Malaria therapy reinoculation data suggest individual variation of an innate immune response and independent acquisition of antiparasitic and antitoxic immunities.

Malaria therapy reinoculation data were examined for the possible detection of effects attributable to stable individual host-specific factors, through correlation between descriptive variables of first and second infections. Such an effect was demonstrated with respect to the first local maximum of the asexual parasite density, i.e., the density at which a host controls parasite growth. The effect was seen between an individual host's first and second Plasmodium falciparum infection, as well as between an individual host's first malaria infection with P. ovale and second malaria infection with P. falciparum. We give reasons to believe that the main underlying mechanism is individual variation of an innate immune response. The data were also examined for systematic changes from first to second P. falciparum infection, as indicators of acquired immunity. In addition to the well-known reduction in parasite density, the data show the early development of apparent parasite tolerance. We give reasons to interpret the latter as antitoxic immunity.

Genesis, sequestration and survival of Plasmodium falciparum gametocytes: parameter estimates from fitting a model to malariatherapy data.

Plasmodium falciparum malaria is one of mankind's main killers. Part of the parasite's life-cycle is spent in human blood, mainly as asexual stages. A fraction of the asexual parasites develops into gametocytes (gamete precursors) while sequestered in deep tissues. After re-entering the circulation, gametocytes can be picked up by a mosquito to continue the parasite's life-cycle. We present estimates of the conversion probability from asexual parasites to circulating gametocytes and of the gametocytes' sequestration and circulation times, obtained for the first time by fitting a dynamic model to individual patients' histories (daily records of 113 neurosyphilitic patients undergoing malariatherapy). The model assumes that the conversion probability can vary among the successive waves of asexual parasitaemia of a patient, and that gametocytes die at an age-dependent rate which increases under high asexual parasite densities. On average, 1 gametocyte per 156 asexual parasites (range 7.4-3700) is produced. The most remarkable findings are the large individual variation of conversion probabilities and circulation times, the average gametocyte circulation time of 6.4 days (range 1.3-22.2 days) which is more than twice the currently accepted value, and the large variation of conversion probabilities among successive waves of asexual parasitaemia without any particular time pattern. The latter finding could be explained by an association between conversion probability and variation of PfEMP1.

Plasmodium falciparum parasitaemia described by a new mathematical model.

A new mathematical model of Plasmodium falciparum asexual parasitaemia is formulated and fitted to 35 malaria therapy cases making a spontaneous recovery after primary inoculation. Observed and simulated case-histories are compared with respect to 9 descriptive statistics. The simulated courses of parasitaemia are more realistic than any previously published. The model uses a discrete time-step of 2 days. Its realistic behaviour was achieved by the following combination of features (i) intra-clonal antigenic variation, (ii) large variations of the variants' baseline growth rate, depending on both variant and case, (iii) innate autoregulation of the asexual parasite density, variable among cases, (iv) acquired variant-specific immunity and (v) acquired variant-transcending immunity, variable among cases. Aspects of the model's internal behaviour, concerning variant dynamics, as well as the respective contributions of the three control mechanisms (iii) - (v), are displayed. Some implications for pathogenesis and control are discussed.

Modelling the transition of asexual blood stages of Plasmodium falciparum to gametocytes.

In this paper, we investigate the transition of asexual blood stages of P. falciparum to gametocytes. The study is based on daily data, collected from 262 individual courses of parasitaemia. We propose several mathematical models that follow biological reasoning. The models are fitted with maximum likelihood and are compared with each other. The models differ in the assumptions made about the mortality of circulating gametocytes and about the transition rate of the asexual parasites. Gametocyte mortality is modelled as being (i) constant over time, (ii) linearly increasing over time, (iii) linearly increasing over gametocyte age, and (iv) exponentially increasing over gametocyte age, respectively. The transition rate is either kept constant per patient or piecewise constant within intervals that correspond to waves of asexual parasitaemia which are assumed to be caused by different Pf(emp1)-variants. According to likelihood ratio tests, the models with age-dependent mortality rate and wave-dependent transition rates are superior to the models with constant transition rate and/or constant or time-dependent mortality rate. The best fits are reached for models with exponentially increasing (Gompertz-type) mortality. Furthermore, an impact of high asexual parasite densities on the survival of gametocytes, interpreted as a cytokine-mediated effect, is evident in some cases.

Review of intra-host models of malaria.

Intra-host models of malaria (and some related models of trypanosomiasis) are reviewed. A first section gives a short description of the different models, their purposes and the authors' conclusions. A second section discusses some common issues, including intra-host populations, the intra-host basic reproduction number (R0) and growth rates, density regulation mechanisms (including acquired immunity), and the models' behaviour compared to that of Plasmodium falciparum in man.

Nature's experiment: what implications for malaria prevention?

PIP: Snow et al. reported, on the basis of hospital admissions from five defined African communities exposed to very different intensities of malaria transmission, a decline in the severity of malaria from areas of low-to-moderate to areas of high transmission. They found, among children aged 0-9 years, a decline in admission rates for all-cause malaria and more so for cerebral malaria, a levelling-off or slight decline in the admission rate for severe malarial anemia, and a lowering of the mean age of all-cause malaria admissions. There are problems, however, with using the intensity of transmission as the independent variable and malaria mortality or the incidence of life-threatening malaria as the dependent variable. Nonetheless, Snow et al.'s observation does not justify withholding preventive measures from people in malaria situations. What Snow et al. have shown, however, is the need for a new synthesis of the epidemiology of malaria. Meanwhile, the choice of preventive measure should depend upon the benefits expected from the strategy and take into consideration that in areas of intense transmission, partial prevention may lead to an increased incidence of cerebral malaria.^ieng

Malaria and mortality: some epidemiological considerations.

Malaria can, a priori, kill on its own ('direct' malaria mortality) or in conjunction with some other cause(s) ('indirect' malaria mortality). There are three distinct approaches to the measurement of malaria mortality: (1) measurement of malaria-specific mortality (based on attributing each death to a single cause) or its surrogate, the admission rate for life-threatening malaria; (2) measurement of the reduction in all-cause mortality after removal (or near removal) of malaria; and (3) the estimation of the malaria mortality required to explain the observed frequency of the HbS gene. There is a strong indication that approaches (2) and (3) yield estimates of total (direct and indirect) malaria mortality which are at least twice as high as those obtained using approach (1), which probably measures mostly direct malaria mortality. There is currently a controversy about the long-term impact on mortality of reducing the intensity of malaria transmission from 'high' to 'intermediate', given the expected loss of immunity. Certain geographical comparisons (of the results of 'nature's experiment') indicate that, when the intensity of transmission is high, the incidence of life-threatening malaria falls. However, the seasonal variation in the intensity of transmission decreases with increases in the intensity; low seasonal variation is probably beneficial, allowing a smoother transition from passive to active immunity, but is unlikely to be reversed by preventive measures. It also seems likely that geographical comparisons produce estimates of predominantly direct mortality, which might not run in parallel with the indirect mortality. A tentative numerical exploration of the problem, using a simple demographic model, indicates that, if indirect malaria mortality is important and the other causes of death are concentrated in early life, the long-term impact on all-cause mortality of reducing exposure (although less than the short-term) will probably always be beneficial, even if there is some increase in direct malaria mortality.

Plasmodium falciparum malaria: some epidemiological implications of parasite and host diversity.

Observations are accumulating concerning: (1) the antigenic diversity of Plasmodium falciparum; (2) the diversity of the genetic immuno-competence of human hosts; (3) the associations between these diversities and disease, protection and defined immune responses; and (4) the possible mechanisms of acquired protection at different steps of the host-parasite interaction. These observations have led to speculations concerning the distribution of disease, the acquisition of protection, and vaccination prospects. Speculations on the latter have varied from pessimism about the possibility of developing a vaccine that would protect most people against most parasites, to optimism based on the hypothesis that a local P. falciparum population is composed of a few discrete subpopulations. If this hypothesis is correct, it may be possible to prevent most severe disease with a narrow-spectrum vaccination against a virulent minority of the subpopulations, or transmission could be interrupted by a relatively low coverage of a broad-spectrum vaccination. A conceptual model that might accommodate the observations is outlined. Its plausibility and testability are considered, as well as some of its implications for the planning and interpretation of epidemiological surveys and intervention trials, and perhaps for selection of antigens for inclusion in vaccines.

The prevalence of naturally acquired multiple infections of Wuchereria bancrofti and human malarias in anophelines.

Malaria and filaria infection rates were determined for anopheline mosquitoes collected whilst biting and resting in village houses in Papua New Guinea. The number of anophelines infected with both parasites was greater than expected from the infection rates of each parasite and this difference was significant in resting collections. The excess of multiply infected mosquitoes is probably a result of a vector population composed of individuals with differing numbers of opportunities to become infected. Malaria-positive Anopheles punctulatus from resting catches had a significantly greater number of Stage 3 Wuchereria bancrofti larvae than malaria-negative mosquitoes. However, multiply infected mosquitoes appear to suffer greater mortality than non-infected or singly infected mosquitoes when the filarial worm reaches the third stage. Any potential increase in transmission resulting from multiple infections is thereby offset by a greater mortality rate in these mosquitoes.

[Malaria and international travel]. / Paludisme et voyages internationaux.

Malaria is one of the main risks to which travellers are exposed. Their protection is complicated by drug-resistance and toxic side-effects. The relevant risks (or chances) are: the risk of malaria, the risk of fatal outcome, the efficacy of prophylaxis, the risk of toxic side-effects, the efficacy of protection against mosquito bites. Data bases used for estimating the risks are reviewed and some of the available risk estimates are given. Sources, content, and utilization of advice are briefly discussed. Improvements are possible in the following areas: collection, analysis and presentation of the relevant data; advice to travellers, and especially its coordination; information of travellers; information of medical practitioners and health services.

The pros and cons of modelling malaria transmission.

The question is approached through three examples. Ross's model, although very simple and formulated a priori, yielded important epidemiological insights: the existence of a threshold contact rate (vectorial capacity); the decreasing sensitivity of the endemic level to changes in the contact rate, as the latter gets larger; the return to the same equilibrium endemic level, as long as the contact rate remains the same; the progressively decreasing impact of a given reduction in the contact rate until a new equilibrium is reached. The second example is Macdonald's model, in particular his sensitivity analysis; two constraints are pointed out: the weakest point, on which to concentrate control efforts, cannot be identified automatically by the sensitivity analysis; the calculation of the expected impact of an intervention commonly assumes too much uniformity (e.g. of human of vector behaviour) and this commonly leads to exaggerated expectations. The third example is the Garki model, briefly considered in terms of its assumptions, of its behaviour, of its actual utilization (only for teaching, so far), and of the cost of its development. Looking forward, three uses of models are discussed. It is suggested that, critically used, they have a place in training, in planning control and in research. With respect to their application to planning, it is argued that the need for new data is not necessarily great, also that some rather difficult direct measurements might be substituted by indirect measurements, a point illustrated by the expected relationships, following the Garki model, between different dimensions of "intensity" of malaria.(ABSTRACT TRUNCATED AT 250 WORDS)

A longitudinal study of human malaria in the West African Savanna in the absence of control measures: relationships between different Plasmodium species, in particular P. falciparum and P. malariae.

The research project in the epidemiology and control of malaria conducted in the Garki District, Kano State, jointly by the Government of Nigeria and the World Health Organization included among its objectives the study of the baseline epidemiology prior to the introduction of any control measures. The present paper analyzes the project's data with respect to the relationships among the three species of Plasmodium present, P. falciparum, P. malariae and P. ovale. Parasitemia with P. falciparum or P. malariae is more likely in the presence than in the absence of the other species. Among persons positive for P. falciparum, those with a higher density of parasitemia are more likely to have P. malariae also than those with a lower density of P. falciparum parasitemia. There is a pronounced seasonal alternation in prevalence between P. falciparum and P. malariae.

A longitudinal study of Plasmodium falciparum malaria in the West African savannah using the ELISA technique.

Malarial antibody levels were measured by the enzyme-linked immunosorbent assay (ELISA) in two West African populations, one exposed to intense malaria transmission and the other protected. The results reflected the transmission of maternal antibody and, in the unprotected population, the subsequent increase of the ELISA values with age reflected the development of the immune response to malaria. Malaria control activities reduced ELISA values in the protected population. The limitations of the ELISA test used in this study are shown by the fact that numerous infants with previous proven parasitaemia were ELISA-negative. Purified antigens are needed to improve the ELISA test for use in serological surveys of malaria.

Abnormal haemoglobins in the Sudan savanna of Nigeria. III. Malaria, immunoglobulins and antimalarial antibodies in sickle cell disease.

Subjects with sickle cell disease were identified in (i) a whole population sample (2742) Garki District, Kano State, Nigeria, and in (ii) the 534 infants born into the population during five years. Eleven (2.1%) newborn had Hb.SS, as was expected from gene frequency (0.146). Prevalence was maintained in the first year of life, but fell to 0.4% at one to four years and to 0.05% (one person) over the age of nine years. Antimalarial intervention for two transmission seasons was followed by an apparent but not significant decrease in Hb.SS mortality. There was one male aged about 40 years who had Hb.SC (the expected number was three). Hb.SS children were compared to normal subjects at the same age, the same village and the same survey; they had significantly less than the expected Plasmodium malariae infection (P less than 0.01) and lower than median P. falciparum densities while below five years (P less than 0.05). Over one year of age, they tended to have below average indirect fluorescent antibody (IFA) (P less than 0.01), indirect haemagglutinating antibody (IHA) (P less than 0.01) titres and number of precipitin rings (not significant) against P. falciparum antigen, and IFA against P malariae (P less than 0.01). They had above average IgM (P less than 0.05), but their IgG concentrations did not differ from normal. We conclude that (i) sickling is sufficient to protect against P. malariae in Hb.SS but not Hb.AS; (ii) sickling prevents intense P. falciparum infection in Hb.SS, as in Hb.AS; (iii) in Hb.SS, there is less antigenic stimulus and hence less antibody against P. falciparum (like Hb.AS) and P. malariae (unlike Hb.AS); (iv) although less intense, malaria is frequently fatal in Hb.SS, especially in age-group one to four years (unlike Hb.AS); (v) IgM levels are high in Hb.SS in response to frequent infections other than malaria (unlike Hb.AS).

Abnormal haemoglobins in the Sudan savanna of Nigeria. IV. Malaria, immunoglobulins and antimalarial antibodies in haemoglobin AC individuals.

Haemoglobin (Hb) AC electrophoretic pattern was found in 0.7% of the population at Garki, Kano State, northern Nigeria, an area where malaria is hyperendemic. Twenty-one Hb.AC subjects at all ages did not differ from the rest of the population in their frequency or density of Plasmodium falciparum, P. malaria or P. ovale infections, nor in their IgM concentrations and titres of specific antimalarial antibodies. However, IgG levels in Hb.AC subjects were frequently above the average of the reference population (P less than 0.05), especially during a period of protection against malaria (P less than 0.01). These observations suggest that the Hb.C gene may be maintained in certain environments by an enhanced ability to produce IgG antibodies against an antigen or antigens other than malaria, and that its geographical relationship to malaria may be a coincidence. This hypothesis needs to be tested where Hb.C is seen at high frequency, in northern Ghana and Upper Volta or Gwoza (Nigeria).

Abnormal haemoglobins in the Sudan savanna of Nigeria. I. Prevalence of haemoglobins and relationships between sickle cell trait, malaria and survival.

The prevalence of different haemoglobins and their interaction with malaria have been studied in Garki, Kano State, Nigeria. Sickle cell trait was present in 24% of newborn and 29% of those aged over five years. Hb.AC was present in 0.7%. Frequency of both haemoglobin variants was greater in Hausa than Fulani. Sickle cell anaemia was almost invariably fatal in early childhood. The distribution curve of percentage of Hb.S in sickle cell trait subjects was normal, and did not demonstrate any high frequency of a gene for alpha-thalassaemia. The presence of beta-thalassaemia minor could not be tested, but Hb.S/beta-thalassaemia was not detected. Hb.S gene frequency appears to have been maintained by a fitness in heterozygotes of 21% over normal homozygotes; increased fertility and high mutation rate did not make any apparent contribution. Hb.AS subjects had on average lower frequency and considerably lower densities of Plasmodium falciparum trophozoites than Hb.AA from the age of 30 to 59 weeks; density was less in sickle cell trait up to age three years in the dry season only. It is suggested that the survival advantage and hence the prevalence of sickle cell trait may be greatest in some hyperendemic areas and less where malaria transmission is extremely high or when it is high and unvaried.