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    Parasitemia and percent infection of An. freeborni mosquitoes fed on A. lemurinus griseimembra monkey AO-0278 infected with the Chesson strain of P. vivax. SP = splenectomy on the 17th day of patent parasitemia.

  • 1

    Ehrman FC, Ellis JM, Young MD, 1945. Plasmodium vivax Chesson strain. Science 101 :377.

  • 2

    Moore JA, Young MD, Hardman NF, Stubbs TH, 1945. Studies on imported malarias: 2. Ability of California anophelines to transmit malarias of foreign origin and other considerations. J Natl Malar Soc 4 :307–329.

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  • 3

    Young MD, Ellis JM, Stubbs TH, 1946. Studies on imported malarias. 5. Transmission of foreign Plasmodium vivax by Anopheles quadrimaculatus. Am J Trop Med 26 :477–482.

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  • 4

    Young MD, Stubbs TH, Ellis JM, Burgess RW, Eyles DE, 1946. Studies on imported malarias. 5. The infectivity of malarias of foreign origin to anophelines of the southern United States. Am J Hyg 43 :326–341.

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  • 5

    Whorton CM, Kirschbaum WR, Pullman TN, Jones R Jr, Craige B Jr, Alving AS, Eichelberger L, Coultson F, 1947. The Chesson strain of Plasmodium vivax malaria. 1. Factors influencing the incubation period. J Infect Dis 80 :223–227.

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  • 6

    Craige B Jr, Alving AS, Jones R Jr, Whorton CM, Pullman TN, Eichelberger L, 1947. The Chesson strain of Plasmodium vivax malaria. II. Relationship between prepatent period, latent period and relapse rate. J Infect Dis 80 :228–236.

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  • 7

    Whorton CM, Yount E Jr, Jones R Jr, Alving AS, Pullman TN, Craige B Jr, Eichelberger L, 1947. The Chesson strain of Plasmodium vivax malaria. III. Clinical aspects. J Infect Dis 80 :237–249.

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  • 8

    Whorton CM, Pullman TN, Kirschbaum WR, Jones R Jr, Alving AS, Craige B Jr, Eichelberger L, Coulston F, 1947. The Chesson strain of Plasmodium vivax malaria. IV. Immunity. J Infect Dis 81 :1–6.

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  • 9

    Craige B, Jones R Jr, Whorton CM, Pullman TN, Alving AS, Eichelberger L, 1947. Clinical standardization of pamaquine (Plasmoquine) in mosquito-induced vivax malaria, Chesson strain. A preliminary report. Am J Trop Med 27 :309–315.

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  • 10

    Young MD, Ellis JM, Stubbs TH, 1947. Some characteristics of foreign vivax malaria induced in neurosyphilitic patients. Am J Trop Med 27 :585–596.

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  • 11

    Alving AS, 1948. Pentaquine (SN-13,276) and isopentaquine (SN-13,274). Therapeutic agents effective in reducing relapse rate in vivax malaria. Proceedings of the 4th International Congress of Tropical Medicine and Malaria, June 1948; Washington, DC.

  • 12

    Alving AS, Craige B Jr, Jones R Jr, Whorton CM, Pullman TN, Eichelberger L, 1948. Pentaquine (SN-13,276), a therapeutic agent effective in reducing the relapse rate in vivax malaria. J Clin Invest 28 :25–33.

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  • 13

    Alving AS, Pullman TN, Craige B Jr, Jones R Jr, Whorton CM, Eichelberger L, 1948. The clinical trial of eighteen analogues of pamaquine (Plasmochin) in vivax malaria (Chesson strain). J Clin Invest 27 :34–35.

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  • 14

    Jones R Jr, Craige B Jr, Alving AS, Whorton CM, Pullman TN, Eichelberger L, 1948. A study of the prophylactic effectiveness of several 9-aminoquinolines in sporozoite -induced vivax malaria (Chesson strain). J Clin Invest 27 :6–11.

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  • 15

    Jones R Jr, Pullman TN, Whorton CM, Craige B Jr, Alving AS, Eichelberger L, 1948. The therapeutic effectiveness of large doses of Paludrine in acute attacks of sporozoite-induced vivax malaria (Chesson strain). J Clin Invest 27 :51–55.

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  • 16

    Pullman TN, Alving AS, Jones R Jr, Whorton CM, Craige B Jr, Eichelberger L, 1948. A study of the prophylactic, curative and suppressive activity of SN-11437 (Metachloridine) in standand infection of vivax malaria. Am J Trop Med 28 :413–423.

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  • 17

    Pullman TN, Craige B Jr, Alving AS, Whorton CM, Jones R Jr, Eichelberger L, 1948. Comparison of chloroquine, quinacrine (atabrine), and quinine in the treatment of acute attacks of sporozoite-induced vivax malaria (Chesson strain). J Clin Invest 27 :46–50.

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  • 18

    Pullman TN, Eichelberger L, Alving AS, Jones R Jr, Craige B Jr, Whorton CM, 1948. The use of SN-10,275 in the prophylaxis and treatment of sporozoite-induced vivax malaria (Chesson strain). J Clin Invest 27 :12–16.

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  • 19

    Young MD, 1948. Adaptibility of exotic malaria parasites to indigenous anophelines. Proceedings of the 4th International Congress of Tropical Medicine and Malaria, June 1948; Washington, DC.

  • 20

    Coatney GR, Cooper WC, Ruhe DS, Young MD, 1949. Studies in human malaria. XVII. Trials of quinacrine, colchicine (SN 12,080) and quinine against Chesson strain vivax malaria. Am J Hyg 50 :194–200.

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  • 21

    Cooper WC, Coatney GR, Imboden CA Jr, Jeffery GM, 1949. Aureomycin in experimental Chesson strain vivax malaria. Proc Soc Exp Biol Med 72 :587–588.

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  • 22

    Coatney GR, Cooper WC, Eyles DE, Culwell WB, White WC, Lints HA, 1950. Studies in human malaria. XXVII. Observations on the use of pentaquine in the prevention and treatment of Chesson strain vivax malaria. J Natl Malar Soc 9 :222–233.

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  • 23

    Coatney GR, Cooper WC, White WC, Lints HA, Culwell WB, Eyles DE, 1950. Studies in human malaria. XXIV. Protective and therapeutic trials of SN 10,751 (Camoquine) against the Chesson strain of Plasmodium vivax. J Natl Malar Soc 9 :67–73.

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  • 24

    Coatney GR, Cooper WC, Young MD, 1950. Studies in human malaria. XXX. A summary of 204 sporozoite-induced infections with the Chesson strain of Plasmodium vivax. J Natl Malar Soc 9 :381–396.

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  • 25

    Cooper WC, Coatney GR, Culwell WB, Eyles DE, Young MD, 1950. Studies in human malaria. XXVI. Simultaneous infection with the Chesson and the St. Elizabeth strains of Plasmodium vivax. J Natl Malar Soc 9 :182–190.

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  • 26

    Cooper WC, Coatney GR, Jeffery GM, Imboden CA Jr, 1950. Studies in human malaria. XXVIII. Observations on the use of chlorguanide against Chesson strain of Plasmodium vivax. J Natl Malar Soc 9 :366–376.

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  • 27

    Edgecomb HJ, Arnold J, Young EH Jr, Alving AS, Eichelberger L, Jeffery GM, Eyles D, Young MD, 1950. Primaquine, SN 13272, a new curative agent in vivax malaria; a preliminary report. J Natl Malar Soc 9 :285–292.

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  • 28

    Imboden CA Jr, Cooper WC, Coatney GR, Jeffery GM, 1950. Studies in human malaria. XXIX. Trials of aureomycin, chloramphenicol, penicillin and dihydrostreptomycin against the Chesson strain of Plasmodium vivax. J Natl Malar Soc 9 :377–380.

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  • 29

    Lints HA, Coatney GR, Cooper WC, Culwell WB, White WC, Eyles DE, 1950. Studies in human malaria. XXII. Prolonged suppression of Chesson strain vivax malaria by the weekly administration of chlorquanide or chloroquine. J Natl Malar Soc 9 :50–58.

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  • 30

    Alving AS, Alnold J, Robinson DH, 1952. Status of Primaquine 1. Mass therapy of subclinical vivax malaria with primaquine. JAMA 149 :1558–1562.

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  • 31

    Coatney GR, Myatt AV, Hernandez T, Jeffery GM, Cooper WC, 1952. Symposium on daraprim. Studies on the compound 50–63. Trans R Soc Trop Med Hyg 46 :496–497.

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  • 32

    Jeffery GM, 1952. The infection of mosquitoes by Plasmodium vivax (Chesson strain) during the early primary parasitemias. Am J Trop Med Hyg 1 :612–617.

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  • 33

    Cooper WC, Myatt AV, Hernandez T, Jeffery GM, Coatney GR, 1953. Studies in human malaria. XXXI. Comparison of primaquine, isopentaquine, SN-3883, and pamaquine as curative agents against Chesson strain vivax malaria. Am J Trop Med Hyg 2 :949–957.

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  • 34

    Hernandez T, Myatt AV, Coatney GR, Jeffery GM, 1953. Studies in human malaria. XXXIV. Acquired resistance to pyrimethamine (Daraprim) by the Chesson strain of Plasmodium vivax. Am J Trop Med Hyg 2 :797–804.

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  • 35

    Coatney GR, Myatt AV, Hernandez T, Jeffery GM, Cooper WC, 1953. Studies in human malaria. XXXII. The protective and therapeutic effects of pyrimethamine (Daraprim) against Chesson strain vivax malaria. Am J Trop Med Hyg 2 :777–787.

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  • 36

    Arnold J, Alving AS, Hockwald RS, Clayman CB, Dern RJ, Beutler E, Jeffery GM, 1954. The effect of continuous and intermittent primaquine therapy on the relapse rate of Chesson strain vivax malaria. J Lab Clin Med 44 :429–438.

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  • 37

    Jeffery GM, Burgess RW, Eyles DE, 1954. Susceptibility of Anopheles quadrimaculatus and A. albimanus to domestic and foreign strains of Plasmodium vivax. Am J Trop Med Hyg 3 :821–824.

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  • 38

    Alving AS, Arnold J, Hockwald RS, Clayman CB, Dern RJ, Beutler E, Flanagan CL, 1955. Potentiation of the curative action of primaquine in vivax malaria by primaquine and chloroquine. J Lab Clin Med 46 :301–306.

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  • 39

    Young MD, Eyles DE, Burgess RW, Jeffery GM, 1955. Experimental testing of the immunity of negros to Plasmodium vivax. J Parasitol 41 :315–318.

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  • 40

    Jeffery GM, 1956. Relapses with Chesson strain Plasmodium vivax following treatment with chloroquine. Am J Trop Med Hyg 5 :1–13.

  • 41

    Jeffery GM, 1958. Infectivity to mosquitoes of Plasmodium vivax following treatment with chloroquine and other antimalarials. Am J Trop Med Hyg 7 :207–211.

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  • 42

    Coatney GR, Michelson O, Burgess RW, Young MD, Pirkle CI, 1958. Chloroquine and pyrimethamine in salt as a suppressive against sporozoite-induced vivax malaria (Chesson strain). Bull World Health Organ 19 :53–67.

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  • 43

    Young MD, Burgess RW, 1959. Pyrimethamine resistance in Plasmodium vivax malaria. Bull World Health Organ 20 :27–36.

  • 44

    Alving AS, Johnson CF, Tarlov AR, Brewer GJ, Kellermeyer RW, Carson PE, 1960. Mitigation of the haemolytic effect of primaquine and enhancement of its action against exoerythrocytic forms of the Chesson strain of Plasmodium vivax by intermittent regimens of drug administration. Bull World Health Organ 22 :621–631.

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  • 45

    Arnold J, Alving AS, Clayman CB, 1961. Induced primaquine resistance in vivax malaria. Trans R Soc Trop Med Hyg 55 :345–350.

  • 46

    Kuvin SF, Tobie JE, Evans CB, Coatney GR, Contacos PG, 1962. Fluorescent antibody studies on the course of antibody production and serum gamma globulin levels in normal volunteers infected with human and simian malarias. Am J Trop Med Hyg 11 :429–436.

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  • 47

    Tobie JE, Kuvin SF, Contacos PG, Coatney GR, Evans CB, 1962. Fluorescent antibody studies on cross reactions between human and simian malaria in normal volunteers. Am J Trop Med Hyg 11 :589–596.

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  • 48

    Coatney GR, Contacos PG, Lunn JS, Kilpatrick JW, Elder HA, 1963. The effect of a repository preparation of the dihydrotriazine metabolite of chlorguanide, CI-501, against the Chesson strain of Plasmodium vivax in man. Am J Trop Med Hyg 12 :504–508.

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  • 49

    Contacos PG, Elder HA, Coatney GR, 1963. Therapeutic trials of a dihydroxynaphthalene (377C54) against Plasmodium falciparum and Plasmodium vivax infections in human volunteers. Am J Trop Med Hyg 12 :513–518.

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  • 50

    Hill GJ II, Knight V, Coatney GR, Lawless DE, 1963. Vivax malaria complicated by aphasia and hemiparesis. Arch Intern Med 112 :863–868.

  • 51

    Coatney GR, Contacos PG, Lunn JS, 1964. Further observations on the antimalarial activity of CI-501 (Camolar) against the Chesson strain of vivax malaria. Am J Trop Med Hyg 13 :383–385.

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  • 52

    Chin W, Lunn JS, Buxbaum J, Contacos PG, 1965. The effect of cycloguanil pamoate (CI -501) against a chlorguanide-resistant Chesson strain of Plasmodium vivax. Am J Trop Med Hyg 14 :922–924.

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  • 53

    Lunn JS, Jacobs RL, Contacos PG, Coatney GR, 1965. Antibody production in Plasmodium vivax infections suppressed by weekly doses of chloroquine. Am J Trop Med Hyg 14 :697–699.

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  • 54

    Powell RD, DeGowin RL, Eppes RB, 1965. Studies on the antimalarial effects of cycloguanil pamoate (CI-501) in man. Am J Trop Med Hyg 14 :913–921.

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  • 55

    Rubenstein M, Mulholland JH, Jeffery GM, Wolff SM, 1965. Malaria induced endotoxin tolerance. Proc Soc Exp Biol Med 118 :283–287.

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    Chin W, Contacos PG, Coatney GR, 1966. The evaluation of quinine sulfate and diaminodiphenyl sulfone (DDS) as suppressive agents against sporozoite-induced Chesson strain vivax malaria. Am J Trop Med Hyg 15 :922–924.

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  • 57

    Contacos PG, Coatney GR, Lunn JS, Chin W, 1966. The urinary excretion and antimalarial activity of CI-501 (cycloguanil pamoate) against vivax and falciparum malaria. Am J Trop Med Hyg 15 :281–286.

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  • 58

    Jeffery GM, 1966. Epidemiological significance of repeated infections with homologous and heterologous strains and species of Plasmodium. Bull World Health Organ 35 :873–882.

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  • 59

    Lunn JS, Chin W, Contacos PG, Coatney GR, 1966. Changes in antibody titers and serum protein fractions during the course of prolonged infections with vivax or with falciparum malaria. Am J Trop Med Hyg 15 :3–10.

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  • 60

    Tobie JE, Abele DC, Hill GJ II, Contacos PG, Evans CB, 1966. Fluorescent antibody studies on the immune response in sporozoite-induced and blood-induced vivax malaria and the relationship of antibody production to parasitemia. Am J Trop Med Hyg 15 :676–683.

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  • 61

    Tobie JE, Wolff SM, Jeffery GM, 1966. Immune response of man to inoculation with Plasmodium cnomolgi and challenge with P. vivax. Lancet 2 :300–302.

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  • 62

    Chin W, Coatney GR, King HK, 1967. An evaluation of CI-564 against blood-induced chlorguanide-sensitive and chlorguanide-resistant strains of vivax malaria. Am J Trop Med Hyg 16 :13–14.

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  • 63

    Clyde DF, Miller RM, DuPont HL, Hornick RB, 1971. Antimalarial effects of tetracyclines in man. J Trop Med Hyg 74 :238–242.

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    Clyde DF, Rebert CC, McCarthy VC, Miller RM, 1971. Prophylaxis of malaria in man using the sulfones DFD and DDS alone and with chloroquine. Mil Med 136 :836–841.

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    Coatney GR, Collins WE, Warren McW, Contacos PG, 1971. The Primate Malarias. Washington, DC: US Govt. Printing Office.

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    Contacos PG, Coatney GR, Collins WE, Briesch PE, Jeter MH, 1973. Five day primaquine therapy: an evaluation of radical curative activity against vivax amalaria infection. Am J Trop Med Hyg 22 :693–695.

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    Neva FA, Howard WA, Glew RH, Krotoski WA, Gam AA, Collins WE, Atkinson JP, Frank MM, 1974. Relationship of serum complement levels to events of the malaria paroxysm. J Clin Invest 54 :451–460.

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    Ungureanu E, Killick-Kendrick R, Garnham PCC, Branzel P, Ramanescu C, Shute PG, 1976. Prepatent periods of a tropical strain of Plasmodium vivax after inoculation of tenfold dilutions of sporozoites. Trans R Soc Trop Med Hyg 70 :482–483.

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    Ward RA, Rutledge LC, Hickman RL, 1969. Cyclical transmission of Chesson vivax malaria to subhuman primates. Nature 224 :1126–1127.

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    Schmidt LH, 1978. Plasmodium falciparum and Plasmodium vivax infections in the owl monkey (Aotus trivirgatus) I. The courses of untreated infections. Am J Trop Med Hyg 27 :671–702.

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    Schmidt LH, 1978. Plasmodium falciparum and Plasmodium vivax infections in the owl monkey (Aotus trivirgatus) II. Responses to chloroquine, quinine, and pyrimethamine. Am J Trop Med Hyg 27 :703–717.

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    Schmidt LH, 1978. Plasmodium falciparum and Plasmodium vivax infections in the owl monkey (Aotus trivirgatus) III. Methods employed in the search for new blood schizonticidal drugs. Am J Trop Med Hyg 27 :718–737.

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    Collins WE, Warren McW, Contacos PG, Skinner JC, Richardson BB, Kearse TS, 1980. The Chesson strain of Plasmodium vivax in Aotus monkeys and anopheline mosquitoes. J Parasitol 66 :488–497.

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    Collins WE, Skinner JC, Broderson JR, Mehaffey P, Sutton BB, 1985. Infection of Aotus azarae boliviensis monkeys with different strains of Plasmodium vivax. J Parasitol 71 :239–243.

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    Collins WE, Skinner JC, Pappaioanou M, Ma NF-S, Broderson JR, Sutton BB, Stanfill PS, 1987. Infection of Aotus vociferans (karyotype V) monkeys with different strains of Plasmodium vivax. J Parasitol 73 :536–540.

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    Collins WE, Skinner JC, Pappaioanou M, Broderson JR, Ma NS-F, Filipski V, Stanfill PS, Rogers L, 1988. Infection of Peruvian Aotus nancymai monkeys with different strains of Plasmodium falciparum, P. vivax, and P. malariae. J Parasitol 74 :392–398.

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    Collins WE, Jeffery GM, 1999. A retrospective examination of sporozoite- and trophozoite-induced infections with Plasmodium falciparum. Am J Trop Med Hyg 61 (Suppl):4–48.

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    Earle WC, Perez M, 1932. Enumeration of parasites in the blood of malarial patients. J Lab Clin Med 17 :1124–1130.

 

 

 

 

 

The Chesson Strain of Plasmodium vivax in Humans and Different Species of Aotus Monkeys

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  • 1 Division of Parasitic Diseases, National Center for Zoonotic, Vector-Borne and Enteric Diseases, and Animal Resources Branch, National Centers for Preparedness, Detection and Control of Infectious Diseases, Centers for Disease Control and Prevention, US Public Health Service, Atlanta, Georgia

Comparison was made between the parasitemia of Chesson strain Plasmodium vivax in humans and in splenectomized Aotus lemurinus griseimembra, A. nancymaae, A. vociferans, and A. azarae boliviensis monkeys. In the monkeys, 56.3% of the animals had maximum counts > 25,000/μL and in humans 59.6% were above this peak parasitemia. In humans, it took an average of 9.3 days to reach the maximum parasite count. In monkeys with no previous infections, it took an average of 18.9 days to reach the maximum parasite count; for those with previous infections, it took an average of 15 days. Human and nonhuman primate data on this parasite suggest that splenectomized Aotus monkeys, particularly A. lemurinus griseimembra, and to a somewhat lesser extent A. vociferans, can mimic the course of Chesson malaria in humans regarding parasitemia and mosquito infection.

INTRODUCTION

After the isolation of the Chesson strain of Plasmodium vivax by Ehrman and others in 1944,1 extensive chemotherapeutic and biologic studies were conducted in humans and in multiple species of anopheline mosquitoes.26 The primary advantage of working with this parasite in humans was the very short relapse period after sporozoite infection and the frequency of subsequent relapses. This made it highly suitable for the testing of causal prophylactic and radical curative drugs directed against P. vivax or P. ovale. The parasite was readily transmitted by native anopheline mosquitoes that were being maintained in the laboratory for experimental studies. Chesson soon became the standard parasite for P. vivax studies in humans, and large amounts of data are still available for comparison with data obtainable from non-human primate studies.

The first successful adaptation of the Chesson strain to nonhuman primates was by Ward and others in 1969.69 They adapted the parasite to New World Aotus trivirgatus (=Aotus lemurinus griseimembra) monkeys and showed cyclic sporozoite transmission using Anopheles bala bacensis balabacensis (=An. dirus), An. stephensi, and An. quadrimaculatus mosquitoes. In addition, a chimpanzee, Pan troglodytes, was infected by sporozoite inoculation. Schmidt 7072 studied the normal course of trophozoite-induced infections in Aotus monkeys and the responses of the parasite to different antimalarial drugs such as chloroquine, quinine, and pyrimethamine.

Initially, we reported on the development of the Chesson strain in 17 splenectomized A. lemurinus griseimembra monkeys and 2 Aotus trivirgatus (=Aotus nancymaae) monkeys.73 Two of these infections were induced by sporozoites. Subsequently, we reported the infection of A. azarae boliviensis, A. vociferans, and several additional A. nancymaae monkeys with the Chesson strain.7476 In addition, infections were induced in splenectomized chimpanzees to obtain massive numbers of infected mosquitoes and large volumes of parasitized erythrocytes for molecular studies.77

Reported here is a summation of our studies with the Chesson strain of P. vivax in the different species of Aotus monkeys and a comparison with the infections in humans infected with the Chesson strain. As indicated, Chesson is one of the few strains of human malaria parasites for which there are data from human studies for comparison with that being generated from nonhuman primate trials. Reported are the results of a retrospective examination of archival data from 89 induced infections with Chesson strain P. vivax for the treatment of paresis and other mental disorders associated with tertiary syphilis during the period between 1943 and 1963.

MATERIALS AND METHODS

Patient management

Consent for whatever treatments the hospital staff determined necessary was granted by the families of the patients or the courts when patients were admitted to the hospital. The decision to infect a neurosyphiletic patient with a specific species or strain causing malaria was made as part of standard patient care provided by the medical staff of either the South Carolina State Hospital or the Georgia State Hospital. Patient care and evaluation endpoints (e.g., fever) were the responsibility of the medical staff. As previously reported,78 during infection, temperature, pulse, and respiration were checked every 4 hours and hourly during paroxysms (fevers) by hospital personnel. During paroxysms, patients were treated symptomatically. Infections were terminated at the direction of the attending physician. Personnel of the US Public Health Service provided the parasites for inoculation and monitored the daily parasite counts to determine the course of infection. All patients undergoing malaria therapy lived in screened wards of the hospital to prevent possible infection of local anophelines.

Treatment

Patients were frequently allowed to maintain parasitemia for relatively short periods of time, mainly from 2 to 11 weeks. Infections were terminated by treatment with standard antimalarial drugs.

Parasitemia

Patients were infected by the intravenous inoculation of parasitized erythrocytes or by sporozoite inoculation by mosquito bite. Estimations of parasite densities were made daily by preparation of thick and thin blood films by the method of Earle and Perez 79 that were stained with Giemsa stain and examined microscopically for the presence of parasites. The threshold for detection was ~10 parasites/μL blood.

Data presentation

Maximum parasite count, the number of days to maximum parasite count, and days of high density parasite counts (≥ 10,000/μL) were critical points for comparison. In humans, it was possible to record the number of days of fever ≥ 101°F and ≥ 104°F. Fever records for the monkeys were meaningless because it was soon determined that the temperatures in individual animals often rose dramatically as a result of the handling.

Monkeys

Aotus lemurinus griseimembra, A. nancymaae, A. vociferans, and A. azarae boliviensis were generally wild-caught animals imported from Colombia, Peru, and Bolivia. A few of the monkeys were laboratory-born. On arrival at the facility, all animals were quarantined for a 2-month conditioning period, during which they were weighed and tested for tuberculosis. Parasitologic and serologic examination indicated that the animals were free of infection with malaria parasites before inoculation. The monkeys were splenectomized before exposure to infection. All surgeries were performed in an AAALAC (Association for the Assessment and Accreditation of Laboratory Animal Care, International)-approved surgical suite appropriate for aseptic surgery. Protocols were reviewed and approved by the Centers for Disease Control and Prevention Institutional Animal Care and Use Committee, in accordance with procedures described in the US Public Health Policy 1986.

Animals were housed doubly or singly to avoid injuries caused by fighting with cage mates. Space recommendations for laboratory animals were followed as set forth in the NIH Guide for the Care and Use of Laboratory animals. All animals were fed a diet that has been proven to provide adequate nutrition and calories in captive Aotus monkeys used in malaria-related research. Feed was free of contaminants and freshly prepared. Daily observations of the animals’ behavior, appetite, stool, and condition were recorded. Medical conditions were treated by an attending veterinarian as they arose.

Mosquitoes

For the human studies, laboratory-reared Anopheles quadrimaculatus (originally from southeastern United States) and An. albimanus (originally from either Panama or the Florida Keys) were fed on the patients to determine infectivity of gametocytes. For the nonhuman primate studies, An. freeborni (from California), An. maculatus (originally from Malaysia), An. culicifacies (originally from India) An. gambiae (originally from The Gambia), An. dirus (originally from Thailand), and An. stephensi (originally from Delhi, India), were laboratory reared and maintained at the CDC/DPD insectaries. During periods when gametocytes were present, mosquitoes were allowed to feed on tranquilized monkeys as previously described. After feeding, mosquitoes were held in an incubator at 25°C and examined 1 week later for the presence of oocysts on their midguts. In the monkey studies, more than one lot (species) of mosquito was often fed on a particular day. For the tabulation of the tables, the results for An. dirus was used, if available, followed by An. freeborni, An. maculatus, and An. stephensi. Only one value was used for each feeding day.

For sporozoite transmission, mosquitoes were either allowed to feed to repletion on a tranquilized monkey or the monkey was injected intravenously with sporozoites dissected from the salivary glands of infected mosquitoes. Blood stage parasitemia was monitored by the daily examination of thick and thin blood films by the method of Earle and Perez.79 Infections were terminated by treatment with various combinations of drugs as described. Drugs were administered by oral intubation to monkeys.

RESULTS

Infections in humans

Ninety-one patients were infected with Chesson strain P. vivax. The maximum parasite counts for the 49 patients in which the Chesson strain was the primary infection ranged from 4,848 to 99,360/μL, with a median maximum parasite count of 32,514/μL (Table 1). This occurred after an average of 9.3 days of patent parasitemia. In those patients that were not treated, there was an average of 12 days of fever ≥ 101°F and 7 days of fever ≥ 104°F. The median maximum fever was 105.6°F. Mosquitoes were infected by feeding on 28 of 30 of the patients; of 145 lots that were fed, 129 (89%), were infected.

The maximum parasite counts for 42 patients that had been previously infected with P. vivax, P. vivax and P. ovale, or P. malariae or P. falciparum are presented in Table 2). The maximum parasite counts for the 26 patients who had been previously infected with P. vivax only ranged from 310/μL to 83,700/μL, with a median of 9,523/μL. This occurred after an average of 7.9 days of patent parasitemia. In the 22 patients who were not treated, there was an average of 6.3 days of fever ≥ 101°F and 3.4 days of fever ≥ 104°F. For the 14 patients with various histories of infection with P. vivax and P. ovale or P. malariae, the maximum parasite counts ranged from 40/μL to 14,315/μL with a median of 7,140/μL. This occurred after an average of 8.2 days of parasitemia. There was an average of 9 days of fever ≥ 101°F and 3.6 days of fever ≥ 104°F. The two patients who were previously infected with P. falciparum and P. vivax or P. falciparum had maximum parasite counts of 18,656/μL and 3,600/μL, respectively. Mosquitoes were infected by feeding on 11 of 16 of the patients; 33 of 64 lots that were fed (51.6%) were infected.

Infections in Aotus monkeys

Eighty-six Aotus monkeys of four different species were infected with Chesson strain P. vivax. For 36 of these, it was their primary infection. In these animals, the maximum parasite count ranged from 1,085/μL to 120,000/μL, with a median maximum parasite count of 14,939/μL. Twenty-nine monkeys had been infected with P. falciparum before being infected with the Chesson strain. The maximum parasite count for these animals ranged from 310/μL to 72,000/μL, with a median count of 12,648/μL. The remaining 21 animals had been infected with combinations of P. falciparum and heterologous strains of P. vivax, P. malariae, and/or P. simium. The median maximum parasite count for these animals was 8,742/μL.

Thirty-one A. lemurinus griseimembra were infected with the Chesson strain (Table 3). Sixteen of the animals had not been previously infected; maximum parasite counts ranged from 5,355/μL to 120,000/μL, with a median count of 26,700/μL. This occurred after an average of 22.7 days of patent parasitemia. As the maximum parasite count increased, so did the number of days that the count remained > 10,000/μL. The remaining 15 animals had been previously infected with P. falciparum, heterologous strains of P. vivax or P. falciparum, and heterologous strains of P. vivax. Maximum parasite counts ranged from 434/μL to 34,224/μL, with a median maximum parasite count of 14,880/μL. This occurred after an average of 13.9 days of patent parasitemia. There were three transmissions with sporozoites from An. gambiae and An. maculatus mosquitoes. Prepatent periods were 19, 24, and 32 days. Mosquitoes were infected by feeding on 19 of 27 of the monkeys; 350 of 848 lots that were fed (41.3%) were infected. On some of the animals, infection was obtained on many days over extended periods of time. This is shown in Figure 1, in which mosquitoes were fed periodically on A. l. griseimembra monkey AO-0278 for > 1 year. This animal was splenectomized on the 17th day of patent parasitemia, 5 days after inoculation of parasitized erythrocytes. An. freeborni mosquitoes continued to be infected during each recrudescence of the infection.

Twenty-two A. nancymaae were infected with the Chesson strain (Table 4). Seven of the monkeys had not been previously infected; maximum parasite counts ranged from 1,209/μL to 92,000/μL, with a median count of 14,787/μL. This occurred after an average of 17.7 days of patent parasitemia. Eleven animals had previously been infected with P. falciparum, and four had been infected with P. simium or combinations of P. falciparum and P. simium or heterologous strains of P. vivax. Maximum parasite counts in these animals with previous malarial experience ranged from 310/μL to 51,480/μL, with a median maximum parasite count of 9,858/μL. This occurred after an average of 14.5 days of patent parasitemia. It was apparent that, although some individual animals supported high-density parasite counts, A. nancymaae was less supportive than A. lemurinus griseimembra. Mosquitoes were infected by feeding on 8 of 14 animals. However, periods of infectivity were short, and infection rates were low; 46 of 113 lots (40.7%) that fed were infected. There were five transmissions with sporozoites from An. maculatus, An. stephensi, and An. dirus mosquitoes. The pre-patent periods were 18, 22, 30, 57, and 58 days.

Eighteen A. vociferans were infected with the Chesson strain (Table 5). Five of the monkeys had not been previously infected; maximum parasite counts ranged from 2,700/μL to 43,450/μL, with a median count of 6,390/μL. This occurred after 14.8 days of patent parasitemia. Eleven animals had previously been infected with P. falciparum, and two had been infected with P. falciparum and either P. simium or P. vivax. Maximum parasite counts for these 13 animals ranged from 1,710 to 56,000/μL, with a median maximum parasite count of 12,648/μL. This occurred after 17.2 days of patent parasitemia. Mosquito infections were obtained by feeding on seven of eight animals; 53 of 108 lots that fed (49.1%) were infected. Infection rates in the mosquitoes were much higher than obtained with A. nancymaae. There were two transmissions with sporozoites from An. stephensi and An. dirus mosquitoes. The pre-patent periods were both 80 days.

Fifteen A. azarae boliviensis were infected with the Chesson strain (Table 6). Eight of the monkeys had not been previously infected; maximum parasite counts ranged from 1,085/μL to 26,412/μL, with a median count of 9,299/μL. This occurred after an average of 15 days of patent parasitemia. Seven animals had previously been infected with P. falciparum, P. malariae, or combinations of P. vivax, P. malariae, and P. falciparum. Maximum parasite counts in these six animals ranged from 1,860/μL to 72,000/μL, with a median of 10,044/μL. This occurred after an average of 13.3 days of patent parasitemia. Mosquitoes were infected by feeding on 8 of 14 monkeys. Infection rates were low; 30 of 154 lots that fed (19.5%) were infected. There was a single transmission with sporozoites from An. culicifacies mosquitoes; the pre-patent period was 15 days.

DISCUSSION

The Chesson strain of P. vivax is one of the very few malaria parasites for which there is a body of information from human volunteer and patient studies, and the strain has been maintained and adapted to New World monkeys. In humans, the median maximum parasite count was 32,160/μL, which is ~0.75% of the erythrocytes infected (1.0% = 40,000/μL). The Chesson strain infections produced high-density maximum parasite counts and, as indicated in Table 1, there were many episodes of fever ≥ 104°F. It is apparent that this strain of P. vivax, originally from the southwestern Pacific region, resulted in severe disease in these patients.

All of the studies reported here were in splenectomized Aotus monkeys, and of these, A. lemurinus griseimembra supported higher-density maximum parasite counts than did the other three species examined. There was, however, a wide variation among individual animals. This is in contrast to strains of P. falciparum in splenectomized Aotus monkeys who do exhibit uniformity in these hosts. As in human infections, P. vivax infections in monkeys continue to have a wide range in maximum parasite count even after a number of passages. Previous infection with P. falciparum had a minimal effect on maximum parasite count in these hosts. However, these hosts infected mosquitoes more readily and at a higher rate of intensity, and A. vociferans showed useful potential as a source of mosquito infection. Rarely did animals that failed to support maximum parasite counts ≥ 10,000/μL turn out to be successful infectors of mosquitoes.

Compared with infections with the Chesson strain in humans, the maximum parasite counts in the splenectomized A. lemurinus griseimembra monkeys with no previous infection were comparable to humans with no previous malaria. In the monkeys, 56.3% of the animals had maximum counts > 25,000/μL (9/16) and 59.6% of humans had these counts (28/47). It took an average of 8.5 days in the 89 humans to reach the maximum parasite count. However, in the monkeys, it took, on average, much longer. For the 16 animals with no previous infections, it took an average of 18.9 days to reach the maximum parasite count; for those with previous infections, it took an average of 15 days.

Relapse was not shown in the 10 sporozoite-induced infections with the Chesson strain in these Aotus monkeys. The reasons for this are unclear and unexplained. It can be postulated that by continuous blood passage in these abnormal hosts, we selected a clonal parasite that no longer has the capacity for relapse. If the parasite were to be passaged back into humans or chimpanzees by sporozoites, it may or may not still be a relapsing parasite, but proof of this possibility has not been attempted. Possibly the demonstration of hypnozoites would be a sufficient indication of relapse potential. Nonetheless, human and nonhuman primate data on this parasite suggest that Aotus monkeys, particularly A. lemurinus griseimembra, and to a somewhat lesser extent A. vociferans, can fairly well mimic the course of Chesson malaria in humans regarding parasitemia and mosquito infection. Thus, one would anticipate that interventions effective in the non-human primate system could lead to success in the human malaria research effort.

Table 1

Maximum parasite counts, day of maximum count, days of fever ≥101°F and ≥ 104°F, and lots of mosquitoes infected on 49 humans infected with the Chesson strain of P. vivax

Table 1
Table 2

Maximum parasite counts, day of maximum count, days of fever ≥ 101°F and ≥ 104°F, and lots of mosquitoes infected on 42 humans infected with the Chesson strain of P. vivax after previous infection with P. vivax, P. ovale or P. malariae, or with P. falciparum

Table 2
Table 3

Maximum parasite counts, days with counts ≥ 10,000/μL, previous infections, and mosquito infections for 31 A. lemurinus griseimembra monkeys infected with the Chesson strain of P. vivax

Table 3
Table 4

Maximum parasite counts, days with counts ≥ 10,000/μL, previous infections, and mosquito infections for 22 A. nancymaae monkeys infected with the Chesson strain of P. vivax

Table 4
Table 5

Maximum parasite counts, days with counts ≥ 10,000/μL, previous infections, and mosquito infections for 18 A. vociferans monkeys infected with the Chesson strain of P. vivax

Table 5
Table 6

Maximum parasite counts, days with counts ≥ 10,000/μL, previous infections, and mosquito infections for 15. A. azarae boliviensis monkeys infected with the Chesson strain of P. vivax

Table 6
Figure 1.
Figure 1.

Parasitemia and percent infection of An. freeborni mosquitoes fed on A. lemurinus griseimembra monkey AO-0278 infected with the Chesson strain of P. vivax. SP = splenectomy on the 17th day of patent parasitemia.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 80, 1; 10.4269/ajtmh.2009.80.152

*

Address correspondence to William E. Collins, Malaria Branch, Division of Parasitic Diseases, National Center for Zoonotic, Vector-Borne and Infectious Diseases, Centers for Disease Control and Prevention, 4770 Buford Highway, Chamblee, GA 30341. E-mail: wec1@cdc.gov

Authors’ addresses: William E. Collins, JoAnn S. Sullivan, Douglas Nace, and John W. Barnwell, Malaria Branch, Division of Parasitic Diseases, National Center for Zoonotic, Vector-Borne and Infectious Diseases, Centers for Disease Control and Prevention, 4770 Buford Highway, Chamblee, GA 30341. Geoffrey M. Jeffery, 1085 Blackshear Dr., Apt. B, Decatur, GA 30033. Allison Williams, Animal Resources Branch, and G. Gale Galland, Division of Global Migration and Quarantine, National Centers for Preparedness, Detection and Control of Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Atlanta, GA 30333. Tyrone Williams, Atlanta Research and Education Foundation, 1670 Clairmont Rd., Decatur, GA 30033.

Acknowledgments: The authors thank the staff of the Animal Resources Branch, the National Center for Infectious Diseases, for the care of the animals.

Financial support: This study was supported in part by an Interagency Agreement 936-3100-AA6-P-00-0006-07 between the US Agency for International Development and the Centers for Disease Control and Prevention.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

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    Tobie JE, Abele DC, Hill GJ II, Contacos PG, Evans CB, 1966. Fluorescent antibody studies on the immune response in sporozoite-induced and blood-induced vivax malaria and the relationship of antibody production to parasitemia. Am J Trop Med Hyg 15 :676–683.

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    Chin W, Coatney GR, King HK, 1967. An evaluation of CI-564 against blood-induced chlorguanide-sensitive and chlorguanide-resistant strains of vivax malaria. Am J Trop Med Hyg 16 :13–14.

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    Clyde DF, Miller RM, DuPont HL, Hornick RB, 1971. Antimalarial effects of tetracyclines in man. J Trop Med Hyg 74 :238–242.

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    Clyde DF, Rebert CC, McCarthy VC, Miller RM, 1971. Prophylaxis of malaria in man using the sulfones DFD and DDS alone and with chloroquine. Mil Med 136 :836–841.

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    Coatney GR, Collins WE, Warren McW, Contacos PG, 1971. The Primate Malarias. Washington, DC: US Govt. Printing Office.

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    Contacos PG, Coatney GR, Collins WE, Briesch PE, Jeter MH, 1973. Five day primaquine therapy: an evaluation of radical curative activity against vivax amalaria infection. Am J Trop Med Hyg 22 :693–695.

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    Neva FA, Howard WA, Glew RH, Krotoski WA, Gam AA, Collins WE, Atkinson JP, Frank MM, 1974. Relationship of serum complement levels to events of the malaria paroxysm. J Clin Invest 54 :451–460.

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    Ungureanu E, Killick-Kendrick R, Garnham PCC, Branzel P, Ramanescu C, Shute PG, 1976. Prepatent periods of a tropical strain of Plasmodium vivax after inoculation of tenfold dilutions of sporozoites. Trans R Soc Trop Med Hyg 70 :482–483.

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    Schmidt LH, 1978. Plasmodium falciparum and Plasmodium vivax infections in the owl monkey (Aotus trivirgatus) I. The courses of untreated infections. Am J Trop Med Hyg 27 :671–702.

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    Schmidt LH, 1978. Plasmodium falciparum and Plasmodium vivax infections in the owl monkey (Aotus trivirgatus) II. Responses to chloroquine, quinine, and pyrimethamine. Am J Trop Med Hyg 27 :703–717.

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    Schmidt LH, 1978. Plasmodium falciparum and Plasmodium vivax infections in the owl monkey (Aotus trivirgatus) III. Methods employed in the search for new blood schizonticidal drugs. Am J Trop Med Hyg 27 :718–737.

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    Collins WE, Warren McW, Contacos PG, Skinner JC, Richardson BB, Kearse TS, 1980. The Chesson strain of Plasmodium vivax in Aotus monkeys and anopheline mosquitoes. J Parasitol 66 :488–497.

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    Collins WE, Skinner JC, Broderson JR, Mehaffey P, Sutton BB, 1985. Infection of Aotus azarae boliviensis monkeys with different strains of Plasmodium vivax. J Parasitol 71 :239–243.

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    Collins WE, Skinner JC, Pappaioanou M, Ma NF-S, Broderson JR, Sutton BB, Stanfill PS, 1987. Infection of Aotus vociferans (karyotype V) monkeys with different strains of Plasmodium vivax. J Parasitol 73 :536–540.

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    Collins WE, Skinner JC, Pappaioanou M, Broderson JR, Ma NS-F, Filipski V, Stanfill PS, Rogers L, 1988. Infection of Peruvian Aotus nancymai monkeys with different strains of Plasmodium falciparum, P. vivax, and P. malariae. J Parasitol 74 :392–398.

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    Collins WE, McClure HM, Swenson RB, Mehaffey P, Skinner JC, 1986. Infection of mosquitoes with Plasmodium vivax from chimpanzees using membrane feeding. Am J Trop Med Hyg 35 :56–60.

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    Collins WE, Jeffery GM, 1999. A retrospective examination of sporozoite- and trophozoite-induced infections with Plasmodium falciparum. Am J Trop Med Hyg 61 (Suppl):4–48.

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    Earle WC, Perez M, 1932. Enumeration of parasites in the blood of malarial patients. J Lab Clin Med 17 :1124–1130.

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