M Juliana McElrath

Fred Hutchinson Cancer Research Center, Seattle, Washington, United States

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Publications (196)1434.24 Total impact

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    ABSTRACT: BACKGROUND. Vector prime-boost immunization strategies induce strong cellular and humoral immune responses. We examined the priming dose and administration order of heterologous vectors in HIV Vaccine Trials Network 078 (HVTN 078), a randomized, double-blind phase Ib clinical trial to evaluate the safety and immunogenicity of heterologous prime-boost regimens, with a New York vaccinia HIV clade B (NYVAC-B) vaccine and a recombinant adenovirus 5-vectored (rAd5-vectored) vaccine. METHODS. NYVAC-B included HIV-1 clade B Gag-Pol-Nef and gp120, while rAd5 included HIV-1 clade B Gag-Pol and clades A, B, and C gp140. Eighty Ad5-seronegative subjects were randomized to receive 2 × NYVAC-B followed by 1 × 1010 PFU rAd5 (NYVAC/Ad5hi); 1 × 108 PFU rAd5 followed by 2 × NYVAC-B (Ad5lo/NYVAC); 1 × 109 PFU rAd5 followed by 2 × NYVAC-B (Ad5med/NYVAC); 1 × 1010 PFU rAd5 followed by 2 × NYVAC-B (Ad5hi/NYVAC); or placebo. Immune responses were assessed 2 weeks after the final vaccination. Intracellular cytokine staining measured T cells producing IFN-γ and/or IL-2; cross-clade and epitope-specific binding antibodies were determined; and neutralizing antibodies (nAbs) were assessed with 6 tier 1 viruses. RESULTS. CD4+ T cell response rates ranged from 42.9% to 93.3%. NYVAC/Ad5hi response rates (P ≤ 0.01) and magnitudes (P ≤ 0.03) were significantly lower than those of other groups. CD8+ T cell response rates ranged from 65.5% to 85.7%. NYVAC/Ad5hi magnitudes were significantly lower than those of other groups (P ≤ 0.04). IgG response rates to the group M consensus gp140 were 89.7% for NYVAC/Ad5hi and 21.4%, 84.6%, and 100% for Ad5lo/NYVAC, Ad5med/NYVAC, and Ad5hi/NYVAC, respectively, and were similar for other vaccine proteins. Overall nAb responses were low, but aggregate responses appeared stronger for Ad5med/NYVAC and Ad5hi/NYVAC than for NYVAC/Ad5hi. CONCLUSIONS. rAd5 prime followed by NYVAC boost is superior to the reverse regimen for both vaccine-induced cellular and humoral immune responses. Higher Ad5 priming doses significantly increased binding and nAbs. These data provide a basis for optimizing the design of future clinical trials testing vector-based heterologous prime-boost strategies. TRIAL REGISTRATION. ClinicalTrials.gov NCT00961883. FUNDING. National Institute of Allergy and Infectious Diseases (NIAID), NIH UM1AI068618, AI068635, AI068614, and AI069443.
    The Journal of clinical investigation. 10/2014;
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    ABSTRACT: Finding an effective human immunodeficiency virus type 1 (HIV-1) vaccine remains a major global health priority.
    Clinical and vaccine Immunology: CVI 09/2014; · 2.60 Impact Factor
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    ABSTRACT: Vaccination with viral vectors or adjuvants can induce early changes in circulating peripheral blood leukocytes that are predictive of a protective immune response. In this study, we define an 11- color whole blood antibody staining Trucount Panel (TP1) to enumerate and phenotype the major leukocyte populations in a human vaccine experimental medicine trial setting. TP1 can be prepared up to 8 weeks prior to use, enabling bulk preparation at a central laboratory and distribution to clinical sites. Cells in whole blood must be stained within 4 hours of draw to detect the major cell populations. Staining of cells with TP1 followed by storage and shipping at -80°C to a central laboratory has little to no effect on the cell concentrations observed. We also present data from an HIV vaccine multicenter clinical trial obtained using the optimized TP1 assay protocol and show that the data produced accurately correlates with complete blood count (CBC) data. Taken together, these data indicate the optimized TP1 panel assay can be used in a multicenter clinical trial setting to increase our understanding of systemic responses to vaccination or disease.
    Journal of immunological methods. 06/2014;
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    ABSTRACT: The RV144 HIV-1 vaccine trial demonstrated partial efficacy of 31% against HIV-1 infection. Studies into possible correlates of protection found that antibodies specific to the V1/V2 region of envelope correlated inversely with infection risk and that viruses isolated from trial participants contained genetic signatures of vaccine-induced pressure in the V1/V2 region. We explored the hypothesis that the genetic signatures in V1/V2 could be partly attributed to selection by vaccine primed T cells. We performed a T-cell based sieve analysis of breakthrough viruses in the RV144 trial and found evidence of predicted HLA binding escape that was greater in vaccine versus placebo recipients. The predicted escape depended on class I HLA A*02 and A*11 restricted epitopes in the MN-strain rgp120 vaccine immunogen. Though we hypothesized that this was indicative of post-acquisition selection pressure, we also found that vaccine efficacy (VE) was greater in A*02(+) compared to A*02(-) participants (VE=54% vs. 3%, p=0.05). Vaccine efficacy against viruses with a lysine residue at site 169, important to antibody binding and implicated in vaccine-induced immune pressure, was also greater in A*02(+) participants (VE=74% vs. 15%, p=0.02). Additionally, a reanalysis of vaccine-induced immune responses focused on those that were shown to correlate with infection risk, suggested that the humoral response may have differed in A*02(+) participants. These exploratory and hypothesis-generating analyses indicate there may be an association between a class I HLA allele and vaccine efficacy, highlighting the importance of considering HLA alleles and host immune genetics in HIV vaccine trials. The RV144 trial was the first to show efficacy against HIV-1 infection. Subsequently, much effort has been directed towards understanding the mechanisms of protection, including this T-cell based sieve analysis which compared the genetic sequences of viruses isolated from infected vaccine and placebo recipients. Though we hypothesized that the observed sieve effect indicated post-acquisition T-cell selection, we also found that vaccine efficacy was greater for participants who expressed HLA A*02, an allele implicated in the sieve analysis. Though HLA alleles have been associated with disease progression and viral load in HIV-1 infection, these data are the first to suggest the association of a class I HLA allele and vaccine efficacy. While these statistical analyses do not provide mechanistic evidence of protection in RV144, they generate testable hypotheses for the HIV vaccine community and they highlight the importance of assessing the impact of host immune genetics in vaccine-induced immunity and protection.
    Journal of Virology 05/2014; · 5.08 Impact Factor
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    ABSTRACT: The HIV Vaccine Trials Network (HVTN) is a global network of 28 clinical trial sites dedicated to identifying an effective HIV vaccine. Cryopreservation of high-quality peripheral blood mononuclear cells (PBMC) is critical for the assessment of vaccine-induced cellular immune functions. The HVTN PBMC Quality Management Program is designed to ensure viable PBMC are processed, stored and shipped for clinical trial assays from all HVTN clinical trial sites. The program has evolved by developing and incorporating best practices for laboratory and specimen quality and implementing automated, web-based tools. These tools allow the site-affiliated processing laboratories and the central Laboratory Operations Unit to rapidly collect, analyze and report PBMC quality data. The HVTN PBMC Quality Management Program includes five key components: 1) Laboratory Assessment, 2) PBMC Training and Certification, 3) Internal Quality Control, 4) External Quality Control (EQC), and 5) Assay Specimen Quality Control. Fresh PBMC processing data is uploaded from each clinical site processing laboratory to a central HVTN Statistical and Data Management Center database for access and analysis on a web portal. Samples are thawed at a central laboratory for assay or specimen quality control and sample quality data is uploaded directly to the database by the central laboratory. Four year cumulative data covering 23,477 blood draws reveals an average fresh PBMC yield of 1.45×10(6)±0.48 cells per milliliter of useable whole blood. 95% of samples were within the acceptable range for fresh cell yield of 0.8-3.2×10(6) cells/ml of usable blood. Prior to full implementation of the HVTN PBMC Quality Management Program, the 2007 EQC evaluations from 10 international sites showed a mean day 2 thawed viability of 83.1% and recovery of 67.5%. Since then, four year cumulative data covering 3338 specimens used in immunologic assays shows that 99.88% had acceptable viabilities (>66%) for use in cellular assays (mean, 91.46% ±4.5%), and 96.2% had acceptable recoveries (50%-130%) with a mean of recovery of 85.8% ±19.12% of the originally cryopreserved cells. EQC testing revealed that since August 2009, failed recoveries dropped from 4.1% to 1.6% and failed viabilities dropped from 1.0% to 0.3%. The HVTN PBMC quality program provides for laboratory assessment, training and tools for identifying problems, implementing corrective action and monitoring for improvements. These data support the benefits of implementing a comprehensive, web-based PBMC quality program for large clinical trials networks.
    Journal of immunological methods 04/2014; · 2.35 Impact Factor
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    ABSTRACT: Background. Depot medroxyprogesterone acetate (DMPA) has been linked to HIV-1 acquisition.Methods. Vaginal microbiota of women using DMPA for up to two years were cultured; mucosal immune cell populations measured by immunohistological staining.Results. Over 12 months, the proportion with H2O2-positive lactobacilli decreased (n=32; 53 vs. 27%; p=0.03). Median vaginal CD3(+) cells also decreased (n=15; 355 vs. 237cells/mm(2); p=0.03), as did CD3(+)CCR5(+)(195 vs. 128cells/mm(2); p=0.04), HLA-DR(+) (130 vs. 96cells/mm(2); p=0.27), and HLA-DR(+)CCR5(+) cells (18 vs. 10cells/mm(2); p=0.33).Conclusion. DMPA contraception does not increase vaginal mucosal CCR5(+) HIV-1 target cells, but does decrease CD3(+) T lymphocytes and vaginal H2O2-producing lactobacilli.
    The Journal of Infectious Diseases 03/2014; · 5.85 Impact Factor
  • Lawrence Corey, M Juliana McElrath
    Nature medicine 03/2014; 20(3):241-2. · 27.14 Impact Factor
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    ABSTRACT: Human vaccine development remains challenging because of the highly sophisticated evasion mechanisms of pathogens for which vaccines are not yet available. Recent years have witnessed both successes and failures of novel vaccine design and the strength of iterative approaches is increasingly appreciated. These combine discovery of novel antigens, adjuvants and vectors in the preclinical stage with computational analyses of clinical data to accelerate vaccine design. Reverse and structural vaccinology have revealed novel antigen candidates and molecular immunology has led to the formulation of promising adjuvants. Gene expression profiles and immune parameters in patients, vaccinees and healthy controls have formed the basis for biosignatures that will provide guidelines for future vaccine design.
    Current opinion in immunology 02/2014; 28C:18-26. · 10.88 Impact Factor
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    ABSTRACT: Background. Clade B DNA and recombinant modified vaccinia Ankara (MVA) vaccines producing virus-like particles displaying trimeric membrane-bound envelope glycoprotein (Env) were tested in a phase 2a trial in human immunodeficiency virus (HIV)-uninfected adults for safety, immunogenicity, and 6-month durability of immune responses.Methods. A total of 299 individuals received 2 doses of JS7 DNA vaccine and 2 doses of MVA/HIV62B at 0, 2, 4, and 6 months, respectively (the DDMM regimen); 3 doses of MVA/HIV62B at 0, 2, and 6 months (the MMM regimen); or placebo injections.Results. At peak response, 93.2% of the DDMM group and 98.4% of the MMM group had binding antibodies for Env. These binding antibodies were more frequent and of higher magnitude for the transmembrane subunit (gp41) than the receptor-binding subunit (gp120) of Env. For both regimens, response rates were higher for CD4(+) T cells (66.4% in the DDMM group and 43.1% in the MMM group) than for CD8(+) T cells (21.8% in the DDMM group and 14.9% in the MMM group). Responding CD4(+) and CD8(+) T cells were biased toward Gag, and >70% produced 2 or 3 of the 4 cytokines evaluated (ie, interferon γ, interleukin 2, tumor necrosis factor α, and granzyme B). Six months after vaccination, the magnitudes of antibodies and T-cell responses had decreased by <3-fold.Conclusions. DDMM and MMM vaccinations with virus-like particle-expressing immunogens elicited durable antibody and T-cell responses.
    The Journal of Infectious Diseases 02/2014; · 5.85 Impact Factor
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    ABSTRACT: We evaluated genetic variants in 51 candidate genes encoding proteins that interact with HIV-1 during the virus life cycle for association with HIV-1 outcomes in an African cohort. Using a nested case-control study within a cohort of heterosexual HIV-1 serodiscordant couples, we genotyped 475 haplotype-tagging (tagSNPs) and 18 Single Nucleotide Polymorphisms (SNPs) previously associated with HIV-1 transmission and/or progression (candidate SNPs) in 51 host genes. We used logistic and Cox proportional hazards regression with adjustment for sex, age, and population stratification to detect SNP associations with HIV-1 acquisition, plasma HIV-1 set-point, and a composite measure of HIV-1 disease progression. Significance thresholds for tagSNP, but not candidate SNP, associations were subjected to Bonferroni correction for multiple testing. We evaluated 491 HIV-1 infected and 335 HIV-1 uninfected individuals for 493 SNPs, 459 of which passed quality control filters. Candidate SNP PPIA rs8177826 and haplotype tagging SNP SMARCB1 rs6003904 were significantly associated with HIV-1 acquisition risk (odds ratio [OR] = 0.14, p=0.03, and 2.11, pcorr= 0.01, respectively). Furthermore, the TT genotype for CCR5 rs1799988 was associated with a mean 0.2 log10 copies/mL lower plasma HIV-1 RNA set-point (p = 0.04). We also identified significant associations with HIV-1 disease progression for variants in FUT2 and MBL2. Using a targeted gene approach, we identified variants in host genes whose protein products interact with HIV-1 during the virus replication cycle and were associated with HIV-1 outcomes in this African cohort.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2014; · 4.65 Impact Factor
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    ABSTRACT: Functional analysis of mononuclear leukocytes in the female genital mucosa is essential for understanding the immunologic effects of HIV vaccines and microbicides at the site of HIV exposure. However, the best female genital tract sampling technique is unclear. WE ENROLLED WOMEN FROM FOUR SITES IN AFRICA AND THE US TO COMPARE THREE GENITAL LEUKOCYTE SAMPLING METHODS: cervicovaginal lavages (CVL), endocervical cytobrushes, and ectocervical biopsies. Absolute yields of mononuclear leukocyte subpopulations were determined by flow cytometric bead-based cell counting. Of the non-invasive sampling types, two combined sequential cytobrushes yielded significantly more viable mononuclear leukocytes than a CVL (p<0.0001). In a subsequent comparison, two cytobrushes yielded as many leukocytes (∼10,000) as one biopsy, with macrophages/monocytes being more prominent in cytobrushes and T lymphocytes in biopsies. Sample yields were consistent between sites. In a subgroup analysis, we observed significant reproducibility between replicate same-day biopsies (r = 0.89, p = 0.0123). Visible red blood cells in cytobrushes increased leukocyte yields more than three-fold (p = 0.0078), but did not change their subpopulation profile, indicating that these leukocytes were still largely derived from the mucosa and not peripheral blood. We also confirmed that many CD4(+) T cells in the female genital tract express the α4β7 integrin, an HIV envelope-binding mucosal homing receptor. CVL sampling recovered the lowest number of viable mononuclear leukocytes. Two cervical cytobrushes yielded comparable total numbers of viable leukocytes to one biopsy, but cytobrushes and biopsies were biased toward macrophages and T lymphocytes, respectively. Our study also established the feasibility of obtaining consistent flow cytometric analyses of isolated genital cells from four study sites in the US and Africa. These data represent an important step towards implementing mucosal cell sampling in international clinical trials of HIV prevention.
    PLoS ONE 01/2014; 9(1):e85675. · 3.53 Impact Factor
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    ABSTRACT: Many participants in microbicide trials remain uninfected despite ongoing exposure to HIV-1. Determining the emergence and nature of mucosal HIV-specific immune responses in such women is important, since these responses may contribute to protection and could provide insight for the rational design of HIV-1 vaccines.
    PLoS ONE 01/2014; 9(7):e101863. · 3.53 Impact Factor
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    ABSTRACT: The phase III RV144 HIV-1 vaccine trial estimated vaccine efficacy (VE) to be 31.2%. This trial demonstrated that the presence of HIV-1-specific IgG-binding Abs to envelope (Env) V1V2 inversely correlated with infection risk, while the presence of Env-specific plasma IgA Abs directly correlated with risk of HIV-1 infection. Moreover, Ab-dependent cellular cytotoxicity responses inversely correlated with risk of infection in vaccine recipients with low IgA; therefore, we hypothesized that vaccine-induced Fc receptor-mediated (FcR-mediated) Ab function is indicative of vaccine protection. We sequenced exons and surrounding areas of FcR-encoding genes and found one FCGR2C tag SNP (rs114945036) that associated with VE against HIV-1 subtype CRF01_AE, with lysine at position 169 (169K) in the V2 loop (CRF01_AE 169K). Individuals carrying CC in this SNP had an estimated VE of 15%, while individuals carrying CT or TT exhibited a VE of 91%. Furthermore, the rs114945036 SNP was highly associated with 3 other FCGR2C SNPs (rs138747765, rs78603008, and rs373013207). Env-specific IgG and IgG3 Abs, IgG avidity, and neutralizing Abs inversely correlated with CRF01_AE 169K HIV-1 infection risk in the CT- or TT-carrying vaccine recipients only. These data suggest a potent role of Fc-gamma receptors and Fc-mediated Ab function in conferring protection from transmission risk in the RV144 VE trial.
    The Journal of clinical investigation 01/2014; · 15.39 Impact Factor
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    ABSTRACT: Male circumcision provides partial protection against multiple sexually transmitted infections (STIs), including HIV, but the mechanisms are not fully understood. To examine potential vulnerabilities in foreskin epithelial structure, we used Wilcoxon paired tests adjusted using the false discovery rate method to compare inner and outer foreskin samples from 20 healthy, sexually active Peruvian males who have sex with males or transgender females, ages 21-29, at elevated risk of HIV infection. No evidence of epithelial microtrauma was identified, as assessed by keratinocyte activation, fibronectin deposition, or parakeratosis. However, multiple suprabasal tight junction differences were identified: 1) inner foreskin stratum corneum was thinner than outer (p = 0.035); 2) claudin 1 had extended membrane-bound localization throughout inner epidermis stratum spinosum (p = 0.035); 3) membrane-bound claudin 4 was absent from inner foreskin stratum granulosum (p = 0.035); and 4) occludin had increased membrane deposition in inner foreskin stratum granulosum (p = 0.042) versus outer. Together, this suggests subclinical inflammation and paracellular transport modifications to the inner foreskin. A setting of inflammation was further supported by inner foreskin epithelial explant cultures secreting higher levels of GM-CSF (p = 0.029), IP-10 (p = 0.035) and RANTES (p = 0.022) than outer foreskin, and also containing an increased density of CCR5+ and CD4+ CCR5+ cells (p = 0.022). Inner foreskin dermis also secreted more RANTES than outer (p = 0.036), and had increased density of CCR5+ cells (p = 0.022). In conclusion, subclinical changes to the inner foreskin of sexually active males may support an inflammatory state, with availability of target cells for HIV infection and modifications to epidermal barriers, potentially explaining the benefits of circumcision for STI prevention.
    PLoS ONE 01/2014; 9(9):e108954. · 3.53 Impact Factor
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    ABSTRACT: HIV replication is unrestrained in vivo in the vast majority of infected subjects, and the ability of some rare individuals to control this virus is poorly understood. Standard immunogenicity assays for detecting HIV-1-specific CD8(+) T-cell responses, such as IFN-γ ELISpot and intracellular cytokine staining, generally fail to correlate with in vivo inhibition of HIV replication. Several viral inhibition assays, which measure the effectiveness of CD8(+) T-cell responses in suppressing HIV replication in vitro, have been described; but most depend on in vitro expansion of CD8(+) T cells, and some show inhibitory activity in HIV-negative individuals. We have optimized an assay to assess the suppressive capability of CD8(+) T cells directly ex vivo, eliminating the potential for altering their function through activation or expansion prior to assay setup, and thereby enhancing the assay's sensitivity by avoiding non-specific inhibition. With this method, the ability of ex vivo CD8(+) T cells to control HIV-1 replication in vitro can be quantified over several orders of magnitude. Specifically, our assay can be used to better define the antiviral function of CD8(+) T cells induced by vaccination, and can provide insight into their ability to control viral replication if HIV infection occurs post-vaccination.
    Journal of immunological methods 12/2013; · 2.35 Impact Factor
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    ABSTRACT: Objective. We evaluated Toll-like receptors (TLRs) single nucleotide polymorphisms (SNPs) for associations with HIV-1 acquisition, set-point and disease progression in African couples.Methods. Seven candidate and 116 haplotype-tagging SNPs (tagSNPs) were genotyped in 504 HIV-1 infected cases, and 343 seronegative controls.Results. TLR9 1635A/G was associated with reduced HIV-1 acquisition among HIV-seronegative controls with high but not low HIV-1 exposure (odds ratio [OR]=0.7; p=0.03 and OR=0.9, p=0.5, respectively). TLR7 rs179012 and TLR2 597C/T reduced set-point; the latter modified by time since HIV-1 acquisition. TLR8 1A/G reduced disease progression.Conclusion. TLR SNPs impact HIV-1 outcomes with epidemiologic factors modifying these relationships.
    The Journal of Infectious Diseases 12/2013; · 5.85 Impact Factor
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    ABSTRACT: A major challenge in the development of an HIV vaccine is contending with the extensive sequence variability found in circulating viruses. Induction of HIV-specific T-cell responses targeting conserved regions or recognizing a high number of epitope variants have each been proposed as a strategy to overcome this challenge. We addressed the ability of cytotoxic T-lymphocytes from 30 untreated HIV-infected subjects with and without control of virus replication to recognize all clade B Gag sequence variants encoded by at least 5% of the sequences in the Los Alamos National Laboratory HIV database (1300 peptides) using IFNγ/IL-2 FluoroSpot. While targeting of conserved regions was similar in both groups (p=0.47), we found that subjects with control of virus replication demonstrate marginally lower recognition of Gag epitope variants compared to subjects with normal progression (p=0.05). In viremic controllers and progressors, we found variant recognition to be associated with viral load (r=0.62, p=0.001). Interestingly, we show that increased overall sequence coverage, defined as the overall proportion of HIV database sequences targeted through the Gag-specific repertoire, is inversely associated with viral load (r=-0.38, p=0.03). Furthermore, we found that sequence coverage, but not variant recognition, correlated with increased recognition of a panel of clade B HIV founder viruses (r=0.50, p=0.004). We propose sequence coverage by HIV Gag-specific immune responses as a possible correlate of protection that may contribute to control of virus replication. Additionally, sequence coverage serves as a valuable measure in which to evaluate the protective potential of future vaccination strategies.
    Journal of Virology 11/2013; · 5.08 Impact Factor
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    ABSTRACT: Background A safe and effective vaccine for the prevention of human immunodeficiency virus type 1 (HIV-1) infection is a global priority. We tested the efficacy of a DNA prime-recombinant adenovirus type 5 boost (DNA/rAd5) vaccine regimen in persons at increased risk for HIV-1 infection in the United States. Methods At 21 sites, we randomly assigned 2504 men or transgender women who have sex with men to receive the DNA/rAd5 vaccine (1253 participants) or placebo (1251 participants). We assessed HIV-1 acquisition from week 28 through month 24 (termed week 28+ infection), viral-load set point (mean plasma HIV-1 RNA level 10 to 20 weeks after diagnosis), and safety. The 6-plasmid DNA vaccine (expressing clade B Gag, Pol, and Nef and Env proteins from clades A, B, and C) was administered at weeks 0, 4, and 8. The rAd5 vector boost (expressing clade B Gag-Pol fusion protein and Env glycoproteins from clades A, B, and C) was administered at week 24. Results In April 2013, the data and safety monitoring board recommended halting vaccinations for lack of efficacy. The primary analysis showed that week 28+ infection had been diagnosed in 27 participants in the vaccine group and 21 in the placebo group (vaccine efficacy, -25.0%; 95% confidence interval, -121.2 to 29.3; P=0.44), with mean viral-load set points of 4.46 and 4.47 HIV-1 RNA log10 copies per milliliter, respectively. Analysis of all infections during the study period (41 in the vaccine group and 31 in the placebo group) also showed lack of vaccine efficacy (P=0.28). The vaccine regimen had an acceptable side-effect profile. Conclusions The DNA/rAd5 vaccine regimen did not reduce either the rate of HIV-1 acquisition or the viral-load set point in the population studied. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00865566 .).
    New England Journal of Medicine 10/2013; · 54.42 Impact Factor
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    ABSTRACT: The contribution of host T-cell immunity and HLA class I alleles to control of HIV replication in natural infection is widely recognized. We assessed whether vaccine-induced T-cell immunity, or expression of certain HLA alleles, impacted HIV control post-infection in the Step MRKAd5/HIV-1 gag/pol/nef Study (ClinicalTrials.gov Identifier: NCT00095576). Vaccine-induced T cells were associated with reduced plasma viremia, with subjects targeting ≥3 Gag peptides presenting with half-log lower mean viral load than subjects without Gag responses. This effect was stronger in participants infected proximal to vaccination, and was independent of our observed association of HLA-B*27, -B*57 and -B*58:01 alleles with lower HIV viremia. These findings support the ability of vaccine-induced T-cell responses to influence post-infection outcome, and provide a rationale for the generation of T-cell responses by vaccination to reduce viremia if protection from acquisition is not achieved.
    The Journal of Infectious Diseases 07/2013; · 5.85 Impact Factor
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    ABSTRACT: CD1 proteins evolved to present diverse lipid Ags to T cells. In comparison with MHC proteins, CD1 proteins exhibit minimal allelic diversity as a result of nonsynonymous single nucleotide polymorphisms (SNPs). However, it is unknown if common SNPs in gene regulatory regions affect CD1 expression and function. We report surprising diversity in patterns of inducible CD1a expression on human dendritic cells (DCs), spanning the full range from undetectable to high density, a finding not seen with other CD1 isoforms. CD1a-deficient DCs failed to present mycobacterial lipopeptide to T cells but had no defects in endocytosis, cytokine secretion, or expression of costimulatory molecules after LPS treatment. We identified an SNP in the 5' untranslated region (rs366316) that was common and strongly associated with low CD1a surface expression and mRNA levels (p = 0.03 and p = 0.001, respectively). Using a CD1a promoter-luciferase system in combination with mutagenesis studies, we found that the polymorphic allele reduced luciferase expression by 44% compared with the wild-type variant (p < 0.001). Genetic regulation of lipid Ag presentation by varying expression on human DCs provides a mechanism for achieving population level differences in immune responses despite limited structural variation in CD1a proteins.
    The Journal of Immunology 07/2013; · 5.52 Impact Factor

Publication Stats

8k Citations
1,434.24 Total Impact Points

Institutions

  • 1999–2014
    • Fred Hutchinson Cancer Research Center
      • • Division of Vaccine and Infectious Disease
      • • Statistical Center for HIV/AIDS Research and Prevention
      • • Division of Clinical Research
      • • Division of Public Health Sciences
      Seattle, Washington, United States
  • 2011–2012
    • Seattle Institute for Biomedical and Clinical Research
      Seattle, Washington, United States
    • New York University
      • Department of Medicine
      New York City, NY, United States
  • 1999–2012
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States
  • 1993–2012
    • University of Washington Seattle
      • • Department of Immunology
      • • Department of Microbiology
      • • Department of Laboratory Medicine
      • • Department of Pathology
      • • Department of Medicine
      Seattle, WA, United States
  • 2008–2011
    • Emory University
      • Department of Pediatrics
      Atlanta, Georgia, United States
  • 1997–2011
    • University of Rochester
      • • Division of Hospital Medicine
      • • School of Medicine and Dentistry
      Rochester, NY, United States
    • Australian National University
      Canberra, Australian Capital Territory, Australia
  • 2010
    • University of California, San Francisco
      San Francisco, California, United States
  • 2009
    • National Institutes of Health
      Maryland, United States
  • 2007
    • Seattle Children's Hospital
      • Children's Hospital and Regional Medical Center
      Seattle, Washington, United States
  • 2005
    • University of Alabama at Birmingham
      • Department of Medicine
      Birmingham, AL, United States
  • 1997–2005
    • Duke University Medical Center
      • Department of Surgery
      Durham, NC, United States
  • 2001
    • Dartmouth Medical School
      • Department of Microbiology and Immunology
      Hanover, NH, United States
    • Beth Israel Deaconess Medical Center
      • Division of Viral Pathogenesis
      Boston, MA, United States
  • 1998
    • Massachusetts General Hospital
      Boston, Massachusetts, United States