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48-495: McElrath has built and maintains an international HIV vaccine laboratory, contributing to the fundamental understanding of how HIV-1 – the most common and pathogenic strain of the virus – enters the mucosa to infect people. Her work centers on developing an HIV vaccine and investigating the complex relationship between HIV and the immune system . She is supported in part by the National Institutes of Health and

96-652: A Phase I trial called HVTN 100 in South Africa tested the combination of a canarypox vector ALVAC and a gp120 protein adapted for the subtype C HIV common in sub-Saharan Africa, with the MF59 adjuvant. Those who received the vaccine regimen produced strong immune responses early on and the regimen was safe. Other strategies that have progressed to phase I trials in uninfected persons include peptides, lipopeptides , DNA , an attenuated Salmonella vector, p24, etc. Specifically, candidate vaccines that induce one or more of

144-511: A decade without antiretroviral treatment, and people repeatedly exposed but not infected. These clinical cohorts have been assembled for longitudinal studies in both Seattle and in two nations where the HIV epidemic is widespread – South Africa and Uganda . On Dec. 1, 2015, the work of McElrath and HTVN scientists pursuing a vaccine to potentially halt HIV and AIDS will be highlighted in an HBO/VICE special report titled "Countdown to Zero." McElrath

192-564: A good safety profile and elicited antibodies to HIV-1. According to Dr. Chil-Yong Kang of Western University 's Schulich School of Medicine & Dentistry in Canada, the developer of this vaccine, antibodies against gp120 and p24 increased to 8-fold and 64-fold, respectively after vaccination. The VRC01 line of research produced an "eOD-GT8" antigen which specifically exposes the CD4 binding site for immunization, refined over time to expose less of

240-543: A non-virulent live attenuated HIV-1 vaccine. For example, a genetically modified form of HIV has been created in which the virus's codons (a sequence of three nucleotides that form genetic code) are manipulated to rely on an unnatural amino acid for proper protein translation, which allows it to replicate. Because this amino acid is foreign to the human body, the virus cannot reproduce. Recent evidence suggests using universal CAR NK cells against HIV HIV Vaccine Trials Network The HIV Vaccine Trials Network (HVTN)

288-425: A reliable antibody response has led to the attempts to develop a vaccine that stimulates a response by cytotoxic T-lymphocytes . Another response to the challenge has been to create a single peptide that contains the least variable components of all the known HIV strains. It had been observed that a few, but not all, HIV-infected individuals naturally produce broadly neutralizing antibodies (BNAbs) which keep

336-680: A therapeutic vaccine called Tat Oyi, which targets the tat protein of HIV. It was tested in France in a double-blind Phase I/II trial with 48 HIV-positive patients who had reached viral suppression on Highly Active Antiretroviral Therapy and then stopped antiretrovirals after getting the intradermal Tat Oyi vaccine. Preventive HIV vaccines There have been no passive preventive HIV vaccines to reach Phase III yet, but some active preventive HIV vaccine candidates have entered Phase III. Therapeutic HIV vaccines No therapeutic HIV vaccine candidates have reached phase 3 testing yet. A July 2012 report of

384-441: Is a non-profit organization which connects physicians and scientists with activists and community educators for the purpose of conducting clinical trials seeking a safe and effective HIV vaccine . Collaboratively, researchers and laypeople review potential vaccines for safety, immune response , and efficacy. The HVTN is a network for testing vaccines, and while its members may also work in vaccine development for other entities,

432-887: Is a member of the Association of American Physicians , American College of Physicians and the Infectious Diseases Society of America . She is a past recipient of the Burroughs Wellcome Clinical Scientist Award in Translational Research, a National Institutes of Health Merit Award, and the GAIA Vaccine Foundation Award. She serves on numerous scientific advisory committees and boards for institutions, government and industry. HIV vaccine development An HIV vaccine

480-888: Is a new animal model strongly resembling that of HIV in humans. Generalized immune activation as a direct result of activated CD4+ T cell killing - performed in mice allows new ways of testing HIV behaviour. NIAID -funded SIV research has shown that challenging monkeys with a cytomegalovirus (CMV)-based SIV vaccine results in containment of virus. Typically, virus replication and dissemination occurs within days after infection, whereas vaccine-induced T cell activation and recruitment to sites of viral replication take weeks. Researchers hypothesized that vaccines designed to maintain activated effector memory T cells might impair viral replication at its earliest stage. Specific vaccines may also need specialized animal models. For example, vaccines designed to produce VRC01-type antibodies require human-like V H alleles to be present. For organisms like mice,

528-445: Is a potential vaccine that could be either a preventive vaccine or a therapeutic vaccine , which means it would either protect individuals from being infected with HIV or treat HIV-infected individuals. It is thought that an HIV vaccine could either induce an immune response against HIV (active vaccination approach) or consist of preformed antibodies against HIV (passive vaccination approach). Two active vaccine regimens, studied in

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576-416: Is a protein on the HIV surface that enables to infect cells. Env extends from the surface of the HIV virus particle. The spike-shaped protein is "trimeric" — with 3 identical molecules, each with a cap-like region called glycoprotein 120 (gp120) and a stem called glycoprotein 41 (gp41) that anchors Env in the viral membrane. Only the functional portions of Env remain constant, but these are generally hidden from

624-723: Is an attending physician at Harborview Medical Center, the University of Washington Medical Center , and Seattle Cancer Care Alliance, the treatment arm of Fred Hutch. She has published nearly 300 papers in peer-reviewed journals, the majority on HIV/AIDS. In 2007, she co-founded the Vaccine Infectious Disease Institute at Fred Hutch and has served as the sole director of the Vaccine and Infectious Disease Division at Fred Hutch since 2011. McElrath's scientific interests include investigations to understand

672-407: Is confirmed safe and effective. On January 17, 2022 IAVI and Moderna launched a phase I trial of a HIV vaccine with mRNA technology. On March 14, 2022 the National Institutes of Health reported that it had launched a "clinical trial of three mRNA HIV vaccines". The phase one trial is expected to conclude July 2023. Preventive HIV vaccines Therapeutic HIV vaccines Biosantech developed

720-634: Is headquartered at the Fred Hutchinson Cancer Research Center in Seattle . The vaccines being tested come from various producers, both commercial and non-profit. Typically, researchers conduct clinical research on human subjects by asking volunteers to give informed consent to participate in an experiment by taking drugs that have not always been proven safe or effective in humans, though their safety has been tested (usually in animals) prior to any human trials. At

768-442: Is induced both in natural infection and by immunization. McElrath and her team also are working to identify the properties of T cells that confer containment or eradication of HIV-1. Their studies span a wide array of immunologic investigations in persons who experience unusual control of HIV-1 infection, including individuals with newly diagnosed infection, those with long-term non-progressive disease who control infection for more than

816-647: The Bill & Melinda Gates Foundation . McElrath obtained a B.S. in biology from Furman University , a Ph.D. in pathology, and an M.D. from the Medical University of South Carolina . After completing her residency in internal medicine, she received her clinical fellowship training in infectious diseases at Columbia Presbyterian Medical Center in New York and her post-doctoral training in molecular immunology at Rockefeller University in New York. During

864-661: The Henry M. Jackson Foundation for the Advancement of Military Medicine to make a pivotal discovery. For the first time, they pinpointed "immune correlates" that were associated with reduced HIV risk. One of their key findings suggested the vaccines might spur some recipients to make antibodies that prevent HIV infection. McElrath's quest to develop an HIV vaccine spurred her effort to launch a new immunology lab Cape Town , South Africa. That facility opened its doors in 2013. In addition to her work with HVTN and at Fred Hutch, McElrath

912-573: The RV 144 and Imbokodo trials, showed they can prevent HIV in some individuals; however, the protection was in relatively few individuals, and was not long lasting. For these reasons, no HIV vaccines have been licensed for the market yet. In 1984, after it was confirmed that HIV caused AIDS, the United States Health and Human Services Secretary Margaret Heckler declared that a vaccine would be available within two years. However, priming

960-655: The adaptive immune system to recognize the viral envelope proteins did not prevent HIV acquisition. Many factors make the development of an HIV vaccine different from other classic vaccines (as of 1996): The epitopes of the viral envelope are more variable than those of many other viruses. Furthermore, the functionally important epitopes of the gp120 protein are masked by glycosylation , trimerisation and receptor-induced conformational changes making it difficult to block with neutralizing antibodies. The ineffectiveness of previously developed vaccines primarily stems from two related factors: The difficulties in stimulating

1008-621: The Env structure. The study appeared on October 23, 2013, in Nature Structural and Molecular Biology . The typical animal model for vaccine research is the monkey, often the macaque . Monkeys can be infected with SIV or the chimeric SHIV for research purposes. However, the well-proven route of trying to induce neutralizing antibodies by vaccination has stalled because of the great difficulty in stimulating antibodies that neutralise heterologous primary HIV isolates. Some vaccines based on

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1056-524: The HIV Vaccines & Microbicides Resource Tracking Working Group estimates that $ 845 million was invested in HIV vaccine research in 2011. Economic issues with developing an HIV vaccine include the need for advance purchase commitment (or advance market commitments ) because after an AIDS vaccine has been developed, governments and NGOs may be able to bid the price down to marginal cost . Theoretically, any possible HIV vaccine must inhibit or stop

1104-639: The HIV virion replication cycle. The targets of a vaccine could be the following stages of the HIV virion cycle: Therefore, the following list comprises the current possible approaches for an HIV vaccine: Here, "damage" means inhibiting or stopping the ability of virion to process any of the Phase II-VII . Here are the different classification of methods: Inhibiting the life functions of infected cells: There have been reports that HIV patients coinfected with GB virus C (GBV-C), also called hepatitis G virus, can survive longer than those without GBV-C, but

1152-604: The HVTN, many current vaccine studies are using products with a safety record that has been established in previous human trials. The Nuremberg Code , the Declaration of Helsinki , and the Belmont Report are legal documents written in layman's terms which local governments use to model their laws for establishing rules for conducting clinical trials, and all contemporary clinical trials of international worth follow all

1200-566: The University of Washington. In 2000, while driving through villages in the coastal areas near Durban , South Africa , she saw the tangible toll of the AIDS epidemic. Elderly women were cradling crying babies and teenagers were tending to children – the orphaned survivors of a decimated generation, she recalled in an interview. At the same time, a large percentage of people in the region also were known to be infected with HIV. She later described

1248-444: The absence of virus replication. Target cell proliferation and oligoclonal expansion are induced by the virus, which suggests repressed immunity seen in mice thus referred to as paraneoplastic syndrome. This is further supported by the good response(s) of MAIDS mice to antineoplastic agents. This animal model is useful in demonstrating the emergence of novel hypotheses about AIDS, including the roles of defective HIV and HIV replication in

1296-626: The difference is that the IRB consists of a professional ethics committee and the CAB consists of any community member who wants to supervise the safety, ethics, efficacy, or any other aspect of the research. The researchers of the HVTN deemed the creation of the CAB necessary for HIV vaccine research when it has not been necessary for other clinical research because the HIV epidemic is especially urgent, new research techniques are available now that did not exist before recent major advances in genetic engineering ,

1344-564: The director of the HIV Vaccine Trials Network (HTVN) Laboratory Center. Headquartered at Fred Hutch, HVTN is the world's largest network dedicated to testing vaccines designed to prevent HIV. The finding launched a push to better understand how the trial vaccines prevented HIV and how they could be improved. That initiative became a major focus of the HVTN's lab program, headed by McElrath. The Thai trial led McElrath, her colleagues and collaborators at Duke University and

1392-471: The early 1980s, while working as a medical resident in the city of Charleston , South Carolina, McElrath became inspired to research HIV/AIDS after caring for many young patients who were dying from a mysterious illness that, ultimately, was identified as acquired immune deficiency syndrome, or AIDS. This desire became more urgent as she focused on infectious diseases in New York City . In 1988, she

1440-684: The following are being sought: In 2011, researchers in National Biotech Centre in Madrid unveiled data from the Phase I clinical trial of their new vaccine, MVA-B . The vaccine induced an immunological response in 92% of the healthy subjects. In 2016, results were published of the first Phase I human clinical trial of a killed whole-HIV-1 vaccine, SAV001 . HIV used in the vaccine was chemically and physically deadened through radiation. The trial, conducted in Canada in 2012, demonstrated

1488-523: The human allele must be inserted into their genome to produce a useful mimic. Murines are also experimental animals in AIDS and also murine AIDS and human AIDS are similar. Immunological analysis and genetic studies reveal resistant gene(s) in the H-2 complex of mice, an indication that genetic differences in mice could modify features of HIV disease. The defective murine leukemia virus is the major etiologic agent of MAIDS, which seems to be able to induce disease in

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1536-413: The human immune responses that control and prevent HIV-1 infection by using multi-disciplinary and cross-platform approaches. She continues to be involved in a global initiative to develop an HIV-1 vaccine, and in research to identify innate and mucosal immune defenses generated following vaccination. McElrath has taken a leadership role or has been a significant contributor to numerous integrated programs at

1584-483: The immune system by the molecule's structure. X-ray analyses and low-resolution electron microscopy have revealed the overall architecture and some critical features of Env. But higher resolution imaging of the overall protein structure has been elusive because of its complex, delicate structure. Three new papers use stabilized forms of Env to gain a clearer picture of the intact trimer. An NCI research team led by Dr. Sriram Subramaniam used cryo-electron microscopy to examine

1632-451: The latter is generally more difficult to produce and did not initially offer any clear advantage over gp120 forms. Overall, they have been safe and immunogenic in diverse populations, have induced neutralizing antibody in nearly 100% recipients, but rarely induced CD8+ cytotoxic T lymphocytes (CTL). Mammalian derived envelope preparations have been better inducers of neutralizing antibody than candidates produced in yeast and bacteria. Although

1680-695: The mission of the HVTN does not include vaccine design. The HVTN is the only HIV vaccine research network sponsored by the American government. It also manages the only large-scale HIV vaccine research trial network in Africa. The HVTN collaborates with the Division of Acquired Immunodeficiency Syndrome (DAIDS). Funding comes from the National Institute of Allergy and Infectious Diseases and National Institutes of Health , which oversee DAIDS. HVTN

1728-757: The national and international level to advance a coordinated effort to curb the HIV epidemic through prevention efforts. Those include: the HIV Vaccine Trials Network , the Gates Foundation Innate Immunity Consortium (PI), the Microbicide Trials Network (Director, Immunology Core), and the Seattle Vaccine Trials Unit (PI). At the McElrath Laboratory at Fred Hutch, a primary goal is to determine how T cell memory

1776-399: The other sites. As it turns out that most (but not all) humans do have the required alleles, the problem shifted to the method of delivery. In 2021, after promising results in tests with mice and primates, scientists announced that they plan to conduct a Phase 1 trial of an mRNA vaccine against HIV if a further developed (via their 'env–gag VLP mRNA platform' which contains eOD-GT8 ) vaccine

1824-454: The patients may be different in other ways. GBV-C is potentially useful in the future development of an HIV vaccine. Live attenuated vaccines are highly successful against polio, rotavirus and measles, but have not been tested against HIV in humans. Reversion to live virus has been a theoretical safety concern that has to date prevented clinical development of a live attenuated HIV-1 vaccine. Scientists are researching novel strategies to develop

1872-487: The pattern of recognition was not uniform among volunteers. The canarypox vector is the first candidate HIV vaccine that has induced cross-clade functional CTL responses. The first phase I trial of the candidate vaccine in Africa was launched early in 1999 with Ugandan volunteers. The study determined the extent to which Ugandan volunteers have CTL that are active against the subtypes of HIV prevalent in Uganda, A and D. In 2015,

1920-411: The percent of volunteers that have detectable CTL to a greater extent than did increase the dose of the viral vector. CTLs from volunteers were able to kill peripheral blood mononuclear cells infected with primary isolates of HIV, suggesting that induced CTLs could have biological significance. Besides, cells from at least some volunteers were able to kill cells infected with HIV from other clades, though

1968-642: The progression of the disease, and also the importance of identifying the HIV targeted cells in vivo. Several vaccine candidates are in varying phases of clinical trials . Most initial approaches have focused on the HIV envelope protein. At least thirteen different gp120 and gp160 envelope candidates have been evaluated, in the US predominantly through the AIDS Vaccine Evaluation Group. Most research focused on gp120 rather than gp41/gp160, as

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2016-458: The public is generally overly-willing to volunteer to receive experimental vaccines for this cause, and yet the educational infrastructure already in place to disseminate information about the inherent risk in participating in vaccine research is lacking in society. For too many reasons, there is no precedent for research of this sort on this scale, and without integrating educational programs about this research into existing community institutions,

2064-415: The rules set by these precedents. However, HIV vaccine research requires more than just these protections, and because of this, from the inception of their research the HVTN has instituted a "community advisory board" (CAB) system in addition to the usual controls. The CAB is similar to an Institutional Review Board (IRB) in that the researchers facilitate the granting of public data to both entities, but

2112-465: The situation as "terribly sobering." In 1996, McElrath joined the faculty at Fred Hutchinson Cancer Research Center , bringing her work toward an HIV vaccine to the center. She was honored for her research with an NIH Merit Award and served as associate editor of the Journal of Infectious Diseases. Over time, she became a full professor at the University of Washington, a full member at Fred Hutch, and

2160-467: The vaccination process involved many repeated " booster " injections, it was challenging to induce and maintain the high anti-gp120 antibody titers necessary to have any hope of neutralizing an HIV exposure. The availability of several recombinant canarypox vectors has provided interesting results that may prove to be generalizable to other viral vectors . Increasing the complexity of the canarypox vectors by including more genes/epitopes has increased

2208-401: The virus envelope have protected chimpanzees or macaques from homologous virus challenge, but in clinical trials, humans who were immunised with similar constructs became infected after later exposure to HIV-1. There are some differences between SIV and HIV that may introduce challenges in the use of an animal model. The animal model can be extremely useful but at times controversial. There

2256-485: The virus suppressed, and these people remain asymptomatic for decades . Since the 2010s a core candidate is VRC01 and similar BNAbs, as they have been found in multiple unrelated people. These antibodies mimic CD4 and compete for the conserved CD4 binding site. These antibodies all share a germline origin in the V H chain , where only a few human alleles of the IVIG1-2 gene are able to produce such an antibody. Env

2304-567: Was named an assistant professor at Rockefeller University. In 1990, McElrath relocated to Seattle to take a position at the University of Washington as an assistant professor and to direct the HIV AIDS Madison Clinic at Harborview Medical Center . Within two years, she shifted her focus back to the bench to pursue the path to an HIV vaccine. She became the director of the AIDS Vaccine Evaluation Unit at

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