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  • 1

    Collins WE, Jeffery GM, 1999. A retrospective examination of sporozoite- and trophozoite-induced infections with Plasmodium falciparum: Development of parasitologic and clinical immunity during primary infection. Am J Trop Med Hyg 61 (Suppl):4–19.

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  • 2

    Collins WE, Jeffery GM, 1999. A retrospective examination of secondary sporozoite- and trophozoite-induced infections with Plasmodium falciparum: Development of parasitologic and clinical immunity following secondary infection. Am J Trop Med Hyg 61 (Suppl):20–35.

    • Search Google Scholar
    • Export Citation
  • 3

    Collins WE, Jeffery GM, 1999. A retrospective examination of secondary sporozoite- and trophozoite-induced infections with Plasmodium falciparum in patients previously infected with heterologous species of Plasmodium: Effect on development of parasitologic and clinical immunity. Am J Trop Med Hyg 61 (Suppl):36–43.

    • Search Google Scholar
    • Export Citation
  • 4

    Collins WE, Jeffery GM, 1999. A retrospective examination of patterns of recrudescence in patients infected with Plasmodium falciparum.Am J Trop Med Hyg 61 (Suppl):44–48.

    • Search Google Scholar
    • Export Citation
  • 5

    Diebner HH, Eichner M, Molineaux L, Collins WE, Jeffery GM, Dietz K, 2000. Modelling the transition to gametocytes from asexual blood stages of Plasmodium falciparum.J Theor Biol 202 :113–127.

    • Search Google Scholar
    • Export Citation
  • 6

    Molineaux L, Diebner HH, Eichner M, Collins WE, Jeffery GM, Dietz K, 2001. Plasmodium falciparum parasitemia described by a new mathematical model. Parasitology 122 :379–391.

    • Search Google Scholar
    • Export Citation
  • 7

    McKenzie FE, Collins WE, Jeffery GM, 2001. Plasmodium malariae blood stage dynamics. J Parasitol 87 :626–638.

  • 8

    Collins WE, Jeffery GM, 2002. A retrospective examination of sporozoite- and trophozoite-induced infections with Plasmodium ovale: development of parasitologic and clinical immunity during primary infection. Am J Trop Med Hyg 66 :492–502.

    • Search Google Scholar
    • Export Citation
  • 9

    Simpson JA, Aarons L, Collins WE, Jeffery GM, White NJ, 2002. Population dynamics of untreated Plasmodium falciparum malaria within the adult host during the expansion phase of the infection. Parasitology 124 :247–263.

    • Search Google Scholar
    • Export Citation
  • 10

    Eichner M, Diebner HH, Molineaux L, Collins WE, Jeffery GM, Dietz K, 2001. Genesis, sequestration, and survival of Plasmodium falciparum gametocytes. Parameter estimates from fitting a model to malariatherapy data. Trans R Soc Trop Med Hyg 95 :497–501.

    • Search Google Scholar
    • Export Citation
  • 11

    Molineaux L, Trauble M, Collins WE, Jeffery GM, Dietz K, 2002. Malaria therapy reinoculation data suggest individual variation in an innate immune response and independent acquisition of antiparasitic and antitoxic immunities. Trans R Soc Trop Med Hyg 96 :205–209.

    • Search Google Scholar
    • Export Citation
  • 12

    McKenzie E, Barnwell JW, Jeffery GM, Collins WE, 2002. Plasmodium vivax blood-stage dynamics. J Parasitol 88 :521–535.

  • 13

    McKenzie FE, Jeffery GM, Collins WE, 2002. Plasmodium malariae infection boosts Plasmodium falciparum gametocyte production. Am J Trop Med Hyg 67 :411–414.

    • Search Google Scholar
    • Export Citation
  • 14

    Collins WE, Jeffery GM, Roberts JM, 2003. A retrospective examination of anemia during infection of humans with Plasmodium vivax.Am J Trop Med Hyg 68 :410–412.

    • Search Google Scholar
    • Export Citation
  • 15

    Collins WE, Jeffery GM, 2003. A retrospective examination of mosquito infection on humans infected with Plasmodium falciparum.Am J Trop Med Hyg 68 :366–371.

    • Search Google Scholar
    • Export Citation
  • 16

    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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A RETROSPECTIVE EXAMINATION OF REINFECTION OF HUMANS WITH PLASMODIUM VIVAX

WILLIAM E. COLLINSDivision of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

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GEOFFREY M. JEFFERYDivision of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

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JACQUELIN M. ROBERTSDivision of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

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DOI:
https://doi.org/10.4269/ajtmh.2004.70.642
Volume/Issue:
Volume 70: Issue 6
Page(s):
642–644
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A retrospective examination was made of archival data collected between 1940 and 1963 to determine the impact of reinfection of patients with Plasmodium vivax with homologous and heterologous strains of the parasite. Following reinfection of 14 patients with a homologous strain, the geometric mean maximum parasite count was reduced from 9,101/μL during the primary infection to 998/μL and the geometric mean daily parasite count for the first 20 days was reduced from 923/μL to 16/μL. Following reinfection of 22 patients with heterologous strains of P. vivax, the geometric mean maximum parasite count was 8,460/μL during the primary infection versus a secondary level of 9,196/μL and the geometric mean daily parasite count decreased from 847/μL/day to 335/μL/day. Reductions in fever episodes ≥101°F and ≥ 104°F appeared to be a more sensitive measure of clinical immunity. Fever episodes ≥104°F in patients with homologous strain reinfections decreased from 1.92 episodes per week to 0.18 compared with 1.24 to 0.57 in patients with heterologous infections. Fever episodes ≥101°F decreased from 2.98 to 0.60 in the homologous strain compared with 2.08 to 1.07 for the heterologous infections. The average maximum fever temperature in the homologous group was 106°F during the primary infection versus 103.4°F for the secondary infection compared with 105.8°F during the primary infections versus 105.6°F for the secondary infection in the heterologous patients.

INTRODUCTION

Studies are being made on the development of immunity to infection with different species of malaria parasites using archival data from patients infected between 1940 and 1963 for the treatment of neurosyphilis.1–15 Sporozoite- and blood-induced infections of Plasmodium vivax were frequently used for these treatments, and at the direction of the medical staff, some patients were subsequently reinfected with homologous and heterologous species and strains of Plasmodium. An examination was made of data from 36 patients previously infected with the St. Elizabeth strain, 14 of whom were reinfected with the homologous St. Elizabeth strain and 22 with heterologous strains of P. vivax.

Reported here are the results of a retrospective examination of these archival data. The goal was to document the relationship between primary and secondary infection as regards 1) maximum parasite count, 2) mean daily parasite count, 3) episodes of fever ≥101°F and ≥104°F, and 4) maximum fever.

MATERIALS AND METHODS

Patient management.

Consent for whatever treatments the hospital staff determined necessary for treatment of the patient was granted by the families of the patients or the courts when patients were admitted to the hospital. The decision to infect a neurosyphilitic patient with a specific malaria was made as part of standard patient care by the medical staff of the South Carolina State Hospital. Patient care and evaluation of the clinical endpoints (e.g., fever) were the responsibilities of the medical staff. As previously reported,1 during infection, temperature, pulse, and respiration were checked every four hours and every hour during paroxysms (fevers) by hospital personnel. During paroxysms, patients were treated symptomatically. Infections were terminated at the direction of the attending physician. The U. S. Public Health Service personnel provided the parasite for inoculation, monitored the daily parasite counts to determine the course of infection, and provided mosquitoes to be fed on the patients to transfer infections from one patient to another. All patients undergoing malaria therapy lived in screened wards of the hospital to prevent possible infection of local anophelines.

Treatment.

Infections were terminated by treatment with various antimalarial drugs. Sporozoite-induced infections were treated with primaquine, as well as a schizonticidal drug such as chloroquine or pyrimethamine.

Strains of P. vivax.

Primary infections in the patients were with the St. Elizabeth strain that was obtained in the 1930s from St. Elizabeth Hospital in Washington, DC. Its exact origin is unknown. The other strains such as Chesson, NG-1512, NG-V90, NG-V94, CBI-109, and Sicily were established from returning servicemen during World War II. Korean strains were isolated from returning servicemen during the Korean War. The Venezuela strain was isolated from a traveler returning from Venezuela.

Parasitemia.

Patients were infected by the intravenous inoculation of parasitized erythrocytes or via sporozoite inoculation. Thick and thin peripheral blood films were made daily by the method of Earle and Perez,16 stained with Giemsa, and examined microscopically for presence of parasites. The threshold for detection was approximately 10 parasites/μL. Asexual and sexual parasites were recorded per microliter of blood. Infections often persisted for many weeks.

Statistical analysis.

Mean parasite counts and maximum fevers during the first versus secondary infections were compared using the Wilcoxon matched pairs signed rank test. Rate ratios of fever episodes were computed and compared using Poisson regression implementing generalized estimating equations to adjust for correlation between observations from the same individuals at different times.

RESULTS

Fourteen patients previously infected with the St. Elizabeth strain of P. vivax were subsequently reinfected with the homologous strain (Table 1). The interval between the primary and the secondary infection ranged from 1 to 96 months. Long intervals between infection did not result in increased parasite counts during secondary infection. During the primary infection, the geometric mean maximum parasite count was 9,101/μ L compared with 998/μL during the secondary infection (P < 0.001). There were 2.98 episodes of fever ≥101°F per person week of infection during the primary infection versus 0.60 during the secondary infection (rate ratio = 0.20, P = 0.002). A total of 1.92 episodes of fever ≥104°F per person week of infection was noted initially compared with 0.18 during the secondary infection (rate ratio = 0.09, P = 0.003). The geometric mean daily parasite count for the first 20 days of patent parasitemia was 924/μL/day versus 16/μL/day during the secondary (P < 0.001).

Twenty-two patients previously infected with the St. Elizabeth strain of P. vivax were subsequently infected with heterologous strains of the parasite (Table 2). The interval between primary and secondary infection ranged from 1 to 164 months. There was no relationship between the interval between infections and the parasitologic outcome during the secondary infection. During the primary infection, the geometric mean maximum parasite count was 8,460/μL compared with 9,196/μL during the secondary infection. There were 2.08 episodes of fever ≥101°F per person week of infection versus 1.07 (rate ratio = 0.52, P = 0.007) and 1.24 episodes ≥104°F versus 0.57 (rate ratio = 0.45, P = 0.004). The geometric mean daily parasite count for the first 20 days of infection was 847/μL/day versus 336/μL/day following reinfection (P = 0.002).

DISCUSSION

Primary infection with the St. Elizabeth strain of P. vivax in 14 patients resulted in geometric mean maximum parasite counts of 9,101/μL and a geometric mean daily parasite count during the first 20 days of patent parasitemia of 924/μL/day. Maximum fevers ranged from 103.8°F to 107.2°F with a median of 106.1°F. Patients averaged 1.92 episodes fever per person week of infection. Maximum parasite counts varied following homologous reinfection with the St. Elizabeth strain, but the geometric mean maximum parasite count was one-tenth of that seen during the primary infection (9,101/μL versus 998/μL). The greatest evidence of immunity to reinfection with the homologous parasite was shown by the decrease in mean daily parasite count from 923/μL/day to 16/μL/day and in fever (≥101°F, from 2.98 episodes/person week infection to 0.60/person week infection; ≥104°F, from 1.09 episodes/person week infection to 0.18 episodes/person week infection).

When patients were reinfected with heterologous strains of P. vivax, the protection was less obvious, although present. Maximum parasite counts were actually higher (9,196 versus 8,460/μL) following reinfection with heterologous parasites, most of which were from the South Pacific region. This suggested that there was either little or no cross-immunity or that these parasites were more adapted to produce high density parasite counts. However, an examination of the geometric mean daily parasite counts for the first 20 days of patent parasitemia showed a reduction from 847/μL/day to 335/μL/day. More evident was a reduction in fever episodes (≥101°F, 2.1 to 1.07 episodes/person week; and ≥104°F, 1.24 to 0.57 episodes/person week).

The development of vaccines against malaria is based somewhat on the premise that previous infection confers a level of measurable immunity and that immunization should mimic or add to this immunity. An examination of these data suggests that vaccines developed against the blood stages of a particular strain of P. vivax may be effective against the homologous strain of the parasite, but less so against heterologous strains.

Table 1

Maximum parasite counts, mean daily parasite counts for first 20 days of patent parasitemia, number of fever episodes ≥101 and ≥104°F, and maximum fever recorded for 14 patients during primary and secondary infections with the St. Elizabeth (St. Eliz.) strain of Plasmodium vivax*
Parasite count/μL Fever (°F) Parasite count/μL Fever (°F)
Patient Strain Route Max. Mean ≥101 Max. ≥104 Interval (months) Strain Route Max. Mean ≥101 Max. ≥104
* Max. = maximum; Sporo = sporozoites.
S-629 St. Eliz. Sporo 10,392 1,234 20 106.4 20 72 St. Eliz. Sporo 50 0.7 0 – 0
S-745 St. Eliz. Sporo 8,320 1,743 27 107.0 18 84 St. Eliz. Sporo 54 1.3 0 – 0
S-768 St. Eliz. Sporo 8,150 856 24 106.0 11 72 St. Eliz. Sporo 140 1.8 2 103.2 0
S-846 St. Eliz. Sporo 10,240 1,936 22 106.4 12 96 St. Eliz. Blood 660 3.9 2 103.0 0
S-1167 St. Eliz. Blood 9,580 1,482 20 107.2 14 9 St. Eliz. Sporo 640 4.2 0 – 0
S-823 St. Eliz. Sporo 11,055 2,481 21 106.4 20 59 St. Eliz. Blood 600 4.3 1 102.0 0
S-911 St. Eliz. Sporo 21,140 2,402 23 106.0 14 20 St. Eliz. Sporo 2,816 8.2 1 103.0 0
S-1019 St. Eliz. Sporo 4,300 1,995 17 106.2 6 78 St. Eliz. Sporo 864 11.7 1 101.0 0
S-1026 St. Eliz. Sporo 752 5 3 103.8 0 1 St. Eliz. Blood 816 14.0 1 103.4 0
S-710 St. Eliz. Blood 22,132 2,964 24 105.8 15 35 St. Eliz. Sporo 2,752 34.9 1 104.0 1
S-1314 St. Eliz. Blood 9,957 120 7 106.0 6 2 St. Eliz. Blood 3,060 44.1 6 104.0 1
S-772 St. Eliz. Blood 8,320 1,004 21 105.2 17 77 St. Eliz. Sporo 3,030 113.6 6 104.0 1
S-938 St. Eliz. Blood 6,750 809 9 105.2 4 6 St. Eliz. Blood 7,528 363.2 4 105.0 2
S-1107 St. Eliz. Blood 34,048 3,063 11 106.6 7 2 St. Eliz. Blood 26,854 456.1 8 105.6 5
Table 2

Maximum parasite counts, mean daily parasite counts for first 20 days of patent parasitemia, number of fever episodes ≥101 and ≥104°F, and maximum fever recorded for 22 patients during primary infection with the St. Elizabeth (St. Eliz.) strain of Plasmodium vivax and secondary infections with heterologous strains of the parasite*
Parasite count/μL Fever (°F) Parasite count/μL Fever (°F)
Patient Strain Route Max. Mean ≥ 101 Max. ≥ 104 Interval (months) Strain Route Max. Mean ≥ 101 Max. ≥ 104
* Max. = maximum; Sporo = sporozoites.
S-1267 St. Eliz. Blood 4,245 29 4 105.0 3 5 Chesson Sporo 3,410 14 0 – 0
S-921 St. Eliz. Blood 704 54 0 – 0 1 Chesson Blood 310 34 0 – 0
S-1005 St. Eliz. Blood 16,640 3,863 23 106.2 15 83 Chesson Sporo 7,425 47 11 105.8 1
S-1234 St. Eliz. Blood 38,673 941 24 106.0 24 51 Chesson Blood 21,780 49 3 105.0 2
S-1180 St. Eliz. Sporo 3,540 587 15 105.6 10 41 Chesson Blood 14,315 76 5 104.4 2
S-447 St. Eliz. Sporo 9,400 996 16 106.4 10 164 Chesson Sporo 2,760 123 0 – 0
S-1017 St. Eliz. Sporo 11,424 2,495 21 106.6 15 21 Korean Sporo 5,208 191 4 105.0 1
S-1202 St. Eliz. Blood 9,600 2,224 23 106.2 13 32 Chesson Blood 9,806 211 5 104.4 1
S-599 St. Eliz. Blood 3,350 415 8 104.6 2 1 NG-V90 Sporo 6,160 324 7 105.4 3
S-950 St. Eliz. Blood 27,584 1,640 18 105.4 9 6 Chesson Blood 13,241 447 8 104.8 3
S-753 St. Eliz. Blood 12,320 1,805 14 105.8 4 2 NG-1512 Blood 9,120 481 6 105.0 2
S-1057 St. Eliz. Sporo 5,856 1,408 22 106.4 19 15 Korean Sporo 12,480 503 6 106.2 5
S-881 St. Eliz. Sporo 2,456 46 11 106.0 7 2 Sicily Blood 9,075 565 10 106.6 4
S-730 St. Eliz. Blood 11,100 714 10 105.2 6 3 NG-1512 Blood 20,600 684 8 106.0 5
S-675 St. Eliz. Sporo 12,350 1,055 6 106.4 3 2 NG-1512 Sporo 14,850 735 7 106.4 2
S-805 St. Eliz. Sporo 1,600 180 11 104.8 4 25 Chesson Sporo 9,240 782 12 105.6 6
S-867 St. Eliz. Blood 10,857 3,040 17 106.2 11 150 Chesson Blood 14,600 860 6 106.8 4
S-643 St. Eliz. Sporo 35,072 2,417 17 106.0 8 3 NG-1512 Blood 16,550 861 5 106.0 4
S-689 St. Eliz. Blood 14,425 3,131 20 106.0 7 2 CBI-109 Blood 5,725 1,023 3 104.8 1
S-554 St. Eliz. Blood 12,500 4,602 28 106.8 16 146 Chesson Blood 22,065 1,198 7 106.4 6
S-880 St. Eliz. Blood 20,988 2,730 20 106.4 15 5 Venezuela Blood 32,633 2,267 19 106.4 10
S-592 St. Eliz. Sporo 6,950 426 2 103.8 0 121 NG-V78 Sporo 19,350 4,785 20 105.2 8

Authors’ addresses: William E. Collins, Division of Parasitic Diseases, Centers for Disease Control and Prevention, Mailstop F-36, 4770 Buford Highway, Atlanta, GA 30341, E-mail: wec1@cdc.gov. Geoffrey M. Jeffery (Public Health Service, retired), 1093 Blackshear Drive, Decatur, GA 30033. Jacquelin M. Roberts, Division of Parasitic Diseases, Centers for Disease Control and Prevention, Mailstop F-22, 4770 Buford Highway, Atlanta, GA 30341, E-mail: jmr1@cdc.gov.

REFERENCES

  • 1↑

    Collins WE, Jeffery GM, 1999. A retrospective examination of sporozoite- and trophozoite-induced infections with Plasmodium falciparum: Development of parasitologic and clinical immunity during primary infection. Am J Trop Med Hyg 61 (Suppl):4–19.

    • Search Google Scholar
    • Export Citation
  • 2

    Collins WE, Jeffery GM, 1999. A retrospective examination of secondary sporozoite- and trophozoite-induced infections with Plasmodium falciparum: Development of parasitologic and clinical immunity following secondary infection. Am J Trop Med Hyg 61 (Suppl):20–35.

    • Search Google Scholar
    • Export Citation
  • 3

    Collins WE, Jeffery GM, 1999. A retrospective examination of secondary sporozoite- and trophozoite-induced infections with Plasmodium falciparum in patients previously infected with heterologous species of Plasmodium: Effect on development of parasitologic and clinical immunity. Am J Trop Med Hyg 61 (Suppl):36–43.

    • Search Google Scholar
    • Export Citation
  • 4

    Collins WE, Jeffery GM, 1999. A retrospective examination of patterns of recrudescence in patients infected with Plasmodium falciparum.Am J Trop Med Hyg 61 (Suppl):44–48.

    • Search Google Scholar
    • Export Citation
  • 5

    Diebner HH, Eichner M, Molineaux L, Collins WE, Jeffery GM, Dietz K, 2000. Modelling the transition to gametocytes from asexual blood stages of Plasmodium falciparum.J Theor Biol 202 :113–127.

    • Search Google Scholar
    • Export Citation
  • 6

    Molineaux L, Diebner HH, Eichner M, Collins WE, Jeffery GM, Dietz K, 2001. Plasmodium falciparum parasitemia described by a new mathematical model. Parasitology 122 :379–391.

    • Search Google Scholar
    • Export Citation
  • 7

    McKenzie FE, Collins WE, Jeffery GM, 2001. Plasmodium malariae blood stage dynamics. J Parasitol 87 :626–638.

  • 8

    Collins WE, Jeffery GM, 2002. A retrospective examination of sporozoite- and trophozoite-induced infections with Plasmodium ovale: development of parasitologic and clinical immunity during primary infection. Am J Trop Med Hyg 66 :492–502.

    • Search Google Scholar
    • Export Citation
  • 9

    Simpson JA, Aarons L, Collins WE, Jeffery GM, White NJ, 2002. Population dynamics of untreated Plasmodium falciparum malaria within the adult host during the expansion phase of the infection. Parasitology 124 :247–263.

    • Search Google Scholar
    • Export Citation
  • 10

    Eichner M, Diebner HH, Molineaux L, Collins WE, Jeffery GM, Dietz K, 2001. Genesis, sequestration, and survival of Plasmodium falciparum gametocytes. Parameter estimates from fitting a model to malariatherapy data. Trans R Soc Trop Med Hyg 95 :497–501.

    • Search Google Scholar
    • Export Citation
  • 11

    Molineaux L, Trauble M, Collins WE, Jeffery GM, Dietz K, 2002. Malaria therapy reinoculation data suggest individual variation in an innate immune response and independent acquisition of antiparasitic and antitoxic immunities. Trans R Soc Trop Med Hyg 96 :205–209.

    • Search Google Scholar
    • Export Citation
  • 12

    McKenzie E, Barnwell JW, Jeffery GM, Collins WE, 2002. Plasmodium vivax blood-stage dynamics. J Parasitol 88 :521–535.

  • 13

    McKenzie FE, Jeffery GM, Collins WE, 2002. Plasmodium malariae infection boosts Plasmodium falciparum gametocyte production. Am J Trop Med Hyg 67 :411–414.

    • Search Google Scholar
    • Export Citation
  • 14

    Collins WE, Jeffery GM, Roberts JM, 2003. A retrospective examination of anemia during infection of humans with Plasmodium vivax.Am J Trop Med Hyg 68 :410–412.

    • Search Google Scholar
    • Export Citation
  • 15↑

    Collins WE, Jeffery GM, 2003. A retrospective examination of mosquito infection on humans infected with Plasmodium falciparum.Am J Trop Med Hyg 68 :366–371.

    • Search Google Scholar
    • Export Citation
  • 16↑

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

Copyright:
Copyright 2004 The American Society of Tropical Medicine 2004
Received:
08 Dec 2003
|
Accepted:
24 Feb 2004
|
Published Online:
Jun 2004
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