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Report:
Leading immunologist
questions TB vaccine safety
Investigators: Ian
Orme, Douglas Lowrie, and Carol Nacy
Thursday Jul
26th, 2001
by John Bonner
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Scanning Electron
Micrograph of
Mycobacterium
tuberculosis.
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Leading US tuberculosis expert,
Ian Orme, last night condemned plans to proceed with human trials of two
vaccines that he says have not received adequate safety clearance. The
accusation brought a swift and sharp rebuttal. Sequella, the Maryland-based
company responsible for the trials, with funding from Bill Gates, today
questioned "Dr Orme's indiscreet and unsubstantiated claims."
Orme, professor of immunology at Colorado State University who screens
TB vaccines for the US National Institutes of Health, says the trials
should be postponed. He recommends more testing and independent validation
of the two candidates - a DNA vaccine developed by Douglas Lowrie at the
National Institute for Medical Research in London and a
"turbo-BCG" vaccine developed by Marcus Horwitz at the University
of California in Los Angeles.
He is particularly concerned about the DNA candidate vaccine. "I
have no wish to upset Sequella or anybody else but when I heard that this
was going to be put in human beings my first reaction was to pray that
no-one will get hurt," he told BioMedNet News. "If it is
put into someone with a latent TB infection it could kill them."
According to the World Health Organization (WHO), which took the
unprecedented step of declaring TB a global emergency in 1993, one third of
the world's population may carry a latent TB infection. Of that third, 10%
are estimated to develop a life-threatening form of the disease.
Sequella, who is co-ordinating the human trials through a subsidiary,
the Sequella Global Tuberculosis Foundation, insists that all necessary
testing and verification is in hand.
"The jury is out on the toxicity of this [DNA] vaccine until the
appropriate toxicity tests are performed with the right vaccine in
preparation for a human Phase I safety trial," noted Carol Nacy, chief
executive of Sequella, which she founded in 1997.
"I hope you are appropriately cautious in reporting Dr Orme's
indiscreet and unsubstantiated claims," she told BioMedNet News
today.
Orme raised his concerns publicly at the 11th International Congress of
Immunology in Stockholm following a presentation on Monday by Margaret
Liu, who last October was appointed vaccine advisor at the Bill and
Melinda Gates Foundation, the charitable trust with $23 billion to spend on
developing and distributing vaccines worldwide.
The Gates Foundation's decision to back the Sequella trials, with $25
million of funding, predates Liu's arrival. Orme says he hopes to persuade
Liu that the Gates Foundation should work more closely with the existing
network of tuberculosis research laboratories, including his own, the
Mycobacteria Research Laboratories at Colorado State University.
Orme became aware of the Sequella contract less than two weeks ago, from
an article in the July 13 issue of Science, in which the two
candidate vaccines were cited among three soon to enter human trials.
"I was completely taken by surprise - it was astonishing," he recalled.
The journal, too, expressed some astonishment. "The [Sequella]
foundation hopes to take three candidate vaccines into the first
small-scale safety trials in humans over the next 12 to 18 months - a step
few would have thought possible three years ago," it reported.
Nevertheless, with the WHO estimating that TB kills 2 million people and
newly infects 1% of the world's population every year, few doubt the need
for swift action.
The standard BCG vaccine administered around the world for more than 70
years is of limited effectiveness. Orme says the race to develop an
alternative is entering the final furlong and there are about 10 potential
candidates that could soon be ready for testing in humans - but that the
Sequella pair is not among them.
With regard to Lowrie's vaccine, Orme says his own laboratory tested the
same DNA plasmid on animal models and got very worrying results. Used as a
prophylactic, the DNA vaccine was perfectly safe, he says, but animals
already exposed to TB died of a Koch reaction, in which circular pockets of
necrosis form in the lungs.
Lowrie says Orme's results are of "great interest [and]
re-emphasize the need for care and caution in any clinical trials but do
not significantly reduce the case for testing this vaccine in people."
He is puzzled by the mechanisms involved in the vaccine's tests, which
elsewhere have been successful.
"The therapeutic DNA vaccine for which Sequella is seeking NIH
approval for safety trials in man is truly outstanding in the potential
that it has demonstrated, in mice in London and in mice and guinea pigs in
Brazil," he noted.
"It caused heavy tuberculosis infections to go into reverse and in
separate experiments it eliminated residual bacteria after the usual
antibacterial drugs had killed most of them. In these and many additional
TB therapy experiments in other laboratories there has been no sign of
harmful effects."
Lowrie's working hypothesis to explain the difference is that
"Orme's mice may have been kept in a super-clean environment and never
exposed to any infections other than tuberculosis. This is an abnormal
situation and does not reflect what happens in the real world," he
said.
"There is a growing consensus of expert opinion that exposure to
common infections may be essential for the proper development of the immune
system. Hence, it is possible that the vaccine will work very well in
people in the real world although failing in some artificial laboratory
conditions," added Lowrie.
Horwitz's new "turbo" form of BCG vaccine worries Orme less
because the safety implications are not so serious. However, his own
findings with recombinant BCG vaccine suggest that the agents can be too
effective, provoking a powerful but short lived response to clear the
antigen and leaving no lasting immunity.
Orme says he would like to see the vaccine's safety tested in another
laboratory - all the other laboratories in the race to find a suitable
vaccine exchange material to confirm the results of their own tests.
Horwitz is unavailable for comment, but Nacy responded vigorously to the
charges. "Dr Horwitz has created a vaccine from a commercial strain of
BCG that enables the BCG to express about five times more Ag 85 than it
does normally (and it produces this antigen normally): this vaccine is
actually better in the very sensitive guinea pig model of TB than the
parent BCG."
Several other laboratories have tested the Horwitz vaccine, she claims,
with guinea pig studies by Toshiko Yamamoto being done in the laboratories
of David McMurray at Texas A&M University, who shares the NIH vaccine
testing contract with Orme.
Support for Sequella's initiative, and in particular for its role in
developing Lowrie's DNA vaccine, comes directly from the NIH. Ann Ginsberg,
chief of the NIH's Respiratory Diseases Branch, runs the TB Research
Materials and Vaccine Testing Contract, which has commissioned work from
the laboratories of Orme, McMurray and others.
"I have full confidence that Sequella will subject this candidate
and all others it develops to full and appropriate toxicity testing before
proceeding to human trials," she concluded.
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