Dr. Greenwood-Lecture at the United Nations University, Tokyo

INTRODUCTION

I am very pleased to have been invited to give this lecture at the United Nations University as part of the celebrations to honour the life and work of Dr. Hideyo Noguchi [SLIDE 2] (PDF:211KB). I first learnt about the career of Dr. Noguchi when I was a medical student at Cambridge University in England 50 years ago. I have always been interested in infectious disease so it is no surprise that I came across his name in my student days as Dr.Noguchi ranks among the most famous microbiologists of the first part of the twentieth century. However, I never imagined that he would be playing such an important part in my own career although, in recent years, I have been frequently reminded of his name as I am a regular visitor to the research laboratories in Accra, Ghana [SLIDE 3] (PDF:207KB)established and supported by the Government of Japan to recognise the ultimate sacrifice that he made whilst trying to determine the cause of yellow fever. I am greatly honoured to be one of the first two recipients of the Africa prize established in his name and I am extremely grateful to the Government and people of Japan for having awarded me this prestigious prize named in his honour and to all the people who have made this and my visit to Japan possible.

I have chosen control of malaria as the subject of my lecture, as this is a topic which is currently receiving a great deal of attention from those who guide and finance international health, and the possibility of eradicating malaria is, once again, being discussed. I don't think that Dr. Noguchi worked directly on malaria himself but during his visits to the tropics, including his last visit to Ghana, he would certainly have been familiar with malaria and the consequences of this devastating infection.

THE MALARIA LIFE CYCLE

Before progressing to the main part of my lecture, I thought that it might be helpful to remind those of you who do not work on infectious diseases of the life cycle of the malaria parasite [SLIDE 4] (PDF:116KB). Malaria is a protozoan parasite transmitted to man by the bite of a female anopheline mosquito, which can usually be recognised because of its characteristic posture. An infected mosquito initiates the infection when it injects sporozoites with its saliva whilst feeding on a human host. A small number, usually 10 - 100, inoculated sporozoites pass through the blood stream to reach the liver where each invades a liver cell, often passing through two or three, before settling down to develop into a schizont. After maturing for a period of about 10 days in the liver, each schizont ruptures to release many thousands of merozoites which invade red blood cells. Further multiplication of the parasite occurs within an infected red blood cell which ruptures after a period of 48 or 72 hours, depending upon the species of parasite, to propagate another round of the infection. It is this stage of the parasite's life cycle that is responsible for the clinical features of malaria - fever, anaemia and sometimes more serious complications. Some merozoites escaping from the liver develop into sexual stages - male or female gametocytes. These may be taken up by another mosquito biting an infected patient. Fertilisation takes place within the stomach of the mosquito where the parasite passes through a number of further developmental stages in the wall of the mosquito's stomach before once again reaching the salivary gland to repeat the cycle. The complete cycle from sporozoite to sporozoite takes about 3 weeks.

Five species of malaria parasite can infect man. Plasmodium falciparum is the most feared because red blood cells infected with this parasite stick to the endothelial lining of small blood vessels causing cerebral malaria and damage to other organs as shown in the next slide [SLIDE 5] (PDF:204KB). P. vivax is the second most important malaria parasite of man. Although this parasite causes severe disease less frequently than P. falciparum, it has an extra stage in its life cycle which is likely to make this parasite particularly difficult to eliminate. Following infection of the liver, some P. vivax sporozoites develop into sleeping forms' hypnozoites, shown in the next slide [SLIDE 6] (PDF:57KB), which may persist for many months or years without the subject knowing that he or she is infected.

THE BURDEN OF MALARIA

Malaria remains one of the world's most important infectious diseases, despite enhanced efforts to control the infection. It has recently been estimated that approximately 2. 6 billion of the world's 6 billion population are still at some risk of malaria and that for over 1 billion people this risk is medium or high. Malaria is currently concentrated in the tropics and sub-tropics as shown in the next slide [SLIDE 7] (PDF:90KB)but it was once prevalent in countries with a temperate climate such as the UK, the United States and Japan. Malaria still causes about one million deaths a year, as indicated in the next slide [SLIDE 8] (PDF:32KB), and about 90% of these deaths occur among children in Africa. It is estimated that about 500 million clinical episodes of malaria occur each year. In many parts of Africa, young children experience one or more attacks of malaria every year and malaria is the most frequent cause of attendance at outpatient clinics and of admissions to paediatric wards. Pregnant women [SLIDE 9] (PDF:128KB)are especially at risk from malaria. Malaria can cause severe anaemia in pregnant women, which can sometimes lead to death, and the harmful effects of malaria in pregnancy may be passed on to the next generation. Malaria is an important cause of low birth weight which is an important risk factor for infant death.
The effects of malaria are not restricted to just the direct medical ones. There is increasing evidence of the importance of malaria in schoolchildren in Africa [SLIDE 10] (PDF:46KB).
Malaria, together with other infections such as hookworm and schistosomiasis, can cause anaemia in children which may reduce their attendance at school and impair their school performance. Exciting recent work by my colleagues at the London School of Tropical Medicine and Hygiene has shown that preventing malaria by giving prophylactic treatment improved the academic performance of Kenyan school children. Malaria in adults can impair work performance and Professor Jeffery Sachs has presented evidence, shown in the next slide [SLIDE 11] (PDF:14KB), that over a period of 25 years, economic performance in countries where malaria is prevalent was, on average, 1.8% less than in countries with a similar social background where malaria does not occur. Control of malaria will reduce the direct burden on the health system but it will also have an indirect effect on economic progress and development.

PAST ATTEMPTS AT MALARIA CONTROL AND ERADICATION

Definitions

Before reviewing past attempts at malaria eradication I need to define the terms that I will use in the rest of my lecture, shown in the next slide [SLIDE 12] (PDF:11KB)as these are often used in a rather indiscriminate and confusing way.
Malaria control: malaria control describes the situation in which malaria is no longer an important clinical problem but in which transmission of the infection continues to occur.
Malaria elimination: malaria elimination, which may be national or regional, describes the situation in which local transmission of malaria has been interrupted. Malaria cases may continue to occur but only as a result of importation from another region or country. This is the situation in countries such as Japan or the UK.
Malaria eradication: this term describes the situation in which transmission of malaria had been interrupted across the world with complete cessation of all transmission - the situation for smallpox and perhaps soon to be the case for guinea worm infection and poliomyelitis - but still far away for malaria.

Phases of malaria control and attempted eradication
Attempts have been made to control malaria for hundreds of years and these can conveniently be divided into five phases which are shown in my next slide [SLIDE 13] (PDF:12KB).

Early phase

Even before the malaria parasite was discovered or the mode of malaria transmission by mosquitoes discovered it was known that malaria was associated with marshes - hence its French name of 'paludisme', paludéen being French for marshy - and the wealthy tried to live away from marshes to protect themselves from the disease. In Europe, many marshes were drained in the eighteenth and nineteenth centuries for agricultural purposes and this contributed to a decline in the incidence of malaria, as did urbanisation. The efficacy of theses general measures in controlling malaria is illustrated by experience in England, shown in the next slide [SLIDE 14] (PDF:83KB), where malaria was largely brought under control before the malaria parasite was discovered or before it was known that malaria was transmitted by mosquitoes.

Focal control programmes

Once the cause of malaria and its mode of transmission had been established, it was possible to mount more focussed control programmes directed at the parasite or its vector and there were a number of early successes. One famous example is that of Panama where Gorgas controlled malaria and yellow fever [SLIDE 15] (PDF:183KB)using a variety of measures, including attacks on the vector and mass drug administration with quinine. These public health interventions permitted completion of the construction of the canal, the first attempt having failed because of the high mortality and morbidity among the work force from malaria and yellow fever. A second widely cited success is that of Soper, shown in [SLIDE 16] (PDF:174KB), who succeeded in eradicating Anopheles gambiae, the main vector of malaria in Africa, from north eastern Brazil after the mosquito had been accidentally introduced from Africa. This required a massive effort and a large work force to eliminate the breeding sites of the mosquito.
Despite successes in controlling malaria in northern Europe during the early part of the 20th century, malaria remained a major problem in many parts of southern Europe and it is often not appreciated that 100 years ago malaria was as devastating a condition in southern Italy as is the case in many parts of Africa today. The ways in which malaria was finally brought under control in Italy, some of which are shown in [SLIDE 17] (PDF:182KB), have recently been reviewed in an excellent book by Professor Frank Snowden, a historian at Yale University. Many approaches were tried including mass administration of quinine and other antimalarial drugs, draining of swamps, improvements in housing 'bonification' and finally use of DDT spraying. It emerged during the course of this long campaign that education and involvement of the community were keys to success, an important lesson for today.

The Global Malaria Eradication Programme

Encouraged by the local successes described above and stimulated by the discovery of chloroquine and DDT, which seemed to have almost magical effects on anopheline mosquitoes, WHO launched a very ambitious malaria eradication programme in 1959 which was to last for another 15 years [SLIDE 18] (PDF:32KB). Although called a malaria eradication programme, eradication is not what was attempted. No serious effort was made to eliminate malaria in Africa so according to the definitions which we use today this was a regional malaria elimination programme not an eradication programme. Although the malaria eradication programme is often considered to have been an expensive failure it was a success if considered as a regional malaria elimination programme. As a result of the programme, the risk of malaria was removed from a population of about 1 billion people, as shown in the next slide [SLIDE 19] (PDF:187KB), and major reductions in the incidence of malaria were achieved in the Indian sub-continent, in particular in Sri Lanka where dramatic results were achieved with indoor residual spraying with DDT as shown in the next slide [SLIDE 20] (PDF:57KB). In 1966, only 18 cases were reported. However, complete interruption of transmission (elimination) was not achieved. Furthermore, increasing resistance to repeated rounds of indoor residual spraying with insecticides emerged, both biological resistance within the mosquito vectors and resistance among the people to the inconvenience of repeated rounds of household spraying when malaria had largely disappeared. Some of the reasons why the malaria eradication programme was abandoned in 1966 are summarised in the next slide [SLIDE 21] (PDF:13KB).

Deterioration of the malaria situation

Abandonment of the global malaria eradication programme by WHO and its replacement with a policy of malaria control through the provision of treatment in the community [SLIDE 22] (PDF:40KB)led to a loss of interest in malaria among the international community and to the progressive deterioration of the malaria situation, especially in Africa, as shown in the next slide [SLIDE 23] (PDF:18KB). This slide shows that although overall child mortality in Africa decreased markedly during the period between 1960 and 1995, mortality from malaria increased. Wars and civil disturbances contributed to this deteriorating situation in Africa but the most important factor was the emergence and spread across Africa during the early 1990s of resistance of P. falciparum to chloroquine and sulphadoxine /pyrimethamine (SP), the drugs with which community health workers were expected to control the infection. Malaria is too complex a problem to be left to community health workers, working alone with little support and armed with only a few, partially effective drugs.

A re-awakening of interest in malaria control

About 10 years ago, after a 25 year period of neglect, malaria once again moved up the list of priorities for the international community. Factors that may have contributed to this change are a general acceptance by richer nations of their global responsibilities to less privileged communities, an appreciation that malaria was holding back the economic development of Africa and the HIV epidemic, which drew attention to Africa where HIV infection is most prevalent.
Whatever the reason for this change in attitude, the importance of controlling malaria is now widely accepted by the leaders of the rich, industrialised countries who are in a position to make a difference, such as those of the G8 group [SLIDE 24] (PDF:43KB). Malaria control now has strong political support. However, political support is of little value unless backed up with money, so that a key factor in moving forward malaria control was the creation of Global Fund to fight AIDS, Tuberculosis and Malaria in 2002 [SLIDE 25] (PDF:48KB). This fund arose from an initiative started by the Government of Japan at the G8 summit in Okinawa and it has been very successful in supporting the scaling up of effective interventions against AIDS, malaria and tuberculosis. In the case of malaria, the Fund has provided about $2.5 billion over the past five years. Major new investments in malaria control have also come from the recently established US President's Malaria Initiative and from the World Bank's Global Strategy and Booster Program. Financial support for malaria control from these and other bilateral donors is now approaching $1 billion a year. This is still not enough, a sum of about $5 billion is thought to be required for an effective global elimination programme, but $1 billion a year for malaria control is about 20 times the amount that was available 10 years ago.
Ensuring that the large sums of money that are now available for malaria control are used wisely requires effective co-ordination between the many groups involved in malaria control. The Roll Back Malaria Partnership [SLIDE 26] (PDF:54KB), a partnership between WHO, UNICEF, UNDP and the World Bank, was established in 1998 to help in this process. RBM initially struggled to find its niche but the partnership, which has been expanded to include the private sector and non-governmental organisations, is now playing a key role in moving forward the global malaria control agenda.
The last 10 years has also seen a substantial increase in support for malaria research which, until about 10 years ago, was of interest to only a few enthusiasts such as myself and poorly funded. The key event that changed this situation was probably a meeting held in Dakar, Senegal in 1997 [SLIDE 27] (PDF:81B)which brought together about 150 scientists from Africa and industrialised countries under the guidance of Dr. Harold Varmus, then director of the NIH, to develop an agreed agenda for malaria research. The strong support for this meeting and the activities that followed it given by Dr. Varmus, a Nobel laureate and at that time probably the most influential person in medical research in the world, sent a strong message to the donor community that research on malaria should not be seen as an academic backwater but as a key component of the world's global research agenda. The establishment three years later of the Bill and Melinda Gates Foundation has helped to make this a reality. During the past seven years, the Foundation has spent nearly $700 million on malaria research including $152 million in 2007.

RECENT SUCESSES IN MALARIA CONTROL

The recent increase in funding for malaria control has been used largely to support scaling up of treatment programmes and vector control using insecticide treated bednets (ITNs) or household indoor residual spraying (IRS). Drugs based on the plant Artemisia annua [SLIDE 28] (PDF:33KB)have now replaced chloroquine as first line treatment for malaria and there has been a belated recognition by the malaria community that, as in the case of tuberculosis and HIV, antimalarial drugs should be given in combinations to prevent the emergence of resistance. Administration of sulphadoxine/pyrimethamine (SP) to pregnant women on two or three occasions during pregnancy [SLIDE 29] (PDF:128KB)is recommended by WHO as this reduces maternal anaemia and low birth weight but this approach is threatened by the emergence of resistance to SP. ITNs [SLIDE 30] (PDF:80KB)are the main new addition to the malaria control toolbox. Initial problems over the need to retreat nets with insecticide at regular intervals has been overcome by the incorporation of insecticide into the netting fibre to create long-lasting nets. Japanese manufacturers have played a key role in the development of long lasting nets. Sumitomo recently established a factory for making these nets in Arusha, Tanzania and I understand that there are plans for another factory in Nigeria.
Scaling up the use of these simple interventions is already beginning to have an effect and there have been recent reports from several countries in Africa with medium or high levels of malaria transmission, including Eritrea, Kenya, Rwanda, Tanzania, southern Mozambique, The Gambia and Zambia, that the incidence of malaria is going down. An example of what has happened on the island of Zanzibar off the east coast of Africa is shown in the next slide [SLIDE 31] (PDF:73KB). Following the introduction of treatment with artemisinin combination therapy, there was a marked fall in the incidence of malaria which became even more marked when insecticide treated nets and indoor residual spraying were introduced. In South East Asia, malaria has been successfully controlled in Vietnam and progress is being made in neighbouring Cambodia although there are worrying reports of resistance to artemisinins in this country.

A NEW MALARIA ELIMINATION PROGRAMME

These recent successes in malaria control, and an appreciation that, in the end, control of malaria rather than its elimination is simply not good enough led to a surprise announcement by Bill and Melinda Gates [SLIDE 32] (PDF:124KB)at a meeting in Seattle on October 17th 2007 that their Foundation is now committed to the elimination of malaria. This ambitious declaration has been fully supported by Dr. Chan, the Director General of the WHO and by the Rollback Malaria Partnership so elimination of malaria is now the official goal. This declaration has invigorated the malaria research and control communities which had, perhaps, become a little complacent that malaria control is the best that can be achieved and, during the months since the Seattle announcement, a number of discussions and working groups have met to discuss how to take this ambitious agenda a step forward.
Are the tools currently available up to the job of interrupting malaria transmission?
The consensus is that this may be possible in areas where the transmission of malaria is unstable or relatively low. During the past few years, with little publicity, malaria has been almost eliminated from many countries in north Africa and the middle east, including Iraq [SLIDE 33] (PDF:73KB)and, in 2007, the United Arab Emirates were officially declared malaria free by WHO. Further progress in eliminating malaria from these parts of the world can be expected in the near future. Expansion of the elimination programme is likely to focus on additional areas where this might be easiest to do such as the South Pacific, including Vanuatu and the Solomon Islands, and southern Africa. The experience of Japanese scientists in successfully eliminating malaria from Okinawa and the island of Aneityum in Vanuatu will be valuable in determining how best this might be done. There is a good chance that with sufficient commitment and provision of adequate financial resources, elimination of malaria in these areas will be possible, although not easy, and it may, therefore, be possible to roll back malaria from the edges towards its heartlands in central Africa and Asia. In these areas, additional new tools will probably be needed to interrupt transmission. What these new tools might be is illustrated in the next slide [SLIDE 34] (PDF:103KB). New drugs are needed which will kill the sexual stages of the parasite and the sleeping forms of P. vivax. These drugs must be extremely safe so that they can be used in mass treatment campaigns during which they will be given to large numbers of people who do not have malaria. Vaccines are needed which will not only provide protection against the clinical effects of the parasite but also induce immune responses to the developmental stages of the parasite and thus stop transmission. Any sporozoite or blood stage vaccine that was highly effective would help in interrupting transmission if deployed across the whole population but vaccines which are particularly targeted at the sexual stages of the parasite ' transmission blocking vaccines' are especially important in this regard. Development of this kind of malaria vaccine has not previously received much support and now needs more attention. Genetic engineering of mosquitoes to make them resistant to malaria is another promising approach. However, it is unlikely that any of these new tools will be available for widespread deployment within the next five years. Success will not be achieved in many countries unless the health services needed to deliver these new tools are substantially improved.

CONCLUSION

My predictions, summarised in the next slide [SLIDE 35] (PDF:39KB), are that during the next 10 years, malaria elimination will be achieved in a number of countries on the margins of the areas of highest transmission in Africa and Asia. In areas of high transmission it should be possible to achieve a much greater degree of control over the clinical effects of malaria than is the case today but interruption of transmission is likely to require the development and deployment of new tools and it is likely to be at least 5-10 years before these are ready for deployment.

ACKNOWLEDGMENTS AND THANK YOU'S

[SLIDE 36] (PDF:158KB).