AIDSWEEKLY Plus; Monday, May 4, 1998
Daniel J. DeNoon, Senior Editor
The vaccine, developed at New York's Albert Einstein College of Medicine and licensed to ID Biomedical Corp., couples envelope peptides from six diverse HIV-1 strains to purified tuberculin protein derivative (PPD).
"We conclude that favorable clinical effects occurred in the patients during the course of vaccination, and that this approach to therapeutic vaccination deserves further study," said Jack Lenz of Albert Einstein College of Medicine, Bronx, New York.
None of the seven HIV(+) patients in the Phase I trial were on active antiretroviral therapy. Only three subjects had measurable HIV viremia at the beginning of the trial.
The subjects received intradermal inoculations at 0, 1, 2, 3, 6, 9, 12, 15, and 18 months. During the course of these immunizations, sera from all patients had increased ability to neutralize heterologous primary HIV-1 isolates.
"We frequently observed that after vaccination, comparable amounts of the patients' sera neutralized over 100-fold higher concentrations of heterologous virus than before vaccination," Lenz reported. "It takes some time. The really large increases take six to 12 months to see."
For the three patients with measurable viral load at the start of the trial, viral loads decreased by 95 percent in two and by 75 percent in the third. These declines in viremia occurred even though the envelope peptides from each patient's predominant viral isolate differed somewhat from those used in the hexavalent vaccine.
The decreases in viral load were sustained for at least six months after vaccination, but within a year of the last vaccination viral load rebounded to previous levels in all three patients. One to seven amino-acid changes could be detected in the V3 loop of virus isolated from these patients after viral rebound.
The PPD-based vaccine has been under development for most of the decade.
At the 1991 International AIDS conference, Arye Rubinstein and colleagues at Albert Einstein College of Medicine reported that mouse monoclonal antibodies against the MD strain of HIV-1 recognized different 13-amino-acid peptides corresponding to the HIV-1 principal neutralizing domains (PND, a highly variable region [V3] of the viral gp120 envelope glycoprotein) of various HIV-1 strains. These IgG1 and IgG2a antibodies were capable of neutralizing several of the target viruses.
Rubinstein et al. created a conjugate vaccine by linking (via glutaraldehyde bond) the PND peptide from HIV-1[MN] to tuberculin purified protein derivative (PPD).
At the 1994 International AIDS conference they announced results from a Phase I clinical trial. HIV seronegative, PPD skin-test positive volunteers received submicrogram, intradermal doses of the vaccine on days 0, 14, 28, 82, and 383. Although the vaccine caused mild, transient local reactions it did not cause any noticeable systemic adverse reactions.
Responders - 10 of the 11 volunteers - developed HIV specific immune responses including salivary IgA antibodies that neutralized the MN strain of HIV. The vaccine also elicited HLA-B7 restricted cytotoxic T lymphocytes (CTL). After the fourth immunization, high- affinity anti-HIV antibodies were detected and persisted for more than one year.
"Long lasting humoral immune responses in the serum and saliva were possibly accompanied by HLA-B7-restricted CTL responses," Rubinstein et al. wrote (1995;9(3):243-51). "This is a vaccine prototype that can be rapidly and inexpensively modified to include other peptide epitopes. It is especially suitable for use in a worldwide multibillion Bacillus Calmette-Guerin (BCG)-primed or tuberculosis-exposed population at risk for HIV-1 infection."
To develop such a vaccine, the researchers created a hexavalent vaccine incorporating PND peptides from six widely different HIV-1 strains: MN, RF, NY-5, CDC-42, ARV-2 and THAI-1. Animal studies showed that this vaccine was more immunogenic than the monovalent PND- MN-PPD vaccine.
At the 1996 International AIDS conference, Rubinstein reported that the hexavalent vaccine had been tested in people with HIV-1 infection.
"Significant increases in the titer of PND-specific antibody and in primary isolate-specific neutralization activity was observed in post-vaccination sera as compared to pre-vaccination sera," Rubinstein et al. wrote in their presentation abstract. "A PPD-V3 loop hexapeptide conjugate vaccine administered intradermally at submicrogram doses can induce neutralizing antibodies to primary HIV isolates."
In a 1997 press release announcing its acquisition of the rights to the vaccine from TheraGuide Inc., New York, ID Biomedical Corp. said that expanded Phase I clinical trials were scheduled for third- quarter 1998 at "facilities affiliated to the U.S. NIH in Brazil and Israel following applications to the relevant authorities."
"In our limited studies, our vaccine has uniformly induced higher titer neutralizing antibodies against wild-type HIV, including neutralizing antibodies against patients' own virus strain," Rubinstein said. "The neutralizing antibodies in HIV positive individuals were higher than those generated by any other HIV vaccine approach to date. In addition, we know of no peptide vaccine that has achieved the CTL responses in the magnitude that we have seen in the HIV negative patients."
The manufacturer indicated that the vaccine will be developed for both therapeutic and prophylactic uses.
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