The primary mission of the VRC Clinical Trials Core (CTC) is to evaluate candidate HIV vaccines in Phase I clinical trials. A secondary mission is to evaluate candidate vaccines for biodefense and emerging infectious diseases. The goals of the CTC are to:

1. Advance promising vaccine candidates into human trials
2. Optimize volunteer safety, confidentiality, knowledge, and convenience
3. Maintain Good Clinical Practice standards exceeding requirements mandated in 21 CFR part 11, including compliance with all regulatory agencies and committees as outlined in 45 CFR part 46
4. Design protocols that achieve clinical development objectives in a scientifically rigorous and time efficient manner
5. Organize the operational aspects of clinical protocols to optimize volunteer safety and minimize length of study
6. Collect and maintain high quality clinical data
7. Collect and distribute high quality clinical samples
8. Collect demographic, behavioral, and marketing data to inform recruitment efforts
9. Perform integrated analyses of clinical and immunological data, and prepare clinical trial data for presentation and publication
10. Provide community education and support to local organizations
11. Provide guidance and assistance to other groups involved in vaccine evaluation
12. Interface internally with VRC production, regulatory, administrative, and laboratory groups, and externally with extramural NIAID, clinical trial networks, regulatory agencies, international organizations, and industry partners to achieve efficient transitions through each stage of the clinical development process
13. Train physician-scientists in the science of vaccinology
14. Conduct clinical trials of therapeutic immunization using preventive vaccine candidates.

The VRC CTC is organized into three major sections: 1) protocol development and management, 2) recruitment and outreach, and 3) clinical operations. The sections are interdependent and work in harmony to accomplish all the tasks required to complete the clinical trials. 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. The major project areas are outlined below.

HIV Vaccine Development. The VRC, NIAID 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 l aunched a Phase I clinical study (VRC 004) of a multiclade, multivalent DNA vaccine at the NIH Clinical Center (Bethesda, MD) 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 way 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 between three global networks, NIAID, USAMRMC, HVTN and the not-for- profit International AIDS Vaccine Initiative (IAVI) are working toward the conduct ofinternational Phase I and II studies of a VRC prime-boost HIV vaccine regimen using the 6-plasmid DNA prime and the rAd5 boost later in 2005.

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.

Alternative smallpox vaccine evaluation. 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.

Ebola vaccine development. 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.

SARS vaccine development. 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 vaccine development. West Nile virus entered the U.S. 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.

Advanced Product Development. The VRC CTC can perform Phase I clinical trials, but advanced product development and larger clinical trials requires 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.

Selected References

Graham BS, Karzon DT. Development of an AIDS vaccine: Biological and ethical challenges. Infect Dis Clin N Am 1990; 4(2):223-243.

Dolin R, Graham BS, Greenberg SB, Tackett CO, Belshe RB, Midthun K, Clements ML, Gorse GJ, Horgan BW, Atmar RL, Karzon DT, Bonnez W, Fernie BF, Montefiori DC, Stablein DM, Smith GE, Koff WC, and the NIAID AIDS Vaccine Clinical Trials Network: Safety and immunogenicity of an HIV-1 recombinant gp160 candidate vaccine in humans. Ann Intern Med 1991; 114:119-127.

Graham BS, Belshe RB, Clements ML, Dolin R, Corey L, Wright PF, Gorse GJ, Midthun K, Keefer MC, Roberts NJ, Jr, Schwartz DH, Agosti JM, Fernie BF, Stablein DM, Montefiori DC, Lambert JS, Hu S-L, Esterlitz JR, Lawrence D, Koff WC, and the AIDS Vaccine Clinical Trials Network. Vaccination of vaccinia-naive adults with HIV-1 gp160 recombinant vaccinia virus in a blinded, controlled, randomized clinical trial. J Infect Dis 1992; 166:244-252.

Graham BS, Matthews TJ, Belshe RB, Clements ML, Dolin R, Wright PF, Gorse GJ, Schwartz DH, Keefer MC, Bolognesi DP, Corey L, Stablein DM, Esterlitz JR, Hu S-L, Smith G, Fast P, Koff WC, and the AIDS Vaccine Clinical Trials Network. Augmentation of human immunodeficiency virus type 1 neutralizing antibody by priming with gp160 recombinant vaccinia and boosting with rgp160 in vaccinia-naive adults. J Infect Dis 1993; 167:533-537.

Montefiori DC, Graham BS, Zhou JT, Zhou JY, Bucco R, Schwartz DH, Cavacini LA, Posner MR, and the NIH-NIAID AIDS Vaccine Clinical Trials Network. V3-specific neutralizing antibodies in sera from HIV-1 gp160-immunized volunteers block virus fusion and act synergistically with human monoclonal antibody to the conformation-dependent CD4 binding site of gp120. J Clin Invest 1993; 92:840-847. Accompanying editorial: Schooley RT. Just (don't) do it. JCI 1993; 92:535.

Graham BS, Gorse GJ, Schwartz DH, Keefer MC, McElrath J, Matthews TJ, Wright PF, Belshe RB, Clements ML, Dolin R, Corey L, Bolognesi DP, Stablein DM, Esterlitz JR, Hu S-L, Smith G, and the AIDS Vaccine Clinical Trials Net­work. Determi­nants of antibody response after rgp160 boosting in vaccinia-naive volunteers primed with gp160 recombinant vaccinia. J Infect Dis 1994; 170:782-786.

Graham BS, Wright PF. Candidate AIDS Vaccines. N Engl J Med 1995; 333:1331-1339.

Mascola JR, Snyder SW, Weislow OS, Belay SM, Belshe RB, Schwartz DH, Clements ML, Dolin R, Graham BS, Gorse GJ, Keefer MC, McElrath MJ, Walker MC, Wagner KF, McNeil JG, McCutchan FE, Burke DS, and the AIDS Vaccine Evaluation Group. Immunization with envelope subunit vaccine products elicits neutralizing antibodies against laboratory-adapted but not primary isolates of human immunodeficiency virus type 1. J Infect Dis 1996; 173:340-348.

Graham BS, Keefer MC, McElrath J, Gorse GJ, Schwartz DH, Belshe RB, Clements ML, Dolin R, Corey L, Wright PF, Sposto R, Stablein DM, Chernoff D, Dekker C, and the AIDS Vaccine Clinical Trials Network. Safety and immunogenicity of a candidate HIV-1 vaccine in healthy adults: Recombinant envelope glycoprotein gp120. Ann Intern Med 1996; 125:270-279.

Graham BS, McElrath MJ, Connor RI, Schwartz DH, Gorse GJ, Keefer MC, Mulligan MJ, Matthews TJ, Wolinsky SM, Montefiori DC, Vermund SH, Lambert JS, Corey L, Belshe RB, Dolin R, Wright PF, Korber BT, Wolff MC, Fast PE, and the AIDS Vaccine Evaluation Group. Analysis of intercurrent HIV-1 infections in Phase I and II trials of candidate AIDS vaccines. J Infect Dis 1998; 177:310-319.

Connor RI, Korber BTM, Graham BS, Hahn BH, Ho DD, Walker BD, Neumans A, Vermund S, Mestecky J, Jackson S, Cao Y, Gao F, Kalams S, Kuntsman K, McDonald D, Fenamore E, McWilliams N, Morrison S, Trkola A, Moore JP, Wolinsky SM. Immunological and virological analyses of persons infected by human immunodeficiency virus type 1 while participating in trials of recombinant gp120 subunit vaccines. J Virol 1998; 72:1552-1576.

Graham BS. Clinical Trials of HIV Vaccines. Ann Rev Med 2002; 53:207-221.

Womack CA, Liu M, Graham BS. Challenges and Current Progress in the Development of HIV/AIDS Vaccines, in New Generation Vaccines. Third Edition, Levine MM, Kaper JB, Rappuoli R, Liu M, Good M, editors. Marcel Dekker, Inc., New York, NY, 2003, pages 573-581.

Lee D, Graham BS, Chiu YL, Gilbert P, McElrath MJ, Belshe R, Buchbinder S, Sheppard HW, Koblin B, Mayer K, Keefer M, Mulligan M, Celum C. Breakthrough infections during Phase I-II prime-boost HIV vaccine trials with canarypox vectors (ALVACTM) and recombinant gp120 or gp160. J Infect Dis 2004; 190:903-907.

McCurdy LH, Larkin BD, Martin JE, Graham BS. Modified vaccinia virus Ankara: Potential as an alternative smallpox vaccine. Clin Infect Dis 2004; 38:1749-1753.

Graham BS, Mascola JR. Lessons from failure - Preparing for future HIV vaccine efficacy trials. J Infect Dis 2005; 191:647-649.

Catanzaro AT, Graham BS. Rationale for Current HIV Vaccine Clinical Trials, in "Recent Advances in HIV Infection Research". Gualberto Buela-Casal and María Paz Bermúdez, editors, University of Granada. Spain. 2005, (in press).

Press here for a list of current clinical trials in the CTC. Press bibliography for a complete list of references for Dr. Graham and visit the Viral Pathogenesis Laboratory (VPL) page to learn more about Dr. Graham's basic research in viral pathogenesis.

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