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Now showing items 1 - 16 of 248

  • Broadly Neutralizing Antibodies for HIV Prevention

    Karuna, Shelly T.   Corey, Lawrence  

    In the last decade, over a dozen potent broadly neutralizing antibodies (bnAbs) to several HIV envelope protein epitopes have been identified, and their in vitro neutralization profiles have been defined. Many have demonstrated prevention efficacy in preclinical trials and favorable safety and pharmacokinetic profiles in early human clinical trials. The first human prevention efficacy trials using 10 sequential, every-two-month administrations of a single anti-HIV bnAb are anticipated to conclude in 2020. Combinations of complementary bnAbs and multi-specific bnAbs exhibit improved breadth and potency over most individual antibodies and are entering advanced clinical development. Genetic engineering of the Fc regions has markedly improved bnAb half-life, increased mucosal tissue concentrations of antibodies (especially in the genital tract), and enhanced immunomodulatory and Fc effector functionality, all of which improve antibodies' preventative and therapeutic potential. Human-derived monoclonal antibodies are likely to enter the realm of primary care prevention and therapy for viral infections in the near future.
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  • A strategic approach to COVID-19 vaccine R&D

    Corey, Lawrence   Mascola, John R.   Fauci, Anthony S.   Collins, Francis S.  

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  • The aspirational necessity of HIV prevention

    Corey, Lawrence   Gray, Glenda E.   Buchbinder, Susan P.  

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  • Combination prevention for COVID-19.

    Cohen, Myron S   Corey, Lawrence  

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  • Valganciclovir for the Suppression of Epstein-Barr Virus Replication

    Yager, Jessica E.   Magaret, Amalia S.   Kuntz, Steven R.   Selke, Stacy   Huang, Meei-Li   Corey, Lawrence   Casper, Corey   Wald, Anna  

    Epstein-Barr virus (EBV) causes infectious mononucleosis and can lead to lymphoproliferative diseases. We evaluated the effects of valganciclovir on oral EBV shedding in a randomized, double-blind, placebo-controlled study. Twenty-six men received oral valganciclovir or daily placebo for 8 weeks, followed by a 2-week "washout period" and then 8 weeks of the alternative treatment. Valganciclovir reduced the proportion of days with EBV detected from 61.3% to 17.8% (relative risk, 0.28; 95% confidence interval [CI], .21-.41; P < .001), and quantity of virus detected by 0.77 logs (95% CI, .62-.91 logs; P < .001). Further investigations into the impact of valganciclovir on EBV-associated diseases are needed.
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  • Immune correlates of the Thai RV144 HIV vaccine regimen in South Africa

    Gray, Glenda E.   Huang, Ying   Grunenberg, Nicole   Laher, Fatima   Roux, Surita   Andersen-Nissen, Erica   De Rosa, Stephen C.   Flach, Britta   Randhawa, April K.   Jensen, Ryan   Swann, Edith M.   Bekker, Linda-Gail   Innes, Craig   Lazarus, Erica   Morris, Lynn   Mkhize, Nonhlanhla N.   Ferrari, Guido   Montefiori, David C.   Shen, Xiaoying   Sawant, Sheetal   Yates, Nicole   Hural, John   Isaacs, Abby   Phogat, Sanjay   DiazGranados, Carlos A.   Lee, Carter   Sinangil, Faruk   Michael, Nelson L.   Robb, Merlin L.   Kublin, James G.   Gilbert, Peter B.   McElrath, M. Juliana   Tomaras, Georgia D.   Corey, Lawrence  

    One of the most successful HIV vaccines to date, the RV144 vaccine tested in Thailand, demonstrated correlates of protection including cross-clade V1V2 immunoglobulin G (IgG) breadth, Env-specific CD4(+) T cell polyfunctionality, and antibody-dependent cellular cytotoxicity (ADCC) in vaccinees with low IgA binding. The HIV Vaccine Trials Network (HVTN) 097 trial evaluated this vaccine regimen in South Africa, where clade C HIV-1 predominates. We compared cellular and humoral responses at peak and durability immunogenicity time points in HVTN 097 and RV144 vaccinee samples, and evaluated vaccine-matched and cross-clade immune responses. At peak immunogenicity, HVTN 097 vaccinees exhibited significantly higher cellular and humoral immune responses than RV144 vaccinees. CD4(+) T cell responses were more frequent in HVTN 097 irrespective of age and sex, and CD4+ T cell Env-specific functionality scores were higher in HVTN 097. Env-specific CD40L(+) CD4(+) T cells were more common in HVTN 097, with individuals having this pattern of expression demonstrating higher median antibody responses to HIV-1 Env. IgG and IgG3 binding antibody rates and response magnitude to gp120 vaccine- and V1V2 vaccine-matched antigens were higher or comparable in HVTN 097 than in RV144 ADCC, and ADCP functional antibody responses were elicited in HVTN 097. Env-specific IgG and CD4(+) Env responses declined significantly over time in both trials. Overall, cross-clade immune responses associated with protection were better than expected in South Africa, suggesting wider applicability of this regimen.
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  • Reevaluating HIV Vaccine Clinical Trials Policy for Infants

    Corey, Lawrence  

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  • Immune correlates of vaccine protection against HIV-1 acquisition.

    Corey, Lawrence   Gilbert, Peter B   Tomaras, Georgia D   Haynes, Barton F   Pantaleo, Giuseppe   Fauci, Anthony S  

    The partial efficacy reported in the RV144 HIV vaccine trial in 2009 has driven the HIV vaccine field to define correlates of risk associated with HIV-1 acquisition and connect these functionally to preventing HIV infection. Immunological correlates, mainly including CD4(+) T cell responses to the HIV envelope and Fc-mediated antibody effector function, have been connected to reduced acquisition. These immunological correlates place immunological and genetic pressure on the virus. Indeed, antibodies directed at conserved regions of the V1V2 loop and antibodies that mediate antibody-dependent cellular cytotoxicity to HIV envelope in the absence of inhibiting serum immunoglobulin A antibodies correlated with decreased HIV risk. More recently, researchers have expanded their search with nonhuman primate studies using vaccine regimens that differ from that used in RV144; these studies indicate that non-neutralizing antibodies are associated with protection from experimental lentivirus challenge as well. These immunological correlates have provided the basis for the design of a next generation of vaccine regimens to improve upon the qualitative and quantitative degree of magnitude of these immune responses on HIV acquisition. Copyright =C2=A9 2015, American Association for the Advancement of Science.
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  • Use of placebos in Phase 1 preventive HIV vaccine clinical trials.

    Huang, Yunda   Karuna, Shelly T   Janes, Holly   Frahm, Nicole   Nason, Martha   Edlefsen, Paul T   Kublin, James G   Corey, Lawrence   McElrath, M Juliana   Gilbert, Peter B  

    Phase 1 preventive HIV vaccine trials are often designed as randomized, double-blind studies with the inclusion of placebo recipients. Careful consideration is needed to determine when the inclusion of placebo recipients is highly advantageous and when it is optional for achieving the study objectives of assessing vaccine safety, tolerability and immunogenicity. The inclusion of placebo recipients is generally important to form a reference group that ensures fair evaluation and interpretation of subjective study endpoints, or endpoints whose levels may change due to exposures besides vaccination. In some settings, however, placebo recipients are less important because other data sources and tools are available to achieve the study objectives. Copyright =C2=A9 2014 Elsevier Ltd. All rights reserved.
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  • Preventing acquisition of HIV is the only path to an AIDS-free generation

    Corey, Lawrence   Gray, Glenda E.  

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  • Selection of HIV vaccine candidates for concurrent testing in an efficacy trial

    DiazGranados, Carlos   Janes, Holly   Huang, Yunda   deCamp, Allan C.   Metch, Barbara   Grant, Shannon   Sanchez, Brittany   Phogat, Sanjay   Koutsoukos, Marguerite   Kanesa-Thasan, Niranjan   Bourguignon, Patricia   Collard, Alix   Buchbinder, Susan   Tomaras, Georgia D.   McElrath, Julie   Gray, Glenda   Kublin, James G.   Corey, Lawrence  

    Phase IIb or III HIV-1 vaccine efficacy trials are generally large and operationally challenging. To mitigate this challenge, the HIV Vaccine Trials Network is designing a Phase IIb efficacy trial accommodating the evaluation of multiple vaccine regimens concurrently. As this efficacy trial would evaluate a limited number of vaccine regimens, there is a need to develop a framework for optimizing the strategic selection of regimens from the large number of vaccine candidates tested in Phase I/IIa trials. In this paper we describe the approaches for the selection process, including the choice of immune response endpoints and the statistical criteria and algorithms. We illustrate the selection approaches using data from HIV-1 vaccine trials.
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  • Image analysis for accurately counting CD4+ and CD8+ T cells in human tissue.

    Diem, Kurt   Magaret, Amalia   Klock, Alexis   Jin, Lei   Zhu, Jia   Corey, Lawrence  

    In situ detection of specific cells offers a unique perspective on the spatial interactions between host immune cells and specific viral pathogens or cancers. Most immunohistochemistry techniques require manual cell counting on biopsied and fixed tissue sections. The availability of sophisticated software packages for analyzing fluorescently labeled tissue has made it possible to quickly and accurately quantitate the number of positive cells on such slides. Manual cell counting was compared to automatic cell counting using the program CellProfiler. The two techniques were used to count CD4+ and CD8+ T cells in human genital skin biopsies from herpesvirus type 2 (HSV-2) infected subjects. Manual counting and CellProfiler demonstrated high correlation both in cell counting as well as detection of immune cell "clustering" in tissue, an important visceral component of localized inflammation and characteristic of most chronic infections. Overall, CellProfiler is an effective and accurate method in addition to or replacement of manual cell counting of fluorescently labeled biopsies. Copyright =C2=A9 2015 Elsevier B.V. All rights reserved.
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  • Human Immunodeficiency Virus Vaccine Trials

    O'Connell, Robert J.   Kim, Jerome H.   Corey, Lawrence   Michael, Nelson L.  

    More than 2 million AIDS-related deaths occurred globally in 2008, and more than 33 million people are living with HIV/AIDS. Despite promising advances in prevention, an estimated 2.7 million new HIV infections occurred in that year, so that for every two patients placed on combination antiretroviral treatment, five people became infected. The pandemic poses a formidable challenge to the development, progress, and stability of global society 30 years after it was recognized. Experimental preventive HIV-1 vaccines have been administered to more than 44,000 human volunteers in more than 187 separate trials since 1987. Only five candidate vaccine strategies have been advanced to efficacy testing. The recombinant glycoprotein (rgp) 120 subunit vaccines, AIDSVAX B/B and AIDSVAX B/E, and the Merck Adenovirus serotype (Ad) 5 viral-vector expressing HIV-1 Gag, Pol, and Nef failed to show a reduction in infection rate or lowering of postinfection viral set point. Most recently, a phase III trial that tested a heterologous prime-boost vaccine combination of ALVAC-HIV vCP1521 and bivalent rgp120 (AIDSVAX B/E) showed 31% efficacy in protection from infection among community-risk Thai participants. A fifth efficacy trial testing a DNA/recombinant(r) Ad5 prime-boost combination is currently under way. We review the clinical trials of HIV vaccines that have provided insight into human immunogenicity or efficacy in preventing HIV-1 infection.
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  • Frequent genital HSV-2 shedding among women during labor in Soweto, South Africa.

    Perti, Tara   Nyati, Mandisa   Gray, Glenda   De Bruyn, Guy   Selke, Stacy   Magaret, Amalia   Huang, Meei-Li   Velaphi, Sithembiso   Corey, Lawrence   Wald, Anna  

    BACKGROUND: Despite high herpes simplex virus type 2 (HSV-2) incidence and prevalence among women in Africa, we are unaware of published neonatal herpes reports. To assess neonatal HSV transmission potential in South Africa, we investigated the frequency of the strongest risk factors: HSV acquisition in late pregnancy and HSV shedding during labor.; METHODS: Women admitted in early labor to a hospital in Soweto underwent HSV serologic testing and genital swab collection for HSV PCR. HSV-2 seronegative women were assessed for seroconversion 4-6 weeks after delivery.; RESULTS: Of 390 women enrolled, 229 (58.7%) were HSV-2 seropositive. Genital HSV-2 was detected in 17.2% of HSV-2 seropositive women, including 26 of 115 HIV-positive and 13 of 110 HIV-negative women (22.6% versus 11.8%; RR, 1.91; 95% CI, 1.04-3.53; P =3D 0.038), but in none of 161 HSV-2 seronegative women. Among the 91 HSV-2 seronegative women followed after delivery, none seroconverted.; CONCLUSIONS: HSV-2 reactivation is common among South African women during labor, especially those with HIV coinfection. To determine the epidemiology of neonatal herpes in South Africa and to investigate whether the lack of reported cases is due to alterations in immune control or HSV-2 virulence, studies evaluating acutely ill neonates for HSV and studies of maternal HSV-2 shedding patterns are needed.=20
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  • Fighting a defiant virus

    Schiffer, Joshua T.   Scott, John   Corey, Lawrence  

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  • HIV-1 Vaccines and Adaptive Trial Designs

    Corey, Lawrence   Nabel, Gary J.   Dieffenbach, Carl   Gilbert, Peter   Haynes, Barton F.   Johnston, Margaret   Kublin, James   Lane, H. Clifford   Pantaleo, Giuseppe   Picker, Louis J.   Fauci, Anthony S.  

    Developing a vaccine against the human immunodeciency virus (HIV) poses an exceptional challenge. There are no documented cases of immune-mediated clearance of HIV from an infected individual, and no known correlates of immune protection. Although nonhuman primate models of lentivirus infection have provided valuable data about HIV pathogenesis, such models do not predict HIV vaccine efficacy in humans. The combined lack of a predictive animal model and undefined biomarkers of immune protection against HIV necessitate that vaccines to this pathogen be tested directly in clinical trials. Adaptive clinical trial designs can accelerate vaccine development by rapidly screening out poor vaccines while extending the evaluation of efficacious ones, improving the characterization of promising vaccine candidates and the identification of correlates of immune protection.
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