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1.
Sandhya Vasan Sarah J. Schlesinger Yaoxing Huang Arlene Hurley Angela Lombardo Zhiwei Chen Soe Than Phumla Adesanya Catherine Bunce Mark Boaz Rosanne Boyle Eddy Sayeed Lorna Clark Daniel Dugin Claudia Schmidt Yang Song Laura Seamons Len Dally Martin Ho Carol Smith Martin Markowitz Josephine Cox Dilbinder K. Gill Jill Gilmour Michael C. Keefer Patricia Fast David D. Ho 《PloS one》2010,5(1)
Background
We conducted a Phase I dose escalation trial of ADVAX, a DNA-based candidate HIV-1 vaccine expressing Clade C/B'' env, gag, pol, nef, and tat genes. Sequences were derived from a prevalent circulating recombinant form in Yunnan, China, an area of high HIV-1 incidence. The objective was to evaluate the safety and immunogenicity of ADVAX in human volunteers.Methodology/Principal Findings
ADVAX or placebo was administered intramuscularly at months 0, 1 and 3 to 45 healthy volunteers not at high risk for HIV-1. Three dosage levels [0.2 mg (low), 1.0 mg (mid), and 4.0 mg (high)] were tested. Twelve volunteers in each dosage group were assigned to receive ADVAX and three to receive placebo in a double-blind design. Subjects were followed for local and systemic reactogenicity, adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA. Cellular immunogenicity was assessed by a validated IFNγ ELISpot assay and intracellular cytokine staining. ADVAX was safe and well-tolerated, with no vaccine-related serious adverse events. Local and systemic reactogenicity events were reported by 64% and 42% of vaccine recipients, respectively. The majority of events were mild. The IFNγ ELISpot response rates to any HIV antigen were 0/9 (0%) in the placebo group, 3/12 (25%) in the low-dosage group, 4/12 (33%) in the mid-dosage group, and 2/12 (17%) in the high-dosage group. Overall, responses were generally transient and occurred to each gene product, although volunteers responded to single antigens only. Binding antibodies to gp120 were not detected in any volunteers, and HIV seroconversion did not occur.Conclusions/Significance
ADVAX delivered intramuscularly is safe, well-tolerated, and elicits modest but transient cellular immune responses.Trial Registration
Clinicaltrials.gov NCT00249106相似文献2.
3.
目的:构建HIV-1重组腺病毒疫苗并初步鉴定其免疫原性。方法:用Adeno-XExpressionSystem试剂盒将HIV—lgagpol基因片段插入到腺病毒载体上,通过脂质体介导将获得的重组腺病毒质粒Adeno—X-gagpol转染至293细胞,使之自主包装成有感染活性的重组腺病毒tad—gagpol,用western-blotting法鉴定其表达情况;用CsCl密度梯度离心法纯化该重组腺病毒,以5×10^8 pfu/mL的滴度lmL单次免疫小鼠,15天后测小鼠体液免疫效果。结果:克隆序列与设计相符,重组腺病毒疫苗能稳定表达gag—pol蛋白,体液免疫中检测出抗p55和p24的特异性抗体。结论:HIV—lgagpol重组腺病毒构建成功,具有一定的体液免疫原性。 相似文献
4.
Hana Kammoun Xavier Roux Dominique Raze Anne-Sophie Debrie Marina De Filette Tine Ysenbaert Nathalie Mielcarek Xavier Saelens Walter Fiers Camille Locht 《PloS one》2013,8(3)
Background
Intranasal delivery of vaccines directed against respiratory pathogens is an attractive alternative to parenteral administration. However, using this delivery route for inactivated vaccines usually requires the use of potent mucosal adjuvants, and no such adjuvant has yet been approved for human use.Methodology/Principal Findings
We have developed a live attenuated Bordetella pertussis vaccine, called BPZE1, and show here that it can be used to present the universal influenza virus epitope M2e to the mouse respiratory tract to prime for protective immunity against viral challenge. Three copies of M2e were genetically fused to the N-terminal domain of filamentous hemagglutinin (FHA) and produced in recombinant BPZE1 derivatives in the presence or absence of endogenous full-length FHA. Only in the absence of FHA intranasal administration of the recombinant BPZE1 derivative induced antibody responses to M2e and effectively primed BALB/c mice for protection against influenza virus-induced mortality and reduced the viral load after challenge. Strong M2e-specific antibody responses and protection were observed after a single nasal administration with the recombinant BPZE1 derivative, followed by a single administration of M2e linked to a virus-like particle without adjuvant, whereas priming alone with the vaccine strain did not protect.Conclusions/Significance
Using recombinant FHA-3M2e-producing BPZE1 derivatives for priming and the universal influenza M2e peptide linked to virus-like particles for boosting may constitute a promising approach for needle-free and adjuvant-free nasal vaccination against influenza. 相似文献5.
呼吸道合胞病毒重组蛋白候选疫苗的质粒构建、表达及免疫原性和保护性研究 总被引:3,自引:0,他引:3
PCR扩增呼吸道合胞病毒(respiratory syncytial virus,RSV)M2 蛋白的CD8+T细胞表位F/M2:81-95和RSV-G蛋白的B细胞表位片段G:125~225(简称G1),以一个Linker连接,插入质粒pET-DsbA中构建原核表达重组质粒, 转染E.coli BL21(DE3)后成功表达了融合蛋白DsbA-G1-Linker-F/M2:81-95(简称D-G1LF/M2),Western-blot结果表明该融合蛋白是RSV特异性的,采用Ni+螯合亲和层析法纯化变性的包涵体溶液,经梯度透析法复性,用该蛋白免疫BALB/c小鼠,结果表明被免疫小鼠肺部及血清中产生了高滴度的抗D-G1LF/M2及抗RSV IgG抗体和中和抗体,同时还诱导产生了RSV特异性的CTL应答;IgG的亚型IgG1/IgG2a的比值为2.66;用RSV攻击免疫后的小鼠,病毒滴定法检测肺部RSV滴度,结果表明D-G1LF/M2对小鼠肺部具有保护作用。 相似文献
6.
Jeff Alexander Jason Mendy Lo Vang Jenny B. Avanzini Fermin Garduno Darly J. Manayani Glenn Ishioka Peggy Farness Li-Hua Ping Ronald Swanstrom Robert Parks Hua-Xin Liao Barton F. Haynes David C. Montefiori Celia LaBranche Jonathan Smith Marc Gurwith Tim Mayall 《PloS one》2013,8(12)
Background
There is a well-acknowledged need for an effective AIDS vaccine that protects against HIV-1 infection or limits in vivo viral replication. The objective of these studies is to develop a replication-competent, vaccine vector based on the adenovirus serotype 4 (Ad4) virus expressing HIV-1 envelope (Env) 1086 clade C glycoprotein. Ad4 recombinant vectors expressing Env gp160 (Ad4Env160), Env gp140 (Ad4Env140), and Env gp120 (Ad4Env120) were evaluated.Methods
The recombinant Ad4 vectors were generated with a full deletion of the E3 region of Ad4 to accommodate the env gene sequences. The vaccine candidates were assessed in vitro following infection of A549 cells for Env-specific protein expression and for posttranslational transport to the cell surface as monitored by the binding of broadly neutralizing antibodies (bNAbs). The capacity of the Ad4Env vaccines to induce humoral immunity was evaluated in rabbits for Env gp140 and V1V2-specific binding antibodies, and HIV-1 pseudovirus neutralization. Mice immunized with the Ad4Env160 vaccine were assessed for IFNγ T cell responses specific for overlapping Env peptide sets.Results
Robust Env protein expression was confirmed by western blot analysis and recognition of cell surface Env gp160 by multiple bNAbs. Ad4Env vaccines induced humoral immune responses in rabbits that recognized Env 1086 gp140 and V1V2 polypeptide sequences derived from 1086 clade C, A244 clade AE, and gp70 V1V2 CASE A2 clade B fusion protein. The immune sera efficiently neutralized tier 1 clade C pseudovirus MW965.26 and neutralized the homologous and heterologous tier 2 pseudoviruses to a lesser extent. Env-specific T cell responses were also induced in mice following Ad4Env160 vector immunization.Conclusions
The Ad4Env vaccine vectors express high levels of Env glycoprotein and induce both Env-specific humoral and cellular immunity thus supporting further development of this new Ad4 HIV-1 Env vaccine platform in Phase 1 clinical trials. 相似文献7.
目的:检测人类免疫缺陷病毒1型(HIV-1) C/B'亚型与痘苗病毒安卡拉株(MVA)的多价重组疫苗的免疫原性,此疫苗中包含HIV-1 C/B'CRF 株的5个基因,分别是env,gag,pol,nef,tat.方法:设105pfu/ml,106 pfu/ml,107 pfu/ml ADMVA 3个剂量组,用ELISPOT方法检测细胞免疫反应.同时,以Gag蛋白作为包被抗原,使用间接ELISA的方法检测体液免疫反应.结果:免疫后的小鼠对插入基因env,gag,pol和nef所表达蛋白均产生了特异性细胞免疫应答,且免疫效果与免疫剂量呈正相关.ELISA结果表明, MVA重组疫苗免疫诱导产生了特异性体液免疫,抗HIV-1Gag的抗体滴度与免疫次数和免疫剂量都存在正相关性.结论:多价MVA重组疫苗能有效地诱导小鼠产生特异的细胞免疫和体液免疫反应. 相似文献
8.
Sandhya Vasan Sarah J. Schlesinger Zhiwei Chen Arlene Hurley Angela Lombardo Soe Than Phumla Adesanya Catherine Bunce Mark Boaz Rosanne Boyle Eddy Sayeed Lorna Clark Daniel Dugin Mar Boente-Carrera Claudia Schmidt Qing Fang Lei Yaoxing Huang Gerasimos J. Zaharatos David F. Gardiner Marina Caskey Laura Seamons Martin Ho Len Dally Carol Smith Josephine Cox Dilbinder Gill Jill Gilmour Michael C. Keefer Patricia Fast David D. Ho 《PloS one》2010,5(1)
Background
We conducted a Phase I dose-escalation trial of ADMVA, a Clade-B''/C-based HIV-1 candidate vaccine expressing env, gag, pol, nef, and tat in a modified vaccinia Ankara viral vector. Sequences were derived from a prevalent circulating HIV-1 recombinant form in Yunnan, China, an area of high HIV incidence. The objective was to evaluate the safety and immunogenicity of ADMVA in human volunteers.Methodology/Principal Findings
ADMVA or placebo was administered intramuscularly at months 0, 1 and 6 to 50 healthy adult volunteers not at high risk for HIV-1. In each dosage group [1×107 (low), 5×107 (mid), or 2.5×108 pfu (high)] volunteers were randomized in a 3∶1 ratio to receive ADMVA or placebo in a double-blinded design. Subjects were followed for local and systemic reactogenicity, adverse events including cardiac adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA, immunoflourescent staining, and HIV-1 neutralization. Cellular immunogenicity was assessed by a validated IFNγ ELISpot assay and intracellular cytokine staining. Anti-vaccinia binding titers were measured by ELISA.ADMVA was generally well-tolerated, with no vaccine-related serious adverse events or cardiac adverse events. Local or systemic reactogenicity events were reported by 77% and 78% of volunteers, respectively. The majority of events were of mild intensity. The IFNγ ELISpot response rate to any HIV antigen was 0/12 (0%) in the placebo group, 3/12 (25%) in the low dosage group, 6/12 (50%) in the mid dosage group, and 8/13 (62%) in the high dosage group. Responses were often multigenic and occasionally persisted up to one year post vaccination. Antibodies to gp120 were detected in 0/12 (0%), 8/13 (62%), 6/12 (50%) and 10/13 (77%) in the placebo, low, mid, and high dosage groups, respectively. Antibodies persisted up to 12 months after vaccination, with a trend toward agreement with the ability to neutralize HIV-1 SF162 in vitro. Two volunteers mounted antibodies that were able to neutralize clade-matched viruses.Conclusions/Significance
ADMVA was well-tolerated and elicited durable humoral and cellular immune responses.Trial Registration
Clinicaltrials.gov NCT00252148相似文献9.
HIV-1B亚型gp120基因密码子优化前后免疫原性的比较 总被引:4,自引:0,他引:4
对HIV-1B亚型gp120基因按照哺乳动物优势密码子的使用原则进行优化,以Westem blot方法比较其体外表达量.将优化前的野生型gp120基因和改造后的modgp120基因插入重组腺伴随病毒载体,构建了重组病毒rAAV-wtgp120和rAAV-modgp120,比较两者免疫Balb/C小鼠后的抗体和CTL应答.Western blot检测结果显示:优化后基因的体外表达量明显高于野生型基因,rAAV-modgp120与rAAV-wtgp120相比可更好地诱导Balb/C小鼠的CTL应答,但检测不到明显的抗体反应.由此得出结论,优化后gp120基因的体外表达量明显高于野生型基因,并且可以诱导更强的特异性CTL应答,但检测不到gp120抗体. 相似文献
10.
Shi-Hsia Hwa Yock Ann Lee Joseph N. Brewoo Charalambos D. Partidos Jorge E. Osorio Joseph D. Santangelo 《PLoS neglected tropical diseases》2013,7(11)
Human enterovirus 71 (EV71) is a significant cause of morbidity and mortality from Hand, Foot and Mouth Disease (HFMD) and neurological complications, particularly in young children in the Asia-Pacific region. There are no vaccines or antiviral therapies currently available for prevention or treatment of HFMD caused by EV71. Therefore, the development of therapeutic and preventive strategies against HFMD is of growing importance. We report the immunogenic and safety profile of inactivated, purified EV71 preparations formulated with aluminum hydroxide adjuvant in preclinical studies in mice and rabbits. In mice, the candidate vaccine formulations elicited high neutralizing antibody responses. A toxicology study of the vaccine formulations planned for human use performed in rabbits showed no vaccine-related pathological changes and all animals remained healthy. Based on these preclinical studies, Phase 1 clinical testing of the EV71 inactivated vaccine was initiated. 相似文献
11.
以冷适应、温度敏感、减毒的B/Ann Arbor/1/66流感病毒株作为重配病毒骨架,对其6个内部基因片段进行了全基因合成,同时人工引入9个氨基酸突变.构建了8个基因的拯救载体,经测序获得序列准确的拯救质粒,命名为:pAB121-PB1, pAB122-PB2, pAB123-PA, pAB124-HA, pAB125-NP, pAB126-NA, pAB127-M和pAB128-NS.在成功拯救冷适应A型流感病毒的基础上,利用反向遗传学技术成功获救了具有感染性的重配B型流感病毒株,命名为rMDV-B.该重配病毒株以B/Ann Arbor/1/66为病毒骨架,其中HA和NA来源于2006~2007年当年流行株B/Malaysia/2506/2004.rMDV-B在鸡胚尿囊液和MDCK细胞中的HA效价可达1∶64~1∶512.实验结果暗示:从单一供体病毒株可以产生有效的减毒活B型流感病毒疫苗候选株,能够为将来人用流感疫苗的设计提供可借鉴的模型. 相似文献
12.
Jason W. Bennett Anjali Yadava Donna Tosh Jetsumon Sattabongkot Jack Komisar Lisa A. Ware William F. McCarthy Jessica J. Cowden Jason Regules Michele D. Spring Kristopher Paolino Joshua D. Hartzell James F. Cummings Thomas L. Richie Joanne Lumsden Edwin Kamau Jittawadee Murphy Cynthia Lee Falgunee Parekh Ashley Birkett Joe Cohen W. Ripley Ballou Mark E. Polhemus Yannick F. Vanloubbeeck Johan Vekemans Christian F. Ockenhouse 《PLoS neglected tropical diseases》2016,10(2)
Background
A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use.Methods
We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15μg, 30μg, or 60μg respectively of VMP001, all formulated in 500μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls.Results
The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period.Significance
This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials. 相似文献13.
Sheetij Dutta Lisa S. Dlugosz Damien R. Drew Xiopeng Ge Diouf Ababacar Yazmin I. Rovira J. Kathleen Moch Meng Shi Carole A. Long Michael Foley James G. Beeson Robin F. Anders Kazutoyo Miura J. David Haynes Adrian H. Batchelor 《PLoS pathogens》2013,9(12)
Malaria vaccine candidate Apical Membrane Antigen-1 (AMA1) induces protection, but only against parasite strains that are closely related to the vaccine. Overcoming the AMA1 diversity problem will require an understanding of the structural basis of cross-strain invasion inhibition. A vaccine containing four diverse allelic proteins 3D7, FVO, HB3 and W2mef (AMA1 Quadvax or QV) elicited polyclonal rabbit antibodies that similarly inhibited the invasion of four vaccine and 22 non-vaccine strains of P. falciparum. Comparing polyclonal anti-QV with antibodies against a strain-specific, monovalent, 3D7 AMA1 vaccine revealed that QV induced higher levels of broadly inhibitory antibodies which were associated with increased conserved face and domain-3 responses and reduced domain-2 response. Inhibitory monoclonal antibodies (mAb) raised against the QV reacted with a novel cross-reactive epitope at the rim of the hydrophobic trough on domain-1; this epitope mapped to the conserved face of AMA1 and it encompassed the 1e-loop. MAbs binding to the 1e-loop region (1B10, 4E8 and 4E11) were ∼10-fold more potent than previously characterized AMA1-inhibitory mAbs and a mode of action of these 1e-loop mAbs was the inhibition of AMA1 binding to its ligand RON2. Unlike the epitope of a previously characterized 3D7-specific mAb, 1F9, the 1e-loop inhibitory epitope was partially conserved across strains. Another novel mAb, 1E10, which bound to domain-3, was broadly inhibitory and it blocked the proteolytic processing of AMA1. By itself mAb 1E10 was weakly inhibitory but it synergized with a previously characterized, strain-transcending mAb, 4G2, which binds close to the hydrophobic trough on the conserved face and inhibits RON2 binding to AMA1. Novel inhibition susceptible regions and epitopes, identified here, can form the basis for improving the antigenic breadth and inhibitory response of AMA1 vaccines. Vaccination with a few diverse antigenic proteins could provide universal coverage by redirecting the immune response towards conserved epitopes. 相似文献
14.
15.
Rangasamy Sneha Priya Menon Veena Irene Kalisz Stephen Whitney Dhopeshwarkar Priyanka Celia C. LaBranche Mullapudi Sri Teja David C. Montefiori Ranajit Pal Sundarasamy Mahalingam Vaniambadi S. Kalyanaraman 《The Journal of biological chemistry》2015,290(14):9195-9208
Human immunodeficiency virus type 1 (HIV-1) isolates from India mainly belong to clade C and are quite distinct from clade C isolates from Africa in terms of their phylogenetic makeup, serotype, and sensitivity to known human broadly neutralizing monoclonal antibodies. Because many of these properties are associated with the envelope proteins of HIV-1, it is of interest to study the envelope proteins of Indian clade C isolates as part of the ongoing efforts to develop a vaccine against HIV-1. To this end, we purified trimeric uncleaved gp145 of a CCR5 tropic Indian clade C HIV-1 (93IN101) from the conditioned medium of 293 cells. The purified protein was shown to be properly folded with stable structure by circular dichroism. Conformational integrity was further demonstrated by its high affinity binding to soluble CD4, CD4 binding site antibodies such as b12 and VRC01, quaternary epitope-specific antibody PG9, and CD4-induced epitope-specific antibody 17b. Sera from rabbits immunized with gp145 elicited high titer antibodies to various domains of gp120 and neutralized a broad spectrum of clade B and clade C HIV-1 isolates. Similar to other clade B and clade C envelope immunogens, most of the Tier 1 neutralizing activity could be absorbed with the V3-specific peptide. Subsequent boosting of these rabbits with a clade B HIV-1 Bal gp145 resulted in an expanded breadth of neutralization of HIV-1 isolates. The present study strongly supports the inclusion of envelopes from Indian isolates in a future mixture of HIV-1 vaccines. 相似文献
16.
Chetan E. Chitnis Paushali Mukherjee Shantanu Mehta Syed Shams Yazdani Shikha Dhawan Ahmad Rushdi Shakri Rukmini Bharadwaj Puneet Kumar Gupta Dhiraj Hans Suman Mazumdar Bijender Singh Sanjeev Kumar Gaurav Pandey Varsha Parulekar Nathalie Imbault Preethi Shivyogi Girish Godbole Krishna Mohan Odile Leroy Kavita Singh Virander S. Chauhan 《PloS one》2015,10(4)
Background
A phase I randomised, controlled, single blind, dose escalation trial was conducted to evaluate safety and immunogenicity of JAIVAC-1, a recombinant blood stage vaccine candidate against Plasmodium falciparum malaria, composed of a physical mixture of two recombinant proteins, PfMSP-119, the 19 kD conserved, C-terminal region of PfMSP-1 and PfF2 the receptor-binding F2 domain of EBA175.Method
Healthy malaria naïve Indian male subjects aged 18–45 years were recruited from the volunteer database of study site. Fifteen subjects in each cohort, randomised in a ratio of 2:1 and meeting the protocol specific eligibility criteria, were vaccinated either with three doses (10μg, 25μg and 50μg of each antigen) of JAIVAC-1 formulated with adjuvant Montanide ISA 720 or with standard dosage of Hepatitis B vaccine. Each subject received the assigned vaccine in the deltoid muscle of the upper arms on Day 0, Day 28 and Day 180.Results
JAIVAC-1 was well tolerated and no serious adverse event was observed. All JAIVAC-1 subjects sero-converted for PfF2 but elicited poor immune response to PfMSP-119. Dose-response relationship was observed between vaccine dose of PfF2 and antibody response. The antibodies against PfF2 were predominantly of IgG1 and IgG3 isotype. Sera from JAIVAC-1 subjects reacted with late schizonts in a punctate pattern in immunofluorescence assays. Purified IgG from JAIVAC-1 sera displayed significant growth inhibitory activity against Plasmodium falciparum CAMP strain.Conclusion
Antigen PfF2 should be retained as a component of a recombinant malaria vaccine but PfMSP-119 construct needs to be optimised to improve its immunogenicity.Trial Registration
Clinical Trial Registry, India CTRI/2010/091/000301 相似文献17.
18.
Douglas H. Smith Peggy Winters-Digiacinto Misrach Mitiku Sara O'Rourke Faruk Sinangil Terri Wrin David C. Montefiori Phillip W. Berman 《PloS one》2010,5(8)
Background
Previous clinical efficacy trials failed to support the continued development of recombinant gp120 (rgp120) as a candidate HIV vaccine. However, the recent RV144 HIV vaccine trial in Thailand showed that a prime/boost immunization strategy involving priming with canarypox vCP1521 followed by boosting with rgp120 could provide significant, although modest, protection from HIV infection. Based on these results, there is renewed interest in the development of rgp120 based antigens for follow up vaccine trials, where this immunization approach can be applied to other cohorts at high risk for HIV infection. Of particular interest are cohorts in Africa, India, and China that are infected with clade C viruses.Methodology/Principal Findings
A panel of 10 clade C rgp120 envelope proteins was expressed in 293 cells, purified by immunoaffinity chromatography, and used to immunize guinea pigs. The resulting sera were collected and analyzed in checkerboard experiments for rgp120 binding, V3 peptide binding, and CD4 blocking activity. Virus neutralization studies were carried out with two different assays and two different panels of clade C viruses. A high degree of cross reactivity against clade C and clade B viruses and viral proteins was observed. Most, but not all of the immunogens tested elicited antibodies that neutralized tier 1 clade B viruses, and some sera neutralized multiple clade C viruses. Immunization with rgp120 from the CN97001 strain of HIV appeared to elicit higher cross neutralizing antibody titers than the other antigens tested.Conclusions/Significance
While all of the clade C antigens tested were immunogenic, some were more effective than others in eliciting virus neutralizing antibodies. Neutralization titers did not correlate with rgp120 binding, V3 peptide binding, or CD4 blocking activity. CN97001 rgp120 elicited the highest level of neutralizing antibodies, and should be considered for further HIV vaccine development studies. 相似文献19.
Amy R. Noe Diego Espinosa Xiangming Li Jordana G. A. Coelho-dos-Reis Ryota Funakoshi Steve Giardina Hongfan Jin Diane M. Retallack Ryan Haverstock Jeffrey R. Allen Thomas S. Vedvick Christopher B. Fox Steven G. Reed Ramses Ayala Brian Roberts Scott B. Winram John Sacci Moriya Tsuji Fidel Zavala Gabriel M. Gutierrez 《PloS one》2014,9(9)
The circumsporozoite protein (CSP) of Plasmodium falciparum is a major surface protein, which forms a dense coat on the sporozoite''s surface. Preclinical research on CSP and clinical evaluation of a CSP fragment-based RTS, S/AS01 vaccine have demonstrated a modest degree of protection against P. falciparum, mediated in part by humoral immunity and in part by cell-mediated immunity. Given the partial protective efficacy of the RTS, S/AS01 vaccine in a recent Phase 3 trial, further improvement of CSP-based vaccines is crucial. In this report, we describe the preclinical development of a full-length, recombinant CSP (rCSP)-based vaccine candidate against P. falciparum malaria suitable for current Good Manufacturing Practice (cGMP) production. Utilizing a novel high-throughput Pseudomonas fluorescens expression platform, we demonstrated greater efficacy of full-length rCSP as compared to N-terminally truncated versions, rapidly down-selected a promising lead vaccine candidate, and developed a high-yield purification process to express immunologically active, intact antigen for clinical trial material production. The rCSP, when formulated with various adjuvants, induced antigen-specific antibody responses as measured by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence assay (IFA), as well as CD4+ T-cell responses as determined by ELISpot. The adjuvanted rCSP vaccine conferred protection in mice when challenged with transgenic P. berghei sporozoites containing the P. falciparum repeat region of CSP. Furthermore, heterologous prime/boost regimens with adjuvanted rCSP and an adenovirus type 35-vectored CSP (Ad35CS) showed modest improvements in eliciting CSP-specific T-cell responses and anti-malarial protection, depending on the order of vaccine delivery. Collectively, these data support the importance of further clinical development of adjuvanted rCSP, either as a stand-alone product or as one of the components in a heterologous prime/boost strategy, ultimately acting as an effective vaccine candidate for the mitigation of P. falciparum-induced malaria. 相似文献
20.
Adriana Weinberg Petronella Muresan Kelly M. Richardson Terence Fenton Teresa Dominguez Anthony Bloom D. Heather Watts Mark J. Abzug Sharon A. Nachman Myron J. Levin for the P team 《PloS one》2015,10(4)
Influenza infections have high frequency and morbidity in HIV-infected pregnant women, underscoring the importance of vaccine-conferred protection. To identify the factors that determine vaccine immunogenicity in this group, we characterized the relationship of B- and T-cell responses to pandemic H1N1 (pH1N1) vaccine with HIV-associated immunologic and virologic characteristics.pH1N1 and seasonal-H1N1 (sH1N1) antibodies were measured in 119 HIV-infected pregnant women after two double-strength pH1N1 vaccine doses. pH1N1-IgG and IgA B-cell FluoroSpot, pH1N1- and sH1N1-interferon γ (IFNγ) and granzyme B (GrB) T-cell FluoroSpot, and flow cytometric characterization of B- and T-cell subsets were performed in 57 subjects.pH1N1-antibodies increased after vaccination, but less than previously described in healthy adults. pH1N1-IgG memory B cells (Bmem) increased, IFNγ-effector T-cells (Teff) decreased, and IgA Bmem and GrB Teff did not change. pH1N1-antibodies and Teff were significantly correlated with each other and with sH1N1-HAI and Teff, respectively, before and after vaccination. pH1N1-antibody responses to the vaccine significantly increased with high proportions of CD4+, low CD8+ and low CD8+HLADR+CD38+ activated (Tact) cells. pH1N1-IgG Bmem responses increased with high proportions of CD19+CD27+CD21- activated B cells (Bact), high CD8+CD39+ regulatory T cells (Treg), and low CD19+CD27-CD21- exhausted B cells (Bexhaust). IFNγ-Teff responses increased with low HIV plasma RNA, CD8+HLADR+CD38+ Tact, CD4+FoxP3+ Treg and CD19+IL10+ Breg.In conclusion, pre-existing antibody and Teff responses to sH1N1 were associated with increased responses to pH1N1 vaccination in HIV-infected pregnant women suggesting an important role for heterosubtypic immunologic memory. High CD4+% T cells were associated with increased, whereas high HIV replication, Tact and Bexhaust were associated with decreased vaccine immunogenicity. High Treg increased antibody responses but decreased Teff responses to the vaccine. The proportions of immature and transitional B cells did not affect the responses to vaccine. Increased Bact were associated with high Bmem responses to the vaccine. 相似文献