????? (Dengue viruses)

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????? (Dengue viruses)

• ??
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• ????????
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???? (Dengue viruses) ?????????(Arthropod-borne
viruses) ????(Flaviviridae)
????(Flavivirus) ??RNA ??? ?? 37-50 nm (???
???? ??? ????.. ) ???????( Dengue fever)
????????????? ??????(Aedes aegypti) ????
????(Aedes albopictus) ??
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??????? DF,25-50???DHF
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• ?????????
• 1915?1931?1942??????????????
• 1942????????????(500?)??
• 1981?????????????????
• 1987?1988??????????????
• 1995?,??????179????8?
• 1996?,???10?
• 2000?,?????140?
• 2001?,?????270?
• 2002?,?????5388?,21?????

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• ?????????
• 2003?,?????86?
• 2004?,?????336?
• 2005?,?????199?
• 2006?,?????949?
• 2007?,?????1961?
• 2008?,?????487?
• 2009?,???1052?
• 2010?8?,???277?,1???

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93????????????
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94????????????
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95????????????-???
???????
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96????????????-???
Updated2007/12/31 1600
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97??????????-???
Updated2008/12/30 1200
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2008??????????-???
Updated2008/12/30 1200
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organism"Dengue virus type 4" 1..113
"anchored capsid (anchC) protein" 1..99
"virion capsid (virC) protein" 114..279
"membrane precursor (prM) protein" 205..279
"membrane (M) protein" 280..774 "envelope
(E) protein" 775..1126 "NS1 protein"
1127..1344 "NS2A protein" 1345..1474 "NS2B
protein" 1475..2092 "NS3 protein" 2093..2219
"NS4A protein" 2220..2242 "2K protein"
2243..2487 "NS4B protein" 2488..3387 "NS5
protein"
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1..113 "anchored capsid (anchC) protein"
1..99 "virion capsid (virC) protein"
114..279 "membrane precursor (prM) protein"
205..279 "membrane (M) protein"
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280..774 "envelope (E) protein"
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280..774 "envelope (E) protein"
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775..1126 "NS1 protein"
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1127..1344 "NS2A protein"
1345..1474 "NS2B protein"
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1475..2092 "NS3 protein"
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1475..2092 "NS3 protein"
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2093..2219 "NS4A protein"
2220..2242 "2K protein"
2243..2487 "NS4B protein"
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2243..2487 "NS4B protein"
2488..3387 "NS5 protein"
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2488..3387 "NS5 protein"
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2488..3387 "NS5 protein"
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2488..3387 "NS5 protein"
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• ?????
• ???58?
• ???????????12???,???
• ????????????????
• ????????? 3940?,??56?
• ??24???,????????????????????????
• ???3?4?,????,???????
• ???????????,?????

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• ????? Dengue Hemorrhagic Fever, DHF
• ?????????
• ????????????,????????
• ??????????? 10?/mm3?(15-40?)
• ????(???????????????)
• ??????????20
• ?????????,?????
• ???????
• ??????? Dengue Shock Syndrome, DSS
• ??????????
• ???,????20mmHg?

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• Four serologically distinct types I, II, III, IV
• Different from nucleotide, amino acid,
  antigenic
• ?????,???????????????
• Mild Dengue fever
• Dengue hemorrhagic fever (DHF)?????
• Dengue shock syndrome (DSS)???????
• ???????????
• Virus virulence ????
• Host age ????
• Nutritional ??
• Genetic ??
• Immunological characterization ????
• Intercurrent infections ?????

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??????????,??????? ????????????? ( antibody
dependent enhancement, ADE) ? ????????????????????
? ???????????????????, ?????-?????,??????????? ?
???T???? ????????(cytokines),??????? ? ???????,???
???????????
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?????(secondary infection) ??????????????????? ?
?????????????????? ?????(??)?????????? ? ???????
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????????? ???? 17D ? ?????? SA 14-14-2
prM(????)?E(??) ? ???cDNA???RNA,??Vero?? ? ??????
??? ? ???????????????
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? ?????????? ?????1-4?prM(????)?E(??) ? ?????????
live-attenuated chimeric vaccine
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TV-1 consists of recombinant DEN1, -2, -3, and
-4, each with a 30-nucleotide deletion in the 3
untranslated region (30). TV-2 consists of
rDEN130, rDEN430, and two antigenic chimeric
viruses, rDEN2/ 430 and rDEN3/430, both also
bearing the 30 mutation. TV-3 consists of
rDEN130, rDEN230, rDEN430, and a 10-fold higher
dose of rDEN3/430. TV-1 and TV-2 were attenuated
in SCID-HuH-7 mice with minimal interference in
replication among the virus components. TV-1, -2,
and -3 were attenuated in rhesus monkeys as
measured by duration and peak of viremia. Each
monkey immunized with TV-1 and TV-3 seroconverted
to the four DEN components by day 28 with
neutralization titers ranging from 152 to 1273
and 159 to 1144 for TV-1 and TV-3,
respectively. TV-2 induced low antibody titers to
DEN2 and DEN3, but a booster immunization after 4
months increased the neutralizing antibody titers
to greater than 1100 against each serotype and
elicited broad neutralizing activity against 19
of 20 DEN subtypes. A single dose of TV-2 induced
protection against wild-type DEN1, DEN3, and DEN4
challenge, but not DEN2. However, two doses of
TV-2 or TV-3 induced protection against DEN2
challenge. Two tetravalent formulations, TV-2 and
TV-3, possess properties of a successful DEN
vaccine and can be considered for evaluation in
clinical trials.
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Protection of Rhesus monkeys against dengue virus
challenge after tetravalent live attenuated
dengue virus vaccination J Infect Dis. 2006
Jun 15193(12)1658-65. Epub 2006 May 9. Sun W,
Nisalak A, Gettayacamin M, Eckels KH, Putnak JR,
Vaughn DW, Innis BL, Thomas SJ, Endy TP.
Department of Virus Diseases, Division of
Communicable Diseases and Immunology, Walter Reed
Army Institute of Research, Silver Spring,
Maryland 20910-7500, USA. wellinton.sun_at_us.army.mi
l
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• Rhesus monkeys develop viremia after dengue virus
  (DENV) inoculation and have been used as an
  animal model to study DENV infection and DENV
  vaccine candidates. We evaluated, in this model,
  the protective efficacy of a live attenuated
  tetravalent DENV vaccine (TDV) candidate against
  parenteral challenge with parental near-wild-type
  DENV strains. Twenty monkeys were vaccinated with
  TDV at 0 and 1 month, and 20 unvaccinated monkeys
  served as controls. Vaccinated animals and their
  controls were inoculated with 10(3)-10(4) pfu of
  challenge virus 4.5 months after the second
  vaccination. Primary vaccination resulted in 95,
  100, 70, and 15 seroconversion to DENV
  serotypes 1, 2, 3, and 4 (DENV-1, -2, -3, and
  -4), respectively. After the second vaccination,
  the seropositivity rates were 100, 100, 90,
  and 70, respectively. Vaccination with TDV
  resulted in complete protection against viremia
  from DENV-2 challenge and in 80, 80, and 50
  protection against challenge with DENV-1, -3, and
  -4, respectively. Our results suggest that the
  TDV can elicit protective immunity against all 4
  DENV serotypes. Interference among the 4 vaccine
  viruses may have resulted in decreased antibody
  responses to DENV-3 and -4, which would require
  reformulation or dose optimization to minimize
  this interference during testing of the vaccine
  in humans.

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????????????? ???????? 4.??????????????? 5.?????
??????? 6.?????????,???????????
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