Dengue immune defenses
Cross-reactive antibodies against different dengue virus serotypes (DENV1-4) can have either protective or pathogenic effects depending on immune responses to the secondary infection serotype. Dias et al. used systems serology to profile DENV-specific antibody responses of previously infected children in a Nicaraguan cohort study to determine correlates of protection against secondary DENV3 infection. Children protected against secondary symptomatic infection had higher titers of total IgG and IgG4 specific to envelope (E) protein and nonstructural protein 1 (NS1) and had antibodies with greater Fc effector functions relative to symptomatic children. Plasma anti-E and anti-NS1 polyclonal antibodies were associated with protection via Fc-driven complement deposition and lysis of DENV virions or infected cells in vitro. Together, these observations indicate that E- and NS1-specific Abs may have Fc effector functions that serve as correlates of protection against DENV.
Preexisting cross-reactive antibodies have been implicated in both protection and pathogenesis during subsequent infections with different dengue virus (DENV) serotypes (DENV1-4). Nonetheless, humoral immune correlates and mechanisms of protection have remained elusive. Using a systems serology approach to evaluate humoral responses, we profiled plasma collected before inapparent or symptomatic secondary DENV3 infection from our pediatric cohort in Nicaragua. Children protected from symptomatic infections had more anti-envelope (E) and anti–nonstructural protein 1 (NS1) total immunoglobulin G (IgG), IgG4, and greater Fc effector functions than those with symptoms. Fc effector functions were also associated with protection from hemorrhagic manifestations in the pre-symptomatic group. Furthermore, in vitro virological assays using these plasma samples revealed that protection mediated by antibody-dependent complement deposition was associated with both lysis of virions and DENV-infected cells. These data suggest that E- and NS1-specific Fc functions may serve as correlates of protection, which can be potentially applied toward the design and evaluation of dengue vaccines.
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REFERENCES AND NOTES
O. J. Brady, P. W. Gething, S. Bhatt, J. P. Messina, J. S. Brownstein, A. G. Hoen, C. L. Moyes, A. W. Farlow, T. W. Scott, S. I. Hay, Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLOS Negl. Trop. Dis. 6, e1760 (2012).
L. Cattarino, I. Rodriguez-Barraquer, N. Imai, D. A. T. Cummings, N. M. Ferguson, Mapping global variation in dengue transmission intensity. Sci. Transl. Med. 12, eaax4144 (2020).
World Health Organization, Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention and Control (2nd ed., 1997).
L. C. Katzelnick, M. Montoya, L. Gresh, A. Balmaseda, E. Harris, Neutralizing antibody titers against dengue virus correlate with protection from symptomatic infection in a longitudinal cohort. Proc. Natl. Acad. Sci. U.S.A. 113, 728–733 (2016).
L. C. Katzelnick, L. Gresh, M. E. Halloran, J. C. Mercado, G. Kuan, A. Gordon, A. Balmaseda, E. Harris, Antibody-dependent enhancement of severe dengue disease in humans. Science 358, 929–932 (2017).
S. B. Halstead, E. J. O’Rourke, Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody. J. Exp. Med. 146, 201–217 (1977).
L. C. Katzelnick, C. Narvaez, S. Arguello, B. Lopez Mercado, D. Collado, O. Ampie, D. Elizondo, T. Miranda, F. Bustos Carillo, J. C. Mercado, K. Latta, A. Schiller, B. Segovia-Chumbez, S. Ojeda, N. Sanchez, M. Plazaola, J. Coloma, M. E. Halloran, L. Premkumar, A. Gordon, F. Narvaez, A. M. de Silva, G. Kuan, A. Balmaseda, E. Harris, Zika virus infection enhances future risk of severe dengue disease. Science 369, 1123–1128 (2020).
S. Bournazos, H. T. M. Vo, V. Duong, H. Auerswald, S. Ly, A. Sakuntabhai, P. Dussart, T. Cantaert, J. V. Ravetch, Antibody fucosylation predicts disease severity in secondary dengue infection. Science 372, 1102–1105 (2021).
T. T. Wang, J. Sewatanon, M. J. Memoli, J. Wrammert, S. Bournazos, S. K. Bhaumik, B. A. Pinsky, K. Chokephaibulkit, N. Onlamoon, K. Pattanapanyasat, J. K. Taubenberger, R. Ahmed, J. V. Ravetch, IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity. Science 355, 395–398 (2017).
N. K. Thulin, R. C. Brewer, R. Sherwood, S. Bournazos, K. G. Edwards, N. S. Ramadoss, J. K. Taubenberger, M. Memoli, A. J. Gentles, P. Jagannathan, S. Zhang, D. H. Libraty, T. T. Wang, Maternal anti-dengue IgG fucosylation predicts susceptibility to dengue disease in infants. Cell Rep. 31, 107642 (2020).
M. R. Capeding, N. H. Tran, S. R. S. Hadinegoro, H. I. H. M. Ismail, T. Chotpitayasunondh, M. N. Chua, C. Q. Luong, K. Rusmil, D. N. Wirawan, R. Nallusamy, P. Pitisuttithum, U. Thisyakorn, I.-K. Yoon, D. van der Vliet, E. Langevin, T. Laot, Y. Hutagalung, C. Frago, M. Boaz, T. A. Wartel, N. G. Tornieporth, M. Saville, A. Bouckenooghe; CYD14 Study Group, Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: A phase 3, randomised, observer-masked, placebo-controlled trial. Lancet 384, 1358–1365 (2014).
L. Villar, G. H. Dayan, J. L. Arredondo-García, D. M. Rivera, R. Cunha, C. Deseda, H. Reynales, M. S. Costa, J. O. Morales-Ramírez, G. Carrasquilla, L. C. Rey, R. Dietze, K. Luz, E. Rivas, M. C. Miranda Montoya, M. Cortés Supelano, B. Zambrano, E. Langevin, M. Boaz, N. Tornieporth, M. Saville, F. Noriega, Efficacy of a tetravalent dengue vaccine in children in Latin America. N. Engl. J. Med. 372, 113–123 (2015).
S. Sridhar, A. Luedtke, E. Langevin, M. Zhu, M. Bonaparte, T. Machabert, S. Savarino, B. Zambrano, A. Moureau, A. Khromava, Z. Moodie, T. Westling, C. Mascareñas, C. Frago, M. Cortés, D. Chansinghakul, F. Noriega, A. Bouckenooghe, J. Chen, S.-P. Ng, P. B. Gilbert, S. Gurunathan, C. A. DiazGranados, Effect of dengue serostatus on dengue vaccine safety and efficacy. N. Engl. J. Med. 379, 327–340 (2018).
S. Henein, C. Adams, M. Bonaparte, J. M. Moser, A. Munteanu, R. Baric, A. M. de Silva, Dengue vaccine breakthrough infections reveal properties of neutralizing antibodies linked to protection. J. Clin. Invest. 131, e147066 (2021).
Z. Moodie, M. Juraska, Y. Huang, Y. Zhuang, Y. Fong, L. N. Carpp, S. G. Self, L. Chambonneau, R. Small, N. Jackson, F. Noriega, P. B. Gilbert, Neutralizing antibody correlates analysis of tetravalent dengue vaccine efficacy trials in Asia and Latin America. J. Infect. Dis. 217, 742–753 (2018).
A. Sabchareon, D. Wallace, C. Sirivichayakul, K. Limkittikul, P. Chanthavanich, S. Suvannadabba, V. Jiwariyavej, W. Dulyachai, K. Pengsaa, T. A. Wartel, A. Moureau, M. Saville, A. Bouckenooghe, S. Viviani, N. G. Tornieporth, J. Lang, Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: A randomised, controlled phase 2b trial. Lancet 380, 1559–1567 (2012).
K. J. Selva, C. E. van de Sandt, M. M. Lemke, C. Y. Lee, S. K. Shoffner, B. Y. Chua, S. K. Davis, T. H. O. Nguyen, L. C. Rowntree, L. Hensen, M. Koutsakos, C. Y. Wong, F. Mordant, D. C. Jackson, K. L. Flanagan, J. Crowe, S. Tosif, M. R. Neeland, P. Sutton, P. V. Licciardi, N. W. Crawford, A. C. Cheng, D. L. Doolan, F. Amanat, F. Krammer, K. Chappell, N. Modhiran, D. Watterson, P. Young, W. S. Lee, B. D. Wines, P. M. Hogarth, R. Esterbauer, H. G. Kelly, H.-X. Tan, J. A. Juno, A. K. Wheatley, S. J. Kent, K. B. Arnold, K. Kedzierska, A. W. Chung, Systems serology detects functionally distinct coronavirus antibody features in children and elderly. Nat. Commun. 12, 2037 (2021).
D. J. DiLillo, G. S. Tan, P. Palese, J. V. Ravetch, Broadly neutralizing hemagglutinin stalk–specific antibodies require FcγR interactions for protection against influenza virus in vivo. Nat. Med. 20, 143–151 (2014).
E. O. Saphire, S. L. Schendel, M. L. Fusco, K. Gangavarapu, B. M. Gunn, A. Z. Wec, P. J. Halfmann, J. M. Brannan, A. S. Herbert, X. Qiu, K. Wagh, S. He, E. E. Giorgi, J. Theiler, K. B. J. Pommert, T. B. Krause, H. L. Turner, C. D. Murin, J. Pallesen, E. Davidson, R. Ahmed, M. J. Aman, A. Bukreyev, D. R. Burton, J. E. Crowe, C. W. Davis, G. Georgiou, F. Krammer, C. A. Kyratsous, J. R. Lai, C. Nykiforuk, M. H. Pauly, P. Rijal, A. Takada, A. R. Townsend, V. Volchkov, L. M. Walker, C.-I. Wang, L. Zeitlin, B. J. Doranz, A. B. Ward, B. Korber, G. P. Kobinger, K. G. Andersen, Y. Kawaoka, G. Alter, K. Chandran, J. M. Dye; Viral Hemorrhagic Fever Immunotherapeutic Consortium, Systematic analysis of monoclonal antibodies against ebola virus GP defines features that contribute to protection. Cell 174, 938–952.e13 (2018).
A. W. Chung, M. P. Kumar, K. B. Arnold, W. H. Yu, M. K. Schoen, L. J. Dunphy, T. J. Suscovich, N. Frahm, C. Linde, A. E. Mahan, M. Hoffner, H. Streeck, M. E. Ackerman, M. J. McElrath, H. Schuitemaker, M. G. Pau, L. R. Baden, J. H. Kim, N. L. Michael, D. H. Barouch, D. A. Lauffenburger, G. Alter, Dissecting polyclonal vaccine-induced humoral immunity against HIV using systems serology. Cell 163, 988–998 (2015).
E. N. Gallichotte, R. S. Baric, A. M. de Silva, in Dengue and Zika: Control and Antiviral Treatment Strategies, Advances in experimental medicine and biology. R. Hilgenfeld, S. G. Vasudevan, Eds. (Springer Singapore, 2018), vol. 1062, pp. 63–76.
A. M. Collins, K. J. L. Jackson, A temporal model of human IgE and IgG antibody function. Front. Immunol. 4, 235 (2013).
K. J. L. Jackson, Y. Wang, A. M. Collins, Human immunoglobulin classes and subclasses show variability in VDJ gene mutation levels. Immunol. Cell Biol. 92, 729–733 (2014).
H. W. King, N. Orban, J. C. Riches, A. J. Clear, G. Warnes, S. A. Teichmann, L. K. James, Single-cell analysis of human B cell maturation predicts how antibody class switching shapes selection dynamics. Sci. Immunol. 6, eabe6291 (2021).
S. Malafa, I. Medits, J. H. Aberle, S. W. Aberle, D. Haslwanter, G. Tsouchnikas, S. Wölfel, K. L. Huber, E. Percivalle, P. Cherpillod, M. Thaler, L. Roßbacher, M. Kundi, F. X. Heinz, K. Stiasny, Impact of flavivirus vaccine-induced immunity on primary Zika virus antibody response in humans. PLOS Negl. Trop. Dis. 14, e0008034 (2020).
K. Laoprasopwattana, D. H. Libraty, T. P. Endy, A. Nisalak, S. Chunsuttiwat, F. A. Ennis, A. L. Rothman, S. Green, Antibody-dependent cellular cytotoxicity mediated by plasma obtained before secondary dengue virus infections: Potential involvement in early control of viral replication. J. Infect. Dis. 195, 1108–1116 (2007).
S. Shresta, Role of complement in dengue virus infection: Protection or pathogenesis? mBio 3, e00003-12 (2012).
S. B. Halstead, Antibody, macrophages, dengue virus infection, shock, and hemorrhage: A pathogenetic cascade. Clin. Infect. Dis. 11, S830–S839 (1989).
P. Avirutnan, N. Punyadee, S. Noisakran, C. Komoltri, S. Thiemmeca, K. Auethavornanan, A. Jairungsri, R. Kanlaya, N. Tangthawornchaikul, C. Puttikhunt, S. Pattanakitsakul, P. Yenchitsomanus, J. Mongkolsapaya, W. Kasinrerk, N. Sittisombut, M. Husmann, M. Blettner, S. Vasanawathana, S. Bhakdi, P. Malasit, Vascular leakage in severe dengue virus infections: A potential role for the nonstructural viral protein NS1 and complement. J. Infect. Dis. 193, 1078–1088 (2006).
P. Sun, B. J. Morrison, C. G. Beckett, Z. Liang, N. Nagabhushana, A. Li, K. R. Porter, M. Williams, NK cell degranulation as a marker for measuring antibody-dependent cytotoxicity in neutralizing and non-neutralizing human sera from dengue patients. J. Immunol. Methods 441, 24–30 (2017).
D. Michlmayr, P. Andrade, K. Gonzalez, A. Balmaseda, E. Harris, CD14+CD16+ monocytes are the main target of Zika virus infection in peripheral blood mononuclear cells in a paediatric study in Nicaragua. Nat. Microbiol. 2, 1462–1470 (2017).
S. Bhakdi, M. D. Kazatchkine, Pathogenesis of dengue: An alternative hypothesis. Southeast Asian J. Trop. Med. Public Health 21, 652–657 (1990).
E. Mehlhop, K. Whitby, T. Oliphant, A. Marri, M. Engle, M. S. Diamond, Complement activation is required for induction of a protective antibody response against West Nile virus infection. J. Virol. 79, 7466–7477 (2005).
J. J. Schlesinger, M. W. Brandriss, E. E. Walsh, Protection against 17D yellow fever encephalitis in mice by passive transfer of monoclonal antibodies to the nonstructural glycoprotein gp48 and by active immunization with gp48. J. Immunol. 135, 2805–2809 (1985).
V. D. Krishna, M. Rangappa, V. Satchidanandam, Virus-specific cytolytic antibodies to nonstructural protein 1 of japanese encephalitis virus effect reduction of virus output from infected cells. J. Virol. 83, 4766–4777 (2009).
W. M. P. B. Wahala, A. A. Kraus, L. B. Haymore, M. A. Accavitti-Loper, A. M. de Silva, Dengue virus neutralization by human immune sera: Role of envelope protein domain III-reactive antibody. Virology 392, 103–113 (2009).
L. C. Katzelnick, E. Harris; Participants in the Summit on Dengue Immune Correlates of Protection, Immune correlates of protection for dengue: State of the art and research agenda. Vaccine 35, 4659–4669 (2017).
L. C. Katzelnick, S. Bos, E. Harris, Protective and enhancing interactions among dengue viruses 1-4 and Zika virus. Curr. Opin. Virol. 43, 59–70 (2020).
B. Schiela, S. Bernklau, Z. Malekshahi, D. Deutschmann, I. Koske, Z. Banki, N. M. Thielens, R. Würzner, C. Speth, G. Weiss, K. Stiasny, E. Steinmann, H. Stoiber, Active human complement reduces the Zika virus load via formation of the membrane-attack complex. Front. Immunol. 9, 2177 (2018).
P. Avirutnan, E. Mehlhop, M. S. Diamond, Complement and its role in protection and pathogenesis of flavivirus infections. Vaccine 26, I100–I107 (2008).
V. A. Bokisch, F. H. Top Jr., P. K. Russell, F. J. Dixon, H. J. Müller-Eberhard, The potential pathogenic role of complement in dengue hemorrhagic shock syndrome. N. Engl. J. Med. 289, 996–1000 (1973).
K. S. Aye, K. Charngkaew, N. Win, K. Z. Wai, K. Moe, N. Punyadee, S. Thiemmeca, A. Suttitheptumrong, S. Sukpanichnant, M. Prida, S. B. Halstead, Pathologic highlights of dengue hemorrhagic fever in 13 autopsy cases from Myanmar. Hum. Pathol. 45, 1221–1233 (2014).
E. Mehlhop, C. Ansarah-Sobrinho, S. Johnson, M. Engle, D. H. Fremont, T. C. Pierson, M. S. Diamond, Complement protein C1q inhibits antibody-dependent enhancement of flavivirus infection in an IgG subclass-specific manner. Cell Host Microbe 2, 417–426 (2007).
E. Mehlhop, S. Nelson, C. A. Jost, S. Gorlatov, S. Johnson, D. H. Fremont, M. S. Diamond, T. C. Pierson, Complement protein C1q reduces the stoichiometric threshold for antibody-mediated neutralization of west nile virus. Cell Host Microbe 6, 381–391 (2009).
S. Thiemmeca, C. Tamdet, N. Punyadee, T. Prommool, A. Songjaeng, S. Noisakran, C. Puttikhunt, J. P. Atkinson, M. S. Diamond, A. Ponlawat, P. Avirutnan, Secreted NS1 protects dengue virus from mannose-binding lectin–mediated neutralization. J. Immunol. 197, 4053–4065 (2016).
E. J. M. Nascimento, A. M. Silva, M. T. Cordeiro, C. A. Brito, L. H. V. G. Gil, U. Braga-Neto, E. T. A. Marques, Alternative complement pathway deregulation is correlated with dengue severity. PLOS ONE 4, e6782 (2009).
S. Cabezas, G. Bracho, A. L. Aloia, P. J. Adamson, C. S. Bonder, J. R. Smith, D. L. Gordon, J. M. Carr, Dengue virus induces increased activity of the complement alternative pathway in infected cells. J. Virol. 92, e00633-18 (2018).
A. Fuchs, T.-Y. Lin, D. W. Beasley, C. M. Stover, W. J. Schwaeble, T. C. Pierson, M. S. Diamond, Direct complement restriction of flavivirus infection requires glycan recognition by mannose-binding lectin. Cell Host Microbe 8, 186–195 (2010).
G. Kuan, A. Gordon, W. Aviles, O. Ortega, S. N. Hammond, D. Elizondo, A. Nunez, J. Coloma, A. Balmaseda, E. Harris, The Nicaraguan Pediatric Dengue Cohort Study: Study design, methods, use of information technology, and extension to other infectious diseases. Am. J. Epidemiol. 170, 120–129 (2009).
A. Balmaseda, E. Sandoval, L. Pérez, C. M. Gutiérrez, E. Harris, Application of molecular typing techniques in the 1998 dengue epidemic in Nicaragua. Am. J. Trop. Med. Hyg. 61, 893–897 (1999).
A. Balmaseda, J. V. Zambrana, D. Collado, N. García, S. Saborío, D. Elizondo, J. C. Mercado, K. Gonzalez, C. Cerpas, A. Nuñez, D. Corti, J. J. Waggoner, G. Kuan, R. Burger-Calderon, E. Harris, Comparison of four serological methods and two reverse transcription-PCR assays for diagnosis and surveillance of Zika virus infection. J. Clin. Microbiol. 56, –e01785-17 (2018).
R. J. Fernández, S. Vázquez, Serological diagnosis of dengue by an ELISA inhibition method (EIM). Mem. Inst. Oswaldo Cruz 85, 347–351 (1990).
A. Balmaseda, S. N. Hammond, Y. Tellez, L. Imhoff, Y. Rodriguez, S. I. Saborío, J. C. Mercado, L. Perez, E. Videa, E. Almanza, G. Kuan, M. Reyes, L. Saenz, J. J. Amador, E. Harris, High seroprevalence of antibodies against dengue virus in a prospective study of schoolchildren in Managua, Nicaragua. Trop. Med. Int. Health TM IH 11, 935–942 (2006).
M. Montoya, L. Gresh, J. C. Mercado, K. L. Williams, M. Jose, G. Gutierrez, G. Kuan, A. Gordon, A. Balmaseda, E. Harris, M. J. Vargas, G. Gutierrez, G. Kuan, A. Gordon, A. Balmaseda, E. Harris, Symptomatic versus inapparent outcome in repeat dengue virus infections is influenced by the time interval between infections and study year. PLoS Negl. Trop. Dis. 7, e2357 (2013).
S. B. Biering, D. L. Akey, M. P. Wong, W. C. Brown, N. T. N. Lo, H. Puerta-Guardo, F. Tramontini Gomes de Sousa, C. Wang, J. R. Konwerski, D. A. Espinosa, N. J. Bockhaus, D. R. Glasner, J. Li, S. F. Blanc, E. Y. Juan, S. J. Elledge, M. J. Mina, P. R. Beatty, J. L. Smith, E. Harris, Structural basis for antibody inhibition of flavivirus NS1–triggered endothelial dysfunction. Science 371, 194–200 (2021).
E. P. Brown, K. G. Dowell, A. W. Boesch, E. Normandin, A. E. Mahan, T. Chu, D. H. Barouch, C. Bailey-Kellogg, G. Alter, M. E. Ackerman, Multiplexed Fc array for evaluation of antigen-specific antibody effector profiles. J. Immunol. Methods 443, 33–44 (2017).
C. M. Boudreau, W.-H. Yu, T. J. Suscovich, H. K. Talbot, K. M. Edwards, G. Alter, Selective induction of antibody effector functional responses using MF59-adjuvanted vaccination. J. Clin. Invest. 130, 662–672 (2020).
M. E. Ackerman, M. Crispin, X. Yu, K. Baruah, A. W. Boesch, D. J. Harvey, A.-S. Dugast, E. L. Heizen, A. Ercan, I. Choi, H. Streeck, P. A. Nigrovic, C. Bailey-Kellogg, C. Scanlan, G. Alter, Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity. J. Clin. Invest. 123, 2183–2192 (2013).
S. Fischinger, J. K. Fallon, A. R. Michell, T. Broge, T. J. Suscovich, H. Streeck, G. Alter, A high-throughput, bead-based, antigen-specific assay to assess the ability of antibodies to induce complement activation. J. Immunol. Methods 473, 112630 (2019).
C. B. Karsten, N. Mehta, S. A. Shin, T. J. Diefenbach, M. D. Slein, W. Karpinski, E. B. Irvine, T. Broge, T. J. Suscovich, G. Alter, A versatile high-throughput assay to characterize antibody-mediated neutrophil phagocytosis. J. Immunol. Methods 471, 46–56 (2019).
W. B. Messer, B. Yount, K. E. Hacker, E. F. Donaldson, J. P. Huynh, A. M. de Silva, R. S. Baric, Development and characterization of a reverse genetic system for studying dengue virus serotype 3 strain variation and neutralization. PLoS Negl. Trop. Dis. 6, e1486 (2012).
M. Huber, M. Fischer, B. Misselwitz, A. Manrique, H. Kuster, B. Niederöst, R. Weber, V. von Wyl, H. F. Günthard, A. Trkola, Complement lysis activity in autologous plasma is associated with lower viral loads during the acute phase of HIV-1 infection. PLOS Med. 3, e441 (2006).
B. W. Johnson, B. J. Russell, R. S. Lanciotti, Serotype-specific detection of dengue viruses in a fourplex real-time reverse transcriptase PCR assay. J. Clin. Microbiol. 43, 4977–4983 (2005).
Science Translational Medicine
Volume 14 | Issue 651
Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 9 September 2021
Accepted: 8 June 2022
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We thank past and present members of the study team based at the Centro de Salud Sócrates Flores Vivas, the National Virology Laboratory in the Centro Nacional de Diagnóstico y Referencia, and the Sustainable Sciences Institute in Nicaragua for their dedication and high-quality work. We are very grateful to the PDCS participants and their families. We thank W. Clay Brown and J. Smith (University of Michigan, USA), L. Premkumar and A. de Silva (University of North Carolina at Chapel Hill, USA), and R. Baric (University of North Carolina at Chapel Hill, USA) for providing us with DENV3 E domain III, full-length recombinant DENV2 NS1 and NS1 wing and β-ladder domains, and a DENV3 infectious clone, respectively. We are also thankful to S. Biering for providing helpful feedback on this manuscript; F. Bustos for discussions on statistical analyses and data presentation; and J. V. Zambrana for providing demographic and infection history data about the samples.
Funding: This research was funded by National Institutes of Health (NIH) grants P01AI106695 (to E.H.) and NIH U19-AI135995 (to D.A.L.). G.A.’s work was supported by Terry and Susan Ragon; the SAMANA Kay MGH Research Scholars award; the Ragon Institute of MGH, MIT and Harvard; the NIH (3R37AI080289-11S1); the Gates Foundation Global Health Vaccine Accelerator Platform funding (OPP1146996 and INV-001650); and the Musk Foundation. The PDCS was supported by the Pediatric Dengue Vaccine Initiative grant VE-1 (to E.H.) from the Bill and Melinda Gates Foundation and NIH subcontract HHSN2722001000026C (to E.H. and A.B.).
Author contributions: E.H., G.A., and A.G.D.J. conceptualized the study. A.G.D.J., C.A., and V.R. conducted systems serology experiments and virological assays. M.M. and P.N. conducted experiments for sample characterization. C.A. and C.L. performed bioinformatic analysis. A.G.D.J, C.A., C.L., S.B., L.K., T.S., D.L., E.H., and G.A. contributed to overall data analysis and visualization. E.H., G.A., and A.B. obtained funding. A.B. and G.K. were responsible for sample acquisition, clinical and laboratory characterization, and generation of databases. E.H., G.A., and D.L. supervised the study. A.G.D.J. and E.H. wrote the first draft of the manuscript. All authors reviewed and edited the manuscript.
Competing interests: G.A. is a founder of Systems Seromyx and an employee of Leyden Labs. E.H.’s laboratory received research funds from Takeda Vaccines Inc. to analyze samples from vaccine recipients. E.H. served on one-time advisory boards for Merck and Takeda. The other authors declare that they have no competing interests.
Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. Materials may be shared with outside investigators subject to availability and following UC Berkeley IRB approval. Please contact the UC Berkeley Center for the Protection of Human Subjects ([email protected]) and E.H. ([email protected]) to arrange for access. The materials used in this study are covered by standard material transfer agreements. There was no unique code generated for this manuscript. Code from this manuscript was adapted from https://github.com/LoosC/systemsseRology.
National Institutes of Health: P01AI106695
National Institutes of Health: U19-AI135995
National Institutes of Health: HHSN2722001000026C
National Institutes of Health: P01AI106695
National Institutes of Health: NIH U19-AI135995
National Institutes of Health: HHSN2722001000026C
Center for Global Health: P01AI106695
Center for Global Health: U19-AI135995
Center for Global Health: 3R37AI080289-11S1
Center for Global Health: OPP1146996
Center for Global Health: INV-001650
Center for Global Health: HHSN2722001000026C
Bill and Melinda Gates Foundation: OPP1146996
Bill and Melinda Gates Foundation: INV-001650
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