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THE FUTURE OF
SARS
Part 3: Cure and
prevention
By John Parker
Part 1: The
origins
Part 2: Will it
return?
Which
public-health measures will help most to prevent a
recurrence of severe acute respiratory syndrome (SARS)?
In all likelihood, the single most important measure
that can be taken is to prevent animal-to-human
transmission. Since it is overwhelmingly probable that
the SARS outbreak began in exactly this manner, even if
scientists are still unsure about the exact identity of
the animal involved, preventing SARS-CoV from leaping
the cross-species barrier could nip any nascent epidemic
in the bud, at far less inconvenience and cost than any
other countermeasure that could be taken.
There
is recent precedent for the success of such an approach.
In Malaysia in 1998-99, the Nipah virus outbreak killed
105 people and resulted in the slaughter of 1.1 million
pigs. A recurrence of Nipah has been prevented, mostly
because of specific measures to prevent contact between
susceptible livestock and bats (bats are the natural
reservoir of the Nipah virus).
The Chinese
government has worked hard to curtail the wild-animal
trade, particularly in those species considered most
likely to be responsible for SARS. Although this policy
is justified, it contains two hidden dangers: first, it
may not be sustained adequately over the long term
(indeed, China reportedly lifted last month the ban on
civet-cat sales it imposed in May); and second, if the
wild-animal trade is simply driven underground rather
than wiped out, the danger may actually increase, since
it will become more difficult for health officials to
monitor animals and their handlers. As with any illicit
product, measures to curtail demand will be as vital for
success as short-term bans. Irrespective of SARS, there
is a clear need within East Asian societies for a
reassessment of the practice of consuming wild game,
especially at a time when increasing economic prosperity
has made adequate animal protein available to almost
everyone.
This is not to say that other measures
should not be employed. The second line of defense is
monitoring at the hospital level; health personnel must
continue to be on the alert for patients with SARS
symptoms, and adequate facilities for testing and
isolation, if necessary, must be available. The media
have an important role to play in ensuring that
government entities are prepared; this is true even in
societies without a free press, such as mainland China
and Vietnam. Although flagging vigilance over time is
inevitable, especially if SARS fails to recur this
autumn, it is vital not to be complacent, because of the
virus's high pandemic potential if it is ever allowed to
escape containment.
For the ordinary person, the
extreme measures that we saw last spring, such as
masking and abstaining from handshakes, are not
necessary at the moment. But masking during the cold and
flu season is not a bad idea, since it will avert other
illnesses besides SARS. Flu shots are advisable not only
because they prevent flu cases, but because easing the
burden on the health-care system due to flu it will
improve its response to any new SARS crisis. Other
hygienic measures, such as curtailing spitting, are also
recommended on general public-health grounds, regardless
of whether SARS recurs or not. As mentioned already,
sustained changes in such practices should make East
Asia inherently less hospitable to infectious diseases
and yield major long-term public-health benefits.
Which countries are most vulnerable to a
recurrence of SARS?
This question is highly
debatable because of a lack of certain information.
Having said that, the weight of the evidence suggests
that mainland China and Vietnam, in that order, are most
at risk.
The risk in China is due to the
well-known factors of population density, consumption of
wild animals, hygienic factors and so on. However, as
already discussed, steps have been taken to alleviate
some of these concerns.
Vietnam may have been
the original source of the animal virus that initiated
the SARS crisis, if the civet hypothesis proves correct.
The remoteness of the northern Vietnamese region, its
porous border with China, and the uncertain quality of
SARS-control measures in rural areas also increases the
risk of another Vietnamese outbreak. However, the
sweltering Vietnamese weather may actually protect the
country in spite of these risks. In the Vietnamese
epidemic, most cases of transmission were from SARS
patients to health-care workers, rather than from SARS
patients to individuals in the wider community. In
addition, the Vietnamese government displayed a laudable
willingness to cooperate quickly with international
health agencies and would presumably do so again in
another crisis.
Other areas - Hong Kong,
Singapore, Taiwan, Korea, Japan and so on - are much
less at risk, on balance. It seems unlikely that a new
SARS outbreak would originate in any of these areas,
given what we know about the likely animal origins of
SARS-CoV. The most significant risk to these areas would
occur if, as happened before, an infected individual
traveled to one of the low-risk countries and initiated
a new local epidemic there. This is more likely to
happen in Hong Kong and Singapore because of the large
number of international air passengers, especially from
mainland China, passing through the two cities; and Hong
Kong, which has a massive cross-border flux with the
mainland, is at higher risk than Singapore.
The
rest of the world has little to fear from SARS in the
short term. However, if a new epidemic does break out,
vigilant observation and screening of air travelers
arriving from the affected countries will be critical in
limiting the spread of the disease. As the Toronto
epidemic showed, even a single infected passenger
allowed through quarantine is enough to create a major
problem.
What are the prospects for anti-SARS
drugs?
Antiviral drugs are a relatively new
phenomenon in medicine. The first one, acyclovir, which
is active against herpes viruses, was only discovered in
the late 1970s. Although the discoverer of acyclovir
eventually claimed a Nobel Prize, antivirals remained a
research backwater for the next decade, mostly for two
reasons. First, most viral illnesses, SARS
notwithstanding, are self-limiting and non-lethal (ie,
the patient generally recovers without medical
intervention). Second, the very nature of viruses tends
to limit the effectiveness of drugs against them.
Antibiotics can be very effective because their
targets, bacteria, are living cells (they feed, move,
reproduce, and metabolize); and precisely because they
are alive, they can be killed. But viruses are orders of
magnitude smaller and simpler than even the humblest
bacterium; they are like little molecular robots whose
only purpose is to find a host cell, take it over, and
use it to make more viruses. Because of viruses'
simplicity and inability to reproduce without a host
cell, many scientists do not consider them to be truly
alive. Unfortunately, this very simplicity makes viruses
difficult to eradicate from the body; it is hard to
"kill" something that was never alive in the first
place. In a sense, a virus can only be disabled or
"broken" - it cannot be killed. This is what antiviral
drugs do: they prevent the virus from reproducing, in a
way that does not harm the host cell.
The
appearance of acquired immune deficiency syndrome (AIDS)
in the early 1980s revolutionized antiviral research,
since the lethality of the human immunodeficiency virus
(HIV) created an urgent need for drugs against it, even
if they had major side-effects. The first successful
anti-HIV drug was azidothymidine (AZT), which appeared
in the mid-1980s. Unfortunately, AZT not only did not
cure AIDS, because it did not eliminate HIV from the
body, but it was of limited usefulness, since patients
taking only AZT inevitably evolved strains of HIV,
within their own bodies, that were resistant to the
drug, leaving the patient worse off than before.
Another 10 years would pass, and an entirely new
class of anti-HIV drugs (protease inhibitors) would have
to be developed, before the next significant advance
occurred. Researchers realized that taking two classes
of antivirals at the same time was dramatically more
effective than taking any single class alone. By
disabling the virus at two different points in its life
cycle, these multiple-drug treatments made it extremely
difficult for HIV to evolve resistance. The effect of
the treatments, which came to be known as HAART (highly
active anti-retroviral therapy), could be so dramatic
that, in some cases, patients literally rose from their
deathbeds, as the one-two punch of the drug therapy
reduced the level of HIV in their blood to undetectable
levels.
More than a dozen anti-HIV drugs are now
available, and a third class of "integrase inhibitors"
has recently joined the protease inhibitors and reverse
transcriptase inhibitors (such as AZT) developed in the
1980s and 1990s. Albeit at a ghastly cost in human life,
HIV has in effect taught the biomedical-research
community how to develop new antivirals quickly. This
bodes well for antivirals against SARS-CoV, and indeed,
the first potential candidates have already appeared.
Probably the most promising candidate at this
point is glycyrrhizin, a complex organic chemical
originally isolated from the roots of the licorice plant
(Glycyrrhiza radix). There has been a major
effort by Russian scientists at the Ufa Research Center
of the Russian Academy of Sciences to investigate the
pharmaceutical properties of compounds derived from this
plant and their chemical derivatives. In a January paper
in Current Medicinal Chemistry reviewing much of this
work, the Russians claimed to have found derivatives
with anti-inflammatory, anti-ulcer and, most relevant,
antiviral properties. One compound was found to be
active in vitro (ie, in the laboratory, not in patients)
against HIV. This finding may have inspired a group of
German researchers at the Frankfurt University Medical
School to test glycyrrhizin against SARS-CoV when
clinical isolates of the SARS virus became available in
the spring. And indeed, the Germans found that
glycyrrhizin was the most active of five compounds
tested in inhibiting replication of SARS-CoV, and
recommended that it be investigated further for clinical
use.
Interestingly, ribavirin, a drug originally
developed to inhibit respiratory syncytial virus (RSV),
a major cold-causing virus, was found by the Germans to
be much less effective than glycyrrhizin. This result
confirmed numerous reports elsewhere in the biomedical
literature confirming the total ineffectiveness of
ribavirin, both in vitro and in patients. The
significance of these findings lies in the fact that
many SARS patients were given ribavirin, especially in
Hong Kong. In light of the research findings, the
decision to do so is questionable. It appears that
patients were given ribavirin more out of a desire to
"do something" than because of any evidence that
ribavirin was active against SARS-CoV. In fairness to
physicians, patients may simply have been clamoring for
any antiviral, and ribavirin was the only drug on the
shelf proven to be effective against cold viruses, so it
was used, even though there was no evidence at all that
it would be useful against the SARS virus. Ironically,
the evidence suggests that the patients who were given
ribavirin should have been given licorice candy or tea
instead, although, of course, health-care workers could
not have known this at the time.
Another
possible candidate is Ampligen, an immunotherapeutic
agent developed by Hemispherx Biopharma of Philadelphia.
On May 21, a Hemispherx press release announced that
Ampligen had been found to have "unusually high and
consistent activity" - the highest of about 70
compounds, including ribavirin, that were tested -
against human coronavirus. It is important to note,
however, that the firm had not tested Ampligen against
SARS-CoV itself (as of late May), but rather against the
related human coronavirus OC-43. Thus there is no
guarantee that the compound would be effective against
SARS-CoV. Presumably, the company intends to test
Ampligen directly against SARS-CoV and will release the
results when that study is completed.
Another
potential route to an antiviral for SARS has been laid
out by a German group led by Rolf Hilgenfeld of the
University of Luebeck. These researchers determined the
structure of a key SARS-CoV enzyme, a protease, and
noticed that it was similar in structure to the protease
enzyme of the rhinovirus (yet another type of
cold-causing virus). Because the rhinovirus enzyme is
known to be inhibited by an experimental antiviral
called AG7088, which is already in trials as a
common-cold drug, the Germans reasoned that AG7088
should be a good starting point for developing new drugs
to use against SARS-CoV. (Since the structure of the two
enzymes is similar, they should be inhibited by
similarly shaped compounds, much as two locks made by
the same company might have similarly shaped keys.)
Although there is no evidence yet that AG7088 itself is
useful against SARS, it should be straightforward to
make chemical derivatives that can then be screened
against the new virus.
Will any of these
compounds actually make it to commercial release? It is
hard to say. Partly, it depends on whether SARS recurs
or not. If it doesn't, pharmaceutical companies will be
reluctant to invest resources in drugs against a
pathogen that may never be seen again. Hemispherx's
compound, which may be a general anti-coronaviral agent,
would seem to have better prospects than most for making
it to market, since there should be other markets for it
besides SARS. Glycyrrhizin may in fact already be
available to the public, in the form of licorice root
(up to 24 percent of the dry weight of licorice root is
glycyrrhizin). I am not aware of any regulations
controlling the sale of licorice root, or food products
made from it. Unfortunately, there are also no published
studies evaluating the effectiveness of such products as
licorice tea, or licorice candy, against SARS-CoV or any
other coronavirus, and it is conceivable that
manufacturing processes used in making these products
might reduce the potency of the natural chemical.
Last, although it is just about certain that
chemicals can be found that will inhibit SARS-CoV (so
far, whenever scientists have looked hard enough for
antivirals against a particular virus, they have always
succeeded eventually), it unfortunately isn't certain
that these chemicals will actually help SARS patients.
This is because the lethality of SARS-CoV seems to come
not from the virus infection itself, but from an
overreaction to the virus by the patient's own immune
system, which results in the destruction of crucial lung
tissue.
Although this theory is not proved,
there is some suggestive evidence for it, such as the
fact that the most severe symptoms of SARS disease seem
to occur after the number of viruses in the patient has
already peaked. The theory also accounts for the
apparent success of steroid drugs in some SARS patients;
steroids typically do nothing against viruses, but do
have modulatory effects on the human immune system.
There is no doubt that, in most people, the immune
system is capable of destroying SARS-CoV by itself,
without any help from antiviral drugs (this is exactly
what happened in the 90 percent of victims who have
recovered).
For some diseases, curing certain
symptoms is enough, in effect, to cure the disease; SARS
may well be one such example. If this is the case, the
search for SARS antivirals may turn out to be a waste of
research effort that should have gone into finding ways
to alleviate the pathological immune overreaction.
What are the prospects for a SARS
vaccine?
As a way of controlling SARS, a vaccine
would be preferable to any conceivable antiviral drug,
because vaccination can prevent a person from developing
SARS in the first place, greatly reducing the burden on
health-care resources compared with drug-based
treatments. But here, too, there are many uncertainties.
Although a vaccine probably can be developed, it is
impossible to say how long this will take, and
vaccination may actually not be the most cost-effective
way of containing SARS.
Is a SARS vaccine
possible? There are some good reasons to believe that
the answer is yes. For example, it is encouraging that
90 percent of SARS victims eventually recover, because
this shows that the immune system can recognize and
overcome the virus, which is a necessary condition for a
vaccine to be successful. Also, there are already proven
veterinary vaccines for coronaviruses; for example, in
many countries, piglets are routinely vaccinated against
enteric coronavirus disease.
On the minus side,
scientists have been humbled by the failure to develop
vaccines against malaria, tuberculosis (TB) and HIV,
despite massive efforts. And SARS-CoV is an RNA
(ribonucleic acid) virus like HIV, which means that it
may mutate so quickly that a new vaccine might need to
be introduced every year, as for influenza. If this is
true - no one knows yet whether it is or not - the
problems of vaccine development and distribution will be
vastly multiplied.
Last, some previous attempts
at coronavirus vaccines have gone disastrously awry. For
example, a candidate vaccine for feline coronavirus
infections was rejected when researchers discovered that
vaccination actually made the symptoms worse when cats
were exposed to the real virus.
Despite these
difficulties, numerous companies around the world have
initiated research into a SARS vaccine. GenVec, a
Maryland-based biotechnology company, received a grant
from the US National Institutes of Health (NIH) to apply
its adenovirus vector vaccine technology to SARS. This
technology, which was originally developed for an HIV
vaccine now in development, uses a harmless adenovirus
to deliver targeted antigens to cells. (An antigen is a
particular physical feature of a disease-causing
organism that can be recognized and attacked by the
immune system.) The advantage of using the adenovirus is
that it can, theoretically, produce a more natural
immune response compared with more traditional
antigen-delivery methods. Although GenVec is working on
vaccines for malaria and dengue fever as well as HIV,
none of its vaccines has actually made it through the
entire approval process so far.
Pharmaceutical
giant GlaxoSmithKline, which has a long track record of
successful vaccine development, has also committed to
accelerate work on a SARS vaccine, in collaboration with
the Pasteur Institute in France. A third effort is being
made by the US biotech company Siga Technologies, in
collaboration with Plexus Vaccine Inc, a Danish firm
recently wholly acquired by Siga. This vaccine would
incorporate a significant innovation made by Danish
scientists that uses bioinformatics (computer analysis
of genetic information) to determine which SARS
antigens, of the many possible antigens that could be
used in a vaccine, are most likely to give a robust
immune response. Because the Danish method is intended
to distinguish between features of the SARS virus that
change rapidly between genetic variants, and those that
remain the same, a Siga/Plexus vaccine may be
particularly important if SARS-CoV does return
periodically in altered forms.
Another
collaborative SARS vaccine effort will occur between
Generex Biotechnology of Toronto and Antigen Express (a
private firm), which would combine buccal (mouth)
delivery technology from Generex with various
vaccine-enhancing technologies from Antigen Express.
Finally, Chiron, another US biotechnology firm, is also
said to be working on a vaccine.
Scientists in
China, the country most affected, have mounted a major
vaccine effort as well. Researchers at Hong Kong
University (HKU), in collaboration with Guangzhou
Medical College and Fudan University in Shanghai, are
trying to develop a vaccine using inactivated virus
particles. This method is considered to be relatively
straightforward and is historically proven, having been
used successfully in the past, but also contains certain
risks. Because the vaccine is made with genuine viruses,
there is always a danger that an infectious virus could
make it through the production process (and cause SARS
in a vaccinated person), even though the preparation
method would be carefully designed to ensure that the
viruses are rendered harmless.
This work appears
to be progressing well; in May, the inactivated-virus
preparation was shown to be non-infectious in cell
culture (addressing the critical safety issue). Then, in
late June, researchers announced that monkeys tested
with the vaccine had developed antibodies to SARS-CoV,
showing that the vaccine had induced the desired immune
response. The next step will be to "challenge" the
monkeys with the real SARS-CoV to show that there is a
protective effect. If the vaccine succeeds in monkeys,
human trials will follow, probably from medical
volunteers.
Other possible avenues to a vaccine
are also being pursued: the China National Biological
Products Corp (CNBPC) has announced that it plans to
spend 500 million yuan (US$60.46 million) on SARS
vaccine development.
How long will it take for a
SARS vaccine actually to appear on the market? In a
sense, several vaccines already exist; the problem is
that they must pass through an exhaustive and lengthy
set of efficacy and safety tests before they can be used
on the public. Because of the many problems that can
occur, and the inherent unpredictability of immune
responses to vaccine preparations, it is essentially
impossible to predict when a vaccine might appear.
So far, every expert quoted has seemed to give a
different timeline. Marie-Paul Kieny, director of the
World Health Organization (WHO) initiative for vaccine
research, said that a vaccine would take "at least a
year". A Chinese vaccine expert (who chose to remain
anonymous) told China Daily that the development process
for the HKU vaccine would take at least two years,
throwing cold water on ill-informed speculation that a
vaccine could be developed "within months". Gary Nabel,
chief of the Vaccine Research Center at the National
Institute of Allergy and Infectious Diseases (part of
the NIH), was quoted as saying that a vaccine could be
developed in three years "if everything went perfectly
... if all the stars were aligned". But Dr Franz Humer,
chief executive officer of Hoffman-La Roche AG, scoffed
at predictions of a vaccine in two years, calling that a
"fairy tale", and cited five to 15 years as a more
plausible figure. Dr Emilio Emini, head of vaccine
development at Merck, refused even to chance a guess,
calling the SARS virus "a black box".
Realistically, these efforts are much more
likely to bear fruit if SARS recurs this autumn, since
private companies will not indefinitely pour resources
into a vaccine for a disease that may never reappear. In
the United States, repeated meetings involving the Food
and Drug Administration, Centers for Disease Control and
Prevention (CDC), NIH and representatives of the
pharmaceutical and biotech industries, and the rapid
issuance of research contracts by the NIH, did a great
deal to spur vaccine research onward when the crisis was
first breaking in April. But it is doubtful whether this
level of commitment can be sustained if SARS simply
disappears.
Finally, vaccination is not
necessarily the best method of defusing the SARS threat;
SARS may simply be a sporadic contagion that is best
controlled through containment. If the measures already
introduced to prevent animal-to-human transmission
succeed, and SARS does not return, then containment will
have already, in effect, defeated SARS. If another
outbreak does occur, and it is brought under control by
rapid isolation and quarantine of the affected
individuals, this will probably be more cost-effective
than mass vaccination, with all the costs that will
entail (costs that would continue into the indefinite
future).
Accordingly, the WHO is now focused on
"putting the virus back in its box" rather than on
vaccine efforts. As Klaus Stohr, a virologist and WHO's
chief scientist for SARS, said: "It will be much less
costly, it will mean much less death and disease for the
next five, 10, 100 years, if we are capable of dealing
with this disease now ... This is our one-off chance to
get rid of this disease. We don't need another pathogen
floating around. We have enough to do with TB, AIDS,
malaria, other upper-respiratory-tract infections,
diarrhea, and so on - we don't need another vaccine
which is going to be a drain on public-health
resources."
Thus, the lack of a SARS vaccine
five years from now may actually be good news - if it
happens because the world has seen the last of SARS-CoV
in humans. Only time will tell.
John
Parker is a freelance writer based in
Vietnam. He has a Master of Science degree in cell
biology.
(Copyright 2003 Asia Times Online
Co, Ltd. All rights reserved. Please contact content@atimes.com for
information on our sales and syndication policies.)
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