Project 523

Background

The Vietnam War was fought between the North Vietnam (supported by the Communist countries such as Soviet Union and China) and the South Vietnam (supported by the United States and its allies). The conflicts started in 1954 and became large-scale battles by 1961. Although in a better warfare position, the People's Army of Vietnam (North Vietnamese Army) and its allies in the South, Viet Cong, suffered increasing mortality because of malaria epidemics. In some battle fields military strengths were reduced to half of the original, and in severe cases 90% of the troops were disabled. Hồ Chí Minh, Prime Minister of the Democratic Republic of Vietnam (then North Vietnam), asked his compatriot Zhou Enlai, the Premier of the People's Republic of China, for medical help. By that time Mao Zedong, the Chairman of the Communist Party of China, had just introduced Cultural Revolution (1966-1971) which had resulted in closing of universities and banishment of many scientists and intellectuals. Mao, however, took Hồ Chí Minh's plea seriously and approved a military project. On 23 May 1967 a mass gathering of about 600 scientists was convened that included military personnel, scientists of different trades, including traditional practitioners. The meeting was the beginning of the military-research programme, code-named Project 523, simply named after the date (23 May) it was launched. The project was divided into two streams, one for developing synthetic compounds, and the other for investigating traditional Chinese medicine. It was classified a top secret state mission. The project itself saved many scientists from the atrocities of Cultural Revolution.

Execution and achievements

As the first line strategy, the troops were given synthetic drugs. Drug combinations using pyrimethamine and dapsone, pyrimethamine and sulfadoxine, and sulfadoxine and piperaquine phosphate were tested in the battlefield. But these drug had serious adverse effects. Therefore, the primary focus was to examine traditional Chinese medicines and look for new compounds. The first drug of interest was changshan, which was depicted in the earliest materia medica, the Canon of the Divine Husbandman’s Materia Medica. It is an extract from the roots of the plant Dichroa febrifuga. Among one of the earliest examined plants was huanghuahao (sweet wormwood, or scientifically, Artemisia annua). These two plants became a huge success in modern pharmacology.

Febrifugine from changshan

The first interest was on changshan, the root extract of Dichroa febrifuga. In the 1940s Chinese scientists had shown that changshan was effective against different species of Plasmodium. American scientists isolated febrifugine as its major active antimalarial compound. The project scientists confirmed the antimalarial activity, but found that it was so potent and toxic—much more potent than quinine—that it was unsuitable for human use. (After the project, the compound is still under investigation with attempts to discover suitable derivatives, among which halofuginone is shown to be an effective drug in malaria, cancer, fibrosis and inflammatory disease.)

Discovery of artemisinin and its derivatives

Artemisia annua extract, called qinghao, was described vividly in the fourth-century Chinese physician Ge Hong's book Zhouhou Beiji Fang (The Handbook of Prescriptions for Emergencies) as a treatment of malarial fever. Tu Youyou and her team were the first to investigate. In 1971 they found that their extract from the dried leaves (collected from Beijing) did not indicate any antimalarial activity. On careful reading of Ge Hong's description they changed their extraction method of using fresh leaves under low temperature. Ge Hong explicitly describes the recipe as: "qinghao, one bunch, take two sheng [2 × 0.2 l] of water for soaking it, wring it out, take the juice, ingest it in its entirety". They found that the fresh plant specimen collected from Sichuan province only could yield the active compound. They made the purified extract into tablets, which but showed very low activity. They soon realized that the compound was very insoluble, and hence, made it in capsules. On 8 March 1972 they reported successful treatment of malaria in experimentally infected mice using the new extract. In August 1972 they reported clinical trial in which 21 malarial patients were cured. In 1973 scientists at the Yunnan Institute of Materia Medica and Shandong Institute of Traditional Medicine and Materia Medica obtained the antimalarial compound in a crystalline form gave the name huanghaosu or huanghuahaosu, which was eventually renamed qinghaosu (yet later to be popularised as artemisinin, after the botanical name). (The chemical structure of artemisinin was worked out only in 1975, and published in 1977.) The same year Tu synthesized the compound dihydroartemisinin from the extract. This compound was more soluble and potent than native compound. Other derivatives artemisinin derivatives were also subsequently synthesized by other workers, of which the most important are artemether and artesunate. All clinical trials by this time confirmed that artemisinins are more effective than the conventional antimalarial drugs, such as chloroquine and quinine. They are now recognised not only as the most potent, but also as the safest and rapidly acting antimalarial drugs.

Artesunate and its combination drugs

Artesunate is synthesized from dihydroartemisinin (DHA) using succinic acid. It is exceptionally chemically stable, and hence, is the only drug among artemisins produced in oral tablets, rectal capsule and intravenous injection. Clinical trials have shown that it is the most potent drug for severe malaria due to Plasmodium falciparum. The World Health Organization has specifically adopted it in 2006 as the only drug for first line treatment of complicated malaria (but in combination with other antimalarials to prevent drug resistance), and is included in the World Health Organization's List of Essential Medicines. Artesunate combination drugs (such as artesunate/amodiaquine and artesunate/mefloquine) are more effective than artemether-based drugs.

Discovery of synthetic drugs

The Project 523 also resulted in the discovery of synthetic drugs such as pyronaridine in 1973, lumefantrine in 1976 and naphthoquine in 1986. These are all antimalarial drugs and are used in artemisinin-combination therapy.

Termination and aftermath

After the fall of Saigon on 30 April 1975, ending the Vietnam War, the military purpose of Project 523 was subsiding. Researchers were not allowed to publish their finding, but were allowed to share their works within the working groups. The first publication in English (and thus circulated outside China) was in the December 1979 issue of the Chinese Medical Journal, authored simply by the Qinghaosu Antimalaria Coordinating Research Group. This attracted the Special Programme for Research and Training in Tropical Diseases (TDR), sponsored by the United Nations Children’s Fund, the United Nations Development Programme, the World Bank and WHO, to collaborate, but the research was not yet open to non-Chinese scientists. By the early 1980s research had practically stopped, and the project was officially terminated in 1981. Then the TDR took the opportunity and organised the first international conference in Beijing on artemisinin and its variants in 1981. Supported by WHO, the Chinese Ministry of Health established the National Chinese Steering Committee for Development of Qinghaosu and its Derivatives to continue the important achievements of Project 523.

The first international collaboration was between Keith Arnold at the Roche Far East Research Foundation, Hong Kong, and Chinese researchers, Jing-Bo Jiang, Xing-Bo Guo, Guo-Qiao Li, and Yun Cheung Kong. They made their first international publication in 1982 in The Lancet, whereby they reported the comparative efficacy of artemisinin and mefloquine on chloroquine-resistant Plasmodium falciparum. (Keith Arnold was among those who developed mefloquine in 1979, and was planning to test the new drug in China. He and his wife Moui became the most important people in translating the historical account of the Project 523 and bringing it to international recognition.) The Division of Experimental Therapeutics at the Walter Reed Army Institute of Research, under the United States Army, was the first to produce artemisinin and its derivatives outside China. Their production paved the way for commercial success.

Invention of Coartem

Artemether was more promising for clinical drug than its parent molecule artemisinin. In 1981 the National Steering Committee for Development of Qinghaosu (artemisinin) and its Derivatives authorised Zhou Yiqing, who was working at the Institute of Microbiology and Epidemiology of the Chinese Academy of Military Medical Sciences, to work on artemether. Zhou showed that artemether combined with another antimalarial lumefantrine was the most potent of all antimalarial drugs. He worked alone for four years, and was joined by Ning Dianxi and his team in 1985. They found that in clinical trials the combined tablet had very high cure rate of severe malaria, more than 95%, including in areas where multi-drug resistance is experienced. They applied for patent in 1991, but was granted only in 2002. In 1992 they got it registered as a new drug in China. Noticing this, Novartis signed a pack for mass production. In 1999 Novartis obtained the international licensing rights and gave the brand name Coartem. The drug was approved by the US Food and Drug Administration in 2009.