• View in gallery

    Prepatent periods for 109 sporozoite-induced infections with the El Limon, Santee-Cooper, and McLendon strains of Plasmodium falciparum.

  • View in gallery

    Frequency of fever, asexual parasitemia, and gametocytemia during the first 100 days in patients with sporozoite-induced infections with the El Limon, Santee-Cooper, and McLendon strains of Plasmodium falciparum. A, frequency of fever (≥ 101°F and ≥ 104°F). B, frequency of asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl. C, frequency of gametocytemia ≥ 100/μl and ≥ 1,000/μl. Patients were given subcurative doses of antimalarial drugs to modify the primary attack.

  • View in gallery

    Frequency of fever, asexual parasitemia, and gametocytemia during the first 100 days in patients with trophozoiteinduced infections with the El Limon, Santee-Cooper, and McLendon strains of Plasmodium falciparum. A, frequency of fever (≥ 101°F and ≥ 104°F). B, frequency of asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl C, frequency of gametocytemia ≥ 100/μl and ≥ 1,000/μl for 108 patients. Patients were given subcurative doses of antimalarial drugs to modify the primary attack.

  • View in gallery

    Frequency of fever, asexual parasitemia, and gametocytemia during the first 100 days in patients with sporozoite-induced infections with the El Limon, Santee-Cooper, and McLendon strains of Plasmodium Jalciparum. A, frequency of fever (≥ 101°F and ≥ 104°F). B, frequency of asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl. C, frequency of gametocytemia ≥ 100/μl and ≥ 1,000/μl. Patients were not given subcurative doses of antimalarial drugs to modify the primary attack.

  • View in gallery

    Frequency of fever, asexual parasitemia, and gametocytemia during the first 100 days in patients with trophozoiteinduced infections with the El Limon, Santee-Cooper, and McLendon strains of Plasmodium falciparum. A, frequency of fever (≥ 101°F and ≥ 104°F). B, frequency of asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl. C, frequency of gametocytemia ≥ 100/μl and ≥ 1,000/μl. Patients were not given subcurative doses of antimalarial drugs to modify the primary attack.

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A Retrospective Examination of Sporozoite- and Trophozoite-Induced Infections with Plasmodium Falciparum: Development of Parasitologic and Clinical Immunity during Primary Infection

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  • 1 Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

A retrospective analysis was made of the parasitologic and fever records of 318 patients who had been infected with the El Limon, Santee Cooper, or McLendon strains of Plasmodium falciparum for treatment of neurosyphilis between 1940 and 1963 to determine the development of parasitologic and clinical immunity during primary infection. The presence of fever ≥ 101 °F and ≥ 104°F, asexual parasite counts ≥ 1,000 and ≥ 10,000/μl, and gametocyte counts ≥ 100/μl and ≥ 1,000/μl are presented. The frequency of fever (number of patients with fever/number of patients remaining in study) for the first 100 days of patent parasitemia, the frequency of parasite counts ≥ 1,000 and ≥ 10,000/μl during the first 100 days of patent parasitemia, and the frequency of gametocyte counts ≥ 100 and ≥ 1,000/μl during the first 100 days of patent parasitemia are presented for 4 groups of patients: 1) sporozoite-induced and 2) trophozoite-induced infections requiring treatment during their primary attack, and 3) sporozoite-induced and 4) trophozoite-induced infections not requiring treatment during the primary attack. For each sporozoite-induced infection, the route of inoculation (bites or syringe), the species of mosquito used, the number of mosquito glands or bites, the intensity of salivary gland infection, and the length of the prepatent period are recorded. Prepatent periods for 109 sporozoite-induced infections ranged from 6 to 28 days. Patients with parasitologic or clinical findings that required suppressive, but non-curative treatment, during the primary attack had higher frequency of fever, parasitemia, and gametocytemia than patients not so treated. Fever was concentrated in the first 2 weeks of patent parasitemia although instances of fever were reported > 100 days after infection. High-density parasitemia was also concentrated early in the infection; instances of parasite counts ≥ 10,000/μl occurred > 75 days after infection. In conclusion, immunity to infection with P. falciparum was shown to develop rapidly. Following primary infection, clinical and parasitologic immunity was evident within 2–3 weeks following the detection of parasites in the peripheral circulation.

Previously of major public health importance in the United States and Europe, malaria is one of the most important parasitic diseases afflicting humans in the tropics. It continues to be the object of extensive biologic, pathologic, immunologic, and epidemiologic study.

Progress in the development of antimalarial vaccines and their eventual introduction into humans has emphasized our need to understand the natural development of immunity to this disease in individual patients, and the effect of prior infection with homologous and/or heterologous strains and species of Plasmodium on subsequent infections. Evaluation of the efficacy of vaccines in humans will be based on reductions in asexual and sexual parasite counts and the frequency and intensity of fever. The construction of the required mathematical models for vaccine as well as chemotherapeutic evaluation will depend on such parasitologic and clinical data. The primary source for information on the course of plasmodial infection in humans is archival data from the time when malariatherapy (the purposeful induction of malaria) was used to treat patients with neurosyphilis. Thus, a database has been extracted from parasitologic and fever records acquired between 1940 and 1963 at National Institutes of Health installations then located at the South Carolina State Hospital in Columbia, South Carolina, and the Georgia State Hospital in Milledgeville, Georgia.

An examination of these data was made to determine 1) the development of parasitologic and clinical immunity during primary infection, 2) the effect on parasitemia and fever of prior infection with a homologous species of Plasmodium, 3) the effect of previous infection with heterologous species of Plasmodium on these parameters, and 4), the effect of previous infection on the frequency of recrudescence. The latter is taken as an indication of the frequency at which new immunologically or antigenically variant populations of parasites emerge during the course of an infection. Such information should allow for a better interpretation of the efficacy of candidate vaccines, and help to establish guidelines for their assessment in humans. Infections with P. falciparum can be clinically severe and life-threatening. Thus, those time periods when high-density parasitemia and high fever are encountered during the course of natural infection will serve as guides for the assessment of candidate vaccines in volunteers.

Because development of P. falciparum vaccines has the greatest priority, an assessment of the available data for this species of Plasmodium was initially prepared. However, similar analyses of data from infections with P. vivax, P. ovale, and P. malariae are being made to provide information that should be useful when candidate vaccines for these infections are developed.

Historical Perspective

Use of malariatherapy. Fever had long been thought to have a beneficial effect on various medical conditions. According to Becker,1 Boisseau in 18322 advised “those afflicted with epilepsy, gout, mania, and the paralytic should go to the Pontine Marshes, where they were certain to contract the fever and be remedied thereafter.”

In 1917,3,4 Wagner-Jauregg induced malaria for the first time to treat paresis. A soldier with tertian malaria (P. vivax) was admitted to the psychiatric clinic at the University Hospital for Nervous and Mental Disease in Vienna, Austria in June 1917. Blood was passaged to 3 patients with “dementia paralytica”, marking the beginning of malaria therapy. As a result of studies on the development of malaria therapy, Wagner-Jauregg was awarded the Nobel Prize for Medicine in 1927.

Table 1

Species of Anopheles, route of inoculation, * and prepatent periods for 55 sporozoite-induced infections with the El Limon strain of Plasmodium falciparum in patients with no previous history of infection

PatientSpecies of AnophelesRoute of inoculationNo. of mosquitoesNo. of + sPrepatent period (days)
G-269albimanusInoc.116     ?  7
G-408albimanusBites20   73  7
G-299albimanusBites31   44  8
G-3 85albimanusBites13   19  8
G-452albimanusBites29   99  8
G-364albimanusBites22   56  8
G-247albimanusBites5   17  8
G-304albimanusBites21   49  8
G-315albimanusBites28   87  8
G-363albimanusBites24   19  8
G-235albimanusBites15   46  8
G-243albimanusBites9   17  8
G-251albimanusBites20   61  8
G-398albimanusBites16   43  8
G-427albimanusBites25   96  8
G-286albimanusBites14   13  9
S-1319quadrimaculatusBites11   27  9
G-428albimanusBites81   71  9
G-303albimanusBites28   69  9
G-290albimanusBites23   71  9
G-416albimanusBites20   62  9
G-414albimanusBites16   41  9
G-407albimanusBites20   44  9
G-419albimanusBites41   62  9
G-476quadrimaculatusBites7     5  9
G-261albimanusBites386     ?  9
G-316albimanusBites28   87  9
G-382albimanusBites13   16  9
G-384albimanusBites13   48  9
S-1309freeborniBites7   15  9
G-493albimanusInoc.4     ?10
G-466albimanusBites20   3910
G-360albimanusBites21   5010
G-327albimanusBites15   2811
S-1312freeborniInoc.19     ?11
S-966quadrimaculatusBites9   2311
G-491quadrimaculatusInoc.7.5  ?11
G-457albimanusBites3     711
G-338albimanusBites20   4311
G-322albimanusBites17   2011
G-314albimanusBites21   5311
G-279albimanusBites8   2611
G-259albimanusBites733     ?11
G-226albimanusBites15   4511
S-1317freeborniBites4     612
S-1316freeborniBites3     712
G-445albimanusBites19   1712
G-350albimanusBites7   1912
G-260albimanusBites379     ?12
S-965quadrimaculatusBites7   1713
G-258albimanusBites473     ?13
G-263albimanus, quadrimaculatusBites518     ?14
G-305albimanusBites25   4615
G-289albimanusBites33   4815
G-310albimanusBites5     416

Patients were exposed by mosquito bite or the subcutaneous or intravenous inoculation (Inoc.) of sporozoites dissected from the salivary glands. Numbers of sporozoites in salivary glands were graded 1 + to 4 + ; total gland ratings = number of + s.

Table 2

Species of Anopheles, route of inoculation,* and prepatent periods for 13 sporozoite-induced Infections With The Santee-Cooper Strain of Plasmodium falciparum in patients with no previous history of infection

PatientSpecies of AnophelesRoute of inoculationNo. of mosquitoesNo. of +sPre-patent period (days)
G-143quadrimaculatusBites  21  71    7
G-140quadrimaculatusBites  38100+  7
G-145quadrimaculatusBites100300    8
G-144quadrimaculatusBites  21  71    9
G-132quadrimaculatusBites  28  71    9
G-179quadrimaculatusBites  10  33    9
G-159quadrimaculatusBites  34  98    9
G-142quadrimaculatusGlands/IV    ?    ?    9
G-152quadrimaculatusBites  11  35  10
G-146quadrimaculatusBites100300+10
G-147quadrimaculatusBites100300+12
G-178albimanusBites    8    5  13
S-713quadrimaculatusBites    2    ?  14

Patients were exposed by mosquito bite or the intravenous (IV) inoculation of sporozaites dissected from the salivary glands. Numbers of sporozoites in salivary glands were graded 1 + to 4 +; total gland ratings = number of +s.

The first detailed report of laboratory-based malarial studies associated with the treatment of neurosyphilitic patients in England was that of Colonel S. P. James (a member of the Malaria Committee of the league of Nations), and P. G. Shute in 1926.5 Because of objections to induction of malarial attacks by the direct inoculation of blood from patient to patient, they conducted extensive studies at the Horton Mental Hospital in Epsom on the use of bites of plasmodial-infected mosquitoes to induce malaria. The clinical, chemotherapeutic, and immunologic aspects for infections with P. vivax, P. falciparum, P. malariae, and P. ovale in some 2,500 patients observed at the Horton Hospital were reported. 69

Malariatherapy in the United States. Malaria therapy was first used in the United States at St. Elizabeth’s Hospital in Washington, DC in December 1922. In 1926, the South Carolina State Hospital in Columbia initiated studies to standardize malariatherapy of neurosyphilitic patients.10 Beginning in 1931, malaria therapy was routinely used in the treatment of cases of neurosyphilis in the Florida State Hospital in Tallahassee.11

Kupper12 (1939) published an extensive review of the literature and a detailed summary of the procedures used for the treatment of general paralysis with malaria as was done at the Station for Malaria Research, International Health Division of the Rockefeller Foundation, Florida at the Florida State Hospital in Tallahassee. It was generally concluded that fever alone was not responsible for the observed beneficial effect; continued parasitemia was also believed to have a beneficial effect on the patients.

Becker1 reported at the time (1949) that induced malaria was indicated as the best method of therapy in paresis, taboparesis, and ocular atrophy. Malariatherapy likewise had a beneficial effect on various types of ocular syphilis, tabes dorsalis with complications, or those forms of syphilis unresponsive to chemotherapy. He summarized the possible modes of action that resulted in a beneficial effect following malariatherapy. Fever, even as low as 102°F, appeared to have a beneficial effect, although this was considered too low to actually kill the spirochetes.13 Breutsch 14 reported intensive tissue changes in post-mortem studies on malaria. There was pronounced stimulation of the reticulo-endothelial system, with a marked stimulation of histocytes; a large number of macrophages were found in the perivascular brain tissue, suggesting a phagocytic effect against the spirochete.

Table 3

Species of Anopheles, route of inoculation,* and prepatent periods for 41 sporozoite-induced infections with the McLendon strain of Plasmodium falciparum in patients with no previous history of infection

PatientSpecies of AnophelesRoute of inoculationNo. of mosquitoesNo. of +sPre-patent period (days)
S-1050quadrimaculatusBites36  ?  9
S-411quadrimaculatusBites  3  ?  9
S-1065quadrimaculatusBites  92710
S-940quadrimaculatusBites15  210
S-402quadrimaculatusBites  7  ?11
S-514quadrimaculatusBites14  211
S-558cruciansBites  6  211
S-1002quadrimaculatusBites385011
S-502quadrimaculatusBites10  ?11
S-400quadrimaculatusBites  6  ?11
S-941quadrimaculatusBites14  ?11
S-954quadrimaculatusBites284911
S-994quadrimaculatusBites15  ?11
S-1067quadrimaculatusBites  6  911
G-15quadrimaculatusBites235411
S-1128quadrimaculatusBites213212
S-1129quadrimaculatusBites182812
S-1150quadrimaculatusBites151612
S-787quadrimaculatusBites15  212
S-1003albimanusBites32  212
S-937quadrimaculatusBites16  213
S-953albimanusBites  1  213
S-1004quadrimaculatusBites  3  913
S-988quadrimaculatusBites153013
S-501quadrimaculatusBites101713
S-789quadrimaculatusBites101713
S-986quadrimaculatusBites112013
S-995quadrimaculatusBites15  ?13
S-1079quadrimaculatusBites  3  513
S-1200quadrimaculatusBites  4  713
S-457quadrimaculatusBites  ?  214
S-519quadrimaculatusBites21  214
S-535quadrimaculatusBites  9  214
S-1212quadrimaculatusBites15  214
S-700quadrimaculatusBites  5  215
S-697quadrimaculatusBites  41415
S-401quadrimaculatusBites15  218
S-403quadrimaculatusBites15  222
S-404quadrimaculatusBites15  222
S-406quadrimaculatusBites  8  222
S-407quadrimaculatusBites  4  228

Patients were exposed by mosquito bite. Numbers of sporozoites in salivary glands were graded 1 + to 4 +; total gland ratings = number of +s.

Figure 1.
Figure 1.

Prepatent periods for 109 sporozoite-induced infections with the El Limon, Santee-Cooper, and McLendon strains of Plasmodium falciparum.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-04

Based on an examination of past malariatherapy studies, Becker1 proposed that quartan malaria (P. malariae) be used for malaria therapy of all black patients, white patients reared in malaria-endemic areas, and subjects reared near the Mediterranean Sea. Plasmodium vivax would be used for white patients with no history of previous malaria. It was recommended that P. falciparum should be used only by expert malariologists. He put forth a list of the complications that may develop during malariatherapy and the recommended treatments. Koop and Solomon5 reported the best results in patients who completed 150 hr of fever > 100°F, whereas Boyd and others11 found that the best results were when the patients had 21 paroxysms ≥ 104°F.

In 1931, a laboratory was established in Columbia, South Carolina to maintain malaria parasites for purposes of infecting patients and to monitor infections in those being treated with malariatherapy.16 Another laboratory was established by the National Institutes of Health at the Georgia State Hospital in Milledgeville, Georgia in March 1946 to provide similar services for the treatment of neurosyphilitic patients. During the period from 1941 to 1954, 1,053 patients were treated with malaria in the Columbia hospital; of these, 779 were men and 274 were women; 418 were white and 635 were black. Of those treated, 126 patients were considered cured and 475 greatly improved.10

The use of malariatherapy for the treatment of neurosyphilis is an historic procedure that has provided much of the available published evidence for the development of immunity during infection with different malarial parasites. An examination of these publications indicated that during infection with any of the 4 human-infecting species of Plasmodium, parasitologic and clinical immunity develops. An initial increase in parasite count is normally accompanied by episodes of fever (paroxysms). As the infection progresses, the parasite count eventually decreases, and the frequency and intensity of fever diminishes or disappears, often in the presence of continued parasitemia. In addition, it was observed that patients who developed immunity to reinfection with the homologous strain of parasite could be reinfected with a heterologous strain. Immunity to infection with one strain of Plasmodium might not give protection to a heterologous strain of the same species or to another species of parasite.9,17

The discovery of penicillin materially reduced the number of patients that developed central nervous system syphilis. Parkhurst and Bowman18 determined changes in cell count, total protein, colloidal gold, and Kolmer Wassermann test results of cerebrospinal fluid in a comparative study of malariatherapy, hyperthermy treatment, and penicillin. Twelve and 18 months after treatment, penicillin was the most effective treatment.

Table 4

Maximum parasitemia (Para.), days of fever (≥ 101 °F and ≥ 104°F), and days of parasitemia in 48 sporozoite-induced infections with the El Limon strain of Plasmodium falciparum in patients with no previous history of infection and who were treated to modify primary parasitemia.

Days of parasitemia

MaximumDays of feverAsexualGametocytes




PatientPara.*Day≥ 101°F≥ 104°F≥ 10≥ 10,000≥ 10≥ 1,000Treatment
G-277    1,090  4  5  0    5  -    0  -Q, P, Ca
G-275       260  5  4  3    5  -    0  -Ca
S-965  20,840  3  5  3    6  1    0  -Ca
G-258    1,936  4  2  1    6  0    0  -Qb, Ca
S-966  20,750  5  4  2    7  2    0  -Ca
G-226  10,980  6  8  3    7  1    0  -Qa
G-350  92,160  7  3  2    9  3  46  9Pa
G-260  12,510  6  3  3  13  1  0  -Qb, Ca
G-263160,56010  6  1  14  6  23  0Qb, Ca
G-289  47,88011  ?  ?  16  8  5016Pa
G-314169,9201113  7  1910  43  0Qb, Ca
G-269115,920  9  5  3  22  7  37  0Qb, Ca
G-382124,560  7  8  3  25  4  5811Pb, Ca
G-476106,560  712  4  2714  4910Qb, Pb, Ca
S-1317  31,419152220  3213  40  0Tb, Ama
G-261  88,5601012  3  32  8  56  0Qb, Ca
G-491    9,180  912  4  36  0  42  0Qb, Ca Pra
G-428  26,400  522  8  3615  57  0Qb, Pb, Ca
G-493  79,200152311  4114  41  0Qb, Ca
G-322107,040  7  ?  ?  4824  50  0Qb, Ca
S-1312  64,496  92412  5414  51  0Qb, Prb, Ca
G-360193,680  6  9  1  69  8  72  1Pb, Qa, Pra
G-316  48,600  910  2110  411112Cb, Pa
G-310126,000  622  41191613414Pb, Ca
G-384  70,560  918  81252314616Pb, Qb, Ca
S-1316109,683  919  913112142  1Qb, Prc
G-327  63,720  916  61363516622Qb, Pb,a
S-1319  52,2701119  814210166  0Prb, Ca
S-1309  71,544  716  5150  917218Qb, Pyc, Ama
G-419  11,1601423  5158  1166  0Pb, Qb
G-303  43,560  717  3160  8154  0Pb
G-414  21,420  7  0  0161  3181  0Qb
G-345  30,0007932  71651817215Pb, Ca
G-408222,480  9  8  11851719025Pb, Qb, Ca
G-445105,480  734  62102524917Pb
G-290110,160  923  921313281  9Qb, Pb
G-416  74,160  912  422115198  2Pb
G-338  32,440  517  622416196  2Pb, Ca
G-264  75,6001010  22272027513Qb, Pc
G-259  13,200  5  9  2235  4147  0Qb, Ca
G-398113,7602028  92421823615Pb, Qb
G-265131,6001413  627416279  2Qb, Pc
G-427  45,720  628  526115279  2Pb
G-466  45,0001518  618113289  1Qb, Pb
G-457  56,8801326  833118359  0Qb
G-279186,4801221  23342426126Qb, Ca
G-407167,760  8  6  13651936836Pb, Qb
G-305  65,880  716  23931539128Pb

Parasites/µl.

a = treatment to cure infection; b = subcurative treatment to modify the primary attack; c = subcurative treatment after primary attack; Q = quinine; C = chloroquine; P = chlorguanide; T = bismuth thioglycolate; Am = amodiaquine; Pr = primaquine; Py = pyrimethamine.

Reported here is a retrospective analysis of the combined records from the Columbia, South Carolina and the Milledgeville, Georgia laboratories on the episodes of fever and parasitemia for patients with no recorded previous history of malaria. It is impossible to determine with absolute certainty if none of the patients included here had been previously infected because there were areas of both states where malaria had been endemic. Subsequently, we will report on those patients known to have been previously infected with homologous and heterologous strains and species of Plasmodium, and the patterns of recrudescence as reported for these patients.1921

Materials and Methods

Patient management. Consent for whatever treatments the hospital staff determined necessary was granted by the families or the courts when patients were admitted to the hospitals. The decision to treat a neurosyphilitic patient with malaria was made as part of patient care (not for purposes of research) by the medical staff of either the South Carolina State Hospital or the Georgia State Hospital. Patient care and evaluation of clinical endpoints (e. g., fever) were the responsibility of the medical staff. During infection, the temperature, pulse, and respiration were checked every 4 hr and houdy during paroxysms by hospital personnel. During episodes of fever (paroxysms), the patients were treated symptomatically. Infections were terminated at the direction of the attending physician if there was a sudden overwhelming infection with parasites, severe anemia, unremitting pyrexia, rapidly enlarged and tender spleen, extreme exhaustion, cardiac disturbances, cyanosis, edema, convulsions, renal disturbances, marked increase in blood urea, development of another infectious disease, severe jaundice, or rapid debilitation involving weight loss.22 The U. S. Public Health Service (PHS) personnel provided the parasites for inoculation and monitored the daily parasite counts to determine the course of the infection. Mosquito colonies were maintained by the PHS staff for mosquito infection and subsequent transmission to other patients as assigned by the hospital staff. All patients undergoing malariatherapy lived in screened wards of the hospital to prevent possible infection of local anophelines.

Table 5

Maximum parasitemia, days of fever (≥ 101°F and ≥ 104°F), and days of parasitemia in 2 sporozoite-induced and 36 blood-induced infections with the Santee-Cooper strain of Plasmodium falciparum in patients with no previous history of infection and who were treated to modify primary parasitemia

Days of parasitemia

MaximumDays of feverAsexualGametocytes




PatientPara.*Day≥ 101°F≥ 104°F≥ 10≥ 10,000≥ 10≥ 1,000Treatment
G-144262,0401412  7  2214  28  0Qa
G-145  85,6801818  8  26  8  5816Qb, Ca
G-238143,280  5  ?  ?    9  3    0  0Ca
G-359105,200  7  7  3    9  3    0  0Pb, Ca
G-170439,920  7  2  0  12  6  32  0Ca
G-109388,800  610  5  1410  17  0Qb, Ca
G-107352,07011  4  0  15  9  48  8Qb
G-121154,08012  0  0  16  8  4710?
G-160201,000  711  8  1712  30  0Qb, Ca
G-202310,320  6  6  4  18  7  27  2Ca
G-114203,76014  7  3  1810  27  7Qb, Ca
G-220  76,6801512  7  2216  4315Qb
G-119129,0401018  9  3014  37  8Qb, Ca
G-127331,2001514  9  3119  3614Qb, Ca
G-98252,000  613  4  3113  4515Qb
G-195503,286  9  ?  ?  3212  32  3Qb
G-116183,600  9  5  3  3613  47  0Qb, Ca
G-222246,240  816  6  3916  44  1Qb
G-227140,40011  6  3  5218  74  7Qb,c
G-183  47,520  911  5151  6116  0Qb
G-221    8,06411  4  1196  0213  0Qb
G-161453,080  711  32371626330Qb
G-200395,280  7  8  524311235  1Qb
G-194105,120  7  2  1288  521418?
G-120265,680  8  7  24791429558Qb
G-365  59,040  610  0  11  6    0  0Qb, Cb,a
G-254  93,60012  3  2  19  6    0  0Qb, Cb,c
G-229132,48012  6  2  2110    0  0Qb, Ca
G-283342,7201128  6  4414    0  0Qb, Pb, Ca
G-270123,1201320  6  7117    0  0Qb, Ca
G-333153,360104013  8121    0  0Qb, Pb, Ca
G-389185,7601118  311720    0  0Qb, Pb, Ca
G-308  98,280  719  413612    0  0Qb, Ca
G-287113,760  612  114111    0  0Qb, Ca
G-280118,800  6  7  421510    0  0Qb, Ca
G-393287,280  821  523435    0  0Qb, Pb
G-240169,920  9  2  123510    0  0Qb
G-368102,960  6  9  4278  5    0  0Pb, Ca

Parasites/µl.

a = treatment to cure infection; b = subcurative treatment to modify the primary attack; c = subcurative treatment after primary attack; Q = quinine; C = chloroquine; P = chlorguanide.

Sporozoite-induced infections.

Treatment. Treatment with non-curative doses of antimalarial drugs (primarily 5 or 10 grains [325 or 650 mg] of quinine sulfate) was often necessary to modify and control the early stages of the infection with P. falciparum. Infections were terminated by the use of drugs appropriate for the different parasites, including chloroquine, amodiaquine, quinine, mepacrine, pyrimethamine, proguanil, and primaquine

Mosquito feeding. Mosquitoes of the species Anopheles quadrimaculatus, An. albimanus, and An. freeborni were allowed to feed on patients during periods of gametocytemia to produce mosquito infections for transmission to additional patients. Samples of fed mosquitoes were dissected after appropriate incubation periods to determine oocyst and/or sporozoite rates and intensity. Whenever possible, salivary gland dissections were done on all mosquitoes fed on recipient patients to determine rates and intensity of sporozoites in the donor mosquitoes. Mosquitoes were usually allowed to feed only a single time during inoculation, but on some occasions, multiple interrupted bites were used-usually three bites per mosquito, but occasionally up to 10 bites. On a few occasions, infection was induced by subcutaneous or intravenous injection of sporozoites dissected in sterile fashion from infected salivary glands. Methods of mosquito rearing, maintenance, and use in malaria transmission have been described in some detail in previous publications.22,23

Table 6

Maximum parasitemia, days of fever (≥ 101°F and ≥ 104°F), and days of parasitemia in 23 sporozoite-induced infections with the McLendon strain of Plasmodium falciparum in patients with no previous history of infection and who were treated to modify primary parasitemia

Days of parasitemia

MaximumDays of feverAsexualGametocytes




PatientPara.*Day≥ 101°F≥ 104°F≥ 10≥ 10,000≥ 10≥ 1,000Treatment
S-1067       940  5  3    2    5  0    0  0Ca
S-954    3,510  2  3    3    5  0    0  0Ca, Qa
S-1065    5,133  4  3    1    6  0    0  0Ca
S-1002  49,700  5  4    4    7  5  41  6Pb,c
S-1128    4,380  6  0    0    8  0    0  0Ca
S-941  43,450  5  5    4    9  3    0  0Ca
G-15141,840  6  3    1    9  4    0  0Ca
S-1129  45,300  7  2    1  11  2    0  0Ca
S-1079  63,912  8  6    5  11  5  4210Tb, Pb,a
S-986  86,200  9  8    7  12  6  43  9Qb, Cb,a
S-789377,520  7  9    7  14  7    0  0Ca
S-400191,600  9  7    5  16  8    0  0Qb
S-995  18,950  513    7  33  4  7415Pb,a
S-1050  28,950  9  9    5  36  2  65  7Trb
S-501  85,400  7  9    3  39  4  31  0Qb
S-1150  53,1001321  14  4611  70  1Pb, Qb,a, Ama
S-988  28,400  716    9  54  3  78  0Qb
S-1004  39,900  5  5+  3  63  4  8117Pb
S-994  44,200  928    8  90  4  93  0Pb, Ca
S-502  23,4001010    5103  6  71  0Qb
S-697  87,760  5  2    1107  3  5713Mb
S-411  67,6001220    312610  56  0Qb
S-1200  73,479  910    5195  319118Pb, Qb, Ca

Parasites/µl.

a = treatment to cure infection; b = subcurative treatment to modify the primary attack; c = subcurative treatment after primary attack; Q = quinine; C = chloroquine; P = chlorguanide; T = bismuth thioglycolate; Tr = terramycin; Am = amodiaquine; M = mepacrine.

Strains of Plasmodium falciparum. McLendon. The McLendon strain was isolated in October 1940 from a patient who was admitted to the South Carolina State Hospital with malaria.24,25

El Limon. The El Limon strain was isolated from a resident of El Limon, Transisthmian Highway, Panama in 1948.26

Santee-Cooper. The Santee-Cooper strain was isolated during the summer of 1946 from a patient living in the vicinity of the Santee-Cooper impoundments in South Carolina.27

Patients were infected either by the intravenous inoculation of parasitized blood or via sporozoites. With the latter, inoculation was either by the bites of infected mosquitoes or by the subcutaneous or intravenous inoculation of sporozoites dissected aseptically from mosquito salivary glands. In some instances, blood or sporozoites were preserved frozen and were thawed immediately before inoculation into the patient.

Parasitemia. Thick and thin peripheral blood films were made daily by the method of Earle and Perez,28 stained with Giemsa, and examined microscopically for the presence of parasites. The threshold of detection was approximately 10 parasites/μl. Asexual and sexual parasites were recorded per microliter of blood. During the later stages of the infection, when parasite counts were very low and intermittently negative, and no symptoms of malaria were evident, blood films were usually made 2 or 3 times a week.

Data presentation. The parasite counts and fever records from the 2 hospitals have been combined. Most of the records made before 1940 were incomplete and were not used. The data presented are based on those records we consider sufficiently complete to be useful. Reported here are data recorded for 318 patients. These patients were infected with P. falciparum for the treatment of paresis and other mental disorders associated with tertiary syphilis. The following data were considered for each patient: 1) the presence of fever ≥ 101°F and ≥ 104°F, 2) parasite counts ≥ 1,000/μl and ≥ 10,000/μl, and 3) the presence of gametocytes ≥ 100/μl and ≥ 1,000/μl for each patient. These parasitologic and fever records were examined to determine the development of immunity following primary malariatherapy. Evidence of developing immunity was the following : 1) reduction of all fever episodes (≥101°F), 2) reduction in severe fever episodes (≥ 104°F), and 3) reduction in days with parasite densities ≥ 10,000/μl, and 4) reduction in days of parasite densities ≥ 1,000/μl.

Four different types of infections were considered: 1) sporozoite-induced infections given antimalarial drugs to modify the primary attack, 2) blood-induced infections in which the primary attack was modified by treatment with drugs, 3) sporozoite-induced infections not given antimalarial drugs to modify the primary attack, and 4) blood-induced infections not given antimalarial drugs to modify the primary attack.

Presented graphically are 1) the frequency of fever ≥101°F and ≥104°F (number of patients with fever/number of patients remaining in study) for each of the first 100 days of patent parasitemia, 2) the frequency of parasite counts ≥ 1,000/μl and ≥ 10,000/μl during the first 100 days of patent parasitemia, and 3) the frequency of gametocyte counts ≥ 100/μl and ≥1,000/μl during the first 100 days of patent parasitemia. Prepatent periods for sporozoite-induced infections are also plotted.

The days of maximum parasitemia, number of days with fever ≥ 101°F and ≥ 104°F, number of days of the asexual parasitemia and gametocytemia ≥ 10/μl, and number of days of the asexual parasitemia ≥ 10,000/μl and gametocytemia ≥ 1,000/μl are presented in tabular form for each of the 318 patients. In addition, the drugs used for modifying or terminating the infection arElisted, For sporozoite-induced infections, the species of mosquito, the route of inoculation (bites or injection by syringe), the number of mosquito bites, the intensity of the salivary gland infection, and the prepatent periods are given. The intensity of infection of the salivary glands was determined by rating the number of sporozoites present at dissection as 1 + (1 – 10 sporozoites), 2+ (11 – 100 sporozoites), 3 + (101 – 1,000 sporozoites), or 4 + (> 1,000 sporozoites). The total number of + ratings was then determined.

Figure 2.
Figure 2.

Frequency of fever, asexual parasitemia, and gametocytemia during the first 100 days in patients with sporozoite-induced infections with the El Limon, Santee-Cooper, and McLendon strains of Plasmodium falciparum. A, frequency of fever (≥ 101°F and ≥ 104°F). B, frequency of asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl. C, frequency of gametocytemia ≥ 100/μl and ≥ 1,000/μl. Patients were given subcurative doses of antimalarial drugs to modify the primary attack.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-04

Results

Patients were divided into 2 major groups. Group I consisted of 181 patients who received subcurative antimalarial drug(s) during their primary parasitemia to modify the parasite count and/or symptoms, and Group II consisted of 137 patients who received no antimalarial drug treatment during the primary course of parasitemia, Four characteristics of the infections were examined: 1) prepatent period for sporozoite-induced infections, 2) frequency of fever ≥ 101 °F and ≥ 104°F, 3) frequency of parasitemia ≥ 10, ≥ 1,000, and ≥ 10,000/μl, and frequency of gametocytemia ≥ 10, ≥ 100 and ≥ 1,000/μl. The respective groups consisted of the following.

Group I. This group was composed of 73 patients with sporozoite-induced infections (48 El Limon strain, 23 McLendon strain, and 2 Santee-Cooper strain) and 108 with blood-induced infections (24 El Limon strain, 23 Santee-Cooper strain, 13 gametocyteless Santee-Cooper strain, and 48 McLendon strain).

Group II. This group was composed of 40 patients with sporozoite-induced infections (12 El Limon strain, 10 Santee-Cooper strain, and 18 McLendon strain) and 97 patients with blood-induced infections (9 El Limon strain, 27 Santee-Cooper strain, 8 gametocyteless Santee-Cooper strain, and 53 McLendon strain).

Prepatent periods of sporozoite-induced infections. El Limon strain. Fifty-five patients (Table 1) from Groups I and II were infected with the El Limon strain of P. falciparum via sporozoite inoculation. Prepatent periods (Table 1) ranged from 7 to 16 days (mean = 9. 8 days, median = 9 days).

Santee-Cooper strain. Thirteen patients were infected with the Santee-Cooper strain of P. falciparum via sporozoite inoculation. Prepatent periods (Table 2) ranged from 7 to 14 days (mean = 9.7 days, median = 9 days).

McLendon strain. Forty-one patients were infected with the McLendon strain of P. falciparum via sporozoite inoculation. Prepatent periods (Table 3) ranged from 9 to 28 days (mean = 13.3 days, median = 13.5 days).

In summary, 109 patients were infected via sporozoites with the El Limon, Santee-Cooper, and McLendon strains of P. falciparum. The prepatent periods for all patients (Figure 1) ranged from 7 to 28 days with a mean and median of 11 days.

Group I-Modified primary attack. Treating of patients with P. falciparum presented the risk of acute malarial disease. Thus, as indicated earlier, criteria were established for the administration of subcurative doses of antimalarial drugs that could allow the continuation of the infection with the expected beneficial effect of malarial therapy. In this section, we present data from patients whose primary episodes of parasitemia were modified with subcurative doses of drug.

Table 7

Maximum parasitemia, days of fever (≥ 101°F and ≥ 104°F), and days of parasitemia in 24 blood-induced infections with the El Limon strain of Plasmodium falciparum in patients with no previous history of infection and who were treated to modify primary parasitemia

Days of parasitemia

MaximumDays of feverAsexualGametocytes




PatientPara.*Day≥ 101°F≥ 104°F≥ 10≥ 10,000≥ 10≥ 1,000Treatment
G-238143,280  5  ?  ?    9  3    0  0Ca
G-372  60,820  7  8  3  10  2    17+    9+Cb
S-1302  79,045  7  4  2  10  4  4013Pya
S-934  78,200  6  4  2  12  3  4213Ca
G-207256,560  7  2+  1  13  8  27  5Qb, Ca
S-1299  23,993  811  6  15  6  4419Qb, Pya
G-234108,720  9  6  4  17  9  32  7Qb, Ca
S-1296  85,6901110  4  21  6  48  0Qb, Ca
S-1298  23,350  511  5  21  3  56  0Qb, Pya
S-1323476,440  810  3  2610  4513Qb, Amb,a
G-209397,440  711  6  3416  5721Qb, Ca
G-301  47,880  6  4  2  34  5  6916Pb
S-1332  93,0541116  9  4112  42  4Qb, Pra, Ca
G-242  95,040  916  6  4116  47  6Qb,c, Ca
S-1297  18,350  9  5  2  48  3  83  0Cb, Pya
G-224136,8001310  7  8825  9412Qb, a
G-246  69,480  416  611214112  6Qb, c, Ca
G-423210,960  7  7  3134  3160  7Pb, Qb
G-174195,840  711  417710209  0Qb
S-1304  89,017  411  2194  2  96  0Pyb
S-1300  63,839  516  6210  420013Pyb, c, Aa
G-439  94,320  627  42102821315Pb
G-285  75,600  822  53532018652Pb, Ca
G-232  99,360  711  43651634434Qb, Ca

Parasites/µl.

a = treatment to cure infection; b = subcurative treatment to modify the primary attack; c = subcurative treatment after primary attack; C = chloroquine; P = chlorguanide; Py = pyrimethamine; Q = quinine; Am = amodiaquine; Pr = primaquine; A = drug treatment unknown.

Seventy-three patients were infected via sporozoite inoculation (48 El Limon strain, 23 McLendon strain, and 2 Santee-Cooper strain) and 107 had blood-induced infections (24 El Limon strain, 22 Santee-Cooper strain, 13 gametocyteless Santee-Cooper strain, and 48 McLendon strain).

Sporozoite-induced infections (fever). El Limon strain. Forty-eight patients (Table 4) were infected via sporozoites with the El Limon strain of P. falciparum. Fever charts were unavailable for patients G-289 and G-322. Of 659 days of fever, 410 (62.2%) occurred during the first 25 days of patent parasitemia, 129 (19.6%) during the 26–50-day period, 56 (8.5%) during the 51–75-day period, and 27 (4.1%) during the 76–100-day period. Thirty-seven episodes of fever (5.6%) were recorded during the 101–209-day period. Eight patients had fever beyond day 100; patient 0–279 had fever on day 209.

Santee-Cooper strain. Two patients (Table 5) were infected via sporozoites with the Santee Cooper strain of P. falciparum. Of the 30 episodes of fever, all occurred during the first 25 days of patent parasitemia.

McLendon strain. Twenty-three patients (Table 6) were infected with the McLendon strain of P. falciparum via sporozoite inoculation. Of the 198 episodes of fever, 135 (68.2%) occurred during the first 25 days of patent parasitemia, 42 (21.2%) during the 26–50-day period, 14 (7.1%) during the 51–75-day period, 6 (3.0%) during the 76–100-day period, and 1 (0.5%) after 100 days. Patient S-411 had fever on day 105. Two patients (S-995 and S-1050) had fever on days 56 and 45 , respectively; this was after the disappearance of asexual parasitemia, but during the period when gametocytes were still present.

A total of 73 patients were infected via sporozoites with the El Limon, McLendon, and Santee-Cooper strains of P. falciparum in which the primary parasitemia was controlled with antimalarial drugs. The frequency of fever during the first 100 days of patent parasitemia (Figure 2A) was primarily concentrated in the first 2–3 weeks.

Sporozoite-induced infections (parasitemia). El Limon strain. Maximum parasitemia (Table 4) ranged from 260 to 222,480/μl. The mean length of asexual parasitemia was 126.7 days and the mean length of total parasitemia including gametocytes was 138.8 days. Of the 537 days of high density (≥ 10,000/μl) parasitemia, 291 (54.2%) occurred during the first 25 days, 137 (25.5%) occurred during the 26–50-day period, 57 (10.6%) occurred during the 51–75-day period, and 29 (5.4%) during the 76–100-day period. Eight patients had a total of 23 episodes of high-density parasitemia beyond day 100.

Santee-Cooper strain. Two patients (Table 5) were infected with the Santee Cooper strain of P. falciparum via sporozoite inoculation. Prepatent periods were 8 and 9 days. Maximum parasitemia (Table 5) was 262,040 and 85,680/μl. The length of asexual parasitemia was 22 and 26 days and the length of total parasitemia including gametocytes was 28 and 58 days. McLendon strain. In 23 patients, maximum parasitemia (Table 6) ranged from 940 to 377,520/μl. The mean length of asexual parasitemia was 42.8 days and the mean length of total parasitemia including gametocytes was 52.7 days. Of the 92 days of high-density parasitemia, 83 (90.2%) occurred during the first 25 days, 5 (5.4%) occurred during the 26–50-day period, and 4 (4.3%) occurred during the 51–75-day period.

Table 8

Maximum parasitemia, days of fever (≥ 101°F and ≥ 104°F), and days of parasitemia in 48 blood-induced infections with the McLendon strain of Plasmodium falciparum in patients with no previous history of infection and who were treated to modify primary parasitemia

Days of parasitemia

MaximumDays of feverAsexualGametocytes




PatientPara.*Day≥ 101°F≥ 104°F≥ 10≥ 10,000≥ 10≥ 1,000Treatment
S-991  13,616 3 0 0   7 3   0 0Ca
S-604  89,920 6 5 5   9 6   0 0Ma
S-1073  14,850 5 5 2   9 2  42 0Pa, Ca
S-1263143,959 6 4 2   9 4  4712Pya
G-167103,680 6 ? ?  10 5   0 0Ca
S-1313  91,114 7 5 1  10 4  29 0Ama
S-1113  28,420 6 6 3  10 2  40 0Caa
S-1285114,822 7 6 6  10 4  4514Pya
S-1144  18,250 914 8  12 3  31 6Pb, Ca
S-1058  27,250 5 6 6  12 2  40 0Ca
S-1184  12,600 8 9 8  12 3  49 0Pa, Ca
S-1272  59,34510 7 5  13 3  16 0Ca
S-972265,000 7 7 3  13 6  33 0Pa, Ca
S-1216  50,600 9 8 6  14 5  25 0Qb, Ca
S-1232  22,9921012 9  15 2  48 0Qb3, Pa, Ca
S-1022  28,440 9 6 2  16 5  38 3Ca
S-732214,9001112 6  2014  36 0Mb, Ca
S-1291  42,848 711 3  22 7  5411Qb, Pya
S-1173  73,100 810 3  2212  5917Pb
S-1199  30,160 71610  33 5  40 9Pb, Ca
S-1185  88,500 7 9 6  33 5  42 3Pb, Ca
S-505   9,250 2 5 2  34 0  18 0Qb
S-1203104,97013 9 9  36 8  4622Qb, Cb, a
S-1329  41,263 820 2  4615  54 6Qb, Ama, Pra
S-410  22,900 412 6  56 7  40 0Qb
S-1193  23,300112610  63 7  7617Pb, c, Ca
S-1221  33,600123325  6910  84 0Qb, Pc, Ca
S-1205111,968 72811  7310  87 4Qb, Ca
S-1201  41,988121410  74 5  80 0Pb, Qc, Ca
S-1164  31,900 52612  88 2  9416Pb, Tc, Ca
S-1165  43,950 53111  90 110612Pb, Tc, Ca
S-1326  21,423 912 1  97 8107 0Qb, Prc
S-392  37,000 7 ? ?107 8≤26 0Tb
S-625  69,250 740 811111  19 0Mb
S-1032  31,750 8 8 2117 120017Pb, c
S-627109,500 824 312233130 0Mb
S-1123  15,650 722 5125 3100 8Pb
S-1235113,267 8 9 2135 714626Qb, Cb, Tc
S-507  53,900 621 7136 7108 0Qb
S-578  84,400 7 5 4138 8123 0Qb, Mb
S-493  61,200 6211113914  80 0Qb
S-1270  56,286 919 51521017812Cb
S-282  19,700 813 315912157 0Qb
S-1251  46,261112711166 7137 1Tb, Ca
S-413  54,400 518 717514  62 0Qb
S-1204  76,978 72513194 922923Qb, Cb, a
S-1124  21,8001014 4197 816220Pb, Ca
S-1344  52,1121024 622211202 5Qb, Pb

Parasites/µl.

a = treatment to cure infection; b = subcurative treatment to modify the primary attack; c = subcurative treatment after primary attack; C = chloroquine; M = mepacrine; P = chlorguanide; Py = pyrimethamine. Am = amodiaquine; Q = quinine; Pr = primaquine; T = bismuth thioglycolate.

For all patients in this sporozoite-inoculated group, the frequency of parasitemia ≥ 1,000 and ≥ 10,000/μl during the first 100 days of patent parasitemia (Fig. 2B) showed a primary peak that was interrupted with drug treatment and a longer sustained period of parasite counts ≥ 1,000/μl from approximately day 15 through day 50. The last day on which > 50% of the patients had parasite counts ≥ 1,000/μl was day 77. Gametocytes (Figure 2C) appeared by the 10th day of patent parasitemia and persisted throughout the first 100 days; high-density gametocytemia (≥ 1,000/μl) persisted to day 84.

Blood-induced infections (fever). El Limon strain. Twenty-four patients (Table 7) were infected with the El Limon strain of P. falciparum via inoculation of parasitized blood. There were 248 episodes of fever for 23 patients. Of these, 187 (75.4%) occurred during the first 25 days, 46 (18.5%) during the 26–50-day period, 12 (4.8%) during the 51–75-day period, and 3 (1.2%) during the 76–100-day period. No fever record was available for patient G-238 and during the first 5 days for patient G-207.

Figure 3.
Figure 3.

Frequency of fever, asexual parasitemia, and gametocytemia during the first 100 days in patients with trophozoiteinduced infections with the El Limon, Santee-Cooper, and McLendon strains of Plasmodium falciparum. A, frequency of fever (≥ 101°F and ≥ 104°F). B, frequency of asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl C, frequency of gametocytemia ≥ 100/μl and ≥ 1,000/μl for 108 patients. Patients were given subcurative doses of antimalarial drugs to modify the primary attack.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-04

Santee-Cooper strain. Twenty-three patients (Table 5) were infected with the gametocyte-producing Santee-Cooper strain of P. falciparum via inoculation of parasitized blood. There were 175 episodes of fever in 21 patients (no fever record was available for patients G-238 and G-195). Of these, 155 (88.6%) occurred during the first 25 days and 20 (11.4%) during the 26–50-day period. One patient (G-121) experienced no episodes of fever.

Santee-Cooper-gametocyteless strain. Thirteen patients (Table 5) were infected with the gametocyteless Santee-Cooper strain of P. falciparum via inoculation of parasitized blood. There were 191 episodes of fever among the 13 patients. Of these, 138 (72.3%) occurred during the first 25 days, 40 (20.9%) during the 26–50-day period, 9 (4.7%) during the 51–75-day period, and 3 (1.6%) during the 76–100-day period. Fever occurred on day 133 in patient G-280.

McLendon strain. Forty-eight patients (Table 8) were infected with the McLendon strain of P. falciparum via inoculation of parasitized blood. Fever charts were unavailable for patients G-167 and S-392. There were 676 episodes of fever for the remaining 46 patients. Of these, 428 (64.3%) occurred during the first 25 days, 154 (23.1%) during the 26–50-day period, 80 (12.0%) during the 51–75-day period, and 8 (1.2%) during the 76–100-day period. Six fevers (0.1%) occurred after the 100-day period.

A total of 104 patients infected via parasitized erythrocytes with the El Limon, McLendon, and Santee-Cooper strains of P. falciparum had records of fevers. The frequency of fever during the first 100 days of patent parasitemia (Figure 3A) exceeded 50 percent until day 11 and thereafter decreased. The last fever was on day 98.

Blood-induced infections (parasitemia). El Limon strain. Maximum parasitemia (Table 7) ranged from 18,350 to 476,440/μl. The mean length of asexual parasitemia was 91.5 days and the mean length of total parasitemia including gametocytes was 107 days. Of the 406 days of high-density parasitemia, 327 (80.5%) occurred during the first 25 day period, 57 (14.0%) during the 26–50-day period, 19 (4.7%) during the 51–75-day period, and 3 (0.7%) during the 76–100-day period.

Santee-Cooper strain. Maximum parasitemia (Table 5) ranged from 8,064 to 503,286/μl. The mean length of asexual parasitemia was 90.3 days and the mean length of total parasitemia including gametocytes was 101.5 days. Of the 237 days of high-density parasitemia, 212 (89.5%) occurred during the first 25 days and 25 (10.5%) during the 26–50-day period.

Santee-Cooper-gametocyteless strain. Maximum parasitemia (Table 5) ranged from 59,040 to 342,720/μl). The mean length of asexual parasitemia was 123.3 days. Of the 175 days of high-density parasitemia, 107 (61.1%) occurred during the first 25 days, 42 (24.0%) during the 26–50-day period, 20 (11.4%) during the 51–75-day period, and 6 (3.4%) during the 76–100-day period.

McLendon strain. Maximum parasitemia (Table 8) ranged from 9,250 to 265,000/μl. The mean length of asexual parasitemia was 71.5 days and the mean length of total parasitemia including gametocytes was 85.9 days. Of the 338 days of high-density parasitemia, 262 (77.5%) occurred during the first 25 days, 51 (15.1%) during the 26–50-day period, 20 (5.9%) during the 51–75-day period, and 5 (1.5%) during the 76–100-day period.

For 108 patients in this blood-induced group, the frequency of asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl during the first 100 days of patent parasitemia (Figure 3B) showed a primary peak that was interrupted with drug treatment and a secondary period of parasite counts > 1,000/μl from day 25 through day 46. Garhetocytes (Figure 3C) in those patients infected with the gametocyte-producing strains appeared as early as seventh day of patent parasitemia and persisted throughout the first 100 days; high-density gametocytemia (≥ 1,000/μl) persisted to day 96.

Group II-Primary attack not modified with drugs. This group of patients had clinical and parasitologic responses that did not require early intervention with subcurative antimalarial drugs. It is possible that some of the patients may have had previous malaria infections at some time before admission although there were no records to indicate this.

Forty patients were infected via sporozoite inoculation (12 El Limon strain, 10 Santee-Cooper strain, and 18 McLendon strain), and 97 patients had blood-induced infections (9 El Limon strain, 27 Santee-Cooper strain, 8 gametocyteless Santee-Cooper strain, and 53 McLendon strain).

Table 9

Maximum parasitemia, days of fever (≥ 101°F and ≥ 104°F), and days of parasitemia in 12 sporozoite-induced and 9 blood-induced infections with the El Limon strain of Plasmodium falciparum in patients with no previous history of infection and not treated to modify primary attack

Days of parasitemia

MaximumDays of feverAsexualGametocytes




PatientPara.*Day≥ 101°F≥ 104°F≥ 10≥ 10,000≥ 10≥ 1,000Treatment
G-243    7,50013  ?  ?  93  2  98  3Ca
G-363  57,200  9 9  7  96  3119  0Ca
G-286126,71011 ?  ?  98  7111  0Ca
G-315  38,000  714  3107  2114  0Ca
G-364102,2401221  41212012310Qc, Prc, Ca
G-452  29,280  519  613310144  0
G-247  90,720  914  317319169  6Ca
G-304  36,000  617  71731518315Ca
G-235  72,00010 6  1227  5189  6Ca
G-299  25,440  8 8  0263  5212  0Ca
G-251172,800  823  626315269  0Ca
G-385  43,2001113  3266  5292  0
S-909  25,560  710  3  16  3  43  6Ca
S-1243  32,575102215  6213  6911Tc, Pyc, Ca
S-1321  38,400  8 5  2  98  610410Prc
S-1301  34,900  91810101  7  8924Pyc
S-1320  49,7001013  412516122  2Prc
G-210  28,320  9 6  3130  3  9812
G-431111,600  910  51651217118Ca
G-230  75,600  4 6  3177  813311
G-212200,160  7 ?  ?2931221115

Parasites/μl.

a = treatment to cure infection; c = subcurative treatment after primary attack; Q = quinine; C = chloroquine; Q = quinine; Pr = primaquine; T = bismuth thioglycolate; Py = pyrimethamine.

Sporozoite-induced infection.

Sporozoite-induced infections (fever). El Limon strain. Fever charts were available for 10 of the 12 patients (Table 9). There were 144 episodes of fever during the first 100 days of patent parasitemia. Of these, 104 (72.2%) occurred during the first 25 days; 30 (20.8%) during the 26–50-day period, and 10 (6.9%) during the 51–75-day period.

Santee-Cooper strain. Ten patients (Table 10) had 86 episodes of fever during the first 100 days of patent parasitemia. Of these, 77 (89.5%) occurred during the first 25 days, 6 (7.0%) during the 26–50-day period, 1 (1.2%) during the 51–75-day period, and 2 (2.3%) during the 75–100-day period.

McLendon strain. Eighteen patients (Table 11) had 181 episodes of fever during the first 100 days of patent parasitemia. Of these, 144 (79.6%) occurred during the first 25 days, 20 (11.0%) during the 26–50-day period, 13 (7.2%) during the 51–75-day period, and 4 (2.2%) during the 76–100-day period.

In summary, 40 patients were infected via sporozoites with the El Limon, Santee-Cooper, and McLendon strains of P. falciparum. Fever charts were available for 38 of these. The fever during the first 100 days of patent parasitemia for these patients (Figure 4A) was primarily concentrated in the first 2 weeks and rapidly diminished. The last fever ≥ 101°F was on day 99.

Sporozoite-induced infections (parasitemia). El Limon strain. Maximum parasitemia in 12 patients (Table 9) ranged from 7,500 to 172,800/μl. The mean length of asexual parasitemia was 167.8 days and the mean length of total parasitemia including gametocytes was 176.3 days. Of the 108 days of high density parasitemia, 74 (68.5%) occurred during the first 25 days, 19 (17.6%) occurred during the 26–50-day period, and 15 (13.9%) occurred during the 51–75-day period.

Santee-Cooper strain. Maximum parasitemia (Table 10) in 10 patients ranged from 13,860 to 181,440/μl. The mean length of asexual parasitemia was 184.7 days and the mean length of total parasitemia including gametocytes was 209.3 days. Of the 72 days of high-density parasitemia, 68 (94.4%) occurred during the first 25 days, and 4 (5.6) occurred during the 26–50-day period.

McLendon strain. Maximum parasitemia (Table 11) in 18 patients ranged from 2,400 to 83,000/μl. The mean length of asexual parasitemia was 88.7 days and the mean length of total parasitemia including gametocytes was 92.6 days. Of the 75 days of high-density parasitemia, 72 (96.0%) occurred during the first 25 days, and 3 (4.0%) occurred during the 26–50-day period.

In summary, 40 patients with no previous history of malaria were infected via sporozoites with the El Limon, Santee-Cooper, and McLendon strains of P. falciparum. High-density parasitemia (Figure 4B) was concentrated in the first 2 weeks of patent parasitemia although parasite counts ≥ 1,000/μl continued to be frequent through the first 75 days of patent parasitemia. Gametocytes (Figure 4C) appeared as early as the ninth day of patent parasitemia and persisted throughout the first 100 days; high-density gametocytemia (≥ 1,000/μl) was last recorded on day 84.

Blood-induced infections (fever). El Limon strain. Nine patients were infected with the El Limon strain of P. falciparum via inoculation of parasitized blood (Table 9). Fever records were complete for 8 of these and indicated 90 epi sodes of fever. Of these, 64 (71.1%) occurred during the first 25 days, 13 (14.4%) during the 26–50-day period, and 13 (14.4%) during the 51–75-day period. No fever record was available for patient G-212 for days 1 through 11.

Table 10

Maximum parasitemia, days of fever (≥ 101°F and ≥ 104°F), and days of parasitemia in 10 sporozoite-induced and 35 blood-induced infections with the Santee-Cooper strain of Plasmodium falciparum in patients with no previous history of infection and not treated to modify primary attack

Days of parasitemia

MaximumDays of feverAsexualGametocytes




PatientPara.*Day≥ 101°F≥ 104°F≥ 10≥ 10,000≥ 10≥ 1,000Treatment
G-152‡181,44010102  88  9137  0
G-147‡  13,860  8  31101  2116  3
S-713‡  24,200  6112108  2112  8
G-132‡  98,64010  641531116710
G-178‡  60,120  9  ??179  5211  5
G-179‡  69,660  8137195  7186  0Qa
G-140‡  16,000  8  43199  3233  5Qa
G-146‡154,984  415102191031917
G-143‡162,0001218523211238  0Qa
G-142‡  23,760  5  623671119810
G-201385,920  7101  1510  3310Qa
S-760    1,016  6  10  21  0  41  0
G-94120,08013115  2217  3616Qa
G-103113,040  5  84  28  6  42  0
G-118  35,280  6  40  29  2  2915
G-122  41,400  8  40  30  4  41  7
S-1018    6,820  6  10  35  0  35  0
G-54  70,920  7  80  39  8  30  7Ca
G-184231,120  6  95  44  3  6511
G-193    8,000  7  00  46  1  55  0
G-189  19,800  7  00  66  1  6612
G-157    5,880  9  30  85  0  32  0
G-156  72,36010195  9018  63  6Ca
G-188  58,08010  ??  9310  9312
G-228  32,160  8  2010013  79  1
G-206  48,400  7  50107  0103  0Qa
G-173117,36010  91121  8149  0
G-203  77,760  81021491418312Qa
G-124  97,560  9  4220817  9822
G-117  47,520  7103211  320912Ca
G-131  18,600  7  65218  522211
G-104133,920  5  622321020526
G-159  31,440  5  32240  7257  9
G-217  59,320  7  00250  616110
G-141  78,840  9  ??332  921210
G-48211,680  4  ??4144134311
G-106131,400  9  853282218411
G-300  45,360  9121  65  6  0  0Ca
G-380  96,4801028710922  0  0Ca
G-248  30,460  6  61149  6  0  0Ca
G-293  60,480  8122152  8  0  0Ca
G-256  90,00011  ??25215  0  0
G-237  61,920  6129306  9  0  0Ca
G-268  29,28022  10375  4  0  0
G-387  77,0401322841715  0  0

Parasites/μl.

a = treatment to cure infection; Q = quinine; C = chloroquine.

Sporozoite-induced infection.

Santee-Cooper strain. Twenty-seven patients were infected with the Santee-Cooper strain of P. falciparum via inoculation of parasitized blood (Table 10). Twenty-four of these had fever records; there were 144 episodes of fever. Of these, 136 (94.4%) occurred during the first 25 days, 7 (4.9%) during the 26–50-day period, and 1 (0.7%) during the 51–75-day period. No fever records were available for 3 of the patients.

Santee-Cooper-gametocyteless strain. Eight patients were infected with the gametocyteless Santee-Cooper strain of P. falciparum via inoculation of parasitized blood (Table 10). Seven patients had 93 episodes of fever. Of these, 80 (86.0%) occurred during the first 25 days, 7 (7.5%) during the 26–50-day period, 5 (5.4%) during the 51–75-day period, and 1 (1.1%) during the 76–100-day period. No fever record was available for patient G-256.

McLendon strain. Fifty-three patients (Table 11) were infected with the McLendon strain of P. falciparum via inoculation of parasitized blood. The 53 patients had 657 episodes of fever. Of these, 507 (77.2%) occurred during the first 25 days, 96 (14.6%) during the 26–50-day period, 42 (6.4%) during the 51–75-day period, and 11 (1.7%) during the 75–100-day penod. One patient (S-439) also had fever on day 104.

Table 11

Maximum parasitemia, days of fever (≥ 101°F and ≥ 104°F), and days of parasitemia in 18 sporozoite-induced infections with the McLendon strain of Plasmodium falciparum in patients with no previous history of infection and not treated to modify primary attack

Days of parasitemia

MaximumDays of feverAsexualGametocytes




PatientPara.*Day≥ 101°F≥ 104°F≥ 10≥ 10,000≥ 10≥ 1,000Treatment
S-1003  45,200  6  4  4    8  2     0  0
S-700  31,200  5 10  3  15  3   15  0
S-940  33,840 12 12  3  18  8   31  0Ca
S-787  83,000  8  9  6  33  6   17  0
S-402  78,000  7  7  2  49  3   38  0
S-457  36,000  9  8  2  61  2   35  0
S-937    5,166  7  9  2  74  0   99  0
S-558    6,860  9 17  4  86  0    ?  ?
S-519  26,600  8 12  4  89  9   46  0
S-514  28,900  7  2  1  92  3   34  0
S-953    2,400 10 13  2  97  0 112  0
S-535  34,700  6  6  2104  2   24  0
S-407  60,800 17 19  5107 15   42  0Qa
S-404  55,000  9 13  3113  8   35  0
S-1212  63,200  8 10  6113  6129  4
S-401  12,700 13 15  3156  2   21  0
S-406  25,700 15 11  3157  5   48  0
S-403  11,600 10  4  3225  1   18  0
S-884  71,500 13  4  2  21 11   21  0Ca
S-910    7,025  4  5  0  25  0   32  4
S-660    8,750  5  7  3  28  0   32  0
S-1088  25,200  7 17 10  28 11   57  9Pa
S-707  16,250  7 13  4  30  3   24  0
S-1220  61,590 13 19 15  33  7   33  4Qc, Ta, Ca
S-565  33,800 10 13  1  36  6   36  0Ca
S-200  12,100  7  5  1  43  1   34  0Ca
S-824  41,500 10 12  4  44 11   41  0
S-622  10,520 10 12  5  44  5   44  0Ca
S-851  15,800  5  2  0  46  1    0  0
S-444  14,800  6  5  0  46  2   41  0
S-475  11,900  6  7  2  51  2   33  0
S-561  55,400  8 11  3  51  7   33  0Qa
S-1249    7,790 11  3 1  52 0   52 0
S-1295  25,922 11 13  3  52  3   73  0Pya
S-811  17,523  3  6  4  54  2   28  0
S-1242      120  3  5  1  55  0   46  0
S-775  23,600  5  5  2  57  2    0  0
S-980  11,750  7  7  0  60  1   70  7
S-815113,200  5  9  4  64  4   38  0
S-548  23,500  7 11  4   67§  3   44  0
S-793124,200  6 18  8 70  10   64  0  0
S-807  31,250 11 14  6 76  7   58  8Pa
S-782  21,500  8  1  7   4 77    6 82  0
S-1246    8,529 11 12  3 77  0   84  8
S-774    8,100  5 10  4 78  0   39   0
S-551    9,650  7  7  3 81  0   39  0
S-607  32,100  9 20  4 84  7   37  0
S-606  31,200  9 23  6 87 10   40  0
S-759  14,600 11 27  8 89  4   89  0
S-858  21,425  8 42  9 89  2 113  0Ca
S-741  26,500  6  9  3 92  5   31  0
S-859  29,500 10 12  8 92 16   75  0Ca
S-895  31,600  9  8  0 93  4   95  9
S-678158,000  9  7  1 98  7   93  0
S-1102  50,568  9  9  3 98  3108  7
S-465  61,200  8  8  3101  8   45  0
S-785121,600 10 13  0101  6   80  0
S-731  78,308  7 17  7102 10   94  0
S-556  48,300  5 14  4103 13   68  0
S-463  52,500  9  7  2103  6   73  0
S-544    6,850  4  8  0104  0   38  0
S-541  20,500 10 16  2107  4   93  0
S-1274  24,480  7  8  3110  1119  0Qa
S-439  17,600  8 25  6112  8   82  0
S-1114  27,180 11 11  6112  4103  1
S-1288  29,419  6 11  3115  8130 13
S-573  15,800  6  3  2132  2   43  0
G-23  66,480  5  8  0134  7   24  0
S-545  46,500  7 37  6147 21   92  0
S-522  24,900  7  4  3157  3   37  0
G-32168,840  7 16  5182 12   52  0

Parasites/µl.

a = treatment to cure infection; c = subcurative treatment after primary attack; C = chloroquine; Q = quinine; P = chlorguanide; T = bismuth thioglycolate; Py = pyrimethamine.

Sporozoite-induced infection.

Observations ceased at day 67.

In summary, 97 patients were infected via infectious blood with the El Limon, Santee-Cooper, and McLendon strains of P. falciparum. The frequency of fever during the first 100 days of patent parasitemia for 93 of these patients (Figure 5A) was concentrated in the first 2 weeks and then rapidly decreased.

Figure 4.
Figure 4.

Frequency of fever, asexual parasitemia, and gametocytemia during the first 100 days in patients with sporozoite-induced infections with the El Limon, Santee-Cooper, and McLendon strains of Plasmodium Jalciparum. A, frequency of fever (≥ 101°F and ≥ 104°F). B, frequency of asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl. C, frequency of gametocytemia ≥ 100/μl and ≥ 1,000/μl. Patients were not given subcurative doses of antimalarial drugs to modify the primary attack.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-04

Blood-induced infections (parasitemia). El Limon strain. In 9 patients, maximum parasitemia (Table 9) ranged from 25,560 to 200,160/μl. The mean length of asexual parasitemia was 129.7 days and the mean length of total parasitemia including gametocytes was 134.8 days. Of 80 days of high-density parasitemia, 61 (76.3%) occurred during the first 25 days, 12 (15.0%) occurred during the 26–50-day period, and 7 (8.8%) occurred during the 51–75-day period.

Figure 5.
Figure 5.

Frequency of fever, asexual parasitemia, and gametocytemia during the first 100 days in patients with trophozoiteinduced infections with the El Limon, Santee-Cooper, and McLendon strains of Plasmodium falciparum. A, frequency of fever (≥ 101°F and ≥ 104°F). B, frequency of asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl. C, frequency of gametocytemia ≥ 100/μl and ≥ 1,000/μl. Patients were not given subcurative doses of antimalarial drugs to modify the primary attack.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-04

Santee-Cooper strain. In 27 patients, maximum parasitemia (Table 10) ranged from 1,016 to 385,920/μl. The mean length of asexual parasitemia was 131.6 days and the mean length of total parasitemia including gametocytes was 138.6 days. Of the 240 days of high density parasitemia, 190 (79.2%) occurred during the first 25 days, 33 (13.8%) during the 26–50-day period, 14 (5.8%) during the 51–75-day period, and 1 (0.4%) during the 76–100-day period. Patient G-48 had high-density parasitemia on days 196 and 198.

Santee-Cooper-gametocyteless strain. In 8 patients, maximum parasitemia (Table 10) ranged from 29,280 to 96,480/μl. The mean length of asexual parasitemia was 228.3 days. Of the 83 days of high-density parasitemia, 67 (80.7%) occurred during the first 25 days, 7 (8.4%) during the 26 to 50 day period, 8 (9.6%) during the 51 to 75 day period, and 1 (1.2%) on day 122 (patient G-268).

McLendon strain: In 53 patients, maximum parasitemia (Table 11) ranged from 120 to 168,840 per μl. The mean length of asexual parasitemia was 79.1 days and the mean length of total parasitemia including gametocytes was 81.7 days. Of the 273 days of high-density parasitemia, 244 (89.4%) occurred during the first 25 days, 16 (5.9%) occurred during the 26–50-day period, and 13 (4.8%) during the 51–75-day period.

In summary, 97 patients with no previous history of malaria were infected via trophozoites with the El Limon, Santee-Cooper, and McLendon strains of P. falciparum and required no drug modification of the primary parasitemia. High-density parasitemia (Figure 5B) was concentrated in the first 2 weeks of patent parasitemia although parasite counts ≥ 1,000/μl continued to be frequent through the first 75 days of patent parasitemia. Gametocytes (Figure 5C) appeared as early as the eighth day of patent parasitemia. The percentage of patients with gametocyte counts ≥ 100/μl decreased markedly by day 38; high-density gametocytemia (≥ 1,000/μl) persisted until day 96.

Discussion

There were two major objectives in conducting a retrospective analysis of clinical and parasitologic parameters associated with induced P. falciparum in humans: 1) to document the initial clinical and parasitologic response and the subsequent development of clinical and parasitologic immunity in humans infected with P. falciparum, and 2) to determine the effect of previous homologous and heterologous malaria on subsequent infection with this parasite. This first report concerns those patients with no previous known history of malarial infection, although a retrospective analysis indicated 2 basic groups of patients, those requiring subcurative doses of antimalarial drugs during their primary attack and those able to contain sustained infections without such intervention.

The prepatent periods as reported here showed a relatively large variation in the interval between sporozoite challenge and the first appearance of parasites as determined by thick blood film examination. Prepatent periods are assumed to be governed by the size of the challenge sporozoite inoculum. However, it was difficult to predict prepatent periods based on the number of infective bites or the intensity of the salivary gland infections. Previous studies8 have shown that prepatent periods in all these strains studied were materially reduced by an increase in the number of infective bites used to induce infection.

Fever was the primary indicator of clinical malaria. Fever, particularly the higher intensity of fevers ≥ 104°F, was generally concentrated in the first 25 days of patent parasitemia. Thus, clinical immunity was apparent within approximately 3 weeks, although many patients sustained parasite counts ≥ 1,000/μl and intermittent low-grade fever for extended periods.

It was somewhat surprising that many of the patients were able to control their parasitemia without the administration of antimalarial drugs. In those who were treated, small doses of quinine (5–10 grains) were usually sufficient to provide at least temporary control of the infection, pending development of immunity sufficient to protect the patient from the more adverse effects of the infection without terminating completely parasitemia or fever. Because it was believed that parasitemia, in addition to fever, was beneficial for the treatment of patients with neurosyphilis, many infections were allowed to continue after fever no longer occurred. Thus, the long-term course of parasitemia could be characterized and documented, as well as the frequency of recrudescences with accompanying fever and higher-density parasite counts.

An examination of the combined fever patterns for all patients suggested that those given antimalarials to modify the infection had a slightly higher frequency of fever > 101 °F. When the number of fever episodes during the first 100 days was tabulated for each group of patients, there were 0.2296 fevers per day in those treated and 0.1352 fevers per day in those not treated. With regard to parasite counts of 1 ,000/μl or more, those requiring treatment had 0.3383 parasite days > 1,000/μl during this period compared with 0.3335 parasite days for those not treated. With regard to gametocyte densities of 100/μl or more, those requiring treatment had 0. 2269 gametocyte days > 100/μl compared with 0.2216 gametocyte days for those not treated.

High-density parasite counts were concentrated in the first 2–3 weeks of detectable parasitemia. However, parasitemia, including garnetocytemia, persisted for extended periods in the patients.

In subsequent reports, 19–21 we will present similar fever and parasite data from patients reinfected with homologous and heterologous strains of P. falciparum, and patients previously infected with P. vivax, P. ovale, and P. malariae. It is hoped that these data will be useful in understanding and predicting the development of clinical and parasitologic immunity following infection with P. falciparum, and assist in the evaluation of candidate antimalaria vaccines.

ACKNOWLEDGMENTS

Acknowledgments : We gratefully acknowledge Dr. Martin D. Young, who directed the U. S. Public Health Service installations in Columbia, S outh Carolina and Milledgeville, Georgia during the time these data were collected. We thank the many members of the technical staff who assisted in the compilation and analysis of the data; we also thank Dr. Suzanne Binder and Mary Bartlett for the invaluable assistance in preparing and editing the manuscript.

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Author Notes

Authors’ addresses: William E. Collins, Division of Parasitic Diseases, Centers for Disease Control and Prevention, Mailstop F-12,4770 Buford Highway, Atlanta, GA 30341-3724. Geoffrey M. Jeffery (Public Health Service, retired), 1093 Blackshear Drive, Decatur, GA 30033.

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