Clinical and Vaccine Immunology最新文献

{"title":"Development of a High-Throughput Respiratory Syncytial Virus Fluorescent Focus-Based Microneutralization Assay.","authors":"Cindy Shambaugh,&nbsp;Sarieh Azshirvani,&nbsp;Li Yu,&nbsp;Jared Pache,&nbsp;Stacie L Lambert,&nbsp;Fengrong Zuo,&nbsp;Mark T Esser","doi":"10.1128/CVI.00225-17","DOIUrl":"https://doi.org/10.1128/CVI.00225-17","url":null,"abstract":"<p><p>Neutralizing antibodies specific for respiratory syncytial virus (RSV) represent a major protective mechanism against RSV infection, as demonstrated by the efficacy of the immune-prophylactic monoclonal antibody palivizumab in preventing RSV-associated lower respiratory tract infections in premature infants. Accordingly, the RSV neutralization assay has become a key functional method to assess the neutralizing activity of serum antibodies in preclinical animal models, epidemiology studies, and clinical trials. In this study, we qualified a 24-h, fluorescent focus-based microneutralization (RSVA FFA-MN) method that requires no medium exchange or pre- or postinfection processing to detect green fluorescent protein-expressing RSV strain A2 (RSVA-GFP)-infected cells, using a high-content imaging system for automated image acquisition and focus enumeration. The RSVA FFA-MN method was shown to be sensitive, with a limit of detection (LOD) and limit of quantitation (LOQ) of 1:10, or 3.32 log₂; linear over a range of 4.27 to 9.65 log₂ 50% inhibitory concentration (IC₅₀); and precise, with intra- and interassay coefficients of variation of <21%. This precision allowed the choice of a statistically justified 3-fold-rise seroresponse cutoff criterion. The repeatability and robustness of this method were demonstrated by including a pooled human serum sample in every assay as a positive control (PC). Over 3 years of testing between two laboratories, this PC generated data falling within 2.5 standard deviations of the mean 98.7% of the time (<i>n</i> = 1,720). This high-throughput and reliable RSV microneutralization assay has proven useful for testing sera from preclinical vaccine candidate evaluation studies, epidemiology studies, and both pediatric and adult vaccine clinical trials.</p>","PeriodicalId":10271,"journal":{"name":"Clinical and Vaccine Immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1128/CVI.00225-17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35597821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kinetics, Longevity, and Cross-Reactivity of Antineuraminidase Antibody after Natural Infection with Influenza A Viruses.","authors":"Don Changsom,&nbsp;Li Jiang,&nbsp;Hatairat Lerdsamran,&nbsp;Sopon Iamsirithaworn,&nbsp;Rungrueng Kitphati,&nbsp;Phisanu Pooruk,&nbsp;Prasert Auewarakul,&nbsp;Pilaipan Puthavathana","doi":"10.1128/CVI.00248-17","DOIUrl":"https://doi.org/10.1128/CVI.00248-17","url":null,"abstract":"<p><p>The kinetics, longevity, and breadth of antibodies to influenza virus neuraminidase (NA) in archival, sequential serum/plasma samples from influenza A virus (IAV) H5N1 infection survivors and from patients infected with the 2009 pandemic IAV (H1N1) virus were determined using an enzyme-linked lectin-based assay. The reverse-genetics-derived H4N1 viruses harboring a hemagglutinin (HA) segment from A/duck/Shan Tou/461/2000 (H4N9) and an NA segment derived from either IAV H5N1 clade 1, IAV H5N1 clade 2.3.4, the 2009 pandemic IAV (H1N1) (H1N1pdm), or A/Puerto Rico/8/1934 (H1N1) virus were used as the test antigens. These serum/plasma samples were also investigated by microneutralization (MN) and/or hemagglutination inhibition (HI) assays. Neuraminidase-inhibiting (NI) antibodies against N1 NA of both homologous and heterologous viruses were observed in H5N1 survivors and H1N1pdm patients. H5N1 survivors who were never exposed to H1N1pdm virus developed NI antibodies to H1N1pdm NA. Seroconversion of NI antibodies was observed in 65% of the H1N1pdm patients at day 7 after disease onset, but an increase in titer was not observed in serum samples obtained late in infection. On the other hand, an increase in seroconversion rate with the HI assay was observed in the follow-up series of sera obtained on days 7, 14, 28, and 90 after infection. The study also showed that NI antibodies are broadly reactive, while MN and HI antibodies are more strain specific.</p>","PeriodicalId":10271,"journal":{"name":"Clinical and Vaccine Immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1128/CVI.00248-17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35597823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Resolution Epitope Positioning of a Large Collection of Neutralizing and Nonneutralizing Single-Domain Antibodies on the Enzymatic and Binding Subunits of Ricin Toxin.","authors":"David J Vance, Jacqueline M Tremblay, Yinghui Rong, Siva Krishna Angalakurthi, David B Volkin, C Russell Middaugh, David D Weis, Charles B Shoemaker, Nicholas J Mantis","doi":"10.1128/CVI.00236-17","DOIUrl":"10.1128/CVI.00236-17","url":null,"abstract":"<p><p>We previously produced a heavy-chain-only antibody (Ab) VH domain (V_HH)-displayed phage library from two alpacas that had been immunized with ricin toxoid and nontoxic mixtures of the enzymatic ricin toxin A subunit (RTA) and binding ricin toxin B subunit (RTB) (D. J. Vance, J. M. Tremblay, N. J. Mantis, and C. B. Shoemaker, J Biol Chem 288:36538-36547, 2013, https://doi.org/10.1074/jbc.M113.519207). Initial and subsequent screens of that library by direct enzyme-linked immunosorbent assay (ELISA) yielded more than two dozen unique RTA- and RTB-specific V_HHs, including 10 whose structures were subsequently solved in complex with RTA. To generate a more complete antigenic map of ricin toxin and to define the epitopes associated with toxin-neutralizing activity, we subjected the V_HH-displayed phage library to additional \"pannings\" on both receptor-bound ricin and antibody-captured ricin. We now report the full-length DNA sequences, binding affinities, and neutralizing activities of 68 unique V_HHs: 31 against RTA, 33 against RTB, and 4 against ricin holotoxin. Epitope positioning was achieved through cross-competition ELISAs performed with a panel of monoclonal antibodies (MAbs) and verified, in some instances, with hydrogen-deuterium exchange mass spectrometry. The 68 V_HHs grouped into more than 20 different competition bins. The RTA-specific V_HHs with strong toxin-neutralizing activities were confined to bins that overlapped two previously identified neutralizing hot spots, termed clusters I and II. The four RTB-specific V_HHs with potent toxin-neutralizing activity grouped within three adjacent bins situated at the RTA-RTB interface near cluster II. These results provide important insights into epitope interrelationships on the surface of ricin and delineate regions of vulnerability that can be exploited for the purpose of vaccine and therapeutic development.</p>","PeriodicalId":10271,"journal":{"name":"Clinical and Vaccine Immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717184/pdf/e00236-17.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35504510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Approaches To Optimize Laboratory Assessment of Antinuclear Antibodies.","authors":"Anne E Tebo","doi":"10.1128/CVI.00270-17","DOIUrl":"https://doi.org/10.1128/CVI.00270-17","url":null,"abstract":"ABSTRACT The presence of antinuclear antibodies (ANAs) is a hallmark of a number of systemic autoimmune rheumatic diseases, and testing is usually performed as part of the initial diagnostic workup when suspicion of an underlying autoimmune disorder is high. The indirect immunofluorescence antibody (IFA) technique is the preferred method for detecting ANAs, as it demonstrates binding to specific intracellular structures within the cells, resulting in a number of staining patterns that are usually categorized based on the cellular components recognized and the degree of binding, as reflected by the fluorescence intensity or titer. As a screening tool, the ANA patterns can guide confirmatory testing useful in elucidating a specific clinical diagnosis or prognosis. However, routine use of ANA IFA testing as a global screening test is hampered by its labor-intensiveness, subjectivity, and limited diagnostic specificity, among other factors. This review focuses on current efforts to standardize the nomenclature of ANA patterns and on alternative methods for ANA determination, as well as on recent advances in image-based computer algorithms to automate IFA testing in clinical laboratories.","PeriodicalId":10271,"journal":{"name":"Clinical and Vaccine Immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1128/CVI.00270-17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35504511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial Comparing the Reactogenicity and Immunogenicity of a Single Standard Dose to Those of a High Dose of CVD 103-HgR Live Attenuated Oral Cholera Vaccine, with Shanchol Inactivated Oral Vaccine as an Open-Label Immunologic Comparator.","authors":"Samba O Sow,&nbsp;Milagritos D Tapia,&nbsp;Wilbur H Chen,&nbsp;Fadima C Haidara,&nbsp;Karen L Kotloff,&nbsp;Marcela F Pasetti,&nbsp;William C Blackwelder,&nbsp;Awa Traoré,&nbsp;Boubou Tamboura,&nbsp;Moussa Doumbia,&nbsp;Fatoumata Diallo,&nbsp;Flanon Coulibaly,&nbsp;Uma Onwuchekwa,&nbsp;Mamoudou Kodio,&nbsp;Sharon M Tennant,&nbsp;Mardi Reymann,&nbsp;Diana F Lam,&nbsp;Marc Gurwith,&nbsp;Michael Lock,&nbsp;Thomas Yonker,&nbsp;Jonathan Smith,&nbsp;Jakub K Simon,&nbsp;Myron M Levine","doi":"10.1128/CVI.00265-17","DOIUrl":"https://doi.org/10.1128/CVI.00265-17","url":null,"abstract":"<p><p>Reactive immunization with a single-dose cholera vaccine that could rapidly (within days) protect immunologically naive individuals during virgin soil epidemics, when cholera reaches immunologically naive populations that have not experienced cholera for decades, would facilitate cholera control. One dose of attenuated <i>Vibrio cholerae</i> O1 classical Inaba vaccine CVD 103-HgR (Vaxchora) containing ≥2 × 10⁸ CFU induces vibriocidal antibody seroconversion (a correlate of protection) in >90% of U.S. adults. A previous CVD 103-HgR commercial formulation required ≥2 × 10⁹ CFU to elicit high levels of seroconversion in populations in developing countries. We compared the vibriocidal responses of Malians (individuals 18 to 45 years old) randomized to ingest a single ≥2 × 10⁸-CFU standard dose (<i>n</i> = 50) or a ≥2 × 10⁹-CFU high dose (<i>n</i> = 50) of PaxVax CVD 103-HgR with buffer or two doses (<i>n</i> = 50) of Shanchol inactivated cholera vaccine (the immunologic comparator). To maintain blinding, participants were dosed twice 2 weeks apart; CVD 103-HgR recipients ingested placebo 2 weeks before or after ingesting vaccine. Seroconversion (a ≥4-fold vibriocidal titer rise) between the baseline and 14 days after CVD 103-HgR ingestion and following the first and second doses of Shanchol were the main outcomes measured. By day 14 postvaccination, the rates of seroconversion after ingestion of a single standard dose and a high dose of CVD 103-HgR were 71.7% (33/46 participants) and 83.3% (40/48 participants), respectively. The rate of seroconversion following the first dose of Shanchol, 56.0% (28/50 participants), was significantly lower than that following the high dose of CVD 103-HgR (<i>P</i> = 0.003). The vibriocidal geometric mean titer (GMT) of the high dose of CVD 103-HgR exceeded the GMT of the standard dose at day 14 (214 versus 95, <i>P</i> = 0.045) and was ∼2-fold higher than the GMT on day 7 and day 14 following the first Shanchol dose (<i>P</i> > 0.05). High-dose CVD 103-HgR is recommended for accelerated evaluation in developing countries to assess its efficacy and practicality in field situations. (This study has been registered at ClinicalTrials.gov under registration no. NCT02145377.).</p>","PeriodicalId":10271,"journal":{"name":"Clinical and Vaccine Immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1128/CVI.00265-17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35504509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Qualification of an Opsonophagocytic Killing Assay To Assess Immunogenicity of a Bioconjugated Escherichia coli Vaccine.","authors":"Darren Abbanat, Todd A Davies, Karen Amsler, Wenping He, Kellen Fae, Sarah Janssen, Jan T Poolman, Germie P J M van den Dobbelsteen","doi":"10.1128/CVI.00123-17","DOIUrl":"10.1128/CVI.00123-17","url":null,"abstract":"<p><p>The global burden of disease caused by extraintestinal pathogenic <i>Escherichia coli</i> (ExPEC) is increasing as the prevalence of multidrug-resistant strains rises. A multivalent ExPEC O-antigen bioconjugate vaccine could have a substantial impact in preventing bacteremia and urinary tract infections. Development of an ExPEC vaccine requires a readout to assess the functionality of antibodies. We developed an opsonophagocytic killing assay (OPA) for four ExPEC serotypes (serotypes O1A, O2, O6A, and O25B) based on methods established for pneumococcal conjugate vaccines. The performance of the assay was assessed with human serum by computing the precision, linearity, trueness, total error, working range, and specificity. Serotypes O1A and O6A met the acceptance criteria for precision (coefficient of variation for repeatability and intermediate precision, ≤50%), linearity (90% confidence interval of the slope of each strain, 0.80, 1.25), trueness (relative bias range, -30% to 30%), and total error (total error range, -65% to 183%) at five serum concentrations and serotypes O2 and O25B met the acceptance criteria at four concentrations (the lowest concentration for serotypes O2 and O25B did not meet the system suitability test of maximum killing of ≥85% of <i>E. coli</i> cells). All serotypes met the acceptance criteria for specificity (opsonization index value reductions of ≤20% for heterologous serum preadsorption and ≥70% for homologous serum preadsorption). The assay working range was defined on the basis of the lowest and highest concentrations at which the assay jointly fulfilled the target acceptance criteria for linearity, precision, and accuracy. An OPA suitable for multiple <i>E. coli</i> serotypes has been developed, qualified, and used to assess the immunogenicity of a 4-valent <i>E. coli</i> bioconjugate vaccine (ExPEC4V) administered to humans.</p>","PeriodicalId":10271,"journal":{"name":"Clinical and Vaccine Immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717180/pdf/e00123-17.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35468435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Article of Significant Interest Selected from This Issue by the Editors","authors":"","doi":"10.1128/cvi.00278-17","DOIUrl":"https://doi.org/10.1128/cvi.00278-17","url":null,"abstract":"A Single High Dose of CVD 103-HgR Live Oral Cholera Vaccine Is More Immunogenic than a Standard Dose or than One or Two Doses of Shanchol Oral Killed Vaccine In a study by Sow et al. (e00265-17), Malian adults were randomly allocated to receive a single standard dose (108 CFU) or a high dose (109 CFU) of CVD 103-HgR live oral cholera vaccine or two doses (2 weeks apart) of Shanchol killed oral cholera vaccine. Inaba serum vibriocidal antibody responses (seroconversion rate, geometric mean titer [GMT], and fold rise) were compared. High-dose CVD 103-HgR exhibited significantly higher seroconversion rates than one or two doses of Shanchol and significantly higher GMTs than standard-dose CVD 103-HgR. A single high dose of CVD 103-HgR is recommended for accelerated evaluation in developing countries to assess effectiveness and practicality in field situations.","PeriodicalId":10271,"journal":{"name":"Clinical and Vaccine Immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79242543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Merozoite Surface Protein 1 from Plasmodium falciparum Is a Major Target of Opsonizing Antibodies in Individuals with Acquired Immunity against Malaria.","authors":"Anja Jäschke,&nbsp;Boubacar Coulibaly,&nbsp;Edmond J Remarque,&nbsp;Hermann Bujard,&nbsp;Christian Epp","doi":"10.1128/CVI.00155-17","DOIUrl":"https://doi.org/10.1128/CVI.00155-17","url":null,"abstract":"<p><p>Naturally acquired immunity against malaria is largely mediated by serum antibodies controlling levels of blood-stage parasites. A limited understanding of the antigenic targets and functional mechanisms of protective antibodies has hampered the development of efficient malaria vaccines. Besides directly inhibiting the growth of <i>Plasmodium</i> parasites, antibodies can opsonize merozoites and recruit immune effector cells such as monocytes and neutrophils. Antibodies against the vaccine candidate merozoite surface protein 1 (MSP-1) are acquired during natural infections and have been associated with protection against malaria in several epidemiological studies. Here we analyzed serum antibodies from semi-immune individuals from Burkina Faso for their potential (i) to directly inhibit the growth of <i>P. falciparum</i> blood stages <i>in vitro</i> and (ii) to opsonize merozoites and to induce the antibody-dependent respiratory burst (ADRB) activity of neutrophils. While a few sera that directly inhibited the growth of <i>P. falciparum</i> blood stages were identified, immunoglobulin G (IgG) from all individuals clearly mediated the activation of neutrophils. The level of neutrophil activation correlated with levels of antibodies to MSP-1, and affinity-purified MSP-1-specific antibodies elicited ADRB activity. Furthermore, immunization of nonhuman primates with recombinant full-size MSP-1 induced antibodies that efficiently opsonized <i>P. falciparum</i> merozoites. Reversing the function by preincubation with recombinant antigens allowed us to quantify the contribution of MSP-1 to the antiparasitic effect of serum antibodies. Our data suggest that MSP-1, especially the partially conserved subunit MSP-1₈₃, is a major target of opsonizing antibodies acquired during natural exposure to malaria. Induction of opsonizing antibodies might be a crucial effector mechanism for MSP-1-based malaria vaccines.</p>","PeriodicalId":10271,"journal":{"name":"Clinical and Vaccine Immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1128/CVI.00155-17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35379464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heat Shock Proteins in Histoplasma and Paracoccidioides.","authors":"Levi G Cleare,&nbsp;Daniel Zamith-Miranda,&nbsp;Joshua D Nosanchuk","doi":"10.1128/CVI.00221-17","DOIUrl":"https://doi.org/10.1128/CVI.00221-17","url":null,"abstract":"<p><p>Heat shock proteins (Hsps) are highly conserved biomolecules that are constitutively expressed and generally upregulated in response to various stress conditions (biotic and abiotic). Hsps have diverse functions, categorizations, and classifications. Their adaptive expression in fungi indicates their significance in these diverse species, particularly in dimorphic pathogens. <i>Histoplasma capsulatum</i> and <i>Paracoccidioides</i> species are dimorphic fungi that are the causative agents of histoplasmosis and paracoccidioidomycosis, respectively. This minireview focuses on the pathobiology of Hsps, with particular emphasis on their roles in the morphogenesis and virulence of <i>Histoplasma</i> and <i>Paracoccidioides</i> and the potential roles of active and passive immunization against Hsps in protection against infection with these fungi.</p>","PeriodicalId":10271,"journal":{"name":"Clinical and Vaccine Immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1128/CVI.00221-17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35401716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA Priming Increases Frequency of T-Cell Responses to a Vesicular Stomatitis Virus HIV Vaccine with Specific Enhancement of CD8⁺ T-Cell Responses by Interleukin-12 Plasmid DNA.","authors":"Shuying S Li,&nbsp;Nidhi K Kochar,&nbsp;Marnie Elizaga,&nbsp;Christine M Hay,&nbsp;Gregory J Wilson,&nbsp;Kristen W Cohen,&nbsp;Stephen C De Rosa,&nbsp;Rong Xu,&nbsp;Ayuko Ota-Setlik,&nbsp;Daryl Morris,&nbsp;Greg Finak,&nbsp;Mary Allen,&nbsp;Hong-Van Tieu,&nbsp;Ian Frank,&nbsp;Magdalena E Sobieszczyk,&nbsp;Drew Hannaman,&nbsp;Raphael Gottardo,&nbsp;Peter B Gilbert,&nbsp;Georgia D Tomaras,&nbsp;Lawrence Corey,&nbsp;David K Clarke,&nbsp;Michael A Egan,&nbsp;John H Eldridge,&nbsp;M Juliana McElrath,&nbsp;Nicole Frahm","doi":"10.1128/CVI.00263-17","DOIUrl":"https://doi.org/10.1128/CVI.00263-17","url":null,"abstract":"<p><p>The HIV Vaccine Trials Network (HVTN) 087 vaccine trial assessed the effect of increasing doses of pIL-12 (interleukin-12 delivered as plasmid DNA) adjuvant on the immunogenicity of an HIV-1 multiantigen (MAG) DNA vaccine delivered by electroporation and boosted with a vaccine comprising an attenuated vesicular stomatitis virus expressing HIV-1 Gag (VSV-Gag). We randomized 100 healthy adults to receive placebo or 3 mg HIV-MAG DNA vaccine (ProfectusVax HIV-1 <i>gag</i>/<i>pol</i> or ProfectusVax <i>nef</i>/<i>tat</i>/<i>vif</i>, <i>env</i>) coadministered with pIL-12 at 0, 250, 1,000, or 1,500 μg intramuscularly by electroporation at 0, 1, and 3 months followed by intramuscular inoculation with 3.4 × 10⁷ PFU VSV-Gag vaccine at 6 months. Immune responses were assessed after the prime and boost and 6 months after the last vaccination. High-dose pIL-12 increased the magnitude of CD8⁺ T-cell responses postboost compared to no pIL-12 (<i>P</i> = 0.02), while CD4⁺ T-cell responses after the prime were higher in the absence of pIL-12 than with low- and medium-dose pIL-12 (<i>P</i> ≤ 0.05). The VSV boost increased Gag-specific CD4⁺ and CD8⁺ T-cell responses in all groups (<i>P</i> < 0.001 for CD4⁺ T cells), inducing a median of four Gag epitopes in responders. Six to 9 months after the boost, responses decreased in magnitude, but CD8⁺ T-cell response rates were maintained. The addition of a DNA prime dramatically improved responses to the VSV vaccine tested previously in the HVTN 090 trial, leading to broad epitope targeting and maintained CD8⁺ T-cell response rates at early memory. The addition of high-dose pIL-12 given with a DNA prime by electroporation and boosted with VSV-Gag increased the CD8⁺ T-cell responses but decreased the CD4⁺ responses. This approach may be advantageous in reshaping the T-cell responses to a variety of chronic infections or tumors. (This study has been registered at ClinicalTrials.gov under registration no. NCT01578889.).</p>","PeriodicalId":10271,"journal":{"name":"Clinical and Vaccine Immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1128/CVI.00263-17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35426386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}