1.2 Parasites and vectors - History of malaria

Question 1

Aims

Answer 1

To describe the most important events in the history of malaria from the origins of human malaria to the present day.

Question 2

Objectives

Answer 2

After working through this session, you should be able toDescribe the main events that have led to our present knowledge of malaria.Explain why particular events occurred when they did.List the most important people involved and the discoveries they made.Explain the background to current concepts of malariacontrol.

Question 3

Introduction

Answer 3

This session describes the most important events in the history of malaria, beginning with speculation about the origins of human malaria parasites in primates and the spread of malaria throughout the world in prehistoric times.The story continues through the written record of 4000 years of human knowledge of malaria as afebriledisease associated with swamps, to the discovery of the parasite and the elucidation of the life-cycle at the end of the 19thcentury.Finally, the history of malaria is brought more up to date with descriptions of the events of the 20thcentury including reference to ideas about control of the disease that have proved effective in the 21stcentury.Humans inherited four of the five parasites belonging to the genusPlasmodiumfrom primate ancestors in sub-Saharan Africa. These four species that we harbour today,P.vivax, P.ovale, P. malariae and P.falciparum, evolved and spread with the migrations of the human race throughout the world.The fifth species, Plasmodium knowlesi,is different. It is azoonosisand is acquired from macaque monkeys in South-East Asia. It is only in recent times that it has been known as a parasite that infects humans. We know about the existence of malaria as a disease from the earliest written records and thereafter throughout history.The first evidence of malaria parasites is reputedly from mosquitoes preserved in amber about 30 million years ago.

Question 4

Introduction

Answer 4

From the earliest times, humans associated malaria fevers with swampy conditions, but it was not until the end of the 19th century that the parasites themselves were seen in the blood for the first time.The life-cycle involving transmission by mosquitoes was discovered a few years later, independently by British and Italian scientists. This is regarded as one of the greatest discoveries in the history of medicine.Half a century later, the stages in the liver were discovered, thus completing our knowledge of the life-cycle. Once the life-cycle was known and understood, it offered greater opportunities to look for ways to control malaria.Laveran discovered malarial pigment – seen in the first figure inside the large polymorphonuclear white blood cell – before he saw what we now know are the asexual ring stages of the parasite seen here and the elongated gametocytes as shown in the second figure. He reputedly first saw the fine lashing movements of microgametes being released from the male gametocytes, shown in the third figure). This event occurs naturally after the blood is ingested by female mosquitoes but can be seen in blood that is kept for a while before being examined.

Question 5

Introduction

Answer 5

The malaria parasites look like signet rings stained purple. In the centre of the film is a larger white blood cell with an irregularly curved, purple-staining nucleus and alongside it some dark brown malaria pigment that it has scavenged after infected red blood cells are ruptured by the parasites.

Question 6

In the beginning…as far as human malaria is concerned

Answer 6

We can only speculate about the origins of human malaria because these parasites have left us no palaeontological record. However, there are some facts that are indisputable, and from these we can deduce a likely sequence of events. The early relatedness and evolutionary origins of monkeys, apes, and the various hominids that include the human species,Homo sapiens, is the subject of much debate. For our discussion, the interest is how and when humans themselves spread throughout the world. There are different opinions but a favoured idea is that the species spread north from central Africa 100,000 years ago, across southern Asia into South-East Asia and thence, in one direction, to Australia and the Solomon Islands. In the other direction,H. sapiensspread north-east to Siberia to reach the land bridge where the Bering Strait now is and from there into the Americas 15,000 years ago. In the meantime, the human species also spread into Europe and central Asia.

Question 7

In the beginning…as far as human malaria is concerned

Answer 7

There are other interpretations of the origins and spread of humans including suggestions that different races of humans arose independently in different parts of the world. The important point, however, is that there were extensive migrations and by about 15,000 years ago, at the end of the Ice Age, humans had spread to and inhabited everywhere on Earth except Antarctica and Melanesia and Polynesia in the Pacific. The last important migration was from the Old World (Europe and Africa) to the New World (the Americas) by sea about 500 years ago.Relating these migrations to the distribution of malaria, it is remarkable that, even as recently (in historical terms) as 1945 , malaria transmission was occurring on every continent (except Antarctica) and in all but a few countries. Since then there has been exceptional progress in country after country, shrinking the malaria map, so that today there are well over 100 countries that are malaria-free whereas there were only 9 or 10 before. Now answer the following question…

Question 8

Question 1 Why do you think it is important to understand the spread ofH. sapiensthrough the world?

Answer 8

This information is relevant because we can assume that some of the pathogens that affect humans came with us from our primate ancestors in Africa, others must have been acquired during the long periods of migration, and most likely, some pathogens would have been lost as populations moved into areas where perhaps there were no vectors to maintain their life-cycles. Malaria parasites would have been among these pathogens. As we have just seen, malaria occurred in almost all countries of the world and it has been helpful to know how the infections were maintained in these different places and what was required to break the cycle and get rid of the parasites.

Question 9

In the beginning…as far as human malaria is concerned

Answer 9

As you will learn in Session 1.3Introduction: The genusPlasmodium, parasites belonging to the genusPlasmodiumare also found in monkeys and apes, so it reasonable to assume that these parasites entered the human evolutionary line long before the apesevolved from monkeys.However, we do not know when these evolved into the four species (P. falciparum,P. vivax,P. ovale,P. malariae) that are common in humans.DNAandRNAanalyses are beginning to provide some clues and this subject is discussed further in Session 1.3Introduction: The genusPlasmodium. Now answer the question that follows…

Question 10

Question 2 As previously stated, some of our ancestors crossed into North America via the Bering Strait. Do you think they were directly responsible for spreading malaria to America?

Answer 10

No, malaria cannot spread without mosquito vectors. As humans moved northwards into colder areas, the opportunities for transmission would diminish and, even if they had chronic infections that we now know they can carry, it is quite likely that our ancestors who crossed via the Bering Strait did not introduce malaria into North America. If this is so, then malaria in the Americas must have come from somewhere else, possibly from South-East Asia or later from Europe with Europeans and their slaves in the 16th century. In the next topic, we’ll review the written record about malaria…

Question 11

The written record

Answer 11

Mere speculation becomes more established fact with the written record. It is fortunate that the periodic malaria fevers are so characteristic; we have numerous records from Chinese writers (from about 2700 BC) and Greek writers (from 850 BC) that malaria was common and widespread.Among the main sources of information are the works of the Greek physician Hippocrates, who lived from about 460 to 370 BC and whose teachings dominated medicine for centuries. Over the next 2400 years, we have many records of fevers in all parts of the world that are almost certainly due to malaria. We’ll consider the marsh connection next…

Question 12

The written record The marsh connection

Answer 12

From the earliest times it was known that malaria was associated with marshes, swamps and other damp areas. There were many theories about the causes of malaria and the most widespread was that the disease was caused by miasmas or poisonous vapours arising from marshes and swamps. Indeed the word malaria is derived from the Italian ‘mala aria’ (bad air).It was not until the end of the 19th century that the connection between malaria and mosquitoes was made and it was realised that the association with marshes and swamps was because the mosquitoes that transmit malaria lay eggs and undergo larval and pupal development in such places. Next, you’ll learn about the discovery of the parasite…

Question 13

The written record Anopheles eggs

Answer 13

Each egg is an elongated oval with a dark centre and a paler “fringe” along its long sides.

Question 14

The written record Anopheles larva

Answer 14

TheAnopheleslarva has an elongated, caterpillar-like pale segmented body with a darker head and a “tail” with a little tuft of hair.

Question 15

The written record Anopheles pupa

Answer 15

TheAnophelespupa has a pale segmented body curled up in a comma shape and a large, darker head. Tufts of hair grow on each of the body’s segment.

Question 16

The written record Discovery of the parasite

Answer 16

Before we can follow this up, we need to return to the 1870s and the ideas ofLouis PasteurandRobert Koch. In 1878, Pasteur first put forward his ‘germ theory of disease’, which suggested that many diseases were caused by microorganisms. This led to a massive effort to find microorganisms in diseases with unknown causes.

Question 17

The written record Discovery of the parasite

Answer 17

The breakthrough as far as malaria was concerned came in 1880 when a French army surgeon,Charles Louis Alphonse Laveran, took a more independent line and began to look for pigment in the blood of patients as it was known spleens of malaria patients contained pigment. He found it in leucocytes and red blood cells , together with various crescentic and round forms. In particular, he observed motile filaments in the fresh blood of a soldier suffering from malaria. These filaments we now know are male gametes that are normally produced and released in the gut of mosquitoes that have taken a blood meal. However, this discovery generated little interest and Laveran sought the advice of the eminent Italian malariologists, Ettore Marchiafava and Angelo Celli. Unfortunately, he failed to convince them that he had found the organism that caused malaria.However, a few years later, Marchiafava and Celli found the erythrocytic forms themselves and named the organismPlasmodium malariae. In 1907, Laveran was awarded the Nobel Prize for his discovery of the malaria parasite and the importance of protozoa as causes of disease.

Question 18

The written record Discovery of the life-cycle

Answer 18

Even after the discovery of the parasites in the blood, and the recognition that they caused malaria, the method of transmission remained a mystery. Several eminent scientists, including Laveran, Marchiafava, Celli and a Scottish expert in tropical medicine, Patrick Manson, devoted themselves to solving this mystery. Manson had already shown that mosquitoes transmitted filariasis and, in 1894, he speculated that mosquitoes might also be the vectors of malaria. However, he encountered considerable opposition to his ideas and had neither the time nor the opportunity to do the necessary experiments to test his hypothesis.

Question 19

The written record Discovery of the life-cycle

Answer 19

At this stage, Manson metRonald Ross, a surgeon in the Indian Medical Service, and persuaded him to take up the challenge. Encouraged by Manson, Ross’s breakthrough came in 1897 when he found stages of the malaria parasite in mosquitoes that had fed on malaria patients (the figures below show, respectively, an extract from Ross’ notebook and an oocyst). In 1898, he demonstrated the whole life-cycle of the avian malariaPlasmodium relictumin the mosquitoCulex pipiensand in larks and sparrows. This earned him the Nobel Prize in 1902. Before he could make the final discovery of the life-cycle of a human malaria parasite, Ross was ordered to stop research on malaria and to concentrate on kala azar (or Leishmaniasis).In the meantime, the Italian malariologists Battista Grassi (shown in the photo), Giuseppe Bastianelli and Amico Bignami had been working along the same lines and they discovered and described the sporogonic part of the cycle of the human malaria parasite in Anopheles mosquitoes, also in 1898. Now complete the activity that follows…

Question 20

Question 3 Why were some of the most important malarial discoveries made in Italy at the end of the 19th century?

Answer 20

Some of the most important malaria-associated discoveries were made in Italy at the end of the 19th century because malaria was a serious socio-economic and health problem for the Italians and caused around 15,000 deaths annually. The connection with swamps had been recognised for over 2000 years.There were also links between malaria research and public health, and earlier Italian scientists had suspected that mosquitoes might be responsible for malaria. Several eminent Italian zoologists, entomologists and clinicians were all interested in malaria and there were major centres of research in Rome and Pavia.The actual experiments on the transmission of malaria were made possible because of expert knowledge of mosquitoes, and increasing knowledge of the parasites was aided by the availability of microscopes with high-quality oil immersion lenses.

Question 21

Question 4 What was Patrick Manson’s role in the discovery of the mosquito transmission of malaria?

Answer 21

Manson had already shown that mosquitoes transmitted filarial worms, so he was prepared to find developmental stages of malaria parasites. He was also aware of the flagellated forms in the blood seen by Laveran and thought that they might be stages in the malaria life-cycle.Manson was unable to investigate this problem himself and needed someone in a malarious area to do the work; he persuaded Ross to undertake it. He also persuaded the India Office to send Ross to India where he virtually directed Ross’s work, including the suggestion that he should look at the malaria parasites of birds. When Ross had made his discoveries, Manson publicised the findings and confirmed that mosquitoes transmitted malaria in human volunteers. Next you’ll learn how the connection between the parasite and the disease was established…

Question 22

The written record The parasite and the disease

Answer 22

Although malaria disease had been known for centuries and the parasite had been discovered in 1880, it took some time to establish the connection between the multiplication of the parasites in the blood and the periodic tertian and quartan fevers characteristic of malaria.This was another Italian triumph: the discovery was made between 1886 and 1889 by Camillo Golgi who later won the Nobel Prize in 1906 for his work on the nervous system. You’ll find a summary of progress next…

Question 23

The written record Summary of progress 1847 - 1900

Answer 23

Before we move on, it is worthwhile to summarise the significant progress that was made in investigations of malaria disease, malaria parasites and their transmission during the period from 1847 to 1900. It is impressive and, coincidently, shows how widespread and important malaria was at that time. 1847 - Dempster introduced spleen palpation of children (in India) as an index ofendemicityof malaria.1848 - In Germany, Virchow and Frerichs recognised that the presence of pigment in internal organs might be related to deaths from intermittent fevers.

Question 24

The written record Summary of progress 1847 - 1901

Answer 24

1878 - In China, Manson showed that a mosquito (Culex fatigans) can act as a vector of human filarial parasites. This prompted his later suggestion of mosquitoes as potential vectors of malaria. 1880 - In Algeria, Laveran discovered and described malaria parasites in human blood.1886 - In Italy, Golgi deduced that tertian (P. vivax)and quartan (P. malariae) malaria must be caused by two different species ofPlasmodium.

Question 25

The written record Summary of progress 1847 - 1902

Answer 25

1889 - In Russia, Danilewski described the morphology of avian malaria parasites and their wide distribution.1889-90 - Celli and Marchiafava in Italy describedP. falciparum.1889-93 - In the USA, Smith and Kilborne demonstrated the role of the arthropod vector (tick) in the transmission of piroplasmosis (Texas fever) in cattle.

Question 26

The written record Summary of progress 1847 - 1903

Answer 26

1891 - Romanowsky developed his polychrome staining method for demonstrating malaria parasites in blood smears.1894-96 - Bruce, in Zululand, showed that an infection caused by a protozoan parasite can be transmitted by a true insect (tsetse fly). He was working on nagana (cattle trypanosomiasis), a disease of horses and cattle when he made the discovery.1894 - Manson suggested that malaria is transmitted from person to person by mosquitoes.

Question 27

The written record Summary of progress 1847 - 1904

Answer 27

1897 - In Secunderabad, India, Ross discovered oocysts on the midgut wall of anAnopheles mosquito.MacCallum in the USA described the sexual phase ofHaemoproteusin the blood of a crow and observed exflagellation of a male gametocyte inP. falciparumand the penetration of a female gametocyte by a ‘flagellum’.1898 - Ross identified the complete cycle of bird malaria in naturally infected sparrows in Calcutta.In Italy, Grassi, Bignami and Bastianelli described the life-cycle stages of human malaria parasites inAnophelesmosquitoes.1900- Manson confirmed the mosquito-malaria transmission theory through his experiments with human volunteers in the Roman Campagna and in London.Now complete the activity that follows…

Question 28

Reading 1 Now read through the paper by Cox (2010) ‘History of the discovery of the malaria parasites and their vectors’.Next, read the paper by Gilles (2002) ‘Historical outline’. This is a comparatively short article and much of it is written as historical milestones that will supplement what is given in the text of this session.

Answer 28

When you’ve finished, answer the following question.

Question 29

Question 5 What evidence did Camillo Golgi cite to support his hypothesis that there was more than one species of Plasmodium in humans?

Answer 29

Golgi knew that the periodic fevers associated with malaria coincided with the erythrocytic schizogonic cycle of the parasite which, in the case of the parasites he was studying, occurred every 48 or 72 hours.He argued that mixtures of broods of the 72-hour parasites could cause fevers every 24 and 72 hours but that there was no way in which they could cause fevers every 48 hours. Therefore, there must be two species of malaria parasite, one causing quartan fevers (P. malariae) and another causing tertian fevers (P. vivax). In the next topic, we’ll consider the missing links…

Question 30

The missing links

Answer 30

Although by the end of the 19th century the life-cycle of the malaria parasite had been discovered, there remained one further question: what happened between the time that the sporozoites were injected and the time parasites appeared in the blood?This question stayed unanswered for nearly half a century; then in 1948 two British scientists, PCC (Cyril) Garnham and Henry Shortt, discovered the exoerythrocytic stage in the liver in monkeys and then in humans. One final problem remained: were the late infections seen in some strains ofP. vivaxdue to recrudescences of subpatent parasitaemias, or to persistent stages in the liver? This puzzle was solved in 1980 when a team led by the American Wojciech (Al) Krotoski and including Garnham discovered the hypnozoite or dormant stage. You’ll read about this in the activity that follows…

Question 31

The missing links

Answer 31

Short, Garnham and colleagues were the first to demonstrate the liver stages of Plasmodium. This schizont is inside a greatly enlarged (or hypertrophied) liver cell and has already undergone multiple nuclear divisions

Question 32

The missing links

Answer 32

More than 30 years later, Krotoski, Garnham and colleagues demonstrated the tiny uninucleate dormant forms called hypnozoites that occur inP. vivaxandP. ovaleand are responsible for relapse infections. This fluorescent antibody staining was able to pick out a hypnozoite alongside a large developing schizont. A large green oval and a much smaller green circle are visible on a background of liver cells stained red-brown with the cell membranes showing as red lines. The large green oval, which is about twice the size of the liver cells, is a developing exoerythrocytic schizont. The small green circle in one other liver cell is a hypnozoite. The hypnozoite is highlighted and labelled.

Question 33

The missing links

Answer 33

This photo of a liver section shows how difficult it is to find hypnozoites without fluorescent staining. In the middle of the section, and very much smaller than the liver cell nuclei, is a darkly stained hypnozoite with one nucleus which has had to be highlighted by a dark circle around it.

Question 34

Reading 2 Turn again to the paper by Cox FEG (2010)History of the discovery of the malaria parasites and their vectorsand re-read the section on exoerythrocytic development (pages 6-7).

Answer 34

Now answer the following question.

Question 35

Question 6 Why do you think it took so long to discover the exoerythrocytic stages of the human malaria parasites?

Answer 35

In 1902-1903, the eminent German parasitologist Fritz Schaudinn claimed to have seen sporozoites directly entering red blood cells. His influence was so great that this was not disputed in spite of the fact that nobody could repeat his findings. In the 1930s, it was found that in avian malarias there was a developmental phase between the inoculation of sporozoites and the appearance of parasites in the blood. This phase occurred in the cells of the lymphoid-macrophage system.Nobody could find these stages in human malaria or suspected that they might occur in the liver until, in 1947, Garnham found the massive tissue schizonts of the related parasite,Hepatocystis kochi, in the livers of monkeys.This discovery made Garnham and his colleague, Shortt, look for the much smaller and scarcer Plasmodium schizonts, first in monkeys and then in human volunteers.Exoerythrocytic schizonts are not seen in naturally-infected patients with malaria because there are so few of them so these volunteer experiments were necessary but could not be performed until the observations on monkeys had been made. The discovery in 1980 of the hypnozoite, the dormant stage responsible for relapse infections, was made first by Krotoski and colleagues in experiments at the London School of Hygiene & Tropical Medicine with the primate malariaPlasmodium cynomolgi, a parasite closely related to the human malaria parasiteP. vivax. Confirmation of their occurrence also inP. vivaxwas made shortly afterwards by the same researchers. In the next topic, you’ll learn about the cure…

Question 36

The cure

Answer 36

Malaria-like symptoms were described in a notable Chinese medical writing in 2700 BCE and in other ancient tablets and papyri, and were later widely recognised in Greece by Homer, Hippocrates and others. There are reports of the use of the leaves of plants such as the cinquefoil (Potentilla reptans) to relieve the tertian and quartan fevers but there is no information about how effective they were. However, in China in the second century BCE, the use of the Qinghao plant,Artemisia annua, was described in a medical treatise intriguingly entitled “52 remedies” found in the Mawangdui tomb and we shall come back to that as it was undoubtedly a remarkable find. See pictures of the “52 remedies” treatise and of artemisia plants

Question 37

The cure

Answer 37

The written history of antimalarial drugs generally begins early in the 17th century when Jesuit priests working in South America became aware that indigenous Indian tribes used the bark of the ‘fever bark trees’ to treat fevers. It was namedCinchona, a mis-spelling of the name of the wife of the Viceroy of Peru, the Countess of Chinchon who was reportedly cured of her fever. The cure was so effective that the bark was soon exported to Europe and widely used as a powder for the treatment of malaria. In 1820, the effective compound was extracted and identified by two French chemists, Pierre Joseph Pelletier and Joseph Bienaimé Caventou as an alkaloid they calledquinine.Soon afterwards, an Englishman, Charles Ledger, established plantations ofCinchonatrees in what was then the Dutch East Indies in order to ensure a plentiful supply of the drug. Quinine was the only drug available for the treatment of malaria until the 1920s and 1930s and is still in use today mainly for the treatment of severe malaria. Next you’ll learn about the development of synthetic drugs…

Question 38

The cure Development of synthetic drugs

Answer 38

During the First World War (1914-1918), there was a shortage of quinine, especially in those countries without direct access toCinchonaplantations and attempts began to develop synthetic antimalarial drugs. Amongst those developed, Mepacrine (Atabrin) was used for routine treatment. In the period from late 1930s to mid 1940s chloroquine,amodiaquine,proguanilandpyrimethaminewere introduced and widely used. Chloroquine in particular was particularly important as it was cheap to produce, and was highly effective.Unfortunately, by the 1960s the first reports of resistance to chloroquine appeared. Chloroquine resistance had spread from SE Asia to East Africa by 1979, to West Africa by 1986, and is now worldwide. Pyrimethamine resistance was first recorded in the 1980s and is also now widespread. The current use of combination therapy and the continued search for new antimalarials will be covered this in more detail in Session 4.2 Treatment: Drug therapies. Next you’ll learn about the development of artemisinin…

Question 39

The cure Artemesinin

Answer 39

However, in this short historical account, we should come back to the Chinese plant Qinghao (Artemisia annua). The antimalarial properties were first identified in 1967 in organic extracts of the leaves. The active component was called qinghaosu but is now known asartemisinin. Further derivatives known as dihydroartemisinin,artemetherandartesunatewere developed. These are highly potent and fast-acting, and are now used in combination with a number of other anti-malarials as artemisinin-based combination therapies (ACTs) the recommended first-line treatment for malariaendemiccountries . In addition, artesunate used as a monotherapy is a better alternative than quinine for treatment of severe falciparum malaria. So, the oldest antimalarial is today the best we have but unfortunately artemisinin-resistantPlasmodium falciparumis found across Southeast Asia and was described in East Africa in 2021. The Chinese scientist Tu You You was a joint winner of the 2015 Nobel Prize for Medicine for her contribution to the discovery of artemisinin. In the next topic, we’ll look at malaria control…

Question 40

Reading 3 Now find the chapterMalariaby McGregor, which is included in the module online reading list (accessible through the module Moodle page). Read from the heading ‘The development of antimalarial drugs’ on page 244 to the end of the paper.

Answer 40

Now answer the following questions.

Question 41

Question 7 Why is theCinchonatree so named?

Answer 41

It is named after the Countess of Chinchon who, it is said, used ‘Jesuit’s bark’ to cure her malaria and later gave it to the citizens of Lima, Peru. The nameCinchonawas coined by Linnaeus, who mis-spelled her name.

Question 42

Question 8 How did the Jesuits maintain their supplies of Cinchona trees in Peru? By shipping inCinchonasaplings in from Chile, By replanting cuttings whenever aCinchonatree was felled; or By limiting the amount of bark stripped from each tree

Answer 42

The Jesuits maintained their supplies of Cinchona trees in Peru by replanting cuttings whenever aCinchonatree was felled.

Question 43

Control of malaria

Answer 43

Before the discovery of the malaria parasite in 1880 and its transmission by mosquitoes in 1898, there was little that could be done to control the disease except for the draining of swamps and marshes near where people lived. In many places this was remarkably successful (although often carried out for other purposes). Modern concepts for the control of malaria date back to the ideas of Ross who realised that it is necessary to break the chain of transmission.This, he suggested, could be achieved by the use of quinine for treatment orprophylaxiscombined with anti-mosquito measures. These measures included reducing the number of places where mosquitoes laid their eggs (e.g. puddles or water tanks), drainage of marshes and swamps and changes in agricultural practice.We’ll review progress in malaria control next…

Question 44

Control of malaria Progress in malaria control

Answer 44

There were many successes, including draining the malarious Pontine marshes in Italy and marshes in England and the Netherlands in the early 1900s. Efforts also concentrated on the destruction of mosquito larvae using oil that prevented them from breathing and the use of the larvicide Paris green.The big breakthrough in malaria vector control came with thedevelopment of the first insecticides effective against adult mosquitoes: pyrethrum between 1935 and 1939, and DDT between 1936 and1939.

Question 45

Control of malaria Progress in malaria control

Answer 45

In a number of countries,elimination of mosquito vectors was achieved in the 1940sincluding from Northern Egypt and Brazil. The elimination from Brazil was particularly interesting as the malaria mosquitoAnopheles gambiaeis not native to the country (it is from sub-Saharan Africa) but had been introduced and soon became widely established. The development ofindoor residual sprayingto kill adult mosquitoes, combined with the use of the newly discoveredantimalarials(chloroquine, amodiaquine, proguanil and pyrimethamine) greatly improved opportunities for malaria control.

Question 46

Control of malaria Progress in malaria control

Answer 46

In 1955, the Fourteenth World Health Assembly adopted the principle of aglobal malaria eradication programme(GMEP) and a malaria eradication campaign was begun under the auspices of the WHO. This was based mainly on the use of pesticides such as DDT. Though widely employed across the world, sub-Saharan Africa and New Guinea were not included as it was not thought feasible with available tools in areas where transmission was high.Mortality andmorbiditydecreased markedlyin most GMEP countries but it became increasingly clear that eradication (or what we would now call elimination) would not be achieved in many of the countries and in 1969, the WHO General Assembly recommended switching thefocus back from eradication to control(we will cover this in more detail in Session 4.1Treatment: Biochemistry). Now complete the activity that follows… In the next topic, we’ll look at vaccination…

Question 47

Reading 4 Turn again to the article by Gilles (2002) ‘Historical outline’ and read it once more.Then read the article by Wernsdorferet al.(2009) ‘Learning from history’. This is particularly good on past attempts to control and then eliminate malaria. As theGlobal Technical Strategyhas once again established elimination targets, taking note of past successes and failures may help to achieve the new targets.

Answer 47

When you’ve finished answer the following questions.

Question 48

Question 9 When were DDT and Dieldrin first used as insecticides?

Answer 48

DDT was first used in 1936-1939, immediately before the Second World War. Dieldrin was developed as an insecticide in 1942-1946, at the end of the Second World War.

Question 49

Question 10 What were the main reasons why, during the GMEP that was launched in 1965, some countries successfully eliminated malaria while others did not?

Answer 49

The countries that succeeded: Made a strong political commitment. Did not need much outside funding. Were technically well organised. Trained their staff well. Had a good health system. Kept the public well informed. Were mostly the lower transmission countries. Countries where elimination programmes failed were basically the opposite in each case. Two points in particular to note: These countries relied on outside funding and there was often donor fatigue. Most of these countries had stable malaria, that is, higher levels of transmission.

Question 50

Question 11 Modern concepts of control of malaria date back to the time of Ronald Ross. How did he suggest this could be achieved?

Answer 50

He recognised the need to break the train of transmission. This he suggested could be done by treatment with quinine (the only drug available at the time) and by use of anti-mosquito measures. These included draining or covering water where mosquitoes bred such as marshes, puddles and water tanks, and changing agricultural practices, which often created these breeding places.

Question 51

Question 12 Do you think his methods would have worked across Africa?

Answer 51

Only on a small scale mainly because the main mosquito vector (A. gambiae) breeds in so many places that could not be drained, and the level of transmission was so high.

Question 52

Question 13 For what discoveries relating to malaria are the following scientists best known? William Trager and James Jensen

Answer 52

Trager and Jensen were the first to develop a method for continuous culture in vitro of Plasmodium falciparum asexual erythrocytic stages. Later, others made it possible to culture gametocyte stages through to maturity and infective to mosquitoes. Being able to culture the parasites in this way transformed drug development investigations and made possible molecular and advanced vaccine design studies.

Question 53

Question 13 For what discoveries relating to malaria are the following scientists best known? Dimitri Romanowsky

Answer 53

Romanowsky discovered the staining methods to show malaria parasites in the blood. These are still used routinely today.

Question 54

Question 13 For what discoveries relating to malaria are the following scientists best known? Sydney James

Answer 54

James recognised that there had to be a stage in the life-cycle between inoculation of sporozoites and the appearance of parasites in the blood. As we have seen, these predicted stages were subsequently discovered.

Question 55

Vaccination

Answer 55

At the end of the 19th century, after the success of Jenner (in protecting individuals against smallpox), and Pasteur and others (in developingvaccinesagainst a number of bacterial and viral diseases including cholera and rabies), it was inevitable that attention should turn to protozoal diseases, particularly malaria.In 1900, the Italian Angelo Celli performed a number of experiments including immunisation with dried infected red blood cells, and the transfer of serum to prevent fever. He did not have any success. There followed a number of successful attempts to transferimmunitywith immune sera in experimental animals. Interestingly, in the 1940s, and long before it was discovered thatPlasmodium knowlesiinfection could be acquired naturally by humans, monkeys were vaccinated with asexual blood stages of the parasite combined withadjuvantto boost the protective immunity.

Question 56

Vaccination

Answer 56

In 1961, Cohen and McGregor demonstrated for the first time that protection could be transferred to malaria-infected children with the gamma globulin (immunoglobulin G) from adults who lived in a malarious country of West Africa, The Gambia. The figure below shows how the serum component reduced the very high parasitaemias to a low level indicating the presence in the serum of protective antibodies. This observation of natural-acquired immunitywas a stimulus to attempts to induce an effective immunity byvaccination. Three different approaches were developed and still continue.We will consider each of these approaches over the next few pages, starting with attenuated sporozoites and other pre-erythrocytic vaccines…

Question 57

Vaccination

Answer 57

The effect on parasite density of passively transfered immunolglobulins.This plot shows the results of a dramatic experiment published in 1961. Gambian children with high malaria infection of around 100,000/ mm3were divided into four groups. One remained untreated, a second was given the serum component called then gamma globulin from UK adults, the third was given gamma-free serum, and the fourth given gamma globulin from Gambian adults. Over ten days, there was a substantial drop in the level of infection in those given Gambian gamma-globulin, from which it was concluded that the Gambian donors had antibodies that gave them protection against malaria. The graph’s vertical axis is labelled “Mean Trophozoite Count/c.mm” and ranges from 1 to 1,000,000 on a logarithmic scale. The horizontal axis is labelled “Days” and ranges from 0 to 10. There are four curves representing the four groups of children 100,000 trophozoites/c.mm on day 1, as follows: untreated (green crosses), UK Gamma Globulin (blue dots), Gamma-free serum (red triangles) and Gambian Gamma Globulin (purple circles). The untreated, UK Gamma Globulin and Gamma-free serum curves fluctuate in numbers during the following days but are still heavily infected on day 9 with counts of 30,000, (untreated), 3000 (UK Gamma Globulin) and 2000 (Gamma-free serum). The Gambian Gamma Globulin curve has a similar pattern until day 4, then falls dramatically. Between days 6 and 10, the trophozoite numbers are between 5 and 20/c.mm.

Question 58

Vaccination Attenuated sporozoites and other pre-erythrocytic vaccines

Answer 58

Attenuated (X-irradiated) sporozoites were shown to be highly protective in laboratory animals, and partially so in limited trials in humans. These studies led to the development of further experimental vaccines based on well-defined sporozoite antigens in the 1980s. Synthetic and recombinant forms were tested in human trials but again with limited success. However, encouraging progress was subsequently made leading to large-scale clinical trials of the vaccine RTS,S. In 2021 this became the first malaria vaccine to be recommended for use by WHO, as we shall see in Session 3.6Epidemiology and Prevention: Vaccination.Next we’ll look at blood-stage antigens…

Question 59

Vaccination Blood-stage antigens

Answer 59

Blood-stage antigens have also been tested as the basis of a vaccine to prevent disease but with limited success so far. Candidates tested include molecules that play an essential role in the invasion of red blood cells by merozoites.The first malaria vaccine to be tested in large scale field trials in the 1990s was SPf 66, a synthetic peptide based on sporozoite and blood stage antigens, developed by the Colombian biochemist Manuel Patarroyo.This was subsequently abandoned as ineffective. Next we’ll look at transmission-blocking vaccines…

Question 60

Vaccination Transmission-blocking vaccines

Answer 60

Antigens from gamete and zygote stages could, in theory, be used to induce antibodies that block transmission so that mosquitoes do not become infected and the transmission cycle gets broken.Initial studies with avian and rodent malarias worked well and, as we shall see later, have progressed to evaluation in humans. In the next topic, we’ll briefly review the connection between malaria and LSHTM…

Question 61

The LSHTM connection

Answer 61

The London School of Hygiene & Tropical Medicine has been involved with malaria for over 100 years. The crest of the School is based on a coin struck to commemorate the deliverance of the Sicilian city of Selinus (now Selinunte) from malaria in the 5th century BC.

Question 62

The LSHTM connection

Answer 62

A few highlights: The London School of Tropical Medicine (LSTM) was founded in 1899 at the Albert Docks in the grounds of the Seaman’s Hospital. Because of Sir Patrick Manson’s involvement in its establishment, it has been referred to as Manson’s Tropical School. Patrick Manson founded the School in 1899. In 1918 the LSTM and the Hospital for Tropical Diseases were moved to Endsleigh Gardens. 1926-29 saw the building of what then became The London School of Hygiene & Tropical Medicine in Keppel Street, the building still occupied today.The Ross Institute was established in 1926, with Sir Ronald Ross Director in Chief of both the Institute and the Hospital for Tropical Diseases. After Ross’ death in 1932, the Ross Institute was incorporated into LSHTM. 1931-2 Sir Rickard Christophers was appointed Professor of Malaria Studies and Director of a new Medical Research Council Malaria Unit.

Question 63

The LSHTM connection

Answer 63

Henry (HE) Shortt became Professor of Medical Protozoology in 1946 and was joined by Cyril (PCC) Garnham in 1947, who later succeeded him as head of Department. This was the start of a remarkable collaboration and, in the following year, they made their ground-breaking discovery of the exoerythrocytic stages of malaria parasites in the liver, first in monkeys and then in humans. In the 1950s Professor George Macdonald devised a mathematical approach to describe the epidemiology of malaria. The model is still widely applied today. In 1980, investigations at the School led by WA (Al) Krotoski with Garnham, LSHTM staff and other colleagues, discovered in a monkey malaria the small dormant stages (hypnozoites) in the liver responsible for relapse infections. The same team subsequently showed these forms occur in a relapsing human malaria, thus completing the malaria life cycle (as far as we know!).

Question 64

The LSHTM connection

Answer 64

Professor Sir Brian Greenwood joined the School in 1996 after a long and distinguished research career in West Africa, including 15 years as Director of the MRC Unit in The Gambia. He directed the Gates Malaria Partnership (funded by a major grant from the Gates Foundation) and a follow-up Malaria Capacity Development Consortium. TheMalaria Centrewas established in 2000 with Brian Greenwood as the first Director. This brings together everyone within the School working on malaria whatever aspect , and has become the basis of a widescale multi-disciplinary approach to malaria prevention,control, surveillance, treatment, biology, capacity development and public engagement. There are now more than 300 members spanning the three Faculties of the School. This is just a snapshot of the School and its involvement in malaria. There are many other outstanding individuals, past and recent, whose contributions are equally deserving of mention but the purpose here is to give you a feel for the institution supporting this malaria module.

Question 65

Question 14 Match the researcher(s) to the discoveries. Malaria parasites in human blood

Answer 65

Laveran

Question 66

Question 14 Match the researcher(s) to the discoveries. Malaria parasites are transmitted by mosquitoes

Answer 66

Ross, Grassi, Bignami and Bastianelli

Question 67

Question 14 Match the researcher(s) to the discoveries. Exoerythrocytic stages in the liver

Answer 67

Garnham and Shortt

Question 68

Question 14 Match the researcher(s) to the discoveries. Hypnozoites

Answer 68

Garnham and Krotoski

Question 69

Question 14 Match the researcher(s) to the discoveries. Quinine as the active ingredient of the bark ofCinchona

Answer 69

Pelletier and Caventou

Question 70

Summary

Answer 70

Malaria fevers have been known for over 4000 years and well documented for over 2000 years. For most of this time, malaria was thought to be caused by vapours rising from marshes.In about 1600, the bark of the ‘fever bark tree’, subsequently namedCinchona, was shown to be effective in the treatment of malaria. Later the effective component of the bark was identified asquinine.In 1880, malaria parasites in the blood were seen for the first time by Laveran in Algeria..In 1898, the life-cycle stages of avian malaria in the mosquito were discovered by Ross in India.In 1898, the corresponding stages of the life-cycle of the human malaria parasites were shown by Grassi, Bignami and Bastianelli in Italy.In 1948, theexoerythrocyticstage of the human malaria parasite in the liver was discovered by Shortt and Garnham at the London School of Hygiene & Tropical Medicine. Thehypnozoitestage responsible for the persistence and relapses ofP. vivaxandP. ovalemalarias were discovered in 1980 by Krotoski, Garnham and colleagues.In 1955, a global malaria eradication programme was adopted under the auspices of the WHO.

Question 71

Summary

Answer 71

In 1969, the programme reverted to one of control. During the 1930s and 40s the drugs chloroquine,amodiaquine,proguanilandpyrimethaminewere synthesised and widely used. Chloroquine became the cornerstone of treatment. In 1960, the first reports ofresistanceofP. falciparumto chloroquine were made.Qinghaosu (artemisinin) was identified as the potent antimalarial component of the plantArtemisia annuaand is now widely used for combination therapy. In 1976, a method for culturingerythrocyticstages ofP. falciparumin vitrowas pioneered by Trager and Jensen. In 2021, WHO made the first recommendation for the widespread use of a malaria vaccine, RTS,S/AS01.

Question 72

Glossary Febrile

Answer 72

Feverish

Question 73

Glossary Zoonosis

Answer 73

A disease for which the infectious agent can pass across species (ie from animals to humans)

Question 74

Glossary DNA

Answer 74

Deoxyribonucleic acid. One of the nucleic acids and the main constituent of chromosomes

Question 75

Glossary RNA

Answer 75

Ribonucleic acid. One of the nucleic acids. The three most common forms of RNA are: messenger RNA, ribosomal RNA, and transfer RNA

Question 76

Glossary Endemicity

Answer 76

A state where an infection is said to be endemic in a human population and is maintained in that population without the need for external inputs

Question 77

Glossary Quinine

Answer 77

The first effective treatment for malaria originally derived from the bark of the cinchona tree

Question 78

Glossary Amodiaquine

Answer 78

Antimalarial related to quinine used for treatment and prophylaxis, particularly in combination with other antimalarials

Question 79

Glossary Proguanil

Answer 79

One of the two drugs that make up Malarone for the treatment of malaria

Question 80

Glossary Pyrimethamine

Answer 80

One of the two anti-folate drugs that make up the antimalarial Fansidar

Question 81

Glossary Drug resistance

Answer 81

The ability of an organism to grow in the presence of a drug

Question 82

Glossary Artemesinin

Answer 82

A drug used especially to treat multidrug resistant strains of falciparum malaria, originally isolated from the plant Artemisia annua (sweet wormwood), long used in traditional Chinese medicine. It has a very short half-life in human circulation, so is usually either infused or else used together with a longer-acting drug such as lumefantrine, amodiaquine or mefloquine

Question 83

Glossary Artemether

Answer 83

A derivative of Artemisinin used for treatment of malaria

Question 84

Glossary Artesunate

Answer 84

A derivative of Artemisinin used for treatment of malaria

Question 85

Glossary Endemic

Answer 85

Epidemiological term describing an infection in a community where it is maintained with constant incidence of cases for many years without external inputs

Question 86

Glossary Prophylaxis

Answer 86

Administration of a drug to prevent development of disease rather than for treatment of existing disease

Question 87

Glossary Morbidity

Answer 87

Any departure, subjective or objective, from a state of physiological or psychological well-being. In practice, morbidity encompasses disease, injury and disability

Question 88

Glossary Vaccines

Answer 88

A suspension of a killed or attenuated microorganism, or part of a microorganism, that is given, usually in the form of an injection, to prevent or treat a specific infectious disease

Question 89

Glossary Immunity

Answer 89

The ability to resist infection

Question 90

Glossary Adjuvant

Answer 90

A pharmacological agent, usually a bacterial antigen, added to a vaccine in order to activate the immune response. This stimulation can be specific (ie a response to a small group of antigens) or non-specific (ie increased immune response to a range of antigens). Adjuvants allow less of the actual vaccine antigen to be administered

Question 91

Glossary Acquired immunity

Answer 91

Antigen-specific adaptive immunity that increases during infection

Question 92

Glossary Vaccination

Answer 92

The administration (by mouth or injection) of antigenic material with intent to bring about an active immunological response in the recipient