Clinical Trials
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Program Areas
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:
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 launched 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 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
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.
Avian Influenza Vaccine Development
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 Vaccine Research Center (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's 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 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.
Ebola/Marburg
Vaccine Development Scientific Update
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.
SARS
Vaccine Development Scientific Update
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.
West
Nile Virus Vaccine Development Scientific Update
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.
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