A large focus of naturally acquired Plasmodium knowlesi infections in human beings

Naturally acquired immunity to falciparum malaria protects millions of people routinely exposed to Plasmodium falciparum infection from severe disease and death. There is no clear concept about how this protection works. There is no general agreement about the rate of onset of acquired immunity or what constitutes the key determinants of protection; much less is there a consensus regarding the mechanism(s) of protection. This review summarizes what is understood about naturally acquired and experimentally induced immunity against malaria with the help of evolving insights provided by biotechnology and places these insights in the context of historical, clinical, and epidemiological observations. We advocate that naturally acquired immunity should be appreciated as being virtually 100% effective against severe disease and death among heavily exposed adults. Even the immunity that occurs in exposed infants may exceed 90% effectiveness. The induction of an adult-like immune status among high-risk infants in sub-Saharan Africa would greatly diminish disease and death caused by P. falciparum. The mechanism of naturally acquired immunity that occurs among adults living in areas of hyper- to holoendemicity should be understood with a view toward duplicating such protection in infants and young children in areas of endemicity.

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Acquired immunity to malaria.

The absolute necessity for rational therapy in the face of rampant drug resistance places increasing importance on the accuracy of malaria diagnosis. Giemsa microscopy and rapid diagnostic tests (RDTs) represent the two diagnostics most likely to have the largest impact on malaria control today. These two methods, each with characteristic strengths and limitations, together represent the best hope for accurate diagnosis as a key component of successful malaria control. This review addresses the quality issues with current malaria diagnostics and presents data from recent rapid diagnostic test trials. Reduction of malaria morbidity and drug resistance intensity plus the associated economic loss of these two factors require urgent scaling up of the quality of parasite-based diagnostic methods. An investment in anti-malarial drug development or malaria vaccine development should be accompanied by a parallel commitment to improve diagnostic tools and their availability to people living in malarious areas.

A review of malaria diagnostic tools: microscopy and rapid diagnostic test (RDT).

PROTRACED COUNTERINSURGENCY: CHINESE COIN STRATEGY IN XINJIANG by MAJ J. Scott LaRonde, USA, 95 pages. In 1949, following the conclusion of its revolutionary war against the Chinese Nationalist forces, the People’s Liberation Army (PLA) peacefully occupied China’s western most province of Xinjiang. For nearly sixty years, the PLA has conducted a counterinsurgency against several, mostly Uyghur-led, separatist movements. Despite periods of significant violence, particularly in the early 1950s and again in the 1990s, the separatist forces have not gained momentum and remained at a level one insurgency. Mao ZeDeng is revered as a master insurgent and the father of Fourth Generation Warfare. Strategists in armies worldwide study his writings on revolutionary and guerilla warfare. This monograph concludes that Mao, as well as the communist leaders who followed him, was also successful at waging protracted counterinsurgency. For nearly sixty years, separatist movements in Xinjiang, Tibet, and Taiwan have all failed. This monograph analyzes the conflict in Xinjiang and concludes that the Chinese continue to defeat the separatist movement in Xinjiang through a strategy that counters Mao’s seven fundamentals of revolutionary warfare.

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Approved for Public Release; Distribution is Unlimited

Part 1 The importance of blood-sucking insects. Part 2 The evolution of the blood-sucking habit: prolonged close association with vertebrates morphological pre-adaptation for piercing. Part 3 Feeding preferences of blood-sucking insects: host choice host choice and species complexes. Part 4 Location of the host: the behavioural framework of host location appetitive searching activation and orientation attraction movement between hosts. Part 5 Ingestion of the blood meal: vertebrate haemostasis insect anti-haemostatic factors probing stimulants phagostimulants mouthparts blood intake. Part 6 Managing the blood meal: midgut anatomy the blood meal gonotrophic concordance nutrition host hormones in the blood meal partitioning of resources from the blood meal autogeny. Part 7 Host - insect interactions: insect distribution on the surface of the host morphological specializations for life on the host host immune responses to insect salivary secretions behavioural defences of the host density dependent effects on feeding success. Part 8 Transmission of parasites by blood-sucking insects: transmission routes specificity in vector-parasite relationships origin of vector parasite relationships.

Biology of Blood-Sucking Insects

The primate malarias.

. Hypnozoites of two strains of the human relapsing malaria parasite, Plasmodium vivax, have been detected among maturing 7- and 10-day pre-erythrocytic schizonts in liver biopsies of chimpanzees infected by intravenous inoculation of sporozoites obtained from dissected salivary glands of heavily infected anopheline mosquitoes. As in the simian relapsing species, P. cynomolgi, the hypnozoites of P. vivax at 7 and 10 days are uninucleate forms of approximately 4–5 µm diameter, lying within the cytoplasm of individual hepatocytes. Their presence in this relapsing human species is added support for the hypnozoite theory of malarial relapse.

Demonstration of Hypnozoites in Sporozoite-Transmitted Plasmodium vivax Infection*

Summary
Four strains of vivax malaria from three Central American countries (Panama, El Salvador, Nicaragua) were studied in volunteers for characteristics of their relapse patterns and for their response to recommended dosage regimens of some standard antimalarial drugs. The relapse patterns of the four Central American vivax strains fell into the “temperate zone” category of relapse pattern; namely, an early primary attack (short prepatent period) followed by a long period of latency before appearance of frequent relapse activity. The characteristics and classification of relapse patterns are discussed.

Studies on the characterization of plasmodium vivax strains from Central America.

In a continuing reexamination of plasmodial tissue stages within the context of the hypnozoite theory of malarial relapse, 2 strains of Plasmodium vivax with distinct and disparate relapse characteristics in humans were studied in chimpanzees. Following intravenous inoculation of massive numbers of salivary gland sporozoites, both the frequently relapsing Chesson strain and a North Korean strain characterized by predominantly delayed relapses exhibited relapse patterns and antimalarial sensitivity in the splenectomized chimpanzee essentially indistinguishable from those seen in humans. Examination of hepatic biopsies obtained at 7 and 10 days after infection revealed both pre-erythrocytic (pre-e) schizonts and hypnozoites in tissue obtained from the animal infected with the Chesson strain, but only rare hypnozoites (no pre-e schizonts) at 7 days in the animal infected with the North Korean strain. These findings, combined with the comparability of relapse behavior--which indicates the suitability of the chimpanzee as a model for the natural (human) host-parasite relationship--are essentially as predicted by the hypnozoite theory, despite the small numbers of tissue forms seen. Pre-erythrocytic schizogony of the Chesson strain in the liver was essentially indistinguishable from that of other strains studied, also underlining the suitability of this model system for tissue stage studies of P. vivax.

Observations on early and late post-sporozoite tissue stages in primate malaria. IV. Pre-erythrocytic schizonts and/or hypnozoites of Chesson and North Korean strains of Plasmodium vivax in the chimpanzee.

The efficacy of clindamycin, a slow acting antimalarial, in combination with a rapid acting schizonticidal drug, quinine, was determined against three multidrug-resistant strains of Plasmodium falciparum (Cambodian I, Burma [Thau] and Panama II). No recrudescences occurred after treatment with quinine 650 mg orally every 8 hours for 3 days and clindamycin 450 mg orally every 6 hours for 3 days, when administered either simultaneously or sequentially. Quinine alone for 3 days was not curative against infections with these strains. During a 3-day course of therapy, blood levels of quinine or clindamycin were not influenced by administration of the other drug.

William E. Collins

Papers

The primate malarias.

Demonstration of Hypnozoites in Sporozoite-Transmitted Plasmodium vivax Infection*

Studies on the characterization of plasmodium vivax strains from Central America.

Observations on early and late post-sporozoite tissue stages in primate malaria. IV. Pre-erythrocytic schizonts and/or hypnozoites of Chesson and North Korean strains of Plasmodium vivax in the chimpanzee.

Evaluation of Clindamycin in Combination With Quinine Against Multidrug-Resistant Strains of Plasmodium Falciparum