AIDSWEEKLY Plus; Monday, August 24 & 31, 1998
Daniel J. DeNoon, Senior Editor

In a debate at the 12th World AIDS Conference, everything seemed to work against the AIDS clinician and researcher who has volunteered to be the first subject to be injected with an attenuated HIV virus.

The meeting room worked against him: the lights prevented him from reading his own slides, forcing a limp end to his presentation.

His debate opponent worked against him: Harvard's Ruth Ruprecht cooly presented updated evidence of the chilling safety problems seen in monkeys injected with a simian version of the vaccine, and suggested that the vaccine virus can mutate into a more pathogenic form.

His own data turned on him: his best argument for the safety of a live-virus HIV vaccine is from a group of Australian blood recipients infected with mutant HIV lacking the same regulatory nef gene that would be removed from the vaccine virus. None of these individuals developed symptoms and all maintained normal CD4(+) T-cell counts for more than 10 years. But Ruprecht revealed new data from these patients, indicating that several of them now have T-cell declines remarkably similar to those portending AIDS in her vaccinated monkeys.

And finally Farthing's audience worked against him: HIV co- discoverer Robert Gallo and others rose to denounce live HIV vaccines as inherently unsafe.

It went well at first. Farthing noted that more than 300 people already have volunteered for a trial of a live HIV vaccine based on the SIV vaccine under development by Harvard's Ronald Desrosiers for Therion Biologics Inc. (see AIDS Weekly Plus, September 8, 1997).

Dubbed "delta nef," the principle feature of this vaccine virus is that it lacks a functional nef gene and therefore is capable only of low-level replication. Monkeys that receive this SIV vaccine take a long time to develop effective immunity, but once they do they tend to resist infection with other strains of SIV. No other vaccine strategy has been as effective.

Farthings strongest argument came from a bizarre twist of fate that may already have provided the first human test of a nef- attenuated HIV vaccine. Between 1981 and 1984, seven people were infected with HIV via blood transfusions from a single donor in Sydney, Australia (see AIDS Weekly Plus, February 19, 1996; January 20, 1997; and March 17, 1997).

All of the members of this Sydney Blood Bank Cohort have been asymptomatic for more 14 to 17 years, with low viral loads and normal CD4 counts (two elderly cohort members died of causes unrelated to HIV disease). Analysis of virus isolated from the donor and the seven infected recipients showed that it fortuitously contained a truncated nef gene (the C-terminal 43 amino acids are missing).

"Even if these patients go on to develop immune suppression in the future, they demonstrate that delta nef can protect," Farthing said. "And Dr. Desrosiers is developing significantly more attenuated vaccines."

These more attenuated vaccines are known as delta 4 (HIV-1 lacking the nef, vpr, vpu, and Nef-responsive element or NRE genes) and delta kURN (the delta 4 vaccine strain with an additional deletion in the gene encoding the NFkB-binding element).

Farthing acknowledged the findings by Ruprecht and others that delta nef SIV can cause disease in monkeys, but downplayed their significance. He noted that the initial findings were made in neonatal animals injected with the virus.

"I question the relevance of this data," he said. "We never inject neonates with live attenuated virus vaccines. The adult data is more discriminating, but not definitive. ... SIV is more pathogenic than HIV."

Refusal to move forward with human tests of a live vaccine, Farthing said, is based on an over-conservative interpretation of available data and on aversion to risk.

"It is this conservative thinking that is suppressing the most promising area of AIDS research," he said. "We do not deny that there will be some risk. There seems to be a zeitgeist that clinical trials should be without risk. I do not believe this - this is what informed consent is all about."

Human testing would begin with a small trial of delta kURN. Any patient with persistent viremia would be treated with highly active antiretroviral therapy (HAART) regimens donated by manufacturers that have already agreed to supply the drugs. Assuming that funding becomes available - sufficient cash is currently not on hand - Farthing predicted that a candidate vaccine would be ready for large- scale trials in one to five years.

He argued that even if a live vaccine is not entirely safe, it would be useful in containing the AIDS pandemic.

In response to Farthing's passionate appeal for action, Ruprecht began modestly.

"My task is to present some sobering data," she said.

Ruprecht put forward her "threshold" hypothesis: that a live HIV or SIV vaccine must be attenuated enough so that it does not replicate beyond a disease threshold; and that the vaccine virus must be robust enough to replicate above a vaccine threshold required to stimulate immunity.

"We are worried that residual virus could replicate from undetectable to the disease threshold," she said.

Her primate studies showed a disturbing pattern. At first, everything appeared to be going well: monkeys inoculated with attenuated SIV controlled infection with the vaccine virus and viremia was undetectable for about four years. But after this time, low-level viremia re-emerged. Alarmingly, this low-level viremia was associated with a persistent decline in CD4(+) T cells.

"The virus can become persistently present in the blood again and cause immune dysfunction," she said. "Clearly our data raises a red flag regarding the safety of multiply attenuated live HIV vaccines."

To date, 11 animals have received the delta 3 SIV vaccine. Five are dead from AIDS; none have normal immune responses. Ruprecht showed a Kaplan-Meier survival curve for the vaccinated animals.

"As you can see it goes down, down, down," she said. "What worries me is that you are seeing death from AIDS at relatively low levels of viremia - something unusual in SIV infection."

The implications of these findings, she said, is that merely weakening the ability of a lentivirus to replicate does not abrogate its pathogenicity.

And why not simply do as Farthing suggested, and further attenuate the vaccine virus? Ruprecht suggested that too much attenuation would result in an ineffective vaccine. She called attention to data from chimpanzee studies - reported by Desrosiers at a 1995 colloquium - in which HIV delta 3 and HIV delta 4 failed to protect the animals from challenge infection.

"HIV delta 3 has not worked in chimpanzees. HIV delta 4 has not worked in chimpanzees. Why further attenuate a vaccine for which there is no evidence of any efficacy?" she asked. "The current generation of attenuated HIV vaccines are not only not safe, but not effective."

Ruprecht ended with a note of hope.

"It's theoretically possible to find the molecular determinants of [HIV] pathogenicity and eliminate them," she said. "Then you would have a truly avirulent vaccine virus."

Ruprecht most chilling argument came during the question-and- answer period, when she revealed new data showing that members of the Sydney Blood Bank Cohort have declining T-cell counts. She called on Jennifer Learmont of the Australian Red Cross Blood Service to confirm this.

"A few [cohort members] have always had low detectable virus load: it's not a re-emergence," Learmont said. "but you're correct in saying that their CD4 counts are slipping. Some are below 500 cells/(micro)L."

As if this distressing news weren't enough to dampen enthusiasm over live HIV vaccines, Robert Gallo delivered a lecture from the floor.

"A retrovirus is forever: that is the difficulty," Gallo said. "All retroviruses cause disease over time. I don't know when you would be able to tell in a pilot study if [a live HIV vaccine] is safe. It would be after your lifetime. HTLV can take 30 years to cause disease."

In response to a question, Ruprecht noted that her laboratory is currently sequencing the re-emergent virus from vaccinated monkeys. Although the results of these studies are not complete, there is evidence that the vaccine virus did indeed mutate.

"I can tell you that the [vaccine] virus has undergone extensive changes," Ruprecht said.

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