91É«ÇéƬ

It is Timkat, the holy day in the Ethiopian Orthodox Church that celebrates Christ’s baptism. A crowd of thousands has gathered in Debre Zeit, a small town about 50 kilometres southwest of Addis Ababa in Ethiopia, to watch the priests as they parade beneath a blaze of brightly coloured silk umbrellas. Among the onlookers is a molecular biologist who once taught at the veterinary school here. He is Tilahun Yilma. ‘I was supposed to become a deacon, so as a boy I learnt whole books of verse in Ge’ez,’ says Yilma. ‘It’s the ancient language of our church. I didn’t understand a word of what it meant, but it helped me later on when I had to memorise anatomy.’

The unalloyed Californian in his voice, the camera and casual sports clothes mark him as a man of two cultures. Yilma is one of thousands of Ethiopians who chose exile during the dictatorship of Colonel Mengistu Haile Mariam between 1977 and 1991, when more than a million people died as a result of famine, armed uprisings and state-authorised terror.

Now Yilma has returned to Ethiopia with a modern solution for an ancient plague – a genetically engineered vaccine to eradicate rinderpest, a highly contagious viral disease that affects cattle. The vaccine is easy to administer, and farmers can produce their own supplies of the vaccine without elaborate scientific techniques.

BIGGEST KILLER OF CATTLE

Rinderpest belongs to the Paramyxoviridae family of viruses, and is classified in the morbillivirus genus along with human measles and canine distemper. With a mortality rate of 95 per cent, the virus is considered the biggest killer of cattle in the developing world. Infected animals develop fever, diarrhoea and ulcers, and usually die within a week.

Yilma developed his rinderpest vaccine six years ago. But his critics, who were vociferous, and the sceptics, who were many, combined to embargo field tests. As a result, he spent years persuading the regulatory authorities that his vaccine, which is a vaccinia virus genetically altered in the laboratory by recombinant-DNA technology, would be safe if released into the environment. ‘Science is easy,’ says Yilma, ‘but dealing with bureaucrats is something else. The vaccine was there before the regulatory people had any idea what DNA was. So when you don’t know, the way to deal with it is to block it.’

Thanks to his unswerving determination, however, trials finally began earlier this year at the Kabete Veterinary Laboratories outside the Kenyan capital of Nairobi. With luck and more persistence, testing could start this year in Ethiopia as well.

Rinderpest is not endemic to Africa. It was introduced into Ethiopia during the Italian invasion of 1888 when three infected animals were included among the cattle the Italians shipped to the port of Massawa. From there it spread westwards across the Sahel. Yilma’s grandmother remembered the following year well even though she was only 12. Marked on the Ethiopian calendar as ‘Yekebit Elkit’, the Year of the Annihilation of Cattle, rinderpest wiped out 90 per cent of the cattle as well as wild ruminants such as buffalo, giraffe and antelope. So close is the link between bovine and human survival that up to 60 per cent of the Ethiopian population subsequently starved to death.

Today, the disease is still a scourge in the Middle East, the Indian subcontinent and the African countries that lie between the Sahara and the Equator. The Horn of Africa, however, has the highest prevalence of rinderpest in the world. Herders in these countries have resorted to rearing the tough zebu breeds of cattle which yield little milk but are more resistant to the disease than European breeds. Even so, rinderpest is so endemic that it kills between 50 and 80 per cent of the cattle. Eradicating the disease could transform the poverty-stricken economies of Ethiopia, Sudan and Somalia. Herds would be enlarged, and it would also open the door to European breeds of cattle. The volume of beef and milk produced would increase, and exports of beef to nearby Saudi Arabia and the United Arab Emirates could bring in millions of dollars worth of much-needed foreign currency.

LOGISTICAL NIGHTMARE

Yilma’s obsession with helping Ethiopians become independent of Western aid began nearly 25 years ago. In 1970, fresh from the University of California with a degree in veterinary medicine, he returned home to head a rinderpest programme in the western province of Harar. It was part of a pan-African attempt funded by Britain, Germany, France, Italy, the US and Canada to eradicate the disease. From 1963 to 1971, 124 million cattle were inoculated with a vaccine developed in the 1950s by British vet Walter Plowright, for the East African Veterinary Institute in Kenya.

The control programme was a logistical and administrative nightmare, recalls Yilma. The vaccine, being live, is unstable in hot conditions and has to be kept cold at all times. But Yilma and his staff were operating in remote areas where there was no refrigeration, only tracks for roads and the temperature soared to 45 degreeC.

Rinderpest, however, seemed to be eradicated. Then just over a decade later, the disease broke out again in Nigeria and soon reached epidemic proportions, spreading rapidly across the Sahel to the Red Sea. Along the Ethiopia-Sudan border, vets were unable to vaccinate cattle because of heavy fighting between the Sudanese government forces and rebels from the south of the Sudan. That epidemic killed an estimated $400 million worth of cattle, wiping $1 billion from the economy.

‘To have a disease come back again after all that work and investment was a devastating experience,’ says Yilma. By this time he had added a doctorate in viral microbiology to his credentials and, distressed by the waste laid to Africa’s development by disease, he decided to develop a vaccine that could easily be reproduced by cattle herders, even in the mayhem of war zones.

Theoretically, the Plowright vaccine was capable of achieving the goal of eradicating rinderpest. However, the vaccine does not lend itself to widespread use on the African continent. Apart from the lack of refrigeration in the field, developing countries do not have the funds for syringes, needles and the vaccine itself; nor the veterinary manpower needed to administer a control programme. Many also lack the facilities for tissue culture that are needed to produce the vaccine in large quantities.

By contrast, the vaccine that emerged from Yilma’s laboratory in the Department of Veterinary Microbiology and Immunology at the University of California at Davis is extremely efficient under the challenging circumstances in Ethiopia and other African countries. Using the techniques of recombinant DNA technology, he has genetically engineered a vaccine that is heat stable, easy to produce, easy to administer and cheap.

A chance encounter in 1983 with Genentech, the first commercial biotechnology company, was a pivotal moment in the development of the vaccine. At the time, Yilma was working at Washington State University, doing research on horses and the role of interferon in immunodeficiency diseases, specifically severe combined immunodeficiency (SCID). Both horses and children can suffer from this illness which is sometimes known as the bubble-boy disease because its most famous victim was encased in a protective plastic bubble.

Genentech had used recombinant-DNA technology to genetically engineer an interferon protein against cancer. When Yilma requested some of this interferon for his own studies, Genentech’s response was to ask him to assist in gathering clinical data on the antiviral activity of interferon. The company was up against a deadline to present these data to the US Food and Drug Administration for the approval needed to market the interferon commercially.

Virologists at two universities in the US had failed to come up with the required data, and the deadline was two months away. Genentech was sufficiently impressed with Yilma’s work (and probably sufficiently desperate) to ask him to have a go. When he succeeded in two weeks, a grateful Genentech agreed to teach him the techniques of molecular biology in his two-month summer break. Delighted by the opportunity to be taught in a field that he thought could provide the means for developing a rinderpest vaccine, he worked 15-hour days.

Three years later, the US Agency for International Development (USAID) received its first funds from Congress for research in molecular biology. Yilma told the agency that if he could have some of the money he would develop a rinderpest vaccine. The USAID was sufficiently impressed to give him a grant for $900 000, its entire allocation. It also stipulated that he find a partner in the private sector, a difficult task because the agency retains the patent of any discovery it funds. But eventually Scios, a biotechnological company based in Mountain View near Stanford, California, agreed to forgo the patent right.

It took Yilma just one year to achieve his goal. The vaccinia virus – which formed the basis of vaccinations against smallpox – provides the foundation for his vaccine. This handy virus is much appreciated by genetic engineers because it is easily manipulated to incorporate foreign genes and then manufactures the proteins they describe.

PROTEIN TRIGGERS

His next step was to identify the proteins on the surface of the rinderpest virus that trigger immune reactions in cattle. Of the eight proteins he identified, two stood out: the haemagglutinin (H) and fusion (F) proteins. The H protein allows the virus to attach to a cell in the host. Once the virus has infected the cell, the F protein fuses the membrane of that cell to other cells, so the infection can spread while sealed off from the host’s immune system. Erling Norrby, of the Department of Virology at the Karolinska Institute in Stockholm, had already demonstrated that these two proteins stimulated the immune system to produce antibodies against measles.

As the rinderpest and measles viruses are related, Yilma extrapolated that the proteins might work against rinderpest as well. He took the genes that code for these two proteins, and spliced them onto the vaccinia virus. By piggybacking the H and F genes onto the vaccinia virus, Yilma designed a vaccine that stimulates the host’s immune system to make antibodies to the H and F proteins, conferring immunity against the rinderpest virus.

In three separate studies, Charles Mebus of the US Department of Agriculture’s Animal and Plant 91É«ÇéƬ Inspection Service (APHIS) tested the vaccine at the Plum Island Animal Disease Center in New York. In all, he inoculated 46 animals, and found they were completely protected from the disease, even when exposed to 1000 times the lethal dose of the rinderpest virus.

Meanwhile, Yilma set about making sure that his modified vaccinia virus was pure before making a master seed stock. Later, when released for general use, the virus can be grown by tissue culture in laboratories, freeze-dried and transported at any temperature in a small phial.

The beauty of this technique is that the vaccine is cheap and easy to use: a herder has only to add water to the phial, give it a good shake and it’s ready. The vaccine can be administered by a simple scratch and is not sensitive to heat or light. And because the vaccinia virus proliferates in skin cells, herders can grow their own supply by inoculating an animal in the abdomen and scraping it once a scab has developed. This yields 250 000 doses.

Transferring the technology to Africa was now in his sights but approval in scientific circles was to remain tantalisingly elusive for several more years. For his optimism was not matched by the five regulatory agencies whose approval he needed for field trials and commercial use. He had to run the gauntlet of the USAID and the APHIS within the US as well as the WHO, the Food and Agricultural Organization and the Office Internationale des Epizooties in Paris.

The scientists who sat on the screening committees were a cautious breed from the old guard of live tissue culture. Unfamiliar with the premise of using snippets of molecular thread to create a vaccine, they were not only suspicious but, in some cases, downright antagonistic.

Unfortunately for Yilma, the approval process for genetically engineered vaccines was already a battleground. When the US Department of Agriculture gave the go-ahead for a vaccine for the pig disease pseudorabies in 1987, the genetic activist Jeremy Rifkin tried to prevent it being released on the grounds that it could be harmful to the environment. Rifkin eventually lost the court battle but his manoeuvring made regulatory officials, particularly those in the USAID, wary of becoming embroiled in further legal wrangles.

To make matters worse, Hilary Koprowski of the Wistar Institute of Anatomy and Biology in Philadelphia, who had developed a genetically engineered vaccine against rabies, bypassed the approval process and in 1986 tested the vaccine on cattle in Argentina without the permission of the US government.

In the end, Koprowski’s rabies vaccine was released in Belgium in 1987. Meat baited with vaccine was scattered round the countryside from aeroplanes and eaten by foxes. By last year, rabies was eradicated in Belgium, and the project is now being expanded into France and Germany. This programme, however, is funded by the EU, which does not co-finance research projects that originate in the US. Yilma knew he needed the continued backing of the USAID for his field trials. He could not afford to lose the agency’s support by taking his work to Europe.

Rifkin has a dual reputation as saviour and fanatic, depending on which camp scientists sit in. But regardless of opinion, he is still a force to be reckoned with. He is currently marshalling his resources to make it illegal for a potential employer or insurer to obtain a lock of someone’s hair, fingernail cutting or blood sample. Analysis of the DNA in these samples, Rifkin points out, would reveal whether an individual is at risk of contracting one of many debilitating diseases that could make him or her a costly employee or poor insurance risk.

In the case of the rinderpest vaccine, the principal protagonist has been Margaret Mellon, a molecular biologist turned lawyer and spokeswoman for a watchdog group called Concerned Scientists. Wary personnel in the USAID drafted her onto the approval committee. Like Rifkin, she argued vociferously that letting genetically engineered genes loose in the environment was dangerous. Her chief objection was to the use of the rinderpest vaccine where there was a high prevalence of people who were HIV positive.

ACCIDENTAL SCRATCHES

When the vaccinia virus was used as a vaccine during the global programme to eradicate smallpox, two or three people in every million inoculated had weakened immune systems and suffered adverse reactions such as swollen glands. If a herder with HIV accidentally scratched himself with the rinderpest vaccine, Mellon argued, it would have an adverse effect on his immune system. Yilma countered this objection by inactivating the TK and HA genes in his vaccinia virus, which reduced the potency of the vaccine tenfold. Privately, he pointed out that the chance of someone accidentally injecting themselves and suffering complications, given known statistics, was two or three per 30 billion inoculations.

Further objections were put up by the WHO and APHIS. Both agencies gave the thumbs down to the strain of vaccinia Yilma had used, because it had proved to be highly neurovirulent when tested on mice – it inflamed the brain and they died of encephalitis. The extreme virulence was the reason Yilma had used the strain, but he agreed to make the vaccine again with an attenuated strain of vaccinia that had been used during the smallpox eradication campaign.

In all, Yilma lobbied the regulatory agencies with diplomacy and dogged determination for five years. The final obstacle was overcome with the appointment of a new USAID committee that included younger scientists familiar with genetic engineering. In June last year, they approved his vaccine and pronounced it fit for field tests.

But the battle is not yet won. Mellon has requested all the approval documents to muster her artillery for a skirmish in the courts. She plans to seek an injunction against tests that are being carried out in Kenya. This may be the reason why the USAID has refused funding for similar tests in Ethiopia.

Yilma, though, is undeterred by the slow recognition of his achievements. ‘Margaret Mellon, eat your heart out. The gene is out of the bottle and in Africa at last,’ he said.

Mary Anne Fitzgerald has been a correspondent in Africa for the past 15 years, writing for The Financial Times, The Independent and The Sunday Times, and is author of Naomd (Picador 5.99 Pounds Sterling)