登革病毒3'UTRΔ30系列疫苗的研究进展
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摘要
登革病毒引发的登革热等疾病每年在全球范围内造成了相当大的经济、医疗、社会负担,严重威胁到人类生命健康。在目前研究的各种登革病毒疫苗中,采用反向遗传技术制得的3'UTRΔ30系列减毒活疫苗由于其免疫原性好,效价高,成本低等特点,在临床试验中展现出良好保护作用,研究推进快。能对四种血清型登革病毒都产生均衡免疫保护的3'UTRΔ30四联疫苗已处于Ⅲ期临床试验阶段,效力强,不良反应少,待随访期结束后有望上市,是当今最有前景的登革减毒灭活疫苗之一。为更深入了解3'UTRΔ30系列疫苗,现主要从起源、制备方法、临床研究等方面进行介绍。
Diseases such as dengue fever caused by denugue virus lead to considerable economic,medical and social burdens every year,which seriously threaten the health of human life. Among the various dengue virus vaccines currently under study,the 3'UTRΔ30 series of live attenuated vaccines prepared by reverse genetics have shown good protection in clinical trials because of their good immunogenicity,high titer and low cost. As a consequence,research on this kind of vaccine advances fast. The 3'UTRΔ30 quadruple vaccine,one of the most promising dengue attenuated inactivated vaccines today,which can produce balanced immune protection against the four serotypes of dengue virus,is in phase III clinical trials,showing strong efficacy and few adverse reactions. It is expected to be on the market after the end of the follow-up period. In order to gain a deeper understanding of the 3'UTRΔ30 series vaccines,the origin,preparation methods and clinical research are mainly focused on.
Diseases such as dengue fever caused by denugue virus lead to considerable economic,medical and social burdens every year,which seriously threaten the health of human life. Among the various dengue virus vaccines currently under study,the 3'UTRΔ30 series of live attenuated vaccines prepared by reverse genetics have shown good protection in clinical trials because of their good immunogenicity,high titer and low cost. As a consequence,research on this kind of vaccine advances fast. The 3'UTRΔ30 quadruple vaccine,one of the most promising dengue attenuated inactivated vaccines today,which can produce balanced immune protection against the four serotypes of dengue virus,is in phase III clinical trials,showing strong efficacy and few adverse reactions. It is expected to be on the market after the end of the follow-up period. In order to gain a deeper understanding of the 3'UTRΔ30 series vaccines,the origin,preparation methods and clinical research are mainly focused on.
引文
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[26]Kirkpatrick B D,Whitehead S S,Pierce K K,et al.The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model.Science Translational Medicine,2016,8(330):330-336.
[27]Scherwitzl I,Mongkolsapaya J,Screaton G.Recent advances in human flavivirus vaccines.Current Opinion in Virology,2017,23:95-101.
[28]Whitehead S S,Durbin A P,Pierce K K,et al.In a randomized trial,the live attenuated tetravalent dengue vaccine TV003 is well-tolerated and highly immunogenic in subjects with flavivirus exposure prior to vaccination.Plos Neglected Tropical Disease,2017,11(5):e0005584.
[29]Guy B,Jackson N.Dengue vaccine:Hypotheses to understand CYD-TDV-induced protection.Nature Reviews Microbiology,2016,14(1):45-54.
[30]Nascimento E J M,George J K,Velasco M,et al.Development of an anti-dengue NS1 Ig G ELISA to evaluate exposure to dengue virus.Journal of Virological Methods,2018,257:48-57.
[31]Guy B,Briand O,Lang J,et al.Development of the sanofi pasteur tetravalent dengue vaccine:One more step forward.Vaccine,2015,33(50):7100-7111.
[32]Villar L,Dayan G H,Arredondo-Garcia J L,et al.Efficacy of a tetravalent dengue vaccine in children in Latin America.New England Journal of Medicine,2015,372(2):113-123.
[33]Capeding M R,Tran N H,Hadinegoro S R,et al.Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia:A phase 3,randomized,observer-masked,placebo-controlled trial.Lancet,2014,384(951):1358-1365.
[34]Whitehead S S.Development of TV003/TV005,a single dose,highly immunogenic live attenuated dengue vaccine;what makes this vaccine different from the Sanofi-Pasteur CYDTMvaccine?Expert Review Vaccines,2016,15(4):509-517.
[35]Wilder-Smith A,Messad E.Age specific differences in efficacy and safety for the CYD-tetravalent dengue vaccine.Expert Review Vaccines,2016,15(4):437-441.
[36]Magnani D M,Silveira C G T,Ricciardi M J,et al.Potent plasmablast-derived antibodies elicited by the National Institutes of Health Dengue Vaccine.Journal of Virology,2017,91(22):e00867-17.
[37]Popper S J,Strouts F R,Lindow J C,et al.Early transcriptional responses after dengue vaccination mirror the response to natural infection and predict neutralizing antibody titers.The Journal of Infectious Diseases.2018,218(12):1911-1921.
[2]Screaton G,Mongkolsapaya J,Yacoub S,et al.New insights into the immunopathology and control of dengue virus infection.Nature Reviews Immunology,2015,15(12):745-759.
[3]Bhatt S,Gething P W,Brady O J,et al.The global distribution and burden of dengue.Nature.2013,496(7446):504-507.
[4]Scoot B,Halstead.Dengue antibody-dependent enhancement:Knowns and unknowns.Microbiology Spectrum,2014,2(6):1-18.
[5]陈柠,石磊泰,俞永新.登革热疫苗最新研究与展望.中国病毒学杂志,2016,6(6):471-480.Chen N,Shi L T,Yu Y X.Research progress and prospective on dengue vaccine.Virologica Sinica,2016,6(6):471-480.
[6]Katzelnick L C,Coloma J,Harris E.Dengue:Knowledge gaps,unmet needs,and research priorities.Lancet Infectious Diseases,2017,17(3):88-100.
[7]Crowe J E.Principles of broad and potent antiviral human antibodies:Insights for vaccine design.Cell Host&Microbe,2017,22(2):193-206.
[8]Fu J,Tan B H,Yap E H,et al.Full-length c DNA sequence of dengue type 1 virus(Singapore strain S275/90).Virology,1992,188(2):953-958.
[9]Whitehead S S,Falgout B,Hanley K A,et al.A live,attenuated dengue virus type 1 vaccine candidate with a 30-nucleotide deletion in the 3'untranslated region is highly attenuated and immunogenic in monkeys.Journal Virology,2003,77(2):1653-1657.
[10]Blaney J E,Durbin A P,Murphy B R,et al.Development of a live attenuated dengue virus vaccine using reverse genetics.Viral Immunology,2006,19(1):10-32.
[11]Men R,Bray M,Clark D,et al.Dengue type 4 virus mutants containing deletions in the 39 noncoding region of the RNAgenome:Analysis of growth restriction in cell culture and altered viremia pattern and immunogenicity in Rhesus Monkeys.Journal of Virology,1996,70(6):3930-3937.
[12]Durbin A P,Karron R A,Sun W,et al.Attenuation and immunogenicity in humans of a live dengue virus type-4 vaccine candidate with a 30 nucleotide deletion in its 3'-untranslated region.American Journal Tropical Medicine&Hygiene,2001,65(5):405-413.
[13]Durbin A P,Whitehead S S,Mc Arthur J,et al.r DEN4Δ30,a live attenuated dengue virus type 4 vaccine candidate,is safe,immunogenic,and highly infectious in healthy adult volunteers.The Journal Infectious Diseases,2005,191(5):710-718.
[14]Troyer J M,Hanley K A,Whitehead S S,et al.A live attenuated recombinant dengue-4 virus vaccine with restricted capacity for dissemination in mosquitoes and lack of transmission from vaccines to mosquitoes.American Journal Tropical Medicine&Hygiene,2001,65(5):414-419.
[15]Mc Arthur J H,Durbin A P,Marron J A,et al.Phase I clinical evaluation of r DEN4Δ30-200,201:A live attenuated dengue 4vaccine candidate designed for decreased hepatotoxicity.American Journal Tropical Medicine&Hygiene,2008,79(5):678-684.
[16]Wright P F,Durbin A P,Whitehead S S,et al.Phase1trial of the dengue virus type 4 vaccine candidate r DEN4Δ30-4995 in healthy adult volunteers.American Journal Tropical Medicine&Hygiene,2009,81(5):834-841.
[17]Whitehead S S,Falgout B,Hanley K A,et al.A live,attenuated dengue virus type 1 vaccine candidate with a 30-nucleotide deletion in the 3 untranslated region is highly attenuated and immunogenic in Monkeys.Journal of Virology,2003,77(2):1653-1657.
[18]Durbin A P,Mc Arthur J,Marron J A,et al.The live attenuated dengue serotype 1 vaccine r DEN1 delta 30 is safe and highly immunogenic in healthy adult volunteers.Human Vaccines,2006,2(4):167-173.
[19]Whitehead S S,Hanley K A,Blaney J E,et al.Substitution of the structural genes of dengue virus type 4 with those of type 2results in chimeric vaccine candidates which are attenuated for mosquitoes,mice,and rhesus monkeys.Vaccine,2003,21(27-30):4307-4316.
[20]Blaney J E,Hanson C T,Firestone C Y,et al.Genetically modified,live attenuated dengue virus type 3 vaccine candidates.American Journal Tropical Medicine&Hygiene,2004,71(6):811-821.
[21]Durbin A P,Mc Arthur J H,Marron J A,et al.r DEN2/4Δ30(ME),a live attenuated chimeric dengue serotype 2 vaccine,is safe and highly immunogenic in healthy dengue-naive adults.Human Vaccines,2006,2(6):255-260.
[22]Durbina A P,Kirkpatrick B D,Pierce K K,et al.Development and clinical evaluation of multiple investigational monovalent DENV vaccines to identify components for inclusion in a live attenuated tetravalent DENV vaccine.Vaccine,2011,29(42):7242-7250.
[23]Durbin A P,Kirkpatrick B D,Pierce K K,et al.A single dose of any of four different live attenuated tetravalent dengue vaccines is safe and immunogenic in flavivirus-naive adults:A randomized,double-blind clinical trial.The Journal Infection Diseases,2013,207(6):957-965.
[24]Kirkpatrick B D,Durbin A P,Pierce K K,et al.Robust and balanced immune responses to all 4 dengue virus serotypes following administration of a single dose of a live attenuated tetravalent dengue vaccine to healthy,flavivirus-naive adults.The Journal Infection Diseases,2015,212(5):702-710.
[25]Durbin A P,Kirkpatrick B D,Pierce K K,et al.A 12-monthinterval dosing study in adults indicates that a single dose of the national institute of allergy and infectious diseases tetravalent dengue vaccine induces a robust neutralizing antibody response.The Journal Infection Diseases,2016,214(6):832-835.
[26]Kirkpatrick B D,Whitehead S S,Pierce K K,et al.The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model.Science Translational Medicine,2016,8(330):330-336.
[27]Scherwitzl I,Mongkolsapaya J,Screaton G.Recent advances in human flavivirus vaccines.Current Opinion in Virology,2017,23:95-101.
[28]Whitehead S S,Durbin A P,Pierce K K,et al.In a randomized trial,the live attenuated tetravalent dengue vaccine TV003 is well-tolerated and highly immunogenic in subjects with flavivirus exposure prior to vaccination.Plos Neglected Tropical Disease,2017,11(5):e0005584.
[29]Guy B,Jackson N.Dengue vaccine:Hypotheses to understand CYD-TDV-induced protection.Nature Reviews Microbiology,2016,14(1):45-54.
[30]Nascimento E J M,George J K,Velasco M,et al.Development of an anti-dengue NS1 Ig G ELISA to evaluate exposure to dengue virus.Journal of Virological Methods,2018,257:48-57.
[31]Guy B,Briand O,Lang J,et al.Development of the sanofi pasteur tetravalent dengue vaccine:One more step forward.Vaccine,2015,33(50):7100-7111.
[32]Villar L,Dayan G H,Arredondo-Garcia J L,et al.Efficacy of a tetravalent dengue vaccine in children in Latin America.New England Journal of Medicine,2015,372(2):113-123.
[33]Capeding M R,Tran N H,Hadinegoro S R,et al.Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia:A phase 3,randomized,observer-masked,placebo-controlled trial.Lancet,2014,384(951):1358-1365.
[34]Whitehead S S.Development of TV003/TV005,a single dose,highly immunogenic live attenuated dengue vaccine;what makes this vaccine different from the Sanofi-Pasteur CYDTMvaccine?Expert Review Vaccines,2016,15(4):509-517.
[35]Wilder-Smith A,Messad E.Age specific differences in efficacy and safety for the CYD-tetravalent dengue vaccine.Expert Review Vaccines,2016,15(4):437-441.
[36]Magnani D M,Silveira C G T,Ricciardi M J,et al.Potent plasmablast-derived antibodies elicited by the National Institutes of Health Dengue Vaccine.Journal of Virology,2017,91(22):e00867-17.
[37]Popper S J,Strouts F R,Lindow J C,et al.Early transcriptional responses after dengue vaccination mirror the response to natural infection and predict neutralizing antibody titers.The Journal of Infectious Diseases.2018,218(12):1911-1921.