Immunotherapy for Infectious Diseases

Active Immunization for HIV Infection 189
infecting agent are themselves infected and subsequently either lost, or inactivated.
Another possible reason for therapeutic vaccine failures is that cellular activation initiated
by these vaccines provides more targets for infection. With the advent of more
potent antiretroviral therapy, it is now possible to protect cells from infection after
immune activation. The accumulating evidence that a deficiency of HIV-specific immunity
exists in subjects unable to control viremia makes this approach to immune reconstitution
compelling.
Early trials focused on envelope-based vaccines, with disappointing results. These
vaccines have induced HIV-1-specific T-helper cell responses in infected individuals,
as well as increased titers of neutralizing antibodies (107–110). However, an analysis
of clinical endpoints failed to observe any benefit from vaccination (111). In addition
to the difficulty of performing these trials in the absence of HAART, part of the difficulty
may also lie in choosing envelope as an immunogen. Envelope-specific proliferative
responses have not been shown to correlate with control of viremia in the absence
of HAART (43,44). It has also been difficult to demonstrate neutralizing antibody
induced by any of the current vaccine candidates, probably because neutralizing antibodies
are directed against oligomeric envelopes on cell surfaces, and these cannot be
induced with monomeric recombinant envelopes (15,18,21,112,113). Finally, the
extreme diversity of envelopes among HIV isolates makes the formulation of an envelope
vaccine a challenge.
Remune is one of the most extensively studied therapeutic vaccine candidates. Originally
proposed by Jonas Salk, this is an inactivated whole virus vaccine that is inactivated
and depleted of the envelope protein during synthesis (114,115). It is derived
from a virus originally obtained in Zaire and contains a clade A envelope and clade G
gag. Thus far, this vaccine has been administered to over 3000 subjects, with few side
effects. Also, in the presence of HAART, Remune has induced significant Gag-specific
T-helper cell responses in HIV-infected persons, which were robust in some vaccine
recipients (116) and have previously only been observed in subjects with long-term
nonprogressive HIV infection with control of viremia (43,44,117). A recent trial of
over 2500 subjects randomized to receive Remune or placebo failed to detect any evidence
of vaccination with Remune on clinical end points. Although there was no benefit
to vaccination, this was during the time that PI-containing HAART regimens were
becoming the standard of care. In a subgroup analysis of subjects vaccinated in the
presence of HAART, subjects that had rebound viremia could not be differentiated
from subjects failing because of drug side effects (118). So, although there was no benefit
from this intent-to-treat analysis, the possibility remains that a benefit from Remune
can be obtained in subjects with relatively intact immune systems in the presence of
HAART.
Other approaches are currently being tested or will soon be tested in clinical trials.
Canarypox vectors are constructed from an avian virus with limited ability to replicate
in mammalian cells. Clinical trials with HIV-negative individuals have shown that vaccines
based on these constructs are able to elicit weak HIV-specific CTL responses,
T-helper responses, and antibodies (119–122). A small trial has demonstrated the safety
of these constructs in HIV-seropositive individuals, but there are no data on the ability
of these vaccines to augment HIV-specific immune responses (123). Immunogenicity
data from several trials will be available within the next 1–2 years.