Publications (49)333.28 Total impact
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Article: Vaccine-induced plasma IgA specific for the C1 region of the HIV-1 envelope blocks binding and effector function of IgG.
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ABSTRACT: Analysis of correlates of risk of infection in the RV144 HIV-1 vaccine efficacy trial demonstrated that plasma IgG against the HIV-1 envelope (Env) variable region 1 and 2 inversely correlated with risk, whereas HIV-1 Env-specific plasma IgA responses directly correlated with risk. In the secondary analysis, antibody-dependent cellular cytotoxicity (ADCC) was another inverse correlate of risk, but only in the presence of low plasma IgA Env-specific antibodies. Thus, we investigated the hypothesis that IgA could attenuate the protective effect of IgG responses through competition for the same Env binding sites. We report that Env-specific plasma IgA/IgG ratios are higher in infected than in uninfected vaccine recipients in RV144. Moreover, Env-specific IgA antibodies from RV144 vaccinees blocked the binding of ADCC-mediating mAb to HIV-1 Env glycoprotein 120 (gp120). An Env-specific monomeric IgA mAb isolated from an RV144 vaccinee also inhibited the ability of natural killer cells to kill HIV-1-infected CD4(+) T cells coated with RV144-induced IgG antibodies. We show that monomeric Env-specific IgA, as part of postvaccination polyclonal antibody response, may modulate vaccine-induced immunity by diminishing ADCC effector function.Proceedings of the National Academy of Sciences 05/2013; · 9.68 Impact Factor -
Article: Infectious Virion Capture by HIV-1 gp120 Specific IgG from RV144 Vaccinees.
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ABSTRACT: The detailed examination of the antibody repertoire from RV144 provides a unique template for understanding potentially protective antibody functions. Some potential immune correlates of protection were untested in the correlates analyses due to inherent assay limitations as well as the need to keep the correlates analysis focused on a limited number of endpoints to achieve statistical power. In an RV144 pilot study, we determined that RV144 vaccination elicited antibodies that could bind infectious virions (including the vaccine strains, HIV-1 CM244 and HIV-1 MN, and an HIV-1 expressing transmitted/founder Env B.WITO.c). Among those vaccinees with the highest IgG binding antibody profile, the majority (78%) captured the infectious vaccine strain virus(CM244) while a smaller proportion of vaccinees (26%) captured HIV-1 transmitted/founder Env virus. We demonstrated that vaccine-elicited HIV-1 gp120 antibodies of multiple specificities (V3, V2, conformational C1, and gp120 conformational) mediated capture of infectious virions. Although capture of infectious HIV-1 correlated with other humoral immune responses, the extent of variation between these humoral responses and virion capture indicates that virion capture antibodies occupy unique immunological space.Journal of Virology 05/2013; · 5.40 Impact Factor -
Article: "Molecular evolution of the HIV-1 Thai epidemic between the time of RV144 immunogen selection to the execution of the vaccine efficacy trial"
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ABSTRACT: The RV144 HIV-1 vaccine trial (Thailand, 2003-2009), using immunogens genetically matched to the regional epidemic, demonstrated the first evidence of efficacy for an HIV-1 vaccine. Here we studied the molecular evolution of the HIV-1 epidemic from the time of immunogen selection to the execution of the efficacy trial. We studied HIV-1 genetic diversity among 390 volunteers who were deferred from enrolment in RV144 due to pre-existing HIV-1 infection using a multi-region hybridization assay, full-genome sequencing, and phylogenetic analyses. The subtype distribution was CRF01_AE: 91.7%, subtype B: 3.5%, B/CRF01_AE recombinants:4.3%, and dual infections: 0.5%. CRF01_AE strains were 31% more diverse than the ones from the 1990s Thai epidemic. 69% of subtype B clustered with cosmopolitan Western B. 93% of B/CRF01_AE recombinants were unique; recombination breakpoints analysis showed that these strains were highly embedded within the larger network that integrates recombinants from East/Southeast Asia. Compared to Thai sequences from the early 1990s, the distance to the RV144 immunogens increased 52%-68% for CRF01_AE Env, and 12-29% for subtype B immunogens. 43-48% of CRF01_AE sequences differed from the vaccine insert in Env V2 positions 169 and 181, which were implicated in vaccine sieve effects in RV144. In conclusion, compared to the molecular picture at the early stages of vaccine development, our results show an overall increase in the genetic complexity of the Thai epidemic and in the distance to vaccine immunogens, which should be considered at the time of the analysis of the trial results.Journal of Virology 04/2013; · 5.40 Impact Factor -
Article: Issues in Women's Participation in a Phase III Community HIV Vaccine Trial in Thailand.
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ABSTRACT: To assess qualities and outcomes of women participating in a large, community- based HIV vaccine trial, the present study was conducted among female participants of RV 144 prime-boost trial in Thailand from 2003-2009. Qualities of participation refer to complete vaccination, retention and status change. Outcomes of participation refer to incident rate, adverse event and participation impact event. A total of 6,334 (38.6%) women participated in the trial, of whom about 50% was classified as low risk and 11% as high-risk. About 85% of participants completed four vaccinations and 76% were included in the per-protocol analysis of on-time vaccination schedule. More women (88%) completed 42 months follow-up compared with men (85%). Women aged 21 and above had more adverse events compared to younger age groups. More women (5%) compared with men (3%) reported participation impact events (PIEs). High-risk women had more PIEs and higher infection rate compared to low risk group. Complete vaccination and retention on last follow-up were more common in married women aged above 21, and being a housewife. Female volunteers showed the same qualities and outcomes of participation as males in HIV vaccine trial. There was no statistically significant difference in vaccine efficacy between men and women especially among the high risk and married women. The study highlighted the important behavioral, social and cultural issues that could be considered for future HIV vaccine trial design.AIDS research and human retroviruses 01/2013; · 2.18 Impact Factor -
Article: Vaccine Induction of Antibodies against a Structurally Heterogeneous Site of Immune Pressure within HIV-1 Envelope Protein Variable Regions 1 and 2.
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ABSTRACT: The RV144 HIV-1 trial of the canary pox vector (ALVAC-HIV) plus the gp120 AIDSVAX B/E vaccine demonstrated an estimated efficacy of 31%, which correlated directly with antibodies to HIV-1 envelope variable regions 1 and 2 (V1-V2). Genetic analysis of trial viruses revealed increased vaccine efficacy against viruses matching the vaccine strain at V2 residue 169. Here, we isolated four V2 monoclonal antibodies from RV144 vaccinees that recognize residue 169, neutralize laboratory-adapted HIV-1, and mediate killing of field-isolate HIV-1-infected CD4(+) T cells. Crystal structures of two of the V2 antibodies demonstrated that residue 169 can exist within divergent helical and loop conformations, which contrasted dramatically with the β strand conformation previously observed with a broadly neutralizing antibody PG9. Thus, RV144 vaccine-induced immune pressure appears to target a region that may be both sequence variable and structurally polymorphic. Variation may signal sites of HIV-1 envelope vulnerability, providing vaccine designers with new options.Immunity 01/2013; · 21.64 Impact Factor -
Article: Analysis of V2 Antibody Responses Induced in Vaccinees in the ALVAC/AIDSVAX HIV-1 Vaccine Efficacy Trial.
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ABSTRACT: The RV144 clinical trial of a prime/boost immunizing regimen using recombinant canary pox (ALVAC-HIV) and two gp120 proteins (AIDSVAX B and E) was previously shown to have a 31.2% efficacy rate. Plasma specimens from vaccine and placebo recipients were used in an extensive set of assays to identify correlates of HIV-1 infection risk. Of six primary variables that were studied, only one displayed a significant inverse correlation with risk of infection: the antibody (Ab) response to a fusion protein containing the V1 and V2 regions of gp120 (gp70-V1V2). This finding prompted a thorough examination of the results generated with the complete panel of 13 assays measuring various V2 Abs in the stored plasma used in the initial pilot studies and those used in the subsequent case-control study. The studies revealed that the ALVAC-HIV/AIDSVAX vaccine induced V2-specific Abs that cross-react with multiple HIV-1 subgroups and recognize both conformational and linear epitopes. The conformational epitope was present on gp70-V1V2, while the predominant linear V2 epitope mapped to residues 165-178, immediately N-terminal to the putative α4β7 binding motif in the mid-loop region of V2. Odds ratios (ORs) were calculated to compare the risk of infection with data from 12 V2 assays, and in 11 of these, the ORs were ≤1, reaching statistical significance for two of the variables: Ab responses to gp70-V1V2 and to overlapping V2 linear peptides. It remains to be determined whether anti-V2 Ab responses were directly responsible for the reduced infection rate in RV144 and whether anti-V2 Abs will prove to be important with other candidate HIV vaccines that show efficacy, however, the results support continued dissection of Ab responses to the V2 region which may illuminate mechanisms of protection from HIV-1 infection and may facilitate the development of an effective HIV-1 vaccine.PLoS ONE 01/2013; 8(1):e53629. · 4.09 Impact Factor -
Article: Antigenicity and Immunogenicity of RV144 Vaccine AIDSVAX Clade E Envelope Immunogen is Enhanced by a gp120 N-terminal Deletion.
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ABSTRACT: An immune correlates analysis of the RV144 HIV-1 vaccine trial revealed that antibody responses to the gp120 V1V2 region correlated inversely with infection risk. The RV144 protein immunogens (A244-rp120, MN-rgp120) were modified by an N-terminal 11 amino-acid deletion (Δ11) and addition of a HSV (Herpes simplex virus)-gD protein derived tag (gD). We investigated the effects of these modifications on gp120 expression, antigenicity and immunogenicity by comparing unmodified A244 gp120 with both Δ11 deletion and gD tag and with Δ11 only. Analysis of A244 gp120, with or without Δ11 or gD, demonstrated that the Δ11 deletion, without the addition of gD, was sufficient for enhanced antigenicity to gp120 C1 region, conformational V2 and V1/V2 gp120 conformational epitopes. RV144- vaccinee sera IgG bound more avidly to A244 gp120 Δ11 than to the unmodified gp120 and their binding was blocked by C1, V2 and V1/V2 antibodies. Rhesus macaques immunized with the three different forms of A244 gp120 proteins gave similar levels of gp120 antibody titers, although higher antibody titers developed earlier in A244 Δ11 gp120 immunized animals. Conformational V1/V2 mAbs gave significantly higher levels of blocking of plasma IgG from A244 Δ11 gp120 immunized animals than IgG from animals immunized with unmodified A244 gp120, thus indicating a qualitative difference in the V1/V2 antibodies induced by A244 Δ11 gp120. These results demonstrate that deletion of N-terminal residues in the RV144 A244 gp120 immunogen improves both envelope antigenicity and immunogenicity.Journal of Virology 11/2012; · 5.40 Impact Factor -
Article: The Thai Phase III HIV Type 1 Vaccine Trial (RV144) Regimen Induces Antibodies That Target Conserved Regions Within the V2 Loop of gp120.
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ABSTRACT: Abstract The Thai Phase III clinical trial (RV144) showed modest efficacy in preventing HIV-1 acquisition. Plasma collected from HIV-1-uninfected trial participants completing all injections with ALVAC-HIV (vCP1521) prime and AIDSVAX B/E boost were tested for antibody responses against HIV-1 gp120 envelope (Env). Peptide microarray analysis from six HIV-1 subtypes and group M consensus showed that vaccination induced antibody responses to the second variable (V2) loop of gp120 of multiple subtypes. We further evaluated V2 responses by ELISA and surface plasmon resonance using cyclic (Cyc) and linear V2 loop peptides. Thirty-one of 32 vaccine recipients tested (97%) had antibody responses against Cyc V2 at 2 weeks postimmunization with a reciprocal geometric mean titer (GMT) of 1100 (range: 200-3200). The frequency of detecting plasma V2 antibodies declined to 19% at 28 weeks post-last injection (GMT: 110, range: 100-200). Antibody responses targeted the mid-region of the V2 loop that contains conserved epitopes and has the amino acid sequence KQKVHALFYKLDIVPI (HXB2 Numbering sequence 169-184). Valine at position 172 was critical for antibody binding. The frequency of V3 responses at 2 weeks postimmunization was modest (18/32, 56%) with a GMT of 185 (range: 100-800). In contrast, naturally infected HIV-1 individuals had a lower frequency of antibody responses to V2 (10/20, 50%; p=0.003) and a higher frequency of responses to V3 (19/20, 95%), with GMTs of 400 (range: 100-3200) and 3570 (range: 200-12,800), respectively. RV144 vaccination induced antibodies that targeted a region of the V2 loop that contains conserved epitopes. Early HIV-1 transmission events involve V2 loop interactions, raising the possibility that anti-V2 antibodies in RV144 may have contributed to viral inhibition.AIDS research and human retroviruses 10/2012; · 2.18 Impact Factor -
Article: Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2.
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ABSTRACT: The RV144 trial demonstrated 31% vaccine efficacy at preventing human immunodeficiency virus (HIV)-1 infection. Antibodies against the HIV-1 envelope variable loops 1 and 2 (Env V1 and V2) correlated inversely with infection risk. We proposed that vaccine-induced immune responses against V1/V2 would have a selective effect against, or sieve, HIV-1 breakthrough viruses. A total of 936 HIV-1 genome sequences from 44 vaccine and 66 placebo recipients were examined. We show that vaccine-induced immune responses were associated with two signatures in V2 at amino acid positions 169 and 181. Vaccine efficacy against viruses matching the vaccine at position 169 was 48% (confidence interval 18% to 66%; P = 0.0036), whereas vaccine efficacy against viruses mismatching the vaccine at position 181 was 78% (confidence interval 35% to 93%; P = 0.0028). Residue 169 is in a cationic glycosylated region recognized by broadly neutralizing and RV144-derived antibodies. The predicted distance between the two signature sites (21 ± 7 Å) and their match/mismatch dichotomy indicate that multiple factors may be involved in the protection observed in RV144. Genetic signatures of RV144 vaccination in V2 complement the finding of an association between high V1/V2-binding antibodies and reduced risk of HIV-1 acquisition, and provide evidence that vaccine-induced V2 responses plausibly had a role in the partial protection conferred by the RV144 regimen.Nature 09/2012; 490(7420):417-20. · 36.28 Impact Factor -
Article: Antibody-Dependent Cellular Cytotoxicity-Mediating Antibodies from an HIV-1 Vaccine Efficacy Trial Target Multiple Epitopes and Preferentially Use the VH1 Gene Family.
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ABSTRACT: The ALVAC-HIV/AIDSVAX-B/E RV144 vaccine trial showed an estimated efficacy of 31%. RV144 secondary immune correlate analysis demonstrated that the combination of low plasma anti-HIV-1 Env IgA antibodies and high levels of antibody-dependent cellular cytotoxicity (ADCC) inversely correlate with infection risk. One hypothesis is that the observed protection in RV144 is partially due to ADCC-mediating antibodies. We found that the majority (73 to 90%) of a representative group of vaccinees displayed plasma ADCC activity, usually (96.2%) blocked by competition with the C1 region-specific A32 Fab fragment. Using memory B-cell cultures and antigen-specific B-cell sorting, we isolated 23 ADCC-mediating nonclonally related antibodies from 6 vaccine recipients. These antibodies targeted A32-blockable conformational epitopes (n = 19), a non-A32-blockable conformational epitope (n = 1), and the gp120 Env variable loops (n = 3). Fourteen antibodies mediated cross-clade target cell killing. ADCC-mediating antibodies displayed modest levels of V-heavy (VH) chain somatic mutation (0.5 to 1.5%) and also displayed a disproportionate usage of VH1 family genes (74%), a phenomenon recently described for CD4-binding site broadly neutralizing antibodies (bNAbs). Maximal ADCC activity of VH1 antibodies correlated with mutation frequency. The polyclonality and low mutation frequency of these VH1 antibodies reveal fundamental differences in the regulation and maturation of these ADCC-mediating responses compared to VH1 bNAbs.Journal of Virology 08/2012; 86(21):11521-32. · 5.40 Impact Factor -
Article: Extended Evaluation of the Virologic, Immunologic, and Clinical Course of Volunteers Who Acquired HIV-1 Infection in a Phase III Vaccine Trial of ALVAC-HIV and AIDSVAX B/E.
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ABSTRACT: Background. The Thai Phase III Trial of ALVAC-HIV and AIDSVAX B/E showed an estimated vaccine efficacy (VE) of 31% to prevent acquisition of human immunodeficiency virus (HIV). Here we evaluated the effect of vaccination on disease progression after infection.Methods. CD4(+) T-cell counts and HIV viral load (VL) were measured serially. The primary analysis evaluated vaccine efficacy (VE(P)) as the percent reduction (vaccine vs placebo) in cumulative probability of a primary composite endpoint of clinical and CD4(+) count components at prespecified time points after infection. Secondary analyses of biomarker-based endpoints were assessed using marginal mean and linear mixed models.Results. There were 61 endpoints in the modified intent-to-treat cohort (mITT; n = 114). There was no evidence for efficacy at 30, 42, 54, and 60 months in the mITT and per protocol (n = 90) cohorts. Estimated VE(P) (mITT) was15.8% (-21.9, 41.8) at 60 months postinfection. There was weak evidence of lower VL and higher CD4(+) count at 60 and 66 months in the vaccine group. Lower mucosal VL was observed among vaccine recipients, primarily in semen (P = .04).Conclusions. Vaccination did not affect the clinical course of HIV disease after infection. A potential vaccine effect on the genital mucosa warrants further study.Trial registration. Clinicaltrials.gov identifier: NCT00337181.The Journal of Infectious Diseases 07/2012; · 6.41 Impact Factor -
Article: HIV epidemic in Asia: optimizing and expanding vaccine development.
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ABSTRACT: The recent evidence in Thailand for protection from acquisition of HIV through vaccination in a mostly heterosexual population has generated considerable hope. Building upon these results and the analysis of the correlates of risk remains among the highest priorities. Improved vaccine concepts including heterologous prime-boost regimens, improved proteins with potent adjuvants and new vectors expressing mosaic antigens may soon enter clinical development to assess vaccine efficacy in men who have sex with men. Identifying heterosexual populations with sufficient HIV incidence for the conduct of efficacy trials represents perhaps the main challenge in Asia. Fostering translational research efforts in Asian countries may benefit from the development of master strategic plans and program management processes.Expert Review of Vaccines 07/2012; 11(7):805-19. · 4.25 Impact Factor -
Article: Risk behaviour and time as covariates for efficacy of the HIV vaccine regimen ALVAC-HIV (vCP1521) and AIDSVAX B/E: a post-hoc analysis of the Thai phase 3 efficacy trial RV 144.
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ABSTRACT: The Thai phase 3 HIV vaccine trial RV 144 showed modest efficacy of a vaccine against HIV acquisition. Baseline variables of age, sex, marital status, and risk did not modify vaccine efficacy. We did a post-hoc analysis of the trial's data to investigate behavioural risk and efficacy every 6 months after vaccination. RV 144 was a randomised, multicentre, double-blind, placebo-controlled efficacy trial testing the combination of the HIV vaccines ALVAC-HIV (vCP1521) and AIDSVAX B/E to prevent HIV infection or reduce setpoint viral load. Male and female volunteers aged 18-30 years were recruited from the community. In this post-hoc analysis of the modified intention-to-treat population (16,395 participants), HIV risk behaviour was assessed with a self-administered questionnaire at the time of initial vaccination in the trial and every 6 months thereafter for 3 years. We classified participants' behaviour as low, medium, or high risk. Both the acquisition endpoint and the early viral-load endpoint were examined for interactions with risk status over time and temporal effects after vaccination. Multiple proportional hazards regression models with treatment and time-varying risk covariates were analysed. Risk of acquisition of HIV was low in each risk group, but 9187 (58·2%) participants reported higher-risk behaviour at least once during the study. Participants classified as high or increasing risk at least once during follow-up were compared with those who maintained low-risk or medium-risk behaviour as a time-varying covariate, and the interaction of risk status and acquisition efficacy was significant (p=0·01), with greater benefit in low-risk individuals. Vaccine efficacy seemed to peak early--cumulative vaccine efficacy was estimated to be 60·5% (95% CI 22-80) through the 12 months after initial vaccination--and declined quickly. Vaccination did not seem to affect viral load in either early or late infections. Future HIV vaccine trials should recognise potential interactions between challenge intensity and risk heterogeneity in both population and treatment effects. The regimen tested in the RV 144 phase 3 trial might benefit from extended immunisation schedules. US Army Medical Research and Materiel Command and Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health.The Lancet Infectious Diseases 05/2012; 12(7):531-7. · 17.39 Impact Factor -
Article: Magnitude and breadth of the neutralizing antibody response in the RV144 and Vax003 HIV-1 vaccine efficacy trials.
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ABSTRACT: A recombinant canarypox vector expressing human immunodeficiency virus type 1 (HIV-1) Gag, Pro, and membrane-linked gp120 (vCP1521), combined with a bivalent gp120 protein boost (AIDSVAX B/E), provided modest protection against HIV-1 infection in a community-based population in Thailand (RV144 trial). No protection was observed in Thai injection drug users who received AIDSVAX B/E alone (Vax003 trial). We compared the neutralizing antibody response in these 2 trials. Neutralization was assessed with tier 1 and tier 2 strains of virus in TZM-bl and A3R5 cells. Neutralization of several tier 1 viruses was detected in both RV144 and Vax003. Peak titers were higher in Vax003 and waned rapidly in both trials. The response in RV144 was targeted in part to V3 of gp120.vCP1521 priming plus 2 boosts with gp120 protein was superior to 2 gp120 protein inoculations alone, confirming a priming effect for vCP1521. Sporadic weak neutralization of tier 2 viruses was detected only in Vax003 and A3R5 cells. The results suggest either that weak neutralizing antibody responses can be partially protective against HIV-1 in low-risk heterosexual populations or that the modest efficacy seen in RV144 was mediated by other immune responses, either alone or in combination with neutralizing antibodies.The Journal of Infectious Diseases 05/2012; 206(3):431-41. · 6.41 Impact Factor -
Article: Optimization and qualification of a multiplex bead array to assess cytokine and chemokine production by vaccine-specific cells.
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ABSTRACT: The magnitude and functional phenotype (e.g. proliferation, immune stimulation) of vaccine-induced T-cell responses are likely to be critical in defining responses that can control pathogenic challenge. Current multi-parameter flow cytometric techniques may not be sufficient to measure all of these different functions, since characterizing T-cell responses by flow cytometry is presently limited to concurrent measurement of at most 10 cytokines/chemokines. Here, we describe extensive studies conducted using standardized GCLP procedures to optimize and qualitatively/quantitatively qualify a multiplex bead array (MBA) performed on supernatant collected from stimulated peripheral blood mononuclear cells (PBMC) to assess 12 cytokines and chemokines of interest. Our optimized MBA shows good precision (intra-assay, inter-day, inter-technician; coefficients of variation <30%) and linearity for most of the analytes studied. We also developed positivity criteria that allow us to define a response as positive or negative with a high degree of confidence. In conclusion, we provide a detailed description of the qualification of an MBA, which permits quantitative and qualitative evaluation of vaccine-induced immunogenicity and analysis of immune correlates of protection. This assay provides an excellent complement to the existing repertoire of assays for assessing immunogenicity in HIV vaccine clinical trials.Journal of immunological methods 05/2012; 382(1-2):117-28. · 2.35 Impact Factor -
Article: Cytokine profiles in HIV-1 subtype CRF01_AE infected individuals with different rates of diseases progression: a multiplex immunoassay.
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ABSTRACT: Cytokines play an important role in controlling the homeostasis of the immune system and contribute to the pathogenesis of HIV infection. The measurement soluble cytokines in plasma of HIV-1 infected individuals with different rates of disease progression may provide additional information to complement prognostic markers and understand disease process. The aim of the present study was to determine the cytokine profiles in plasma of Thai HIV-1 CRFO1_AE infected individuals with different rates of disease progression by using a multiplex system for simultaneous detection of 7 cytokines. The authors used a multiplex immunoassay method to measure 7 cytokines (IL-2, IL-4, IL-6, IL-7, IL-10, IL-15 and IFN-gamma) in plasma of 23 progressors (PRs; symptomatic or AIDS within 5 years and CD4+ < 200/mm3), 23 slower progressors (SPs; asymptomatic more than 5 years and CD4+ > 350/mm3) and 23 normal healthy individuals. Both PRs and SPs demonstrated significantly higher levels of IL-7, IL-10 and IFN-gamma than healthy controls (p < 0.05). No significant difference in IL-6 between SPs and healthy controls but significant difference between RPs and controls were found. Furthermore, PRs showed significantly higher levels of plasma IL-6 (p = 0.001), IL-7 (p = 0.016), IL-10 (p < 0.001) and IFN-gamma (p = 0.026) than SPs. No significant difference in IL-2, IL-4 and IL-15 was found among 3 groups (PRs, SPs and healthy control). These results suggested that a Th1 to Th2 cytokine switch did not occur. However, the measurements of plasma levels of cytokines could be used for predicting disease progression.Journal of the Medical Association of Thailand = Chotmaihet thangphaet 05/2012; 95 Suppl 5:S116-23. -
Article: The Thai phase III trial (RV144) vaccine regimen induces T cell responses that preferentially target epitopes within the V2 region of HIV-1 envelope.
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ABSTRACT: The Thai HIV phase III prime/boost vaccine trial (RV144) using ALVAC-HIV (vCP1521) and AIDSVAX B/E was, to our knowledge, the first to demonstrate acquisition efficacy. Vaccine-induced, cell-mediated immune responses were assessed. T cell epitope mapping studies using IFN-γ ELISPOT was performed on PBMCs from HIV-1-uninfected vaccine (n = 61) and placebo (n = 10) recipients using HIV-1 Env peptides. Positive responses were measured in 25 (41%) vaccinees and were predominantly CD4(+) T cell-mediated. Responses were targeted within the HIV Env region, with 15 of 25 (60%) of vaccinees recognizing peptides derived from the V2 region of HIV-1 Env, which includes the α(4)β(7) integrin binding site. Intracellular cytokine staining confirmed that Env responses predominated (19 of 30; 63% of vaccine recipients) and were mediated by polyfunctional effector memory CD4(+) T cells, with the majority of responders producing both IL-2 and IFN-γ (12 of 19; 63%). HIV Env Ab titers were higher in subjects with IL-2 compared with those without IL-2-secreting HIV Env-specific effector memory T cells. Proliferation assays revealed that HIV Ag-specific T cells were CD4(+), with the majority (80%) expressing CD107a. HIV-specific T cell lines obtained from vaccine recipients confirmed V2 specificity, polyfunctionality, and functional cytolytic capacity. Although the RV144 T cell responses were modest in frequency compared with humoral immune responses, the CD4(+) T cell response was directed to HIV-1 Env and more particularly the V2 region.The Journal of Immunology 04/2012; 188(10):5166-76. · 5.79 Impact Factor -
Article: Immune-correlates analysis of an HIV-1 vaccine efficacy trial.
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ABSTRACT: In the RV144 trial, the estimated efficacy of a vaccine regimen against human immunodeficiency virus type 1 (HIV-1) was 31.2%. We performed a case-control analysis to identify antibody and cellular immune correlates of infection risk. In pilot studies conducted with RV144 blood samples, 17 antibody or cellular assays met prespecified criteria, of which 6 were chosen for primary analysis to determine the roles of T-cell, IgG antibody, and IgA antibody responses in the modulation of infection risk. Assays were performed on samples from 41 vaccinees who became infected and 205 uninfected vaccinees, obtained 2 weeks after final immunization, to evaluate whether immune-response variables predicted HIV-1 infection through 42 months of follow-up. Of six primary variables, two correlated significantly with infection risk: the binding of IgG antibodies to variable regions 1 and 2 (V1V2) of HIV-1 envelope proteins (Env) correlated inversely with the rate of HIV-1 infection (estimated odds ratio, 0.57 per 1-SD increase; P=0.02; q=0.08), and the binding of plasma IgA antibodies to Env correlated directly with the rate of infection (estimated odds ratio, 1.54 per 1-SD increase; P=0.03; q=0.08). Neither low levels of V1V2 antibodies nor high levels of Env-specific IgA antibodies were associated with higher rates of infection than were found in the placebo group. Secondary analyses suggested that Env-specific IgA antibodies may mitigate the effects of potentially protective antibodies. This immune-correlates study generated the hypotheses that V1V2 antibodies may have contributed to protection against HIV-1 infection, whereas high levels of Env-specific IgA antibodies may have mitigated the effects of protective antibodies. Vaccines that are designed to induce higher levels of V1V2 antibodies and lower levels of Env-specific IgA antibodies than are induced by the RV144 vaccine may have improved efficacy against HIV-1 infection.New England Journal of Medicine 04/2012; 366(14):1275-86. · 53.30 Impact Factor -
Article: HLA class II restriction of HIV-1 clade-specific neutralizing antibody responses in ethnic Thai recipients of the RV144 prime-boost vaccine combination of ALVAC-HIV and AIDSVAX(®) B/E.
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ABSTRACT: Immune responses to vaccines may be influenced or associated with allelic variants of host genes such as those encoding human leucocyte antigens (HLA). We have molecularly determined the HLA class II DR and DQ gene, allele and haploype profiles in HIV-1 negative ethnic Thai recipients of an HIV-1 prime boost vaccine regimen, designed to induce neutralizing antibody (NAb) responses to HIV-1 CRF01_AE. Non-response to vaccine associated with DRB1*11 (3/32 responders vs. 7/13 non-responders, p(c)=0.027) and DRB1*16:02 (0/32 responders vs. 4/13 non-responders, p(c)=0.078) alleles. Furthermore, vaccine recipients with HLA-DQ heterodimers encoded by DQA1*05:01 and DQB1*03:01 alleles, were much less likely to produce NAb (p=0.009). These data suggest that the lack of response to a vaccine designed to induce clade-specific NAb to HIV-1 is associated with the presence of certain HLA class II alleles and heterodimers in some Southeast Asians.Vaccine 11/2011; 30(5):832-6. · 3.77 Impact Factor -
Article: The Armed Forces Research Institute of Medical Sciences: five decades of collaborative medical research.
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ABSTRACT: The Armed Forces Research Institute of Medical Sciences (AFRIMS) is a 50-year-old joint institute of the US and Royal Thai Army Medical Departments located in Bangkok, Thailand. Investigators from the Institute have carried out research in Thailand and the region, in collaboration with many partners, focused on a large number of tropical infectious diseases. In celebration of the 50th anniversary, this paper summarizes highlights of this research, focusing on malaria, Japanese encephalitis, dengue, diarrhea and HIV. In addition, research done in support of the medical problems of refugees and of the health of Thai peace-keeping forces are summarized. The research carried out by AFRIMS and added to the scientific literature has contributed significantly to advancement in multiple areas of tropical infectious disease.The Southeast Asian journal of tropical medicine and public health 05/2011; 42(3):477-90. · 0.60 Impact Factor
Top co-authors
Top Journals
Institutions
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2013
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NYU Langone Medical Center
New York City, NY, USA
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2012–2013
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U.S. Military HIV Research Program
Bethesda, MD, USA -
Duke University Medical Center
Durham, NC, USA -
Duke University
- Department of Surgery
Durham, NC, USA -
Walter Reed Army Institute of Research
Silver Spring, MD, USA
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2003–2013
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Mahidol University
- • Faculty of Tropical Medicine
- • Faculty of Medicine Siriraj Hospital
- • Department of Clinical Tropical Medicine
Bangkok, Bangkok, Thailand
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2009–2012
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Ministry of Public Health, Thailand
- Department of Disease Control
Bangkok, Bangkok, Thailand
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2002–2011
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Armed Forces Research Institute of Medical Sciences
- Department of Retrovirology
Bangkok, Bangkok, Thailand
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2006
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Centers for Disease Control and Prevention
Atlanta, MI, USA
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