The malaria vaccine: seventy years of the great immune hope.

The cluster of seminal microbiological discoveries at the end of the 19th century through to the first quarter of the 20th century gave rise to the expectation that the control of malaria would be by scientific technology (as opposed to the 'brute force' of bonification/massive engeneering works) and that technology would be immunization by a malaria vaccine. Immunology's foundation was in microbiology and the two related disciplines matured concurrently. Immunization with dead or inactivated microorganisms became immunology's strongest arm, affording protection against many major diseases such as smallpox, anthrax, rabies, yellow fever and tetanus. So why not malaria? In the pre-World War II era there were no chemotherapeutic/prophylactic drugs practical for the control of malaria and a vaccine seemed the easy, rational path to that objective. From 1910 to about 1950 there were numerous attempts in humans and primate and avian models to devise a malaria vaccine. However, it soon became apparent that the malaria parasites, because of their complex, stage-specific antigenic identity as well as their relatively poor immunogenicity, would be much more difficult to use as a vaccine than the bacteria or viruses. There were some experimental successes, but none in humans.

Immunoblot characterization of IgG, IgM and IgE antibodies elicited during the course of fatal and non-fatal infections of Plasmodium berghei in DBA/2 and Balb/c mice.

When infected with the CRS line of Plasmodium berghei ANKA, DBA/2 mice died of a fulminating infection around day 20 post-infection whereas Balb/c mice had crises around day 15 then low or subpatent parasitaemias until approximately day 73, when sterile immunity is believed to have supervened. Immunoblots for parasite-specific immunoglobulins G, M and E were made from the sera taken during the course of infection in each mouse strain. Although both strains elicited antibodies to a 128-kDa antigen by day 8, this was solely of the IgG class in the DBA/2 but of both IgG and IgM in the Balb/c. Crisis and subpatency were associated with the appearance of IgG and IgM antibodies to 74- and 80-kDa antigens. The most vigorous immune response was observed in sera from the Balb/c mice on day 73, with antibodies to many antigens of 19-180 kDa; IgE antibody (to antigens of 38 and 45 kDa) was then evident for the first time.

Immunoglobulin complex deposits in Plasmodium falciparum-infected placentas from Malawi and Papua New Guinea.

Term placentas from 35 patients infected with Plasmodium falciparum were obtained in Malawi in southeast Africa and six term placentas from patients infected with P. falciparum were obtained in Wewak, Papua New Guinea, Melanesia. The placental tissues were examined by light microscopy and by an immunohistologic method to compare the pathologic changes of placentas in the two malaria-endemic countries. Using the number of parasitized red blood cells (PRBC) in intervillous spaces, pregnant women from Malawi with placental parasitemia were categorized into three groups. In the high PRBC group (> 20%, group I), there was no deposition of IgE in fetal blood vessels. In contrast, IgE was observed in fetal blood vessels of the intermediate PRBC group (1-10%, group II) and low PRBC group (< 1%, group III). In all six placentas from Papua New Guinean women, deposition of immune complexes, including IgE, was observed in the fetal blood vessels. All placentas with deposition of IgE in fetal blood vessels showed no sequestration of malaria parasites in intervillous spaces. Our data indicate that the amount of deposition of IgE in the placenta from women infected with P. falciparum is inversely correlated with the degree of parasitemia at that site.

Plasmodium falciparum-specific immunoglobulin G (IgG), IgM, and IgE antibodies in paired maternal-cord sera from east Sepik Province, Papua New Guinea.

Enzyme-linked immunosorbent assay (ELISA) and Western blot (immunoblot) serological analyses for immunoglobulin G (IgG), IgM, and IgE antibodies to Plasmodium falciparum were made from 46 maternal-cord serum pairs obtained from parturient East Sepik (Papua New Guinea) women and their newborn. Concurrent study of these women had shown that placental parasitemia rates were related to parity with the highest rate (41%) in the primiparous group and the lowest rate (3%) in the women who had given birth more than three times (> 3 parity group). Overall ELISA positivity rates for antimalarial IgG, IgM, and IgE antibodies in the maternal sera were 54.3, 28.2, and 8.3%, respectively, while those for the cord sera were 36.9, 0, and 16.6% respectively. Seropositivity rates were not related to maternal parity group, except for maternal IgE, in which there was a higher rate, of borderline significance, in the > 3 parity group than in the primiparous group. Cord IgE positivity was largely independent of maternal positivity and vice versa. Cord and maternal IgG immunoblot pairs showed near homology. IgG antibodies to the P. falciparum antigens of sizes < 36 kDa were either weak or absent in parity group 1 and 2 maternal-cord serum pairs. Neither ELISA or immunoblot revealed IgM antibody in the cord serum samples. Maternal IgM antibodies showed a heterogeneity of responses both between paired IgG immunoblots and between different serum samples. The IgE immunoblots exhibited a similar diversity, albeit of less complexity. The presence of P. falciparum-specific IgE in the cord sera would indicate that prenatal immune hypersensitization of the fetus to malaria had occurred.

Bancroftian filariasis in an isolated hunter-gatherer shifting horticulturist group in Papua New Guinea.

A survey for Wuchereria bancrofti microfilaraemia using membrane filtration was carried out among the Hagahai, a recently contacted Papua New Guinea group of hunter-gatherer shifting horticulturists. Adult men had a significantly higher microfilaraemia rate than women. Children aged > 15 years had significantly fewer infections than adults and the microfilaraemia densities were considerably lower. Two subjects exhibited matutinal microfilarial periodicity, peaking at approximately 06 h 00. The possible reasons for the epidemiological and microfilarial findings are discussed.

Prenatal immune hypersensitization to malaria: Plasmodium falciparum-specific IgE antibody in paired maternal and cord sera from Papua New Guinea.

In a study of malaria and pregnancy in East Sepik Province of Papua New Guinea 45 maternal and cord serum pairs were tested for Plasmodium falciparum-specific IgE antibody. There were 17 positive sera: 6 cases of maternal serum alone, 5 cases of cord serum alone and 3 pairs of maternal and cord sera. IgE antibody positivity rates in the mothers increased with parity, whereas placental parasitaemia rates decreased. Cord serum positivity was not affected by parity. Immunoblots of the sera revealed a diversity of IgE antibodies to specific antigens of the P. falciparum lysate, but an IgE antibody to a 48kd antigen was present in all positive maternal and cord sera.

Placental pathology in Plasmodium berghei-infected rats.

The pathologic changes in placentae of pregnant rats infected with Plasmodium berghei at different stages of gestation were studied using light and electron microscopy and immunohistochemistry. The major changes observed were thickening and duplication of the trophoblastic basement membrane, and accumulation of parasitized erythrocytes and occasional mononuclear cells in the maternal blood space. Immunohistochemical examination of nine placentae revealed that six stained positively for IgG, two for IgM, and four for P. berghei antigen. No C3 deposition was detected. The findings in this study indicate that the variable parasitologic-clinical course from benign to fatal of P. berghei infection in pregnant rats makes it a potentially valuable model of human gestational malaria infection.

Placental Plasmodium falciparum parasitaemia in East Sepik (Papua New Guinea) women of different parity: the apparent absence of acute effects on mother and foetus.

The effects of malaria were studied in a group of parturient women of East Sepik Province, Papua New Guinea. Further information was gathered from a search of hospital records and interviews with village aid post orderlies. Examination of placental blood revealed a Plasmodium falciparum parasitaemia rate of 41% of the primiparae, 23% in parous 2, 25% in parous 3, and 3% in multiparae greater than 3. Approximately one-half of those with placental parasitaemia had a concomitant detectable peripheral parasitaemia. Placental parasitaemias were of relatively low density, averaging 1.6%. There were no instances in the observed series of births, hospital records, or village studies of the occurrence of severe malaria in the mother or its acute effects on the foetus. Neither birthweight nor maternal or cord blood haematocrit was related to the presence or absence of placental parasitaemia. Neonatal birthweight and risk of delivering a low birthweight (less than 2.5 kg) baby was statistically associated only with maternal parity. The possible reasons for the relatively benign effect of malaria in the pregnant women of this population are discussed.

Characterization of a model of malaria in the pregnant host: Plasmodium berghei in the white rat.

This study characterizes a Plasmodium berghei white rat model of P. falciparum malaria in the pregnant human. Seventy-day-old and 114-day-old female rats, given an infecting inoculum at time of mating, had higher parasitemias and a more severe anemia than age- and sex-matched controls. Under these experimental conditions, the parasitemia went to crisis in all animals and there were no fatal infections. In contrast, all animals died when the infection was initiated 7 days after conception, a timing that brought a coincidence of peak parasitemia and term. Pregnancy during the post-crisis subpatent period did not cause recrudescence. At the time of delivery, the parasitemia was consistently higher in the placental (crush smear) blood than in the peripheral (tail) blood. This difference was greatest in animals giving birth shortly before or 1-2 days after the parasitemic crisis. Very young, compact parasite forms predominated in the placental blood, whereas trophozoites predominated in the peripheral blood.

Plasmodium-specific immunoglobulin E in sera from an area of holoendemic malaria.

Serum samples obtained from adults living in an area of holoendemic malaria in Papua New Guinea and from control residents of Hawaii were tested for Plasmodium-specific immunoglobulin (Ig) E antibody by the enzyme-linked immunosorbent assay. Fifteen (33.3%) of the New Guinea sera had absorbance values indicative of seropositivity. Only half of the IgE-positive sera were concomitantly positive for antimalarial IgG antibody. All of the control sera were negative for antibody of both immunoglobulin classes.