[Laveran, the military doctor]. / Laveran, le médecin militaire.

Son of Louis-Theodore Laveran, holder of the Chair of Diseases and Epidemics in the Armies at the Val-de-Grâce and grandson of an artillery commander through his mother, Alphonse, born in Paris on June 18, 1845, follows in his father's footsteps by entering the Imperial School of Military Health in Strasbourg at the age of 18.After his thesis, he participated in 1870 in the war against Prussia. He was taken prisoner in Metz. He then prepared for the competitive examination to become a professor, which he passed in 1874. He was appointed to the Chair of the Val-de-Grâce, which his father had created. He then went to Algeria. It was at the military hospital in Constantine on November 6, 1880 that he indisputably discovered the haematozoa responsible for malaria in the blood of a soldier in the crew train.In 1884, he was appointed to the Chair of Military Hygiene and Legal Medicine at Val-de-Grâce. At the end of his professorship in 1894, after being refused a posting to Paris to continue his research and not being consulted for the preparation of the Madagascar expedition, which turned into a health disaster in 1895, he retired prematurely in 1897. Hosted by Émile Duclaux and Émile Roux at the Pasteur Institute in Paris, he continued his research mainly on protozoa as agents of human and animal diseases until his death. His work in medical protozoology earned him the Nobel Prize in Physiology or Medicine in 1907. During the Great War, with the benefit of his experience, he warned the Minister of War in January 1916 about the risk of malaria incurred by the army of the East in the delta of the Vardar River in Salonika. The spring would prove him right.An illustrious military doctor and scientist of international renown, Laveran died on May 18, 1922 in Paris.

[Laveran and the French Academy of Medicine]. / Laveran et l'Académie nationale de médecine.

In November 1880, Alphonse Laveran, stationed at the Constantine military hospital, addressed to the Academy of Medicine a "Note on a new parasite found in the blood of several patients with malaria fever". Léon Colin, professor at the Val-de-Grâce school, is the rapporteur, but he is not convinced by these observations, nor by two additional notes sent by Laveran in December 1880 and October 1881. This skepticism is shared by other academicians such as Joseph Laboulbène and Émile Duclaux.Twelve years will be necessary for Laveran to overcome the disbelief of the French scientific community. Three fundamental books donated to the Academy testify to the tenacity with which he gradually succeeded in convincing most of his colleagues: Traité des fièvres palustres avec la description des microbes du paludisme in 1884, Des hématozoaires du paludisme in 1887, and Du paludisme et de son hématozoaire in 1891.Laveran was elected to the Academy of Medicine on December 26, 1893. His resignation from the Military Health Corps enabled him to participate assiduously in meetings and to intervene in debates concerning infectious and tropical diseases, hygiene and prophylaxis. Obtaining the Nobel Prize in 1907 for his work on malaria, trypanosomiasis and colonial diseases crowned his work while honoring the Academy. Laveran was elected vice-president for the year 1919 and president for 1920, the year of the centenary of the Academy, the celebration of which he organized to the detriment of his health. He died two years later, having fulfilled his duty to the end of his strength.

[Malaria in 2022: clinical and therapeutic aspects]. / Le paludisme en 2022 : aspects cliniques et thérapeutiques.

In 2022 as in 1884, the clinical presentation of uncomplicated malaria is unspecific: fever of variable intensity, continuous or rhythmic, chills, flu syndrome, headache, respiratory and digestive disorders. At any time, it can evolve into a severe form (ex-pernicious attack or cerebral malaria) or even lethal. By reading again Alphonse Laveran's book on malarial fevers, we realized to what extent the observations made at that time allowed for a methodical and orderly description of the clinical forms of malaria, very close to what we can still observe today. No symptom or sign is pathognomonic of the disease. Only the detection of plasmodia or "malaria microbes" by direct or immuno-chromatographic methods allows for diagnostic confirmation, which is a prerequisite for the implementation of a curative treatment.Serendipity, synthetic chemistry and traditional medicine are the three methods that led to the discovery and large-scale production of antimalarial drugs. Serendipity for quinine, synthetic chemistry for chloroquine, and research conducted around traditional Chinese medicine for artemisinin and its derivatives. The latter have marked a real revolution in the management of malaria, both in its uncomplicated and severe forms. However, as with other antimalarial drugs, its medium- and long-term efficacy is compromised by the emergence and spread of resistance in malaria parasites, particularly P. falciparum. The control and eradication of malaria therefore require continued research in both prevention and therapy.The disease so well described by Alphonse Laveran has not yet said its last word….

[Towards elimination of human African trypanosomiasis]. / Vers l'élimination de la maladie du sommeil.

Human African Trypanosomiasis (HAT) is caused by Trypanosoma brucei which is transmitted by the tsetse fly insect vector (Glossina spp). It is one of the 20 Neglected Tropical Diseases (NTD) listed by the WHO. These diseases affect the poorest and most vulnerable communities, for which the WHO has established a dedicated 2021-2030 roadmap. At the time of Alphonse Laveran, HAT devastated the African continent. In the 1960s, the disease was nearly under control, but it strongly re-emerged in the 1990s. A coordinated effort of all stakeholders, with national control programs as the main actors, a strong contribution of research and important donations by the private sector, allowed to decrease the HAT burden significantly. Since 2018, less than 1000 cases are detected annually. We here review new diagnostics, treatments and vector control tools that have been implemented jointly and successfully in several endemic countries.The next key challenge will be to sustain the gains. Newly emerging research questions include long-term carriage of trypanosomes and adaptation of tools to low prevalence contexts. Challenges out of the research area comprise the continued need of funding, maintenance of dedicated human resources, and the key question of access. Sustainable elimination as "interruption of transmission", which is the 2030 NTD roadmap target, can be reached, if these challenges are solved. We stress the importance of continuing to combine the efforts in the fight against the disease, because sustainable elimination of HAT is the best long-term prevention strategy against re-emergence. As such, HAT elimination can serve as an example for other infectious diseases.

[Understanding the mode of transmission of malaria agents: an astonishing series of hypotheses, observations, research and controversy]. / Compréhension du mode de transmission des agents du paludisme: une étonnante suite d'hypothèses, d'observations, de recherches et de controverses.

In 1880, Laveran observed the causative agent of malaria. As early as 1884, he considered that mosquitoes could be responsible for the transmission of haematozoa, a hypothesis which resulted from the observation and reflection of an informed hygienist. But, as Laveran himself said, "the opinion that I defended was considered by most observers to be highly unlikely".Nearly 15 years after the discovery of the haematozoan, the elucidation of the mechanism of transmission still proved difficult to establish. A link with the existence of swamps had been established a long time before, but the true mode of transmission remained a mystery until the end of the 19th century. The implication, by Manson in 1877, of mosquitoes in the cycle of the Bancroftian filaria, then other observations of the same order, ended up attracting the attention of malariologists. Laveran himself was quickly convinced of the role of mosquitoes in carrying out the natural cycle and propagating Plasmodium, but this theory had as many detractors as supporters.In 1897, Ross showed the presence of oocysts on the stomach of mosquitoes previously gorged on a malaria patient, then in 1898, of sporozoites of bird plasmodia in mosquitoes. He was convinced that, through their bite, these insects were responsible for the transmission of human malaria agents, without being able to prove it. The results obtained by Ross were immediately confirmed in Italy by Grassi and his collaborators who, in November 1898, described the stages of Plasmodium in man and, through various experiments carried out in collaboration with British researchers, showed the role of Anopheles, a result far from being accepted by all. Skepticism persisted for a long time.An excellent protozoologist, Laveran was not an entomologist. He was however among the first defenders of the anopheline theory. He worked extensively on establishing the relationships between Anopheles mosquitoes and malaria and took a close interest in the environmental conditions of the transmission. In his mind, malaria fever should henceforth be classified as a preventable disease. An era of hope thus dawned: malaria prophylaxis, based on fight against mosquitoes, could begin.

[Laveran and the eradication of malaria in Corsica]. / Laveran et l'éradication du paludisme en Corse.

The observation of miasmas and fevers was attested in the region of Biguglia, South of Bastia, in 1499, confirmed during the 17th century. Drainage works on the eastern coast were started in 1770, abandoned during the revolutionary period, restarted under the Second Empire, with few results on the endemic. Thus in 1875, 80% of the inhabitants of the eastern plain were considered on their appearance to suffer malaria. The rural population was miserable, the mortality high. However, it was not possible to distinguish the responsibility of malaria among the other fevers.In 1899 and following years, A. Laveran was in Corsica. He confirmed the presence of Anopheles in the localities where malaria was present. He encouraged the creation in Bastia in 1902 of the Corsican League against Malaria and he chaired it. The actions of this League were based on the fight against the larvae by chemical destruction, on the use of mosquito nets and on massive and free preventive "quininisation". A sanitation and development law for Corsica was passed in 1911. Initial results were observed, confirmed by Léger and Arlo (1913) [6]. After WW1, the activities started again, in particular by Sergent and Sergent. An antimalarial application station, subsidized by the Rockefeller Foundation, was created in Bastia in 1925, supported by the laboratory of parasitology of the Faculty of Medicine of Paris. Plasmodium falciparum was predominant, transmitted essentially by Anopheles labranchiae of the maculipennis complex, up to an altitude of 500 m. The role of population displacements, linked to pastoral practices, the absence of stables and therefore of zoonotic deviation of anopheles were underlined.The liberation of Corsica in October 1943 allowed the installation by the American army of numerous airfields on the eastern plain. An intense local mosquito control by DDT was then carried out, impressing the population. However, malaria prospered on the island with an acme of indices in 1947. From 1948, campaigns of spraying insecticide against adults, chemical control of larvae or use of larvivorous fish, treatment of patients in dispensaries led to very good results. Since 1953, malaria transmission is interrupted in Corsica excepted 30 indigenous cases in 1970-71. Currently, the situation in Corsica of an anophelism without malaria is considered to be under control with a low risk of resumption of a localized transmission.

[Laveran and the Nobel Prize in Physiology or Medicine]. / Laveran et le Prix Nobel de physiologie ou de médecine.

This article recalls the conditions under which the first Nobel Prizes were awarded. The scientific personalities who nominated Alphonse Laveran for the prize from 1901 to 1907 are recalled, among them Ronald Ross, winner in 1902. In 1907, Karl Axel Hampus Mörner submitted Alphonse Laveran for the prize. He was then the rector of the Karolinska Institutet, as well as the chairman of the Nobel Committee and the Nobel Assembly, and had never before expressed an interest in one scientist more than another. The previous year, the Nobel Assembly had for the first time awarded the prize for physiology or medicine to two laureates, Camillo Golgi and Santiago Ramón y Cajal "in recognition of their work on the structure of the nervous system". In 1907, the numerous, repeated and simultaneous nominations of Élie Metchnikoff and Paul Ehrlich were probably the subject of an important debate, which finally turned out in favour of Alphonse Laveran. We explain why we think the choice of the president prevailed. In 1908, when Laveran became one of the nominators of the prize, his main competitors of 1907 were finally crowned simultaneously "in recognition of their work on immunity".The long delay between the discovery of the malarial parasite (1880) and the award of the prize "in recognition of his work on the role played by protozoa in the appearance of diseases" is put into perspective and illustrates what will almost always be the practice, contrary to Alfred Nobel's rule of awarding the prize within a year after the discovery. The particular circumstances of the award of the prize in 1907 are described.The donation that Alphonse Laveran made on December 22nd 1907 to the Pasteur Institute out of the amount of his prize was 100,000 francs, i.e. a little more than half of the 190,000 francs grant received from the Nobel Committee. Its value, in terms of purchasing power in euros 2021, is estimated at over 400,000 euros. The use made of it by the Pasteur Institute is clearly shown in the minutes of its Board of Directors in 1908, as having been mainly devoted to the fitting out and equipment of the Laboratory of Tropical Diseases that Laveran was calling for in the buildings recently purchased on Rue Falguière (Paris); the donation was not used for the construction of new buildings.

[In the wake of Alphonse Laveran]. / Dans le sillage d'Alphonse Laveran.

Alphonse Laveran (Nobel Prize 1907) played a pioneering role in discovering the causative agent of malaria, a disease that has existed since time immemorial, and long emblematic of the miasma theory until the end of the 19th century. In 1880, this unknown military doctor discovered the role of a hematazoan in malaria, designated Plasmodium. This was the first protozoan to be discovered in an infectious disease, at a time when bacteria were mainly suspected. This major discovery led to the identification of the role of mosquitoes in the spread of malaria by Ronald Ross (Nobel Prize 1902) and Battista Grassi. The recurrence of malaria attacks over many years was for a long time an enigma only solved after the Second World War by the discovery of the exo-erythrocytic cycle of Plasmodium. Progress was then made in treatment, from cinchona bark, quinine and chloroquine, to the recent discovery of artemisinin in 1972 by the Chinese researcher Tu Youyou (Nobel Prize 2015).

[Malaria today]. / Le paludisme aujourd'hui.

Malaria, a parasitic disease the pathogen of which was discovered by Alphonse Laveran in 1880 in the blood of febrile patients, remains in 2022 the most frequent endemic disease in tropical and subtropical countries. In its latest "World Malaria Report" available in November 2021, the WHO deals in great detail with the data collected in the field in 2019-2020, their progression over the last 20 years, and the measures to be taken to try to better control this life-threatening endemic. The number of malaria cases is estimated at 232 million in 2019 in 87 endemic countries, down from 245 million in 2000. The WHO African Region alone accounts for 94% of cases and the most frequent and severe infections due to Plasmodium falciparum species. If children under the age of 5 are not treated promptly, they can die. Globally, the number of malaria deaths declined steadily over the period 2000-2019, from 897,000 in 2000 to 568,000 in 2019, with nearly 95% of deaths occurring in 31 countries, primarily in sub-Saharan Africa. In other WHO regions, including Southeast Asia, malaria deaths decreased by 74%, with 35,000 deaths in 2000 compared to 9,000 in 2019. Malaria can be controlled worldwide, and possibly eradicated, if public information campaigns are strengthened and sufficient funds are made available.

[Research on infectious diseases in the French Armed Forces Health Service: one hundred years after Alphonse Laveran]. / Recherche sur les maladies infectieuses dans le Service de santé des armées: cent ans après Alphonse Laveran.

The army has always been particularly exposed to the risk of infection, which Alphonse Laveran already analyzed in 1875 in his Traité des maladies et épidémies des armées. Nowadays, the risk of infection is still present, which is why the Armed Forces Health Service (SSA) employs modern research resources in this area structured around the Armed Forces Biomedical Research Institute (IRBA) supported by the Military Training Hospitals (HIA), the Armed Forces Epidemiology and Public Health Center (CESPA), and the Val-de-Grâce School.These resources meet current research needs in infectious and tropical diseases and are preparing to respond to future emergences.Recently, the SSA research has stood out in several epidemics and emergences that have affected the French Armed Forces and the national population.

[Vaccination against malaria]. / Vaccination contre le paludisme.

Vaccination against malaria is an old dream that reemerged in 2015 with the European Medicines Agency's favourable opinion on a first antimalarial vaccine, RTS,S/ AS01. Six years later, the World Health Organization (WHO) is advising a wide deployment of this vaccine in sub-Saharan Africa and in regions with high and moderate transmission where Plasmodium falciparum circulates. This follows favourable results from the pilot programme in Ghana, Kenya and Malawi involving over 800,000 children since 2019. This article addresses the objectives and main vaccine candidates targeting the different stages of parasite development, highlighting the progress and limitations of these different approaches. The RTS,S saga has been a milestone in vaccine development, with a first-generation vaccine recommended by the WHO for use in children over 5 months of age in sub-Saharan Africa and other areas of moderate to high transmission of P. falciparum malaria, in combination with other prevention measures. Research efforts continue to better understand the correlates of protection. With advances in vaccine platforms, new multi-antigen, multi-stage, and even multi-species approaches might emerge and brighten the horizon for malaria control.

[Unconventional Laveran]. / Laveran décalé.

Charles Louis Alphonse Laveran - 18 June 1845 - 18 May 1922: first French Nobel Prize in Medicine, "in recognition of his work on the role played by protozoa in causing diseases". One hundred years after his death, only written records remain of his work and life. The witnesses to this period are no more. Alphonse Laveran has become an "object" of history.He was deeply involved in a turbulent historical period, marked by crises of regime change (Monarchy/Empire/Republic), military events (French colonial expansion in North Africa from 1830, the wars of 1870 and 1914-1918) and their consequences (the medical impact of infections in the colonial empire and during armed conflicts, the Dreyfus affair, among others), the advent of Pasteurian "microbiology" and the deciphering of the causes and modes of transmission of infectious diseases. A player on the edge of the military and civilian worlds, with their own, sometimes incompatible, visions of the aims and objectives to be pursued, Alphonse Laveran lived through these upheavals in a society in the throes of change, in his family and scientific environment.Paradoxically, the primary sources available to us for learning about this scientist and man are both abundant and "scarce" for us in the 21st century. His scientific publications and many of his speeches at various academies, committees and meetings are for the most part public and accessible, giving us a vision of a professional in scientific and medical research in action, presenting and convincing people of his ideas and theoretical and practical insights. The writings of his contemporaries, both public and private, shed light on - distort? - the man's many facets. On the other hand, there are few surviving sources on the man and his vision of life, his life and that of his family and friends.We will rely on the archives that have been preserved, in particular by the organisations that welcomed him during his military and civilian career, as well as by his wife Marie Laveran and his colleague Marie Phisalix, one of the first doctors of medicine in France and a renowned herpetologist. These two female figures have preserved and contributed to his memory. Let's take a closer look at the man behind the scientist, as we can imagine him through the traces that remain.

[Epidemiology of malaria in the French Armed Forces]. / Épidémiologie du paludisme dans les armées françaises.

Because of the individual morbidity and lethality and the resulting collective incapacity, malaria has always been a risk for the Armed Forces in operation. The fight against malaria is a real public health plan carried out by the Armed Forces Health Service (SSA) for the benefit of the Forces. This plan has four main components: vector control, which targets larvae and adult mosquitoes of the genus Anopheles, personal vector protection, which limits human-vector contact, chemoprophylaxis, and early diagnosis and treatment of malaria.Since 2001, the epidemiology of malaria in the Armed Forces have suffered from large-scale epidemics during operational engagements in Côte d'Ivoire, Guyana and the Central African Republic. The start of a military operation is accompanied by strategic and logistical priorities that take precedence over prevention. In addition, the rigorous application of personal protection measures remains difficult and even more so in a combat situation.The development of urban malaria in Africa, the use of causal chemoprophylaxis, the alternative to "nothing but insecticides", and the development of efficient diagnostic tools allowing for early and adapted management are the challenges ahead for the SSA.

[Laveran, the Pasteurian researcher]. / Laveran, le pasteurien.

At the end of his professorial mandate at the Val de Grâce hospital, Alphonse Laveran, who was Chief Doctor, was appointed to Lille and then Nantes. These assignments however deprived him of a hospital service where he could carry on his research. In 1896, faced with the inflexibility of his military hierarchy, he applied for early retirement; he was then 50 years old. Dr Roux welcomed him to the Pasteur Institute as a honorary department head, where he started a second career as a volunteer. He would spend the following 25 years there, addressing the great protozoology issues. Together with Félix Mesnil, he undertook the study of trypanosomiasis and leishmaniases. In 1907 he was awarded the Nobel Prize in physiology and medicine to honor "his work on the role of protozoa as pandemic vectors". He allocated a large part of his prize money to set up a parasitology laboratory at the Pasteur Institute, where all the discoveries and observations carried out in the colonies would converge. In 1908, he funded the Society of Exotic Pathology. He authored no less than 600 publications where his memorable research is recorded. Despite his somewhat outwardly rigid appearance, the man proved to be of amiable approach thanks to "the simplicity of his manners, his amenity and his great heart".