INTRODUCTION
After the isolation of the Chesson strain of Plasmodium vivax by Ehrman and others in 1944,1 extensive chemotherapeutic and biologic studies were conducted in humans and in multiple species of anopheline mosquitoes.2–6 The primary advantage of working with this parasite in humans was the very short relapse period after sporozoite infection and the frequency of subsequent relapses. This made it highly suitable for the testing of causal prophylactic and radical curative drugs directed against P. vivax or P. ovale. The parasite was readily transmitted by native anopheline mosquitoes that were being maintained in the laboratory for experimental studies. Chesson soon became the standard parasite for P. vivax studies in humans, and large amounts of data are still available for comparison with data obtainable from non-human primate studies.
The first successful adaptation of the Chesson strain to nonhuman primates was by Ward and others in 1969.69 They adapted the parasite to New World Aotus trivirgatus (=Aotus lemurinus griseimembra) monkeys and showed cyclic sporozoite transmission using Anopheles bala bacensis balabacensis (=An. dirus), An. stephensi, and An. quadrimaculatus mosquitoes. In addition, a chimpanzee, Pan troglodytes, was infected by sporozoite inoculation. Schmidt 70–72 studied the normal course of trophozoite-induced infections in Aotus monkeys and the responses of the parasite to different antimalarial drugs such as chloroquine, quinine, and pyrimethamine.
Initially, we reported on the development of the Chesson strain in 17 splenectomized A. lemurinus griseimembra monkeys and 2 Aotus trivirgatus (=Aotus nancymaae) monkeys.73 Two of these infections were induced by sporozoites. Subsequently, we reported the infection of A. azarae boliviensis, A. vociferans, and several additional A. nancymaae monkeys with the Chesson strain.74–76 In addition, infections were induced in splenectomized chimpanzees to obtain massive numbers of infected mosquitoes and large volumes of parasitized erythrocytes for molecular studies.77
Reported here is a summation of our studies with the Chesson strain of P. vivax in the different species of Aotus monkeys and a comparison with the infections in humans infected with the Chesson strain. As indicated, Chesson is one of the few strains of human malaria parasites for which there are data from human studies for comparison with that being generated from nonhuman primate trials. Reported are the results of a retrospective examination of archival data from 89 induced infections with Chesson strain P. vivax for the treatment of paresis and other mental disorders associated with tertiary syphilis during the period between 1943 and 1963.
MATERIALS AND METHODS
Patient management
Consent for whatever treatments the hospital staff determined necessary was granted by the families of the patients or the courts when patients were admitted to the hospital. The decision to infect a neurosyphiletic patient with a specific species or strain causing malaria was made as part of standard patient care provided by the medical staff of either the South Carolina State Hospital or the Georgia State Hospital. Patient care and evaluation endpoints (e.g., fever) were the responsibility of the medical staff. As previously reported,78 during infection, temperature, pulse, and respiration were checked every 4 hours and hourly during paroxysms (fevers) by hospital personnel. During paroxysms, patients were treated symptomatically. Infections were terminated at the direction of the attending physician. Personnel of the US Public Health Service provided the parasites for inoculation and monitored the daily parasite counts to determine the course of infection. All patients undergoing malaria therapy lived in screened wards of the hospital to prevent possible infection of local anophelines.
Treatment
Patients were frequently allowed to maintain parasitemia for relatively short periods of time, mainly from 2 to 11 weeks. Infections were terminated by treatment with standard antimalarial drugs.
Parasitemia
Patients were infected by the intravenous inoculation of parasitized erythrocytes or by sporozoite inoculation by mosquito bite. Estimations of parasite densities were made daily by preparation of thick and thin blood films by the method of Earle and Perez 79 that were stained with Giemsa stain and examined microscopically for the presence of parasites. The threshold for detection was ~10 parasites/μL blood.
Data presentation
Maximum parasite count, the number of days to maximum parasite count, and days of high density parasite counts (≥ 10,000/μL) were critical points for comparison. In humans, it was possible to record the number of days of fever ≥ 101°F and ≥ 104°F. Fever records for the monkeys were meaningless because it was soon determined that the temperatures in individual animals often rose dramatically as a result of the handling.
Monkeys
Aotus lemurinus griseimembra, A. nancymaae, A. vociferans, and A. azarae boliviensis were generally wild-caught animals imported from Colombia, Peru, and Bolivia. A few of the monkeys were laboratory-born. On arrival at the facility, all animals were quarantined for a 2-month conditioning period, during which they were weighed and tested for tuberculosis. Parasitologic and serologic examination indicated that the animals were free of infection with malaria parasites before inoculation. The monkeys were splenectomized before exposure to infection. All surgeries were performed in an AAALAC (Association for the Assessment and Accreditation of Laboratory Animal Care, International)-approved surgical suite appropriate for aseptic surgery. Protocols were reviewed and approved by the Centers for Disease Control and Prevention Institutional Animal Care and Use Committee, in accordance with procedures described in the US Public Health Policy 1986.
Animals were housed doubly or singly to avoid injuries caused by fighting with cage mates. Space recommendations for laboratory animals were followed as set forth in the NIH Guide for the Care and Use of Laboratory animals. All animals were fed a diet that has been proven to provide adequate nutrition and calories in captive Aotus monkeys used in malaria-related research. Feed was free of contaminants and freshly prepared. Daily observations of the animals’ behavior, appetite, stool, and condition were recorded. Medical conditions were treated by an attending veterinarian as they arose.
Mosquitoes
For the human studies, laboratory-reared Anopheles quadrimaculatus (originally from southeastern United States) and An. albimanus (originally from either Panama or the Florida Keys) were fed on the patients to determine infectivity of gametocytes. For the nonhuman primate studies, An. freeborni (from California), An. maculatus (originally from Malaysia), An. culicifacies (originally from India) An. gambiae (originally from The Gambia), An. dirus (originally from Thailand), and An. stephensi (originally from Delhi, India), were laboratory reared and maintained at the CDC/DPD insectaries. During periods when gametocytes were present, mosquitoes were allowed to feed on tranquilized monkeys as previously described. After feeding, mosquitoes were held in an incubator at 25°C and examined 1 week later for the presence of oocysts on their midguts. In the monkey studies, more than one lot (species) of mosquito was often fed on a particular day. For the tabulation of the tables, the results for An. dirus was used, if available, followed by An. freeborni, An. maculatus, and An. stephensi. Only one value was used for each feeding day.
For sporozoite transmission, mosquitoes were either allowed to feed to repletion on a tranquilized monkey or the monkey was injected intravenously with sporozoites dissected from the salivary glands of infected mosquitoes. Blood stage parasitemia was monitored by the daily examination of thick and thin blood films by the method of Earle and Perez.79 Infections were terminated by treatment with various combinations of drugs as described. Drugs were administered by oral intubation to monkeys.
RESULTS
Infections in humans
Ninety-one patients were infected with Chesson strain P. vivax. The maximum parasite counts for the 49 patients in which the Chesson strain was the primary infection ranged from 4,848 to 99,360/μL, with a median maximum parasite count of 32,514/μL (Table 1). This occurred after an average of 9.3 days of patent parasitemia. In those patients that were not treated, there was an average of 12 days of fever ≥ 101°F and 7 days of fever ≥ 104°F. The median maximum fever was 105.6°F. Mosquitoes were infected by feeding on 28 of 30 of the patients; of 145 lots that were fed, 129 (89%), were infected.
The maximum parasite counts for 42 patients that had been previously infected with P. vivax, P. vivax and P. ovale, or P. malariae or P. falciparum are presented in Table 2). The maximum parasite counts for the 26 patients who had been previously infected with P. vivax only ranged from 310/μL to 83,700/μL, with a median of 9,523/μL. This occurred after an average of 7.9 days of patent parasitemia. In the 22 patients who were not treated, there was an average of 6.3 days of fever ≥ 101°F and 3.4 days of fever ≥ 104°F. For the 14 patients with various histories of infection with P. vivax and P. ovale or P. malariae, the maximum parasite counts ranged from 40/μL to 14,315/μL with a median of 7,140/μL. This occurred after an average of 8.2 days of parasitemia. There was an average of 9 days of fever ≥ 101°F and 3.6 days of fever ≥ 104°F. The two patients who were previously infected with P. falciparum and P. vivax or P. falciparum had maximum parasite counts of 18,656/μL and 3,600/μL, respectively. Mosquitoes were infected by feeding on 11 of 16 of the patients; 33 of 64 lots that were fed (51.6%) were infected.
Infections in Aotus monkeys
Eighty-six Aotus monkeys of four different species were infected with Chesson strain P. vivax. For 36 of these, it was their primary infection. In these animals, the maximum parasite count ranged from 1,085/μL to 120,000/μL, with a median maximum parasite count of 14,939/μL. Twenty-nine monkeys had been infected with P. falciparum before being infected with the Chesson strain. The maximum parasite count for these animals ranged from 310/μL to 72,000/μL, with a median count of 12,648/μL. The remaining 21 animals had been infected with combinations of P. falciparum and heterologous strains of P. vivax, P. malariae, and/or P. simium. The median maximum parasite count for these animals was 8,742/μL.
Thirty-one A. lemurinus griseimembra were infected with the Chesson strain (Table 3). Sixteen of the animals had not been previously infected; maximum parasite counts ranged from 5,355/μL to 120,000/μL, with a median count of 26,700/μL. This occurred after an average of 22.7 days of patent parasitemia. As the maximum parasite count increased, so did the number of days that the count remained > 10,000/μL. The remaining 15 animals had been previously infected with P. falciparum, heterologous strains of P. vivax or P. falciparum, and heterologous strains of P. vivax. Maximum parasite counts ranged from 434/μL to 34,224/μL, with a median maximum parasite count of 14,880/μL. This occurred after an average of 13.9 days of patent parasitemia. There were three transmissions with sporozoites from An. gambiae and An. maculatus mosquitoes. Prepatent periods were 19, 24, and 32 days. Mosquitoes were infected by feeding on 19 of 27 of the monkeys; 350 of 848 lots that were fed (41.3%) were infected. On some of the animals, infection was obtained on many days over extended periods of time. This is shown in Figure 1, in which mosquitoes were fed periodically on A. l. griseimembra monkey AO-0278 for > 1 year. This animal was splenectomized on the 17th day of patent parasitemia, 5 days after inoculation of parasitized erythrocytes. An. freeborni mosquitoes continued to be infected during each recrudescence of the infection.
Twenty-two A. nancymaae were infected with the Chesson strain (Table 4). Seven of the monkeys had not been previously infected; maximum parasite counts ranged from 1,209/μL to 92,000/μL, with a median count of 14,787/μL. This occurred after an average of 17.7 days of patent parasitemia. Eleven animals had previously been infected with P. falciparum, and four had been infected with P. simium or combinations of P. falciparum and P. simium or heterologous strains of P. vivax. Maximum parasite counts in these animals with previous malarial experience ranged from 310/μL to 51,480/μL, with a median maximum parasite count of 9,858/μL. This occurred after an average of 14.5 days of patent parasitemia. It was apparent that, although some individual animals supported high-density parasite counts, A. nancymaae was less supportive than A. lemurinus griseimembra. Mosquitoes were infected by feeding on 8 of 14 animals. However, periods of infectivity were short, and infection rates were low; 46 of 113 lots (40.7%) that fed were infected. There were five transmissions with sporozoites from An. maculatus, An. stephensi, and An. dirus mosquitoes. The pre-patent periods were 18, 22, 30, 57, and 58 days.
Eighteen A. vociferans were infected with the Chesson strain (Table 5). Five of the monkeys had not been previously infected; maximum parasite counts ranged from 2,700/μL to 43,450/μL, with a median count of 6,390/μL. This occurred after 14.8 days of patent parasitemia. Eleven animals had previously been infected with P. falciparum, and two had been infected with P. falciparum and either P. simium or P. vivax. Maximum parasite counts for these 13 animals ranged from 1,710 to 56,000/μL, with a median maximum parasite count of 12,648/μL. This occurred after 17.2 days of patent parasitemia. Mosquito infections were obtained by feeding on seven of eight animals; 53 of 108 lots that fed (49.1%) were infected. Infection rates in the mosquitoes were much higher than obtained with A. nancymaae. There were two transmissions with sporozoites from An. stephensi and An. dirus mosquitoes. The pre-patent periods were both 80 days.
Fifteen A. azarae boliviensis were infected with the Chesson strain (Table 6). Eight of the monkeys had not been previously infected; maximum parasite counts ranged from 1,085/μL to 26,412/μL, with a median count of 9,299/μL. This occurred after an average of 15 days of patent parasitemia. Seven animals had previously been infected with P. falciparum, P. malariae, or combinations of P. vivax, P. malariae, and P. falciparum. Maximum parasite counts in these six animals ranged from 1,860/μL to 72,000/μL, with a median of 10,044/μL. This occurred after an average of 13.3 days of patent parasitemia. Mosquitoes were infected by feeding on 8 of 14 monkeys. Infection rates were low; 30 of 154 lots that fed (19.5%) were infected. There was a single transmission with sporozoites from An. culicifacies mosquitoes; the pre-patent period was 15 days.
DISCUSSION
The Chesson strain of P. vivax is one of the very few malaria parasites for which there is a body of information from human volunteer and patient studies, and the strain has been maintained and adapted to New World monkeys. In humans, the median maximum parasite count was 32,160/μL, which is ~0.75% of the erythrocytes infected (1.0% = 40,000/μL). The Chesson strain infections produced high-density maximum parasite counts and, as indicated in Table 1, there were many episodes of fever ≥ 104°F. It is apparent that this strain of P. vivax, originally from the southwestern Pacific region, resulted in severe disease in these patients.
All of the studies reported here were in splenectomized Aotus monkeys, and of these, A. lemurinus griseimembra supported higher-density maximum parasite counts than did the other three species examined. There was, however, a wide variation among individual animals. This is in contrast to strains of P. falciparum in splenectomized Aotus monkeys who do exhibit uniformity in these hosts. As in human infections, P. vivax infections in monkeys continue to have a wide range in maximum parasite count even after a number of passages. Previous infection with P. falciparum had a minimal effect on maximum parasite count in these hosts. However, these hosts infected mosquitoes more readily and at a higher rate of intensity, and A. vociferans showed useful potential as a source of mosquito infection. Rarely did animals that failed to support maximum parasite counts ≥ 10,000/μL turn out to be successful infectors of mosquitoes.
Compared with infections with the Chesson strain in humans, the maximum parasite counts in the splenectomized A. lemurinus griseimembra monkeys with no previous infection were comparable to humans with no previous malaria. In the monkeys, 56.3% of the animals had maximum counts > 25,000/μL (9/16) and 59.6% of humans had these counts (28/47). It took an average of 8.5 days in the 89 humans to reach the maximum parasite count. However, in the monkeys, it took, on average, much longer. For the 16 animals with no previous infections, it took an average of 18.9 days to reach the maximum parasite count; for those with previous infections, it took an average of 15 days.
Relapse was not shown in the 10 sporozoite-induced infections with the Chesson strain in these Aotus monkeys. The reasons for this are unclear and unexplained. It can be postulated that by continuous blood passage in these abnormal hosts, we selected a clonal parasite that no longer has the capacity for relapse. If the parasite were to be passaged back into humans or chimpanzees by sporozoites, it may or may not still be a relapsing parasite, but proof of this possibility has not been attempted. Possibly the demonstration of hypnozoites would be a sufficient indication of relapse potential. Nonetheless, human and nonhuman primate data on this parasite suggest that Aotus monkeys, particularly A. lemurinus griseimembra, and to a somewhat lesser extent A. vociferans, can fairly well mimic the course of Chesson malaria in humans regarding parasitemia and mosquito infection. Thus, one would anticipate that interventions effective in the non-human primate system could lead to success in the human malaria research effort.
Maximum parasite counts, day of maximum count, days of fever ≥101°F and ≥ 104°F, and lots of mosquitoes infected on 49 humans infected with the Chesson strain of P. vivax
Maximum parasite counts, day of maximum count, days of fever ≥ 101°F and ≥ 104°F, and lots of mosquitoes infected on 42 humans infected with the Chesson strain of P. vivax after previous infection with P. vivax, P. ovale or P. malariae, or with P. falciparum
Maximum parasite counts, days with counts ≥ 10,000/μL, previous infections, and mosquito infections for 31 A. lemurinus griseimembra monkeys infected with the Chesson strain of P. vivax
Maximum parasite counts, days with counts ≥ 10,000/μL, previous infections, and mosquito infections for 22 A. nancymaae monkeys infected with the Chesson strain of P. vivax
Maximum parasite counts, days with counts ≥ 10,000/μL, previous infections, and mosquito infections for 18 A. vociferans monkeys infected with the Chesson strain of P. vivax
Maximum parasite counts, days with counts ≥ 10,000/μL, previous infections, and mosquito infections for 15. A. azarae boliviensis monkeys infected with the Chesson strain of P. vivax
Parasitemia and percent infection of An. freeborni mosquitoes fed on A. lemurinus griseimembra monkey AO-0278 infected with the Chesson strain of P. vivax. SP = splenectomy on the 17th day of patent parasitemia.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 80, 1; 10.4269/ajtmh.2009.80.152
Parasitemia and percent infection of An. freeborni mosquitoes fed on A. lemurinus griseimembra monkey AO-0278 infected with the Chesson strain of P. vivax. SP = splenectomy on the 17th day of patent parasitemia.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 80, 1; 10.4269/ajtmh.2009.80.152
Parasitemia and percent infection of An. freeborni mosquitoes fed on A. lemurinus griseimembra monkey AO-0278 infected with the Chesson strain of P. vivax. SP = splenectomy on the 17th day of patent parasitemia.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 80, 1; 10.4269/ajtmh.2009.80.152
Address correspondence to William E. Collins, Malaria Branch, Division of Parasitic Diseases, National Center for Zoonotic, Vector-Borne and Infectious Diseases, Centers for Disease Control and Prevention, 4770 Buford Highway, Chamblee, GA 30341. E-mail: wec1@cdc.gov
Authors’ addresses: William E. Collins, JoAnn S. Sullivan, Douglas Nace, and John W. Barnwell, Malaria Branch, Division of Parasitic Diseases, National Center for Zoonotic, Vector-Borne and Infectious Diseases, Centers for Disease Control and Prevention, 4770 Buford Highway, Chamblee, GA 30341. Geoffrey M. Jeffery, 1085 Blackshear Dr., Apt. B, Decatur, GA 30033. Allison Williams, Animal Resources Branch, and G. Gale Galland, Division of Global Migration and Quarantine, National Centers for Preparedness, Detection and Control of Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Atlanta, GA 30333. Tyrone Williams, Atlanta Research and Education Foundation, 1670 Clairmont Rd., Decatur, GA 30033.
Acknowledgments: The authors thank the staff of the Animal Resources Branch, the National Center for Infectious Diseases, for the care of the animals.
Financial support: This study was supported in part by an Interagency Agreement 936-3100-AA6-P-00-0006-07 between the US Agency for International Development and the Centers for Disease Control and Prevention.
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
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