1.
Guarner J, Hale GL (2019) Four human diseases with significant public health impact caused
by mosquito-borne flaviviruses: West Nile, Zika, dengue and yellow fever. Semin Diagn Pathol
36:170-176
2.
Pierson TC, Diamond MS (2020) The continued threat of emerging flaviviruses. Nat
Microbiol 5:796-812
3.
Krol E, Brzuska G, Szewczyk B (2019) Production and Biomedical Application of Flaviviruslike Particles. Trends Biotechnol 37:1202-1216
4.
Neufeldt CJ, Cortese M, Acosta EG, Bartenschlager R (2018) Rewiring cellular networks by
members of the Flaviviridae family. Nat Rev Microbiol 16:125-142
5.
Daep CA, Munoz-Jordan JL, Eugenin EA (2014) Flaviviruses, an expanding threat in public
health: focus on dengue, West Nile, and Japanese encephalitis virus. J Neurovirol 20:539-560
6.
Hombach J, Barrett AD, Cardosa MJ, Deubel V, Guzman M, Kurane I, Roehrig JT, Sabchareon
A, Kieny MP (2005) Review on flavivirus vaccine development. Proceedings of a meeting
jointly organised by the World Health Organization and the Thai Ministry of Public Health,
26-27 April 2004, Bangkok, Thailand. Vaccine 23:2689-2695
7.
Andersen LK, Davis MD (2017) Climate change and the epidemiology of selected tick-borne
and mosquito-borne diseases: update from the International Society of Dermatology Climate
Change Task Force. Int J Dermatol 56:252-259
8.
Gould EA, Higgs S (2009) Impact of climate change and other factors on emerging arbovirus
diseases. Trans R Soc Trop Med Hyg 103:109-121
9.
Harrigan RJ, Thomassen HA, Buermann W, Smith TB (2014) A continental risk assessment
of West Nile virus under climate change. Glob Chang Biol 20:2417-2425
10.
Munoz AG, Thomson MC, Goddard L, Aldighieri S (2016) Analyzing climate variations at
multiple timescales can guide Zika virus response measures. Gigascience 5:1-6
11.
Zell R, Krumbholz A, Wutzler P (2008) Impact of global warming on viral diseases: what is
the evidence? Curr Opin Biotechnol 19:652-660
12.
Paz S (2015) Climate change impacts on West Nile virus transmission in a global context.
Philos Trans R Soc Lond B Biol Sci 370
13.
Semenza JC, Rocklov J, Ebi KL (2022) Climate Change and Cascading Risks from Infectious
Disease. Infect Dis Ther 11:1371-1390
14.
Walther GR, Post E, Convey P, Menzel A, Parmesan C, Beebee TJ, Fromentin JM, HoeghGuldberg O, Bairlein F (2002) Ecological responses to recent climate change. Nature
416:389-395
15.
Waller C, Tiemensma M, Currie BJ, Williams DT, Baird RW, Krause VL (2022) Japanese
Encephalitis in Australia - A Sentinel Case. N Engl J Med 387:661-662
16.
Yakob L, Hu W, Frentiu FD, Gyawali N, Hugo LE, Johnson B, Lau C, Furuya-Kanamori L,
Magalhaes RS, Devine G (2022) Japanese encephalitis emergence in Australia: the potential
50
population at risk. Clin Infect Dis
17.
Marchand E, Prat C, Jeannin C, Lafont E, Bergmann T, Flusin O, Rizzi J, Roux N, Busso V,
Deniau J, Noel H, Vaillant V, Leparc-Goffart I, Six C, Paty MC (2013) Autochthonous case of
dengue in France, October 2013. Euro Surveill 18:20661
18.
Kobayashi D, Murota K, Fujita R, Itokawa K, Kotaki A, Moi ML, Ejiri H, Maekawa Y, Ogawa
K, Tsuda Y, Sasaki T, Kobayashi M, Takasaki T, Isawa H, Sawabe K (2018) Dengue Virus
Infection in Aedes albopictus during the 2014 Autochthonous Dengue Outbreak in Tokyo
Metropolis, Japan. Am J Trop Med Hyg 98:1460-1468
19.
Misra UK, Kalita J (2010) Overview: Japanese encephalitis. Prog Neurobiol 91:108-120
20.
Sharma S, Mathur A, Prakash V, Kulshreshtha R, Kumar R, Chaturvedi UC (1991) Japanese
encephalitis virus latency in peripheral blood lymphocytes and recurrence of infection in
children. Clin Exp Immunol 85:85-89
21.
Chancey C, Grinev A, Volkova E, Rios M (2015) The global ecology and epidemiology of West
Nile virus. Biomed Res Int 2015:376230
22.
Hayes EB, O'Leary DR (2004) West Nile virus infection: a pediatric perspective. Pediatrics
113:1375-1381
23.
Slavov SN, Otaguiri KK, Kashima S, Covas DT (2016) Overview of Zika virus (ZIKV)
infection in regards to the Brazilian epidemic. Braz J Med Biol Res 49:e5420
24.
Brasil P, Pereira JP, Jr., Moreira ME, Ribeiro Nogueira RM, Damasceno L, Wakimoto M,
Rabello RS, Valderramos SG, Halai UA, Salles TS, Zin AA, Horovitz D, Daltro P, Boechat M,
Raja Gabaglia C, Carvalho de Sequeira P, Pilotto JH, Medialdea-Carrera R, Cotrim da Cunha
D, Abreu de Carvalho LM, Pone M, Machado Siqueira A, Calvet GA, Rodrigues Baiao AE,
Neves ES, Nassar de Carvalho PR, Hasue RH, Marschik PB, Einspieler C, Janzen C, Cherry
JD, Bispo de Filippis AM, Nielsen-Saines K (2016) Zika Virus Infection in Pregnant Women
in Rio de Janeiro. N Engl J Med 375:2321-2334
25.
Salvador FS, Fujita DM (2016) Entry routes for Zika virus in Brazil after 2014 world cup: New
possibilities. Travel Med Infect Dis 14:49-51
26.
Vasilakis N, Cardosa J, Hanley KA, Holmes EC, Weaver SC (2011) Fever from the forest:
prospects for the continued emergence of sylvatic dengue virus and its impact on public health.
Nat Rev Microbiol 9:532-541
27.
Whitehead SS, Blaney JE, Durbin AP, Murphy BR (2007) Prospects for a dengue virus vaccine.
Nat Rev Microbiol 5:518-528
28.
Halstead SB (1988) Pathogenesis of dengue: challenges to molecular biology. Science
239:476-481
29.
Halstead SB (2003) Neutralization and antibody-dependent enhancement of dengue viruses.
Adv Virus Res 60:421-467
30.
Anderson KB, Gibbons RV, Thomas SJ, Rothman AL, Nisalak A, Berkelman RL, Libraty DH,
Endy TP (2011) Preexisting Japanese encephalitis virus neutralizing antibodies and increased
51
symptomatic dengue illness in a school-based cohort in Thailand. PLoS Negl Trop Dis
5:e1311
31.
Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A, Balmaseda A, Harris
E (2017) Antibody-dependent enhancement of severe dengue disease in humans. Science
358:929-932
32.
Katzelnick LC, Narvaez C, Arguello S, Lopez Mercado B, Collado D, Ampie O, Elizondo D,
Miranda T, Bustos Carillo F, Mercado JC, Latta K, Schiller A, Segovia-Chumbez B, Ojeda S,
Sanchez N, Plazaola M, Coloma J, Halloran ME, Premkumar L, Gordon A, Narvaez F, de Silva
AM, Kuan G, Balmaseda A, Harris E (2020) Zika virus infection enhances future risk of severe
dengue disease. Science 369:1123-1128
33.
Barrows NJ, Campos RK, Powell ST, Prasanth KR, Schott-Lerner G, Soto-Acosta R, GalarzaMunoz G, McGrath EL, Urrabaz-Garza R, Gao J, Wu P, Menon R, Saade G, Fernandez-Salas
I, Rossi SL, Vasilakis N, Routh A, Bradrick SS, Garcia-Blanco MA (2016) A Screen of FDAApproved Drugs for Inhibitors of Zika Virus Infection. Cell Host Microbe 20:259-270
34.
Boldescu V, Behnam MAM, Vasilakis N, Klein CD (2017) Broad-spectrum agents for flaviviral
infections: dengue, Zika and beyond. Nat Rev Drug Discov 16:565-586
35.
Kok WM (2016) New developments in flavivirus drug discovery. Expert Opin Drug Discov
11:433-445
36.
Stiasny K, Aberle JH, Chmelik V, Karrer U, Holzmann H, Heinz FX (2012) Quantitative
determination of IgM antibodies reduces the pitfalls in the serodiagnosis of tick-borne
encephalitis. J Clin Virol 54:115-120
37.
Kauffman EB, Kramer LD (2017) Zika Virus Mosquito Vectors: Competence, Biology, and
Vector Control. J Infect Dis 216:S976-S990
38.
Harris AF, McKemey AR, Nimmo D, Curtis Z, Black I, Morgan SA, Oviedo MN, Lacroix R,
Naish N, Morrison NI, Collado A, Stevenson J, Scaife S, Dafa'alla T, Fu G, Phillips C, Miles
A, Raduan N, Kelly N, Beech C, Donnelly CA, Petrie WD, Alphey L (2012) Successful
suppression of a field mosquito population by sustained release of engineered male
mosquitoes. Nat Biotechnol 30:828-830
39.
Gabrieli P, Smidler A, Catteruccia F (2014) Engineering the control of mosquito-borne
infectious diseases. Genome Biol 15:535
40.
Harris AF, Nimmo D, McKemey AR, Kelly N, Scaife S, Donnelly CA, Beech C, Petrie WD,
Alphey L (2011) Field performance of engineered male mosquitoes. Nat Biotechnol 29:10341037
41.
Sabet A, Goddard J (2022) Promise or Peril: Using Genetically Modified Mosquitoes in the
Fight Against Vector-Borne Disease. Am J Med 135:281-283
42.
Maezono K, Kobayashi S, Tabata K, Yoshii K, Kariwa H (2021) Development of a highly
specific serodiagnostic ELISA for West Nile virus infection using subviral particles. Sci Rep
11:9213
52
43.
Inagaki E, Sakai M, Hirano M, Muto M, Kobayashi S, Kariwa H, Yoshii K (2016) Development
of a serodiagnostic multi-species ELISA against tick-borne encephalitis virus using subviral
particles. Ticks Tick Borne Dis 7:723-729
44.
Martin DA, Muth DA, Brown T, Johnson AJ, Karabatsos N, Roehrig JT (2000)
Standardization of immunoglobulin M capture enzyme-linked immunosorbent assays for
routine diagnosis of arboviral infections. J Clin Microbiol 38:1823-1826
45.
Kuno G (2003) Serodiagnosis of flaviviral infections and vaccinations in humans. Adv Virus
Res 61:3-65
46.
Crill WD, Chang GJ (2004) Localization and characterization of flavivirus envelope
glycoprotein cross-reactive epitopes. J Virol 78:13975-13986
47.
Dejnirattisai W, Jumnainsong A, Onsirisakul N, Fitton P, Vasanawathana S, Limpitikul W,
Puttikhunt C, Edwards C, Duangchinda T, Supasa S, Chawansuntati K, Malasit P,
Mongkolsapaya J, Screaton G (2010) Cross-reacting antibodies enhance dengue virus
infection in humans. Science 328:745-748
48.
Rathore APS, St John AL (2020) Cross-Reactive Immunity Among Flaviviruses. Front
Immunol 11:334
49.
Tabata K, Itakura Y, Toba S, Uemura K, Kishimoto M, Sasaki M, Harrison JJ, Sato A, Hall WW,
Hall RA, Sawa H, Orba Y (2022) Serological characterization of lineage II insect-specific
flaviviruses compared with pathogenic mosquito-borne flaviviruses. Biochem Biophys Res
Commun 616:115-121
50.
Auguste AJ, Langsjoen RM, Porier DL, Erasmus JH, Bergren NA, Bolling BG, Luo H, Singh
A, Guzman H, Popov VL, Travassos da Rosa APA, Wang T, Kang L, Allen IC, Carrington CVF,
Tesh RB, Weaver SC (2021) Isolation of a novel insect-specific flavivirus with
immunomodulatory effects in vertebrate systems. Virology 562:50-62
51.
Guzman H, Contreras-Gutierrez MA, Travassos da Rosa APA, Nunes MRT, Cardoso JF,
Popov VL, Young KI, Savit C, Wood TG, Widen SG, Watts DM, Hanley KA, Perera D, Fish
D, Vasilakis N, Tesh RB (2018) Characterization of Three New Insect-Specific Flaviviruses:
Their Relationship to the Mosquito-Borne Flavivirus Pathogens. Am J Trop Med Hyg 98:410419
52.
Harrison JJ, Hobson-Peters J, Colmant AMG, Koh J, Newton ND, Warrilow D, BielefeldtOhmann H, Piyasena TBH, O'Brien CA, Vet LJ, Paramitha D, Potter JR, Davis SS, Johansen
CA, Setoh YX, Khromykh AA, Hall RA (2020) Antigenic Characterization of New Lineage II
Insect-Specific Flaviviruses in Australian Mosquitoes and Identification of Host Restriction
Factors. mSphere 5
53.
Hobson-Peters J, Harrison JJ, Watterson D, Hazlewood JE, Vet LJ, Newton ND, Warrilow D,
Colmant AMG, Taylor C, Huang B, Piyasena TBH, Chow WK, Setoh YX, Tang B, Nakayama
E, Yan K, Amarilla AA, Wheatley S, Moore PR, Finger M, Kurucz N, Modhiran N, Young PR,
Khromykh AA, Bielefeldt-Ohmann H, Suhrbier A, Hall RA (2019) A recombinant platform
53
for flavivirus vaccines and diagnostics using chimeras of a new insect-specific virus. Sci Transl
Med 11
54.
Wastika CE, Harima H, Sasaki M, Hang'ombe BM, Eshita Y, Qiu Y, Hall WW, Wolfinger MT,
Sawa H, Orba Y (2020) Discoveries of Exoribonuclease-Resistant Structures of InsectSpecific Flaviviruses Isolated in Zambia. Viruses 12
55.
Piyasena TBH, Newton ND, Hobson-Peters J, Vet LJ, Setoh YX, Bielefeldt-Ohmann H,
Khromykh AA, Hall RA (2019) Chimeric viruses of the insect-specific flavivirus Palm Creek
with structural proteins of vertebrate-infecting flaviviruses identify barriers to replication of
insect-specific flaviviruses in vertebrate cells. J Gen Virol 100:1580-1586
56.
Colmant AMG, Hobson-Peters J, Slijkerman TAP, Harrison JJ, Pijlman GP, van Oers MM,
Simmonds P, Hall RA, Fros JJ (2021) Insect-Specific Flavivirus Replication in Mammalian
Cells Is Inhibited by Physiological Temperature and the Zinc-Finger Antiviral Protein. Viruses
13
57.
Bardina SV, Bunduc P, Tripathi S, Duehr J, Frere JJ, Brown JA, Nachbagauer R, Foster GA,
Krysztof D, Tortorella D, Stramer SL, Garcia-Sastre A, Krammer F, Lim JK (2017)
Enhancement of Zika virus pathogenesis by preexisting antiflavivirus immunity. Science
356:175-180
58.
Garg H, Yeh R, Watts DM, Mehmetoglu-Gurbuz T, Resendes R, Parsons B, Gonzales F, Joshi
A (2021) Enhancement of Zika virus infection by antibodies from West Nile virus seropositive
individuals with no history of clinical infection. BMC Immunol 22:5
59.
Saito Y, Moi ML, Takeshita N, Lim CK, Shiba H, Hosono K, Saijo M, Kurane I, Takasaki T
(2016) Japanese encephalitis vaccine-facilitated dengue virus infection-enhancement
antibody in adults. BMC Infect Dis 16:578
60.
Orba Y, Matsuno K, Nakao R, Kryukov K, Saito Y, Kawamori F, Loza Vega A, Watanabe T,
Maemura T, Sasaki M, Hall WW, Hall RA, Pereira JA, Nakagawa S, Sawa H (2021) Diverse
mosquito-specific flaviviruses in the Bolivian Amazon basin. J Gen Virol 102
61.
Kumar S, Stecher G, Li M, Knyaz C, Tamura K (2018) MEGA X: Molecular Evolutionary
Genetics Analysis across Computing Platforms. Mol Biol Evol 35:1547-1549
62.
Letunic I, Bork P (2021) Interactive Tree Of Life (iTOL) v5: an online tool for phylogenetic
tree display and annotation. Nucleic Acids Res 49:W293-W296
63.
Clark DC, Lobigs M, Lee E, Howard MJ, Clark K, Blitvich BJ, Hall RA (2007) In situ reactions
of monoclonal antibodies with a viable mutant of Murray Valley encephalitis virus reveal an
absence of dimeric NS1 protein. J Gen Virol 88:1175-1183
64.
Sasaki M, Anindita PD, Phongphaew W, Carr M, Kobayashi S, Orba Y, Sawa H (2018)
Development of a rapid and quantitative method for the analysis of viral entry and release
using a NanoLuc luciferase complementation assay. Virus Res 243:69-74
65.
Slon Campos JL, Poggianella M, Marchese S, Mossenta M, Rana J, Arnoldi F, Bestagno M,
Burrone OR (2017) DNA-immunisation with dengue virus E protein domains I/II, but not
54
domain III, enhances Zika, West Nile and Yellow Fever virus infection. PLoS One
12:e0181734
66.
Blitvich BJ, Firth AE (2015) Insect-specific flaviviruses: a systematic review of their discovery,
host range, mode of transmission, superinfection exclusion potential and genomic
organization. Viruses 7:1927-1959
67.
Berneck BS, Rockstroh A, Fertey J, Grunwald T, Ulbert S (2020) A Recombinant Zika Virus
Envelope Protein with Mutations in the Conserved Fusion Loop Leads to Reduced Antibody
Cross-Reactivity upon Vaccination. Vaccines (Basel) 8
68.
Priyamvada L, Quicke KM, Hudson WH, Onlamoon N, Sewatanon J, Edupuganti S,
Pattanapanyasat K, Chokephaibulkit K, Mulligan MJ, Wilson PC, Ahmed R, Suthar MS,
Wrammert J (2016) Human antibody responses after dengue virus infection are highly crossreactive to Zika virus. Proc Natl Acad Sci U S A 113:7852-7857
69.
Goncalvez AP, Engle RE, St Claire M, Purcell RH, Lai CJ (2007) Monoclonal antibodymediated enhancement of dengue virus infection in vitro and in vivo and strategies for
prevention. Proc Natl Acad Sci U S A 104:9422-9427
70.
Mansfield KL, Horton DL, Johnson N, Li L, Barrett ADT, Smith DJ, Galbraith SE, Solomon
T, Fooks AR (2011) Flavivirus-induced antibody cross-reactivity. J Gen Virol 92:2821-2829
71.
Allwinn R, Doerr HW, Emmerich P, Schmitz H, Preiser W (2002) Cross-reactivity in flavivirus
serology: new implications of an old finding? Med Microbiol Immunol 190:199-202
72.
Chiou SS, Crill WD, Chen LK, Chang GJ (2008) Enzyme-linked immunosorbent assays using
novel Japanese encephalitis virus antigen improve the accuracy of clinical diagnosis of
flavivirus infections. Clin Vaccine Immunol 15:825-835
73.
Rey FA, Stiasny K, Vaney MC, Dellarole M, Heinz FX (2018) The bright and the dark side of
human antibody responses to flaviviruses: lessons for vaccine design. EMBO Rep 19:206-224
74.
Huang KJ, Yang YC, Lin YS, Huang JH, Liu HS, Yeh TM, Chen SH, Liu CC, Lei HY (2006)
The dual-specific binding of dengue virus and target cells for the antibody-dependent
enhancement of dengue virus infection. J Immunol 176:2825-2832
75.
de Alwis R, Williams KL, Schmid MA, Lai CY, Patel B, Smith SA, Crowe JE, Wang WK, Harris
E, de Silva AM (2014) Dengue viruses are enhanced by distinct populations of serotype crossreactive antibodies in human immune sera. PLoS Pathog 10:e1004386
76.
Gunawardana SA, Shaw RH (2018) Cross-reactive dengue virus-derived monoclonal
antibodies to Zika virus envelope protein: Panacea or Pandora's box? BMC Infect Dis 18:641
77.
Vogt MR, Dowd KA, Engle M, Tesh RB, Johnson S, Pierson TC, Diamond MS (2011) 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 85:11567-11580
78.
Roehrig JT, Bolin RA, Kelly RG (1998) Monoclonal antibody mapping of the envelope
glycoprotein of the dengue 2 virus, Jamaica. Virology 246:317-328
55
79.
Stiasny K, Kiermayr S, Holzmann H, Heinz FX (2006) Cryptic properties of a cluster of
dominant flavivirus cross-reactive antigenic sites. J Virol 80:9557-9568
80.
Sukupolvi-Petty S, Austin SK, Purtha WE, Oliphant T, Nybakken GE, Schlesinger JJ, Roehrig
JT, Gromowski GD, Barrett AD, Fremont DH, Diamond MS (2007) Type- and subcomplexspecific neutralizing antibodies against domain III of dengue virus type 2 envelope protein
recognize adjacent epitopes. J Virol 81:12816-12826
81.
Rockstroh A, Moges B, Barzon L, Sinigaglia A, Palu G, Kumbukgolla W, Schmidt-Chanasit J,
Sarno M, Brites C, Moreira-Soto A, Drexler JF, Ferreira OC, Ulbert S (2017) Specific
detection of dengue and Zika virus antibodies using envelope proteins with mutations in the
conserved fusion loop. Emerg Microbes Infect 6:e99
82.
Kam YW, Leite JA, Amrun SN, Lum FM, Yee WX, Bakar FA, Eng KE, Lye DC, Leo YS, Chong
CY, Freitas ARR, Milanez GP, Proenca-Modena JL, Renia L, Costa FTM, Ng LFP, ZikaUnicamp N (2019) ZIKV-Specific NS1 Epitopes as Serological Markers of Acute Zika Virus
Infection. J Infect Dis 220:203-212
83.
Wan J, Wang T, Xu J, Ouyang T, Wang Q, Zhang Y, Weng S, Li Y, Wang Y, Xin X, Wang X, Li
S, Kong L (2021) Novel Japanese encephalitis virus NS1-based vaccine: Truncated NS1 fused
with E. coli heat labile enterotoxin B subunit. EBioMedicine 67:103353
84.
Dejnirattisai W, Wongwiwat W, Supasa S, Zhang X, Dai X, Rouvinski A, Jumnainsong A,
Edwards C, Quyen NTH, Duangchinda T, Grimes JM, Tsai WY, Lai CY, Wang WK, Malasit
P, Farrar J, Simmons CP, Zhou ZH, Rey FA, Mongkolsapaya J, Screaton GR (2015) A new
class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected
with dengue virus. Nat Immunol 16:170-177
85.
Tsai WY, Lai CY, Wu YC, Lin HE, Edwards C, Jumnainsong A, Kliks S, Halstead S,
Mongkolsapaya J, Screaton GR, Wang WK (2013) High-avidity and potently neutralizing
cross-reactive human monoclonal antibodies derived from secondary dengue virus infection.
J Virol 87:12562-12575
86.
Dai L, Xu K, Li J, Huang Q, Song J, Han Y, Zheng T, Gao P, Lu X, Yang H, Liu K, Xia Q, Wang
Q, Chai Y, Qi J, Yan J, Gao GF (2021) Protective Zika vaccines engineered to eliminate
enhancement of dengue infection via immunodominance switch. Nat Immunol 22:958-968
87.
Chabierski S, Barzon L, Papa A, Niedrig M, Bramson JL, Richner JM, Palu G, Diamond MS,
Ulbert S (2014) Distinguishing West Nile virus infection using a recombinant envelope
protein with mutations in the conserved fusion-loop. BMC Infect Dis 14:246
88.
Urakami A, Ngwe Tun MM, Moi ML, Sakurai A, Ishikawa M, Kuno S, Ueno R, Morita K,
Akahata W (2017) An Envelope-Modified Tetravalent Dengue Virus-Like-Particle Vaccine
Has Implications for Flavivirus Vaccine Design. J Virol 91
89.
Slon-Campos JL, Dejnirattisai W, Jagger BW, Lopez-Camacho C, Wongwiwat W, Durnell LA,
Winkler ES, Chen RE, Reyes-Sandoval A, Rey FA, Diamond MS, Mongkolsapaya J, Screaton
GR (2019) A protective Zika virus E-dimer-based subunit vaccine engineered to abrogate
56
antibody-dependent enhancement of dengue infection. Nat Immunol 20:1291-1298
90.
Henchal EA, Gentry MK, McCown JM, Brandt WE (1982) Dengue virus-specific and
flavivirus group determinants identified with monoclonal antibodies by indirect
immunofluorescence. Am J Trop Med Hyg 31:830-836
91.
Pantoja P, Perez-Guzman EX, Rodriguez IV, White LJ, Gonzalez O, Serrano C, Giavedoni L,
Hodara V, Cruz L, Arana T, Martinez MI, Hassert MA, Brien JD, Pinto AK, de Silva A, Sariol
CA (2017) Zika virus pathogenesis in rhesus macaques is unaffected by pre-existing immunity
to dengue virus. Nat Commun 8:15674
92.
Willis E, Hensley SE (2017) Characterization of Zika virus binding and enhancement potential
of a large panel of flavivirus murine monoclonal antibodies. Virology 508:1-6
93.
Okuya K, Hattori T, Saito T, Takadate Y, Sasaki M, Furuyama W, Marzi A, Ohiro Y, Konno S,
Hattori T, Takada A (2022) Multiple Routes of Antibody-Dependent Enhancement of SARSCoV-2 Infection. Microbiol Spectr 10:e0155321
94.
Takada A, Ebihara H, Feldmann H, Geisbert TW, Kawaoka Y (2007) Epitopes required for
antibody-dependent enhancement of Ebola virus infection. J Infect Dis 196 Suppl 2:S347-356
57
Summary in Japanese
病原性蚊媒介性フラビウイルス（MBFV）は、異なるウイルス種間で構造タン
パク質のアミノ酸配列が高度に保存されている。そのため、これらの構造タンパク
質を認識する抗体は、交差反応性を示す。その交差反応性抗体は、幅広いフラビウ
イルスの構造タンパク質に結合するため、ウイルス種特異的な抗体を検出可能な血
清診断法は未だ開発されていない。本研究では、これまで報告されてきた MBFV 間
ではなく、MBFV と昆虫特異的フラビウイルス（ISFV）間の抗原性を比較し、異な
る抗原性を有するウイルスアミノ酸配列を用いて、交差反応性抗体の非特異的な結
合を低減させるウイルス抗原作出を試みた。
第一章
MBFV と比較した lineage II ISFV の血清学的性状解析
第一章では、分子系統学的に MBFV に近縁な lineage II ISFV の構造タンパク
質の抗原性を MBFV の構造タンパク質と比較した。まず、系統樹解析を実施した結
果、lineage II ISFV は lineage IIa ISFV と lineage IIb ISFV にクラスターが別れること
が明らかになった。そこで、これら二種類の lineage II ISFV の抗原性をそれぞれの
ウイルスに対する抗血清を用いて評価した。これまでに所属研究室で分離してきた
lineage IIa ISFV である PSFV と lineage IIb ISFV である BJV をマウスに免疫するこ
とにより、抗血清を作出した。それらの抗血清は一部の MBFV（DENV:デングウイ
ルス、ZIKV:ジカウイルス、JEV:日本脳炎ウイルスおよび WNV:ウエストナイルウイ
ルス）の感染細胞抗原に対し結合活性を示し、更に、それらの抗体は、フラビウイ
ルス感染症で問題となっている抗体依存性感染増強（ADE）活性をそれぞれの
MBFV に対して有していることを示した。また、PSFV 及び BJV に対する抗血清間
で、MBFV の ADE 活性が異なることも明らかにした。本結果から、lineage IIa ISFV
と lineage IIb ISFV では、抗原性が異なることが示唆され、lineage IIa ISFV である
PSFV と lineage IIb ISFV である BJV が MBFV（DENV、ZIKV、JEV 及び WNV）と
類似した抗原性の構造タンパク質を有していることを示した。本結果により、MBFV
感染歴のある患者が、ISFV 感染蚊に吸血されることにより、MBFV に対する抗体
が再活性化され、更にその抗体が ADE を誘導する可能性が示唆された。しかしな
がら、ISFV が感染した蚊の吸血により吸血対象へウイルスが導入されるかについ
ては不明であるため今後、更なる研究が必要である。
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第二章
フラビウイルス種特異的な抗体の検出及び誘導を可能にするウイルスタ
ンパク質デザイン
第二章では、MBFV、lineage II ISFV 及び lineage I ISFV の fusion loop（FL）ド
メインの抗原性を利用した交差反応を低減させるウイルスタンパク質の創出を試
みた。FL ドメインは、異なるフラビウイルス種間で高度に保存されており、抗 FL
抗体は幅広いフラビウイルスで交差反応することが報告されている。本研究では、
lineage I ISFV の FL ドメインは MBFV や lineage II ISFV と異なる抗原性を有するこ
とを明らかにした。更に、lineage I ISFV の FL ドメインの一部を搭載した MBFV
（DENV、ZIKV、JEV 及び WNV）の変異型ウイルス様粒子（SVP）を作出し、その
変異型 SVP へのフラビウイルス感染血清の交差反応性と、その免疫により誘導さ
れる抗体の交差反応性を評価した。その結果、野生型 SVP と比較して、変異型 SVP
ではフラビウイルス感染血清（同ウイルス種・株）の交差反応性を低減させ、ウイ
ルス種特異的な結合シグナルを検出できた。また、チャレンジフラビウイルス（同
ウイルス種・異なるウイルス株）の感染血清においても、強いウイルス種特異的な
結合シグナルを検出することができた。さらに、変異型 SVP を免疫した血清におい
て、交差反応性が低下し、ADE 活性が抑制された抗体が誘導され、それらの抗体は
中和活性を有することを示した。本成果は、変異型 SVP を ELISA 抗原として用い
ることにより、交差反応性抗体の非特異的な結合を減少させ、ウイルス特異的な抗
体が検出できる血清診断法への応用可能性を示した。更に、変異型 SVP 免疫血清で
は、野生型 SVP と比べ劇的に ADE 活性が抑制され、一部に中和活性が認められた。
以上の結果から、変異型 SVP は新規フラビウイルスワクチン抗原の候補になり得
ることが期待される。しかしながら、交差反応エピトープは FL ドメイン以外にも
存在する。そのため、今後、更なる交差エピトープを抗原性が異なる lineage I ISFV
に置換することにより、血清診断法及びワクチン開発に応用可能なウイルス抗原の
作出を目指す。
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