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Some diseases just won’t lie down. Up until a few years ago, for instance,
the West thought it had tuberculosis licked. But back it has come, with
some help from HIV and its crippling effect on immunity. Now tropical
disease experts fear that yellow fever – a disease that terrorised people
in American and European seaports in the 18th and 19th centuries – is about
to stage a comeback too. And if it does, will there be enough vaccine to
go round? David Magrath, chief of the WHO’s Biologicals Unit, which monitors
world vaccine supply, is almost certain there is insufficient vaccine available
internationally to deal with large outbreaks in major urban areas.

A couple of decades ago this shortage might not have mattered. But recent
years have seen a steady increase in the numbers of yellow fever epidemics,
cases and deaths in tropical Africa, one of the disease’s two traditional
stamping grounds. In the other, Latin America, the mosquitoes that carry
the virus are returning in force, having been all but wiped out in the first
half of this century .

The scene is now set, say epidemiologists, for yellow fever to spread
from the Amazon forest, where it smoulders on in small epidemics, to the
sprawling cities of Latin America’s eastern seaboard. And from there the
virus could spread further still, says Jim Le Duc, a virologist and epidemiologist
working for the WHO. Mosquitoes capable of carrying the virus are widespread
in plenty of countries outside Africa and Latin America, including the US
and Australia. What would happen if the virus hitched a ride to these countries
in airline passengers flying from infected Latin American cities? Le Duc
fears the worst: ‘If we don’t do anything about it, we could be in for a
major worldwide catastrophe.’

His is not the only call for urgent action. Thomas Monath, vice-president
of OraVax Inc., an American biotechnology company in Cambridge, Massachusetts,
and a world authority on yellow fever, bemoans ‘the indifference of international
health planners’ to the threat of yellow fever. And Robert Shope, who heads
the Yale Arbovirus Research Unit, believes there is a further reason to
act swiftly. In future, he says, global warming might encourage aedes mosquitoes,
the type that transmit yellow fever, to spread northwards, increasing the
risk of disease outbreaks in North America.

What are the options? Although there is no cure for yellow fever, an
excellent vaccine was developed some fifty years ago. The problem is that
these days the vaccine is used mostly to snuff out epidemics after they
appear, leaving the majority of people, particularly children, unprotected.
Changing this would require an injection of funds from richer countries,
says Le Duc, as would attacking the mosquitoes, the only other way to keep
the disease at bay.

Le Duc’s pessimism is understandable. He spends much of his time tracking
the spread of dengue, a mosquito-borne disease similar to yellow fever but
less lethal. According to the WHO, dengue ‘is spreading . . . throughout
the globe, affecting tens of millions (of people) annually’. Worse, the
Aedes aegypti mosquitoes that carry dengue are also the main carriers of
yellow fever in cities. Wherever dengue flares up, Le Duc knows that an
outbreak of yellow fever could follow. ‘Many places are seeing their first
ever dengue epidemics,’ he says, including Brazil, Venezuela and Australia.

Nor is this the only ominous trend. Worldwide, epidemics of yellow fever
have become almost annual events, particularly in Africa. And numbers of
cases, which shuffled along in the few hundreds annually from 1948 – when
countries began reporting them to the WHO – to the early 1980s, have soared
over the past few years to over 3000. Officially, that is. The actual figures
are likely to be 10 to 500 times higher, judging from epidemiological studies
conducted on yellow fever in Africa over the past 25 years. In reality,
says the WHO, Africa probably suffers about 200 000 cases of yellow fever
and as many as 30 000 deaths a year.

Alarm bells are also ringing over the spread of a ‘new’ potential carrier
of yellow fever known as the Asian tiger mosquito (Aedes albopictus). In
1985, it travelled from Japan to the southern US in a shipment of used tyres.
It is now abundant in the US and Brazil, seems to be spreading to other
countries in Latin America and has become well established in Africa. Experiments
show that it can easily pick up and transmit viruses, including dengue
and yellow fever. Researchers in Brazil have recently discovered exam-ples
of A. albopictus carrying the dengue virus in the wild.

Fast breeders

But more worrying still, say experts, is the spread of city-dwelling
A. aegypti. Unlike the early epidemics in Latin America, Africa’s yellow
fever problem has so far been confined largely to communities living in
the savannah and forest fringes. Species like A. aegypti played little
part in such epidemics. But that is now changing. Swelling cities and their
suburban proliferations are providing an ever richer choice of mosquito
breeding sites in water-filled old tyres and other discarded cavities. A.
aegypti is spreading fast in Africa and, as a result, the risk of an urban
conflagration of yellow fever there grows greater by the year.

In Latin America, meanwhile, A. aegypti is rising Lazarus-like from
the grave. In 1947, the nine countries most afflicted by urban yellow fever
– Panama, Venezuela, the Guyanas, Surinam, Brazil, Bolivia, Peru, Ecuador
and Colombia – unleashed a vast campaign against the mosquito, attacking
it with DDT and destroying its urban breeding grounds. By 1965 the virus
had been forced back into the Amazon forest, to continue its existence in
jungle-dwelling mosquitoes and monkeys. But now its old urban ally is back,
breeding in the trash of proliferating shanty towns, and causing epidemics
of dengue.

These city-dwelling mosquitoes have yet to spark off a yellow fever
epidemic, though they have certainly been spreading dengue. In Latin America,
yellow fever is still reported in no more than a few hundred woodcutters
and other forest workers each year. But the peace is a fragile one. The
swelling ranks of urban mosquitoes could easily pick up the virus from the
thousands of rural immigrants who go to the cities seeking work every year,
or even from monkeys that venture close to the city outskirts. To make matters
worse, the mosquitoes have begun to show resistance to many standard insecticides.

‘We’re right back to the situation of the early part of this century,’
says Monath. ‘The mosquito was present in all the coastal towns of Brazil.
The virus was rife in the Amazon forest. And immigrants with no immunity
were coming over in boatloads from the Old World.’

From forest to city

Monath’s interest in yellow fever grew at the US Centers for Disease
Control in Atlanta, where he worked as a virologist for 20 years. OraVax,
the biotechnology company he joined in 1992, specialises in designing oral
vaccines for diarrhoea, hepatitis and stomach cancer, and has no commercial
interest in making or selling yellow fever vaccines. But this doesn’t blunt
Monath’s concern. He estimates that some 121 million people with no immunity
are living in coastal areas of Brazil infested with A. aegypti. And to cap
it all, A. albopictus – which, unlike A. aegypti, is just as happy in the
forest as in the city – is spreading throughout the continent. The fear
is that this mosquito could act as a versatile go-between, transferring
virus from forest to city. ‘Everything,’ Monath warns, ‘is in place for
a major urban outbreak.’

If such an outbreak occurs, then beware of air travel. Monath points
out that an infected passenger could carry the virus in a few hours from
Rio to, say, Miami or New Orleans, where large populations of A. aegypti
have long set up residence. The last urban epidemic to strike the US occurred
in New Orleans in 1905, when 5000 people went down with the disease and
1000 died. Could history repeat itself? ‘Very likely,’ says Monath, ‘although
with the efficient disease surveillance system now in place in the United
States, plus the widespread use of anti-mosquito screening and air conditioning,
the risk is less than it was.’

But this is no reason for complacency, he insists: ‘There’s hardly a
yellow fever expert left in the United States and there’s only one firm
producing small amounts of Food and Drug Administration-approved yellow
fever vaccine.’ The US Institute of Medicine is more precise in its pessimism.
Its recent report on ‘Emerging Infections’ predicts ‘with some confidence
that (in the event of a yellow fever outbreak in New Orleans) 100 000 people
would become ill . . . and 10 000 would likely die within 90 days . . .
(largely) because ‘acceptable’ pesticidal approaches effective for control
of the vector are not available . . . there are no effective drugs and .
. . no US manufacturer could produce sufficient vaccine in a timely fashion’.

Connaught Laboratories in Swiftwater, Pennsylvania, is, it is true,
the only source of vaccine approved for use in the US. A spokesperson for
the company says it produces at least 1 million doses of vaccine a year,
with another 50 000 in stock, plus a ‘considerable amount’ of vaccine in
bulk that could be made ready for use in about a week. Would that be enough
to deal with a putative New Orleans epidemic threatening 500 000 people?
Probably not, says Magrath of the WHO. Globally, he adds, production of
yellow fever vaccine ‘is almost on a cottage industry scale’ and ‘too inflexible
to respond quickly to a major crisis’.

Lethal shortage

UNICEF buys most of the vaccine produced in the world – between 6 and
20 million doses a year, according to the agency’s procurement officer Hyuk-Soo
Kwon. ‘We can usually get the vaccine from the suppliers to the trouble
spot within 48 hours,’ says Kwon, who reckons enough vaccine is being made
to deal with the current spate of large epidemics in Africa, as well as
the much smaller outbreaks in Latin America.

But this doesn’t reassure Monath. ‘It would take just about the whole
world’s vaccine supply simply to deal with an outbreak in, say, Rio or Sao
Paulo.’ Together, these two megacities would need about 25 million doses
of vaccine. And if the current spread of dengue and its mosquito carrier
is any guide, notes Monath, a further 3 million doses might be needed to
vaccinate people in Australia’s Northern Territory and Queensland.

Then there is Asia, where A. aegypti abounds, dengue is rampant and
the size of the population that would require vaccinating is, in Monath’s
words, ‘mind-staggering’.

Ever since the Panama Canal opened in 1914, Asia has felt threatened
by the risk of yellow fever crossing the seas from America (not Africa,
whose eastern seaboard has remained relatively free of the disease). Experiments
have shown that the strains of A. aegypti found in Asia are capable of carrying
the yellow fever virus and of infecting animals. Just why the disease has
not entered Asia remains, as Monath puts it, ‘one of virology’s great mysteries’.

Imperial doctors

Le Duc is far from complacent about the threat of urban yellow fever.
But for him, there is a more immediate problem to tackle in Africa. Ninety-five
per cent of the world’s reported cases occur in Africa and yellow fever
is endemic in 33 of the continent’s 46 countries (see Map). Since France
gave up its African colonies in the early 1960s, vaccination campaigns have
been used only to ‘fire-fight’ epidemics: there have been no attempts to
immunise whole populations before the event. The legacy of earlier French
campaigns lives on, however.

Of the 33 African countries where yellow fever is or could be a problem,
most epidemics have occurred in countries that were never part of the French
empire. Britain’s imperial doctors decided to leave their indigenous subjects
to the mercy of the virus: ostensibly because they were unhappy about the
sometimes fatal side effects caused by the vaccine the French were using
in West Africa – the only vaccine available at the time that was easy enough
to administer in the primitive conditions of the African bush. Among ex-British
African colonies, Nigeria has been particularly hard hit, with nine epidemics
between 1950 and 1991. Ethiopia, Gambia, Ghana and the Sudan have also had
their share of outbreaks. And the latest epidemic in Africa has just ended
in Kenya, with an officially reported 54 cases and 28 deaths.

What most worries Susan Robertson, a medical officer with the WHO’s
Expanded Programme on Immunisation (EPI), is that the proportion of children
affected in these outbreaks appears to be rising with each new epidemic.
‘We have a fabulous vaccine. It gives just about lifelong pro-tection with
a single shot. We’ve had it for the past 50 years. And yet we’re not using
it to protect the millions of African children who risk getting yellow fever
every year.’

With others in the EPI, Robertson is crusading for the inclusion of
the yellow fever vaccine in the immunisation ‘package’ that is currently
given to almost 80 per cent of the world’s children, protecting them against
polio, measles, TB, diphtheria, whooping cough and tetanus. ‘Adding yellow
fever vaccine to the EPI package would be easy,’ she says. As for cost,
researchers estimate that it would add only 65 to 78 cents to the $6 to
$7 tab for the package given to each child. By contrast, vaccinating people
against yellow fever after an outbreak has been estimated, in the case of
Nigeria for example, to cost nearly $8 per person.

Eleven of the 33 high risk African countries have already begun to
vaccinate children, with financial help from a variety of donors. A further
six countries have said they will follow suit. But progress is slow: only
2 million of the estimated 19 million infants in the 33 countries are getting
the vaccine. Monath finds it ‘intolerable that we’ve had to wait up until
now, after so many enormous epidemics and thousands of deaths, for the international
community to take yellow fever seriously’.

Robertson and Le Duc are trying to raise funds not only for the vaccine
– about $5 million a year – but for research, training and laboratory materials
– about $100 000 – to ensure quick and accurate diagnosis of the infection.
Only then, they say, will we get a true idea of its extent. Without fairly
sophisticated laboratory equipment, the disease can be easily mistaken for
other conditions, notably viral hepatitis, malaria, and typhus.

For Africa at least, the international health community seems to be
moving into high gear in the fight against yellow fever. But in the New
World, where the danger is smouldering and could spark global epidemics,
efforts to reduce the risk have barely begun, says Le Duc. The prescription
is as simple as it is clear: improve basic sanitation and water supply,
clear up trash to remove mosquito breeding sites and, where feasible,
immunise people at risk. The only uncertainty is when the world will wake
up to the danger and provide the cash.

John Maurice is a freelance medical writer based in France.

* * *

1: Horror of a deadly virus

‘It’s one of the most terrible diseases you can have,’ says Michel Barme,
currently deputy director of the Pasteur Institute in Paris but with several
years’ first-hand experience of the disease in the African bush when he
worked in the 1960s as a vaccine expert in Senegal. ‘I’d put it third in
the horror list, after rabies and tetanus,’ adds Barme.

The yellow fever virus is one of several hundred known ‘arboviruses’
– viruses that travel and multiply in biting insects, mainly mosquitoes
and ticks, from which they infect animals and humans. About 80 of these
arboviruses cause disease in humans, mostly producing nothing more than
mild flu-like illnesses. But not the yellow fever virus, the smallest and
most deadly of the bunch. It consists of a single strand of the genetic
material RNA packed into a particle encased in a protein-sugar envelope.
It can infect just about any type of cell in the body but has a particular
liking for liver and brain tissue. Having invaded a cell, the virus copies
its genetic information into DNA and then it begins to replicate, making
more and more particles. These eventually destroy the cell and spread to
infect others.

Most patients go through two ‘colourful’ stages of the disease, each
lasting two or three days. First, they have a red congestive stage with
red flushed face and neck, red-tipped tongue, red bleeding nose and gums.
Then, the notorious yellow stage appears which gives the disease its name
– yellow from the jaundice caused by the virus attacking the liver.

Black might just as aptly denote this stage, from the blood that the
patient swallows and vomits or passes in stools as the virus eats its way
into internal organs and causes widespread internal bleeding. Finally, depending
on how the coin falls, the patient either recovers and is awarded with lifelong
immunity to a second attack, or organs fail and the patient goes into coma
and dies. Treatment is merely supportive – bed rest, and drugs to lessen
the fever, pain and vomiting and fluids to prevent dehydration.

* * *

2: Back to the jungle

A century ago scientists discovered that yellow fever is caused by a
virus, the first one to be linked to a human disease. They also discovered
that it is carried by mosquitoes. Immediately, health officers began clearing
cities of any collections of water where the mosquito could breed. Garbage
and trash disappeared from the streets. Patients were surrounded by anti-mosquito
screens, to protect mosquitoes from infection and prevent them from further
spreading the virus.

Thanks to these campaigns, many cities became free of the disease for
the first time in centuries – Havana (1901), Panama City (1904), New Orleans
(1905), Rio de Janeiro (1909). But just after the First World War, epidemics
began to recur. In 1932, yellow fever researchers made a discovery that
helped to explain why. The virus, they found, can infect monkeys in the
jungle with the help of mosquitoes in the forest canopy.

This finding dashed hopes of ever eradicating the disease. Even in cities,
health officials could no longer relax after a rigorous anti-mosquito campaign.
The mosquito-monkey-mosquito cycle would still be ticking over quietly in
the forest.

The discovery of the jungle cycle also suggested that yellow fever is
really a disease of animals and may have existed for thousands of years
in the jungle before humans encountered it. The only consolation is: when
dead monkeys start falling from the tree-tops, forest dwellers now know
that the yellow fever virus must be active in the area.

Good news, though, was just round the corner. In the late 1930s two
yellow fever vaccines became available, one made by the French at the Pasteur
Institute in Dakar, Senegal, the other by American researchers at what was
then called the Rockefeller Institute. Both used live yellow fever virus,
but the French reduced its virulence by successive passages through mouse
brains, whereas the Americans, wishing to wean the virus off its propensity
for brain tissue, passed their vaccine – designated ’17D’, after the virus
strain used – through chick embryonic tissue.

Both vaccines were extremely effective in priming the immune system
against yellow fever. But the American vaccine became inactive very quickly
when exposed to hot conditions and needed to be administered by injection.

By contrast the French vaccine was much easier to use, especially for
mass vaccination in the rough conditions of the tropical bush. Health workers
could give it by scarification at the same time as they scratched smallpox
vaccine into the skin and it could also withstand exposure to heat. And,
indeed, the French neurotropic vaccine more or less extinguished the disease
in the area, having been given to more than 80 million inhabitants of French
West Africa in the 1940s and 1950s. The only problem with the French vaccine
was, in fact, its fondness for brain tissue.

In a significant proportion of children – estimated by some experts
to be around 1 in 1000 but by others as high as 1 per cent – it caused an
inflammatory disease (encephalitis) that was sometimes fatal. It certainly
gave the British a strong argument for not undertaking mass yellow fever
immunisation in their African colonies. When the French pulled out of Africa
in 1959 to 1961, routine yellow fever vaccination came to a halt in many
countries and the French vaccine fell out of use, except for emergency
epidemics, and then, officially at least, only for adults.

In 1982, the Pasteur Institute in Dakar stopped making it and the 17D
vaccine had the field to itself. Although in 1983 the Paris Pasteur Institute
increased 17D’s resistance to heat, health officials still recommend its
use through a ‘cold chain’ or refrigeration system, just in case local health
workers fail to respect its two-week storage limit at 37 °C.

Today, 17D is the only vaccine WHO recommends for travellers and for
people living in areas where the yellow fever virus lurks. Of the 200 million
people vaccinated since 1945 only 19 people have developed encephalitis,
18 of them children, one of whom died.