ABSTRAK
DEMAM BERDARAH DENGUE
DAN
PERKEMBANGAN VAKSINNY A
Liva Wijaya, 2005. Pembimbing utama: Fanny Rahardja, dr., Msi.
Demam Berdarah Dengue (DBD) merupakan permasalahan masyarakat global.
Hal ini menjadi salah satu penyebab hospitalisasi dan kematian diantara
anak-anak, terutama di negara berkembang. Ledakan DBD telah terjadi di negara kita
beberapa bulan yang lalu dan ini berhubungan dengan angka kematian yang
siknifikan terutama di kalangan pediatri.
Makalah ini menjelaskan struktur virus, faktor epidemiologi, manifestasi klinik,
patogenesis DBD, dan terutama mengenai perkembangan vaksinnya. Tujuan dari
makalah ini adalah untuk mempelajari perkembangan vaksin Dengue.
Saat ini, tidak ada vaksin yang tersedia tetapi terdapat 4 kelompok penelitian
mengenai hal tersebut. Vaksin-vaksin
itu adalah vaksin virus hidup yang
dilemahkan, vaksin chimera, vaksin subunit dan vaksin asam nukleat. Bukti-bukti
terakhir menunjukan bahwa terdapat kandidat vaksin yang memiliki efikasi dan
efisiensi yang optimal untuk mencegah penyakit Dengue. Untuk saat ini, vaksin
itu adalah vaksin virus hidup yang dilemahkan.
Untuk mengurangi kejadian penyakit Dengue terutama DBD dapat dilakukan
berbagai usaha seperti menemukan teknik lain untuk memproduksi vaksin dan
meneliti kemungkinan digunakannya imunoglobulin, interferon, dan obat-obat
lain sebagai terapi pilihan untuk mencegah teIjadinya penyakit atau manifestasi
klinik yang berat. Jangan lupa mengenai nyamuk dan lingkungan karena
diperlukan
penanganan
khusus
yang
komprehensif
bila
menginginkan
menurunnya penyakit Dengue.
Kata kunci: Demam Berdarah Dengue, Vaksin, Perkembangan
IV
~--ABSTRACT
DENGUE HEMORRHAGIC FEVER
AND
ITS VACCINE DEVELOPMENT
Liva Wijaya,
2005; The main tutor: Fanny Rahardja, dr., Msi.
Dengue hemorrhagic fever (DHF) has been a major global public health
problem. It becomes one of causes of hospitalization and death among children,
especially in developing countries. A DHF outbreak had occurred at our cOlmffy
several months ago and it associated lllith significant mortality, particularly in the
pediatric population.
This paper explained about the structure of the vin/s, epidemiological factor,
clinical
manifestations,
pathogenesis
of DHF,
and
especially
about
the
development of its vaccines. The objective of this paper is to study Dengue
vaccine's development.
At this time, there is no vaccine available but there are 4 groups researches of
Dengue vaccines. They are life attenuated vaccine, chimera vaccine, subunit
vaccine and nucleic acid vaccine. The latest evidences show that there is a
vaccine candidate that has an optimal efficacy and efficiency to prevent Dengue
disease that already to use. For this time, that vaccine is life attenuated vaccine.
In order to reduce the incidence of Dengue disease especially DHF, we can do
a lot of efforts such as find the other techniques of vaccine production and
research the possibility of immunoglobulin, interferon, and other drugs as one of
choices of therapy of Dengue disease to prevent the disease or the severe clinical
manifestations. Don't forget about the mosquitoes and environment, because it
needs special actions which are comprehensive if we want to decrease the
incidence of Dengue disease.
Key-word'): Dengue Hemorrhagic Fever, Vaccine, Development
DAFT AR ISI
Halaman
JUDUL I
LEMBAR PERSETUmAN
... ...ii
SURAT PERNY AT AAN iii
AB STRAK
IVABSTRACT
,v
PRAKA T A VI
DAFT AR ISI viii
DAFT AR T ABEL x
DAFT AR GAMBAR ...xiv
DAFT AR DIAGRAM .xvi
DAFT AR GRAFIK xvii
DAFT AR LAMPIRAN .xix
BAB I. PENDAHULUAN
1. 1. Latar Belakang . ... . . ... . .. ... .. . .. .. .. . . .. 1
1.2. Identifikasi Masalah .. 2
1.3. Maksud dan Tujuan Penulisan 3
1.4. Manfaat Penulisan 3
1.5. Metodologi 3
BAB II. TINJAUAN PUST AKA
2.1. Pengertian 4
2.2. Penyebab 4
2.2.1. Genom Virus ... ... ... ... 5
2.2.2. Protein Virus 6
2.2.3. Proses Replikasi Virus ...10
2.2.4. Proses Pembentukan Protein .12
2.3. Epidemiologi .15
2.3.1. Sejarah dan Persebaran Geografi .15
2.3.2. Penj amu.. . ., .. ... . .. .. .... .. ... .... ... .. .... .. .. ...
17
2.3.3. Penyebar ...19
2.3.4. Transmi si ... ... ... .... ... .. .... . ... ... .. ... .. .... .... .. ... .. ...21
2.4. Diagnosis Klinis ...22
2.4. 1. Demam Dengue 23
2.4.2. Demam Berdarah Dengue .25
2.5. Imunopatogenesis.. . .. . .. .. . . . .. . . ... . . .. .. .. . . .. . . .. .. ... . . .28
2.5.1. Infeksi Primer Dengue ..29
2.5.1.1. Respon Imun Nonspesifik .29
2.5.1.2. Respon Imun Spesifik .39
2.5.2. Infeksi Sekunder Dengue dengan Serotipe Heterolog 43
2.6. Vaksin . . . .. . . .. . . .. . . .. . . .46
2.6.1. Ltfe Attenuated Vaccine.
...46
2.6.1.1. Vaksin Virus yang Dilemahkan Melalui Pembiakan Berulang48
2.6.1.2. Recombinant Life Attenuated Virus Vaccines
68
2.6.1.2.1. Infectious cDNA clone-Derived Dengue Vaccine...68
2.6.1.2.1.1. DENY ll30
69
2.6.1.2.1.2. DENVMutF
90
2.6.1.2.2. Vaksin Chimera
98
2.6.1.2.2.1. Chimera-Vax
...
98
2.6.1.2.2.2. Vaksin DENI-4 prM dan E inserted to
DEN2 16681 PDK53
106
2.6.1.2.3. Recombinant Subunit Vaccines
ll0
2.6.3. Nucleid acid system
.114
2.6.3.1. Naked DNA
114
2.6.3.2. Vaksin Plasmid DNA yang Mengkode Protein prM dan E
115
2.6.3.3. DEN2 DNA .VaccineBy Incorporation of Lysosome Associated
Membrane Protein (LAMP) Sequences and Use of Plasmids
Expressing GM-CSF
.120
2.6.3.4. Vaksin DNA DEN2 yang Mengandung Protein NSI
120
2.6.4. NonreplicatingDengue Vaccine
...121
2.6.4.1. Inactivated Whole Virus .. ... ... 121
2.6.4.2. Structural Proteins Purifiedfrom Whole Virus 121
2.6.4.3. Nonstructural Proteins Purifiedfrom Infected Cells 122
2.6.4.4. Synthetic Peptide .123
BAB III. PEMBAHASAN ... .125
BAB IV. KESIMPULAN DAN SARAN 133
4.1. Kesimpulan .133
4.2. Saran ... ... ... .. . .. ... .. ... .. .
133
DAFT AR PUST AKA .134
LAMPIRAN .149
RIW AY AT HIDUP .152
IX
DAFTAR TABEL
Halaman
Tabel 2.1
Kriteria gejala post vaksinasi sukarelawan dewasa
54
Tabel 2.2
Komposisi dari ketujuh formulasi kandidat vaksin Dengue
55
Tabel 2.3
lumlah sukarelawan dengan reaksi klinik yang parah dan abnormalitas biologis
yang berat. yang diteliti setelah dosis pertama vaksinasi virus Dengue tetravalen
yang dilemahkan 57
Tabel 2.4
Formulasi vaksin pada sukarelawan anak 60
Tabel 2.5
Tingkat infeksi. penyebaran. dan transmisi VIruS oleh Aedes aegypti setelah
diinfeksi secara oral dan parentral 63
Tabel 2.6
Perbedaan nukleotida dan asam amino pada DEN 4 wild type dan yang sudah
yang dilemahkan
70
Tabel 2.7
Kriteria gejala post vaksinasi vaksin .130
... 72Tabel2.8
Respon sukarelawan post vaksinasi 2M30 73
x
---Xl
Tabel2.9
Respon imunologis pada penerima vaksin 74
Tabel 2.10
Perbandingan tingkat pe1emahan pada beberapa virus DEN4 76
Tabel 2.11
Perbandingan infeksi DEN4wt dan 2M30 pada nyamuk 77
Tabe12.12
Gambaran fenotip virus yang mengandung mutasi charge cluster to alanine pada
gen NS5
79
Tabel 2.13
Lokasi mutasi DEN4 yang dikonservasi di DENl, DEN2, dan atau DEN3 82
Tabe12.14
Gamabaran fenotip virus rDEN4 yang mengalami mutasi double charge cluster to
alanine pada gen NS5
83
Tabel 2.15
Perbandingan sifat pelemahan pada DENlwt, DEN1mutF, DENL130
86
Tabe12.16
Mutasi ~30 dan mutF tidak menurunkan infektivitas rDENl yang diinokulasi
secara intratorakal ke T Spledens
.. ... 88Tabel 2.17
xu
Tabe12.18
Tingkat
infektivitas
dan imunogenesitas
rata-rata DEN 1\VP tipe liar dan
DEN 1mutF
94
Tabe12.19
Hasil penelitian II; titer antibodi netralisasi dalam serum kera yang dipapar
dengan 106pfuDEN 1WP
...95
Tabel 2.20
Hasil penelitian II; viremia pada kera Flavivirus naive dan yang imun terhadap
DEN1mutF setelah dipapar dengan DENIWP 96
Tabel 2.21
Efikasi imunogenesitas dan protektif chimera D2/1 pada tikus AG 129 108
Tabel 2.22
Imunogenesitas chimera D2/3 dan DEN2/4 pada tikus AG129 109
Tabel 2.23
Kadar antibodi netralisasi terhadap DEN2 pada tikus yang telah divaksin 117
Tabel 2.24
Respon limfosit T sitotoksik terhadap DEN2 pada tikus yang telah divaksinasi. 118
Tabel 2.25
Gambaran antibodi netralisasi dan proteksi setelah paparan virus pada kera yang
telah divaksin 1-2 dosis vaksin DNA DEN2
118
Tabel 2.26
Gambaran antibodi netralisasi dan proteksi setelah paparan virus pada kera yang
Xlll
Tabel3.1
Perkembangan penelitian vaksin Dengue sampai saat ini
125
Tabel3.2
DAFTAR GAMBAR
Halaman
Gambar 2.1Genom virus Dengue 5
Gambar 2.2
Aedes aegypti 20
Gambar 2.3
Kultur monosit 6 jam setelah diinfeksi virus DEN2 34
Gambar 2.4
Vakuola yang berisi benda-bend a yang dicerna 34
Gambar 2.5
Lokalisasi DEN2 dalam vakuola monosit yang telah terinfeksi selama 6 jam 34
Gambar 2.6
Respon sel imun terhadap infeksi virus Dengue 45
Gambar 2.7
Kunkel method (Biorad Mutagenesis) 79
Gambar 2.8
Delesi 30 nukleotida pada region 3'
85
Gambar 2.9
Mutasi stem loop di daerah 3' NCR 91
xv
Gambar 2.10
Perbedaan DENlwt dan DENlmutF
97
Gambar 2.11
Teknik pembentukan DEN l/YF
100
Gambar 2.12
Protein prM dan E DEN3 10 I
Gambar 2.13
Konstruksi Chimera YFIDEN3
101
Gambar 2.14
Konstruksi Chimera YF IDEN4 103
Gambar 2.15
DAFT AR DIAGRAM
Halaman
Diagram 2.1
Proses replikasi virus
12
Diagram 2.2
Manifestasi klinis infeksi virus Dengue 23
Diagram 2.3
Spektrum klinik Demam Berdarah Dengue 26
Diagram 2.4
Kemungkinan infeksi Dengue 28
DAFTAR GRAFIK
Halaman
Grafik 2.1
Persentase penerima vaksin dengan titer antibodi ~ 1:10 pada semua sukarelawan
terhadap setiap serotipe, 3 serotipe, dan 4 serotipe pada hari ke-28 dan atau hari
ke-60 setelah dosis pertama (n=43) dan hari ke-28 setelah dosis kedua (n=41) ...58
Grafik 2.2
Persentase penenma vaksin dengan abnormalitas biologis pada AL T, jumlah
trombosit, hitung 1eukosit, hitung PMN setelah dosis pertama
... . . . 58Grafik 2.3
Persentase penenma vaksin dengan abnormalitas biologis pada AL T, jumlah
trombosit, hitung leukosit, hitung PMN setelah dosis kedua 59
Grafik 2.4
Persentase penenma vaksin dengan antibodi netralisasi ~ 1: 10 untuk setiap
formulasi vaksin terhadap (A) serotipe 1 dan 2, (B) serotipe 3 dan 4, (C) pada 3
serotipe dan 4 serotipe, pada hari ke-28 dan atau 60 setelah dosis pertama dan hari
ke-28 setelah dosis kedua vaksin 59
Grafik 2.5
Jumlah sukarelawan yang mengalami ruam setelah divaksinasi 2M30 74
Grafik 2.6
Jumlah sukarelawan yang mengalami viremia setelah divaksinasi 2M30 75
Grafik 2.7
XVlll
Grafik 2.8
Perbandingan viremia yang disebabkan oleh vaksin rekombinan
85
Grafik 2.9
Pertumbuhan DENlmutF dalam sel LLCMK2 (A) dan sel C6/36 (B) 92
Grafik 2.10
Kadar virus dalam serum setelah infeksi 104pfu DEN1\\1J>
95
Grafik 2.11
Kadar virus dalam serum sesudah diinokulasi 106pfu DEN1\\1J>
97
Grafik 2.12
Ciri khas pertumbuhan chimera dalam sel LLCMK2 107
Grafik 2.13
Ciri khas pertumbuhan chimera pada sel vero 108
Grafik 2.14
DAFTAR LAMPIRAN
Halaman
Lampiran
].Gambar imunopatogenesis Demam Berdarah Dengue 149
Lampiran 2.
Diagram mekanisme sinyal TNFa 149
Lampiran 3.
Diagram mekanisme kerja INFo/p... ... 150
Lampiran 4.
Daftar gen yang diekspresikan sel yang terinfeksi virus Dengue 150
Lampiran 5.
Diagram mekanisme dan kemungkinan efek yang teIjadi selama infeksi VIruS
Dengue pada endotel. 151
Nama Gen Fungsi
h-IAP I, Human inhibitor of apop/osis Anti-apoptosis
proteill- J gene
ESDN, Endothelial and smooth muscle Pengaturan pertumbuhan sel
cell derived neurophilin like protein endotel/vaskular
2-5 oligodenyla/e .s~Vlllhetasegene lnduksi IFNa/p
2-5 oligodel1)'late sylllhetase- like gene lnduksi IFNo./p
Mx I, lvfywrirus (iJ!f!lIenza) resistance Respon IFN tipe 1
J, homolog Qf murine (inte~feron
-inducible protein p78) gene
RGS
2,
Regulator
oj
G protein
Aktivasi sel B dan T
signaling 2 gene
Galectin 9, LecTin, galacToside binding,
Anti-apoptosis, adesi sel, dan proliferasi
soluble binding 9 gene
sel
Lampiran 3. Diagram mekanisme kerja IFNo.
FN RECEPTOR
Induceds~
2-5(r:)l:n~..e
G
Protain Kln-. PKR
==- =
(In.ct.ve) ~.b:
IbRNA d8ANA .. ,ATP P..ot~i.u
"no 'H5(A)
1
~ Pt<A.pho~d
(8C1J d)
-.
~
~
(h"l.c::t"",e) (activ.'.d) .J .- - - \ CTP --+- ~DP
~ elF2 fJ. .,F2 n I
Pt1o~-"" ,. ".-0_AAA.A Aill
-!
TI-nn"J pdo..., ~ Degraded ~E_ efF?-G'TP,It1hibirioll.-
...F a.:.
~1
eIF2-GDP, Phosphorylated
<N~'...nc:1'on.t ) .. Inhibition of Protein Synlheela
150
http://www.jpk.~ld.cu/curso-denQ U8- [nemorias/conferencia~:[naqistfales/23. pdf.
Lampiran 4. Daftar gen yang diekspresikan sel yang terinfeksi virus Dengue
RIWAYAT HIDUP
Nama
: Liva Wijaya
Nomor Pokok Mahasiswa: 0110091
Tempat dan Tanggal\ahir: Mojokerto, 16 Maret 1984
Alamat
: Sukakarya III/16 Bandung, Jawa Barat
Pemuda 50 Mojosari, Jawa Timur
Riwayat Pendidikan
TK Bhayangkari, Mojosari, tahun \u\us 1989
SDN Seduri II, Mojosari, tahun lulus 1995
SLTP Taruna Nusa Harapan, Mojokerto, tahun lulus 1998
SMU Taruna Nusa Harapan, Mojokerto, tahun lulus 2001
BABI
PENDAHULUAN
1.1. Latar Belakang
Penyakit Dengue merupakan penyakit tropikal dan subtropikal yang saat ini
menjadi
permasalahan
global.
Epidemi
penyakit
Dengue
dan dengue-like
dilaporkan terjadi pada sepanjang abad 19 dan awal abad 20 di Amerika, Eropa
Selatan, Afrika Utara, Mediterania Timur, Asia, Australia, dan berbagai pulau di
Samudra Hindia, Pasifik Utara dan Tengah serta Karibia. Pada 40 tahun terakhir
insidensi dan distribusi Demam Dengue (DD) dan Demam Berdarah Dengue
(DBD) meningkat (WHO, 1997). Saat ini, penyakit ini terjadi di lebih dari 100
negara dan mengancam kesehatan 2,5 juta orang bahkan lebih. Setiap tahun,
diperkirakan terdapat 50-100 juta kasus infeksi Dengue, mengakibatkan
200.000-500.000 kematian, tingkat kematian 5% (CDC, 2003; Aaskov, 2003). Baru-bam
ini, terjadi kejadian luar biasa Demam berdarah Dengue (DBD) di negara kita.
Dari bulan Januari sampai 4 April 2004 KLB menyebabkan 52.013 kasus
hospitalisasi dan 603 kematian yang tercatat di Departemen Kesehatan RI.
http://w\\'w.\'v.ho.llJt/csr/doll/2004 04 OS/en/.
Penyakit Dengue yang disebabkan oleh virus Dengue. Genus Flavivirus ini
dapat bermanifestasi asimtomatis, DD, DBD dan Sindrom Syok Dengue (SSD)
(WHO, 1997). Virus ini disebarkan oleh nyamuk Aedes sp. DD merupakan
penyakit infeksi yang ditandai dengan febris akut dan disertai gejala flu-like
.syndrome. Yang lebih berbahaya adalah manifestasi dari DBD karena selain
gejala DD, terdapat pula penurunan trombosit, gejala perdarahan, dan berlanjut ke
dalam SSD yang ditandai dengan kegagalan sirkulasi dan dapat berakhir dengan
kematian. DBD terjadi apabila penderita DD mendapat paparan kedua kali oleh
virus dengan serotipe berbeda (secondaJ)I heterologous il?!ectiolltheory). Penyakit
Dengue ini dapat menyerang segala kelompok usia dan segala tingkat sosial
ekonomi.
2
Tingginya
insidensi
dan angka
kematian,
memlCu dilakukan
berbagai
penelitian pengembangan vaksin sebagai usaha profilaksis. Macam kandidat
vaksin yang sedang di ujicoba saat ini adalah live-attenuated vaccine, Chimeric
virus vaccine, plasmid DNA vaccine, dan inactivated (sub-unit) virus vaccine
(Rothman, 2004). Untuk mendapatkan vaksin tersebut diperlukan antigen yang
dapat memberikan imunitas protektif melawan keempat serotipe virus Dengue
(Guzman, 1998). Efikasi dan keamanan beberapa kandidat vaksin baru sedang
dievaluasi dan dibuktikan di percoban klinik pada manusia (Chang, Kuno, Purdy,
and Davis, 2004)
Saat sekarang ini, penyakit Dengue secara epidemiologi dikelompokkan
berdasarkan dampaknya, yaitu berdampak rendah, sedang, dan berat. Sebagai
contoh terdapat virus yang dapat mempertahankan siklus sylvatic sehingga tingkat
transmisi ke manusia rendah, terdapat juga virus yang hanya dapat menyebabkan
DD saja, atau terdapat virus yang dapat menyebabkan penyakit Dengue yang lebih
berat,
misalnya
DBD
dan
SSD.
Meskipun
faktor
yang
mempengaruhi
epidemiologi penyakit ini sangat banyak, penelitian menduga bahwa terdapat
suatu protein struktural virus yang dapat meningkatkan replikasi virus dalam
tubuh manusia dan meningkatkan transmisi oleh vektor. Bagaimanapun, respon
imun dan faktor genetik juga mempengaruhi virulensi dan presentasi penyakit
(Hesse, 2003).
Melihat gambaran penyakit yang beragam tersebut sangat diperlukan vaksin
yang imunogenik, aman (efek samping rendah), murah, dan efektif.
1.2. Identifikasi Masalah
3
1.3. Maksud dan Tujuan Penulisan
1.3.1. Maksud Penulisan
Mengetahui cara kerja vaksin Dengue dalam tubuh manusia.
1.3.2. Tujuan Penulisan
Mengetahui perbandingan efikasi vaksin Dengue yang dapat digunakan
untuk profilaksis pada manusia.
1.4. Manfaat Penulisan
1.4.1. Manfaat akademis
Memperluas pengetahuan masyarakat mengenai vaksin Dengue.
1.4.2. Manfaat Praktis
Menambah referensi mengenai kemungkinan-kemungkinan digunakannya
vaksin Dengue sebagai profilaksis pada Manusia.
1.5. Metodologi
BABIV
KESIMPULAN DAN SARAN
4.1. Kesimpulan
Diantara perkembangan vaksin Dengue yang sangat pesat saat ini, kandidat
vaksin Nfe attenuated dengan pembiakan berulang terbukii efekiif melindungi dan
imunogenik pad a manusia dewasa dan anak-anak.
4.2. Saran
Masih perlu dicari teknik:
1. Bagaimana mengolah l{fe attenuated vaccine pembiakan berulang supaya
mutasi lebih terkendali sehingga hasil yang teIjadi sesuai yang diinginkan.
2. Bagaimana supaya respon sel T ekuivalen dan adekuat terhadap vaksin.
3. Teknik produksi vaksin lain yang mungkin suatu saat dapat menggantikan
vaksin l{fe attenuated dengan pembiakan berulang yang saat ini paling
maju perkembangannya.
4. Penelitian molekuler mengenai regio-regio tertentu pad a genom virus yang
bersifat imunogenik dan melemahkan agar dapat direkayasa lebih lagi.
5. Penelitian masih perlu dilanjutkan untuk membentuk suatu imunitas
pasif/immunoglobulin sebagai usaha pencegahan. Selain itu perlu juga
dipelajari lebih lanjut penggunaan interferon sebagai obat dan berbagai
antivirus yang dapat menghambat invasi virus ke dalam sel.
6. Penelitian mengenai penghambat interaksi protein E VIruS dengan
permukaan sel inang.
DAFTAR PUSTAKA
Almond l Clemens l, Engel's H, Halstead S., Khiem HR, Pabloz-Mendez A, et al. 2002. Accelerating the development and introduction of dengue vaccine fool' poor children, 5-8 December 2001, Ho Chi Minh City, VietNam.
Vaccine, 20: p. 3043-3046.
Amin P., Bhandare S., and Srivastava A 2001. Dengue, Dengue Haemorrhagic
Fever,
Dengue
Shock
Syndrome.
http://www.bl1i.orQ.!journal/200I 4303 iulvOlircvicw 380.11t111
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Anderson R, Wang S., Osiowy C. and Issekutz AC. 1997. Activation ofEndothelial Cells via Antibody-enhanced Dengue Virus infection of Peripheral Blood Monocytes. 1. Virol., 71 (6): p. 4226-4232.
Anna
Durbin,
Phase
I
http://c linicaltrials. gOY!ct{Q.ui!infilipharu~ssjonid=269
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Blaney lE. Jr, Manipon G.G., Firestone c.Y, Johnson D.H, Hanson c.T., Murphy RR, et al. 2003. Mutations which enhance the replication of dengue virus type 4 and an antigenic chimeric dengue virus type 2/4 vaccine candidate in Vero cells. Vaccine, 21 (27-30): p. 4317-27.
Blaney Jr lE., Johnson D.H, Firestone c.Y, Hanson C.T., Murphy B.R, and
Whitehead
S.S.
2001.Chemical Mutagenesis of Dengue Virus Type
4 Yields Mutant Viruses Which Are Temperature Sensitive in Vero Cells or
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