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The CTC performs Phase I studies of candidate vaccines and also conducts natural history studies, and clinical screening protocols that help support basic research efforts and other needs of the Immunology laboratories.
Major program areas of the CTC include:
The VRC is developing a novel prime-boost HIV vaccine strategy directed at the three most globally prevalent HIV subtypes (clades). VRC's HIV prime-boost candidate is designed to elicit immune responses to HIV sequences from clades A, B, and C, which together cause nearly 90 percent of incident HIV infections around the world. In November 2002, the VRC CTC launched a Phase I clinical study (VRC 004) of a multiclade, multivalent DNA vaccine at the National Institutes of Health (NIH) Clinical Center (Bethesda, Maryland) as the first step in developing the prime-boost regimen. The DNA vaccine is the "priming" component of a prime-boost strategy. The "boost" is delivered by a replication incompetent recombinant adenovirus serotype 5 (rAd5) vector with matching gene inserts. The prime-boost concept means that the immune responses elicited by the DNA "priming" vaccine are subsequently increased by the "booster" injection with the rAd5 vaccine. VRC 004 was designed to elicit immune responses directed at the HIV Envelope proteins from clades A, B, and C, and a fusion protein combining antigens from clade B HIV Gag, Pol and Nef. This was the first multiclade, multivalent HIV DNA vaccine to enter human trials. It marked an important milestone in the search for a vaccine strategy to target the global HIV epidemic.
The initial study of the 4-plasmid DNA vaccine demonstrated that it was safe, well-tolerated and frequently induced human HIV-specific immune responses as measured by laboratory assays using peptide pools representing the vaccine antigens. In December 2003, a larger Phase I clinical trial (HVTN 052) to further evaluate safety, immune response and vaccine schedule was initiated through the NIAID Division of AIDS (DAIDS) HIV Vaccine Trials Network (HVTN) at several domestic sites. HVTN 052 completed accrual in October 2004. A third Phase I clinical trial (RV 156) of the DNA vaccine candidate opened January 2005 in Uganda and is being conducted through the Makerere University-Walter Reed Project (MUWRP) of the US Army Medical Research and Material Command (USAMRMC) and NIAID.
The first Phase I study of the rAd5 vaccine (VRC 006) was launched in July 2004 at the VRC Clinic, NIH Clinical Center. The booster vaccine developed by VRC is a multigene adenoviral vector also designed to elicit immune responses to HIV clades A, B, and C. Protocol enrollment and immunization with escalating doses of this candidate vaccine was completed in November 2004.
A Phase I evaluation of the rAd5 vector vaccine as a boost was performed as HVTN 057. In this study, which opened to accrual in November 2004, subjects who received priming vaccinations in the HVTN 052 study may choose to enroll in a Phase I study of booster vaccination with the rAd5-HIV candidate. In January 2005, VRC 009 opened to allow subjects from VRC 004 to receive a booster vaccination with the rAd5 candidate vaccine. These studies are the first opportunity to observe the safety and immunogenicity of the full multiclade, multivalent prime-boost vaccine regimen designed for prevention of HIV infection.
Refinement of the vaccine constructs continue at the VRC. A new version of the multiclade DNA vaccine (a 6-plasmid product), which is expected to be more immunogenic, has completed the vaccination phase of a Phase I study (VRC 007) at the VRC Clinic. In an unprecedented collaboration among three global networks, NIAID, USAMRMC, HVTN, and the not-for-profit International AIDS Vaccine Initiative (IAVI) are working toward the conduct of international Phase I and II studies of a VRC prime-boost HIV vaccine regimen using the 6-plasmid DNA prime and the rAd5 boost. Clinical investigation of the use of VRC's HIV vaccine candidates in HIV-infected volunteers has also been initiated through the DAIDS' Adult AIDS Clinical Trials Group (AACTG). The study ACTG 5187 is the first Phase I clinical trial of a VRC DNA vaccine candidate in HIV- infected volunteers. There are also plans at the VRC to design a future Phase I prime-boost study for HIV-infected volunteers at the VRC Clinic.
Global HIV Vaccine Development Scientific Update
Although smallpox has been eradicated for more than 25 years, the threat of bioterrorism has motivated the evaluation of new approaches to vaccination against smallpox. The CTC performed studies of modified Vaccinia Ankara (MVA) in vaccinia-naïve (VRC 201) and vaccinia-immune (VRC 203) subjects to define safety and immunogenicity, and to evaluate correlates of immune protection from a subsequent inoculation with Dryvax, the currently licensed smallpox vaccine composed of replication-competent vaccinia. MVA is an attenuated virus that was originally developed and tested in the 1960s and 1970s. It is produced in chicken cells and has very limited ability to replicate in mammalian cells. Therefore it has a good safety profile in both animals and humans. The studies were initiated between the summer of 2002 and were unblinded in April 2005.
In response to the need to develop improved influenza vaccines protective against both seasonal influenza and avian influenza strains with the potential for pandemic outbreaks, the VRC has initiated a program to develop novel vaccine approaches.
The first VRC investigational vaccine for clinical evaluation is an H5 DNA vaccine that builds on the existing VRC DNA plasmid platform technology. On December 15, 2006, the VRC received notice from the Food and Drug Administration (FDA) that the VRC Investigational New Drug (IND) application for the H5 Influenza DNA vaccine was safe to proceed for clinical study. The VRC Clinical Trials Core started its first injection within two weeks. This investigational vaccine is the first product produced entirely within the VRC Vaccine Production Program (VPP) and the first vaccine manufactured at the VRC/VPP to be taken into a Phase I clinical study.
Ebola, Marburg, Lassa, and other hemorrhagic fever viruses cause outbreaks of highly lethal disease in equatorial Africa. They are also important agents to consider in biodefense planning. Therefore, the VRC is developing a vaccine platform for Ebola viruses that may then be applied to other viruses with a similar pathogenesis. As in HIV, there are two components in the vaccine concept. DNA expressing the glycoproteins (GP) from the Sudan/Gulu and Zaire strains, and the nucleoprotein (N) from Zaire, is one component, and a recombinant Adenovirus vector combination is the second component. The DNA vaccine has been evaluated in a placebo-controlled, randomized, dose escalation Phase I trial (VRC 204) initiated in November 2003 by the VRC CTC in the NIH Clinical Center.
Ebola/Marburg Vaccine Development Scientific Update
The SARS coronavirus (CoV) appeared suddenly in the spring of 2003 as an epidemic respiratory disease with a high mortality rate. The virus was identified and sequenced with unprecedented speed, and a globally coordinated public health effort contained the spread of infection. The potential for this type of virus to cause a global pandemic motivated the rapid development of candidate vaccines. Based on the available sequence data, the VRC developed a DNA vaccine that expresses a modified version of the gene encoding the spike (S) glycoprotein and showed that it was immunogenic and efficacious in available animal models. A Phase I trial (VRC 301) was initiated in December 2004, 19 months after the sequence was known, to evaluate the SARS CoV candidate vaccine.
West Nile virus entered the United States in 1999 and rapidly spread from the East Coast to all 48 continental states by 2004. It causes an encephalitis in a subset of infected persons associated with a significant mortality rate, particularly in the elderly. The VRC has developed a candidate vaccine based on the DNA platform technology. A Phase I trial (VRC 302) started in April 2005 to evaluate this product that expresses the genes from two envelope proteins from the virus, M and E, in a single plasmid.
The VRC CTC can perform Phase I clinical trials, but advanced product development and larger clinical trials require partnership with extramural clinical trial networks and industry. The CTC is very involved in the development and maintenance of relationships with these critical partners, and plays an important role in the preparation, conduct, oversight, and interpretation of extramural clinical trials.
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Last Updated May 17, 2010