluation of immunoglobulin E-specific antibodies and viral antigens in nasopharyngeal secretions of children with respiratory syncytial virus infections. J Clin Microbiol. (1993) 31:819–23.
    1. Welliver RC, Duffy L. The relationship of RSV-specific immunoglobulin E antibody responses in infancy, recurrent wheezing, and pulmonary function at age 7-8 years. Pediatr Pulmonol. (1993) 15:19–27. 10.1002/ppul.1950150104
    1. Smith-Norowitz TA, Mandal M, Joks R, Norowitz LT, Weaver D, Durkin HG, et al. . IgE anti-respiratory syncytial virus antibodies detected in serum of pediatric patients with asthma. Hum Immunol. (2015) 76:519–24. 10.1016/j.humimm.2015.06.002
    1. Dakhama A, Lee YM, Ohnishi H, Jing X, Balhorn A, Takeda K, et al. . Virus-specific IgE enhances airway responsiveness on reinfection with respiratory syncytial virus in newborn mice. J Allergy Clin Immunol. (2009) 123:138–145.e135. 10.1016/j.jaci.2008.10.012
    1. Welliver RC, Kaul TN, Ogra PL. The appearance of cell-bound IgE in respiratory-tract epithelium after respiratory-syncytial-virus infection. N Engl J Med. (1980) 303:1198–202. 10.1056/NEJM198011203032103
    1. Welliver RC, Sun M, Rinaldo D, Ogra PL. Predictive value of respiratory syncytial virus-specific IgE responses for recurrent wheezing following bronchiolitis. J Pediatr. (1986) 109:776–80. 10.1016/S0022-3476(86)80692-8
    1. Lee Chung H, Jang YY. High serum IgE level in the children with acute respiratory syncytial virus infection is associated with severe disease. J Allergy Clin Immunol. (2016) 137:AB110 10.1016/j.jaci.2015.12.486
    1. Wagner DK, Nelson DL, Walsh EE, Reimer CB, Henderson FW, Murphy BR. Differential immunoglobulin G subclass antibody titers to respiratory syncytial virus F and G glycoproteins in adults. J Clin Microbiol. (1987) 25:748–50.
    1. Wagner DK, Muelenaer P, Henderson FW, Snyder MH, Reimer CB, Walsh EE, et al. . Serum immunoglobulin G antibody subclass response to respiratory syncytial virus F and G glycoproteins after first, second, and third infections. J Clin Microbiol. (1989) 27:589–92.
    1. Jounai N, Yoshioka M, Tozuka M, Inoue K, Oka T, Miyaji K, et al. . Age-specific profiles of antibody responses against respiratory syncytial virus infection. EBioMed. (2017) 16:124–35. 10.1016/j.ebiom.2017.01.014
    1. Stevens TL, Bossie A, Sanders VM, Fernandez-Botran R, Coffman RL, Mosmann TR, et al. . Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Nature. (1988) 334:255–8. 10.1038/334255a0
    1. Tregoning JS, Wang BL, McDonald JU, Yamaguchi Y, Harker JA, Goritzka M, et al. . Neonatal antibody responses are attenuated by interferon-γ produced by NK and T cells during RSV infection. Proc Natl Acad Sci USA. (2013) 110:5576–81. 10.1073/pnas.1214247110
    1. Reuman PD, Keely SP, Schiff GM. Comparison of class and subclass antibody response to live and UV-inactivated RSV administered intranasally in mice. J Med Virol. (1991) 35:198–205. 10.1002/jmv.1890350310
    1. Hiatt A, Bohorova N, Bohorov O, Goodman C, Kim D, Pauly MH, et al. . Glycan variants of a respiratory syncytial virus antibody with enhanced effector function and in vivo efficacy. Proc Natl Acad Sci USA. (2014) 111:5992–7. 10.1073/pnas.1402458111
    1. Umana P, Jean-Mairet J, Moudry R, Amstutz H, Bailey JE. Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat Biotechnol. (1999) 17:176–80. 10.1038/6179
    1. Shields RL, Lai J, Keck R, O'Connell LY, Hong K, Meng YG, et al. . Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J Biol Chem. (2002) 277:26733–40. 10.1074/jbc.M202069200
    1. Ferrara C, Grau S, Jager C, Sondermann P, Brunker P, Waldhauer I, et al. . Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcgammaRIII and antibodies lacking core fucose. Proc Natl Acad Sci USA. (2011) 108:12669–74. 10.1073/pnas.1108455108
    1. Forthal DN, Gach JS, Landucci G, Jez J, Strasser R, Kunert R, et al. . Fc-glycosylation influences Fcγ receptor binding and cell-mediated anti-HIV activity of monoclonal antibody 2G12. J Immunol. (2010) 185:6876–82. 10.4049/jimmunol.1002600
    1. Zeitlin L, Pettitt J, Scully C, Bohorova N, Kim D, Pauly M, et al. . Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant. Proc Natl Acad Sci USA. (2011) 108:20690–4. 10.1073/pnas.1108360108
    1. Junttila TT, Parsons K, Olsson C, Lu Y, Xin Y, Theriault J, et al. . Superior in vivo efficacy of afucosylated trastuzumab in the treatment of HER2-amplified breast cancer. Cancer Res. (2010) 70:4481–9. 10.1158/0008-5472.CAN-09-3704
    1. Dalle S, Reslan L, Besseyre de Horts T, Herveau S, Herting F, Plesa A, et al. . Preclinical studies on the mechanism of action and the anti-lymphoma activity of the novel anti-CD20 antibody GA101. Mol Cancer Ther. (2011) 10:178–85. 10.1158/1535-7163.MCT-10-0385
    1. Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science. (2006) 313:670–3. 10.1126/science.1129594
    1. Dekkers G, Treffers L, Plomp R, Bentlage AEH, de Boer M, Koeleman CAM, et al. . Decoding the human immunoglobulin G-Glycan repertoire reveals a spectrum of Fc-receptor- and complement-mediated-effector activities. Front Immunol. (2017) 8:877. 10.3389/fimmu.2017.00877
    1. Maverakis E, Kim K, Shimoda M, Gershwin ME, Patel F, Wilken R, et al. . Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review. J Autoimmun. (2015) 57:1–13. 10.1016/j.jaut.2014.12.002
    1. Rook GA, Steele J, Brealey R, Whyte A, Isenberg D, Sumar N, et al. . Changes in IgG glycoform levels are associated with remission of arthritis during pregnancy. J Autoimmun. 4:779–94. 10.1016/0896-8411(91)90173-A
    1. van de Geijn FE, Wuhrer M, Selman MH, Willemsen SP, de Man YA, Deelder AM, et al. . Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: results from a large prospective cohort study. Arthritis Res Ther. (2009) 11:R193. 10.1186/ar2892
    1. Mahan AE, Jennewein MF, Suscovich T, Dionne K, Tedesco J, Chung AW, et al. Antigen-specific antibody glycosylation is regulated via vaccination. PLoS Pathog. (2016) 12:e1005456 10.1371/journal.ppat.1005456
    1. Shim H. One target, different effects: a comparison of distinct therapeutic antibodies against the same targets. Exp Mol Med. (2011) 43:539–49. 10.3858/emm.2011.43.10.063
    1. He W, Tan GS, Mullarkey CE, Lee AJ, Lam MM, Krammer F, et al. . Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus. Proc Natl Acad Sci USA. (2016) 113:11931–6. 10.1073/pnas.1609316113
    1. Cleary KLS, Chan HTC, James S, Glennie MJ, Cragg MS. Antibody distance from the cell membrane regulates antibody effector mechanisms. J Immunol. (2017) 198:3999–4011. 10.4049/jimmunol.1601473
    1. Jegaskanda S, Job ER, Kramski M, Laurie K, Isitman G, de Rose R, et al. . Cross-reactive influenza-specific antibody-dependent cellular cytotoxicity antibodies in the absence of neutralizing antibodies. J Immunol. (2013) 190:1837–48. 10.4049/jimmunol.1201574
    1. Bakalar MH, Joffe AM, Schmid EM, Son S, Podolski M, Fletcher DA. Size-dependent segregation controls macrophage phagocytosis of antibody-opsonized targets. Cell. (2018) 174:131–142.e113. 10.1016/j.cell.2018.05.059
    1. Connors M, Collins PL, Firestone CY, Murphy BR. Respiratory syncytial virus (RSV) F, G, M2 (22K), and N proteins each induce resistance to RSV challenge, but resistance induced by M2 and N proteins is relatively short-lived. J Virol. (1991) 65:1634–7.
    1. Akerlind-Stopner B, Hu A, Mufson MA, Utter G, Norrby E. Antibody responses of children to the C-terminal peptide of the SH protein of respiratory syncytial virus and the immunological characterization of this protein. J Med Virol. (1993) 40:112–20. 10.1002/jmv.1890400207
    1. Kumari S, Crim RL, Kulkarni A, Audet SA, Mdluli T, Murata H, et al. . Development of a luciferase immunoprecipitation system assay to detect IgG antibodies against human respiratory syncytial virus nucleoprotein. Clin Vaccine Immunol. (2014) 21:383–90. 10.1128/CVI.00594-13
    1. Schepens B, Sedeyn K, Vande Ginste L, De Baets S, Schotsaert M, Roose K, et al. . Protection and mechanism of action of a novel human respiratory syncytial virus vaccine candidate based on the extracellular domain of small hydrophobic protein. EMBO Mol Med. (2014) 6:1436–54. 10.15252/emmm.201404005
    1. Capella C, Chaiwatpongsakorn S, Gorrell E, Risch ZA, Ye F, Mertz SE, et al. . Prefusion F, postfusion F, G antibodies and disease severity in infants and young children with acute respiratory syncytial virus infection. J Infect Dis. (2017). 10.1093/infdis/jix489
    1. Gilman MS, Castellanos CA, Chen M, Ngwuta JO, Goodwin E, Moin SM, et al. . Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors. Sci Immunol. (2016) 1:eaaj1879. 10.1126/sciimmunol.aaj1879
    1. Mousa JJ, Kose N, Matta P, Gilchuk P, Crowe JE, Jr. A novel pre-fusion conformation-specific neutralizing epitope on the respiratory syncytial virus fusion protein. Nat Microbiol. (2017) 2:16271. 10.1038/nmicrobiol.2016.271
    1. Ngwuta JO, Chen M, Modjarrad K, Joyce MG, Kanekiyo M, Kumar A, et al. . Prefusion F-specific antibodies determine the magnitude of RSV neutralizing activity in human sera. Sci Transl Med. (2015) 7:309ra162. 10.1126/scitranslmed.aac4241
    1. Fedechkin SO, George NL, Wolff JT, Kauvar LM, DuBois RM. Structures of respiratory syncytial virus G antigen bound to broadly neutralizing antibodies. Sci Immunol. (2018) 3:eaar3534. 10.1126/sciimmunol.aar3534
    1. Johnson SM, McNally BA, Ioannidis I, Flano E, Teng MN, Oomens AG, et al. . Respiratory syncytial virus uses CX3CR1 as a receptor on primary human airway epithelial cultures. PLoS Pathog. (2015) 11:e1005318. 10.1371/journal.ppat.1005318
    1. Boyoglu-Barnum S, Todd SO, Chirkova T, Barnum TR, Gaston KA, Haynes LM, et al. . An anti-G protein monoclonal antibody treats RSV disease more effectively than an anti-F monoclonal antibody in BALB/c mice. Virology. (2015) 483:117–25. 10.1016/j.virol.2015.02.035
    1. Tripp RA, Jones LP, Haynes LM, Zheng H, Murphy PM, Anderson LJ. CX3C chemokine mimicry by respiratory syncytial virus G glycoprotein. Nat Immunol. (2001) 2:732–8. 10.1038/90675
    1. Fuentes S, Coyle EM, Beeler J, Golding H, Khurana S. Antigenic fingerprinting following primary RSV infection in young children identifies novel antigenic sites and reveals unlinked evolution of human antibody repertoires to fusion and attachment glycoproteins. PLoS Pathog. (2016) 12:e1005554. 10.1371/journal.ppat.1005554
    1. Goodier MR, Lusa C, Sherratt S, Rodriguez-Galan A, Behrens R, Riley EM. Sustained immune complex-mediated reduction in CD16 expression after vaccination regulates NK cell function. Front Immunol. (2016) 7:384. 10.3389/fimmu.2016.00384
    1. van Egmond M, Vidarsson G, Bakema JE. Cross-talk between pathogen recognizing Toll-like receptors and immunoglobulin Fc receptors in immunity. Immunol Rev. (2015) 268:311–27. 10.1111/imr.12333
    1. Bournazos S, Woof JM, Hart SP, Dransfield I. Functional and clinical consequences of Fc receptor polymorphic and copy number variants. Clin Exp Immunol. (2009) 157:244–54. 10.1111/j.1365-2249.2009.03980.x
    1. Warmerdam PA, van de Winkel JG, Gosselin EJ, Capel PJ. Molecular basis for a polymorphism of human Fc gamma receptor II (CD32). J Exp Med. (1990) 172:19–25. 10.1084/jem.172.1.19
    1. Salmon JE, Edberg JC, Brogle NL, Kimberly RP. Allelic polymorphisms of human Fc gamma receptor IIA and Fc gamma receptor IIIB. Independent mechanisms for differences in human phagocyte function. J Clin Invest. (1992) 89:1274–81. 10.1172/JCI115712
    1. Koene HR, Kleijer M, Algra J, Roos D, von dem Borne AE, de Haas M. Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H phenotype. Blood. (1997) 90:1109–14.
    1. Wu J, Edberg JC, Redecha PB, Bansal V, Guyre PM, Coleman K, et al. . A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest. (1997) 100:1059–70. 10.1172/JCI119616
    1. Guerrero-Plata A, Ortega E, Gomez B. Persistence of respiratory syncytial virus in macrophages alters phagocytosis and pro-inflammatory cytokine production. Viral Immunol. (2001) 14:19–30. 10.1089/08828240151061347
    1. Li X, Kimberly RP. Targeting the Fc receptor in autoimmune disease. Expert Opin Ther Targets. (2014) 18:335–50. 10.1517/14728222.2014.877891
    1. Mellor JD, Brown MP, Irving HR, Zalcberg JR, Dobrovic A. A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer. J Hematol Oncol. (2013) 6:1. 10.1186/1756-8722-6-1
    1. Forthal DN, Gabriel EE, Wang A, Landucci G, Phan TB. Association of Fcγ receptor IIIa genotype with the rate of HIV infection after gp120 vaccination. Blood. (2012) 120:2836–42. 10.1182/blood-2012-05-431361
    1. Li SS, Gilbert PB, Tomaras GD, Kijak G, Ferrari G, Thomas R, et al. . FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial. J Clin Invest. (2014) 124:3879–90. 10.1172/JCI75539
    1. Dettogni RS, Tristao-Sa R, Dos Santos M, da Silva FF, Louro ID. Single nucleotide polymorphisms in immune system genes and their association with clinical symptoms persistence in dengue-infected persons. Hum Immunol. (2015) 76:717–23. 10.1016/j.humimm.2015.09.026
    1. Moraru M, Black LE, Muntasell A, Portero F, Lopez-Botet M, Reyburn HT, et al. . NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: epistatic interaction of CD16A and IgG1 allotypes of variable affinities modulates antibody-dependent cellular cytotoxicity and susceptibility to clinical reactivation. J Immunol. (2015) 195:1676–84. 10.4049/jimmunol.1500872
    1. Janssen R, Bont L, Siezen CL, Hodemaekers HM, Ermers MJ, Doornbos G, et al. . Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. J Infect Dis. (2007) 196:826–34. 10.1086/520886
    1. IMpact 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. (1998) 102(3 Pt 1):531–7.
    1. Wang D, Cummins C, Bayliss S, Sandercock J, Burls A. Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation. Health Technol Assess. (2008) 12:iii, ix–x, 1–86. 10.3310/hta12360
    1. Mejias A, Garcia-Maurino C, Rodriguez-Fernandez R, Peeples ME, Ramilo O. Development and clinical applications of novel antibodies for prevention and treatment of respiratory syncytial virus infection. Vaccine. (2017) 35:496–502. 10.1016/j.vaccine.2016.09.026
    1. Falloon J, Yu J, Esser MT, Villafana T, Yu L, Dubovsky F, et al. An adjuvanted, postfusion F protein-based vaccine did not prevent respiratory syncytial virus illness in older adults. J Infect Dis. (2017) 216:1362–70. 10.1093/infdis/jix503
    1. Tripp RA, Power UF, Openshaw PJM, Kauvar LM. Respiratory syncytial virus: targeting the G protein provides a new approach for an old problem. J Virol. (2018) 92:e01302–17. 10.1128/JVI.01302-17
    1. Boyoglu-Barnum S, Chirkova T, Todd SO, Barnum TR, Gaston KA, Jorquera P, et al. . Prophylaxis with a respiratory syncytial virus (RSV) anti-G protein monoclonal antibody shifts the adaptive immune response to RSV rA2-line19F infection from Th2 to Th1 in BALB/c mice. J Virol. (2014) 88:10569–83. 10.1128/JVI.01503-14
    1. Lu LL, Chung AW, Rosebrock TR, Ghebremichael M, Yu WH, Grace PS, et al. . A functional role for antibodies in tuberculosis. Cell. (2016) 167:433–43 e414. 10.1016/j.cell.2016.08.072
    1. Ackerman ME, Barouch DH, Alter G. Systems serology for evaluation of HIV vaccine trials. Immunol Rev. (2017) 275:262–70. 10.1111/imr.12503

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe