Assessment of different sources of variation in the antibody responses to specific malaria antigens in children in Papua New Guinea.

BACKGROUND: A potential problem for malaria vaccine development and testing is between-host variation in antibody responses to specific malaria antigens. Previous work in adults in an area highly endemic for Plasmodium falciparum in Papua New Guinea found that genetic regulation partly explained heterogeneity in responsiveness. We have now assessed the relative contributions of environmental and genetic factors in total IgG responses to specific malaria antigens in children, and quantified temporal variation within individuals of total IgG responses. METHODS: Total IgG responses against schizont extract, merozoite surface protein-1, merozoite surface protein-2, ring-infected erythrocyte surface antigen, and SPf66 were measured by ELISA. Variance component analysis was used to estimate the variation explained by genetic and environmental factors in these antibody responses. Intra- and inter-class correlations of antibody responses within relative pairs were estimated. We adjusted for age, P. falciparum density, sex and village differences either within or prior to the analysis. RESULTS: For all malaria antigens, temporal variation in the total IgG response was the predominant source of variation. There was substantial familial aggregation of all IgG responses, but it remained unclear how much this clustering was attributable to genetic factors and how much to a common environment in the household. The remaining variance, which could not be explained by either of the above, was very small for most of the antigens. CONCLUSIONS: Temporal variation and clustering of immune responses to specific malaria antigens need to be taken into account when planning, conducting and interpreting immuno-epidemiological and vaccine studies.

Genetic analysis of IgG subclass responses against RESA and MSP2 of Plasmodium falciparum in adults in Papua New Guinea.

Contributions of environmental and genetic factors to IgG subclass responses against Plasmodium falciparum antigens RESA and MSP2 were investigated among adults in a highly endemic area of Papua New Guinea. Heritabilities were estimated using variance component analysis. Familial aggregation of several responses was found, including IgG1, IgG2 and IgG3 responses against RESA, IgG1 and IgG3 responses against the 3D7 form of MSP2 and IgG1, IgG2 responses against the FC27 form of MSP2. Allowance for sharing of houses explained some of the non-genetic variance but not the familial aggregation. The variance of IgG3 responses against RESA and IgG1, IgG2 against MSP2 (FC27) was partly explained by sharing of HLA class II genotypes, although heritability was low. Segregation analyses indicated that any genetic regulation was more complex than governed by a single major gene. Such host genetic variation in responses to specific malaria antigens has implications for immuno-epidemiology and vaccine development.

Malaria infection and morbidity in infants in relation to genetic polymorphisms in Tanzania.

To investigate the effects of host polymorphisms on malaria morbidity and infection, the frequency distributions of TNF alpha promotor gene and sickle cell trait were studied in infants in an area highly endemic for Plasmodium falciparum transmission in Tanzania. Differences in parasite prevalence, density, febrile episodes with and without parasitaemia, PCV levels and the frequencies of different MSP-2 parasite infections were assessed by genotype. The frequency of the TNF alpha promotor allele 2 was 0.09, and the trait was in Hardy-Weinberg equilibrium. There were no differences in malariametric indices between infants with the normal TNF alpha promoter gene and those who were heterozygous for this trait. Infants heterozygous for the TNF alpha promotor gene appeared to have fewer febrile episodes when they were free of parasites. The two infants homozygous for the TNF alpha promoter allele 2 had both a much higher incidence of fever, independently of parasitaemia, than the average for the other genotypes. The frequency of the sickle cell allele S was 0.06 and the trait was also in Hardy-Weinberg equilibrium. Infants heterozygous for the sickle cell trait had significantly lower parasite densities, but similar prevalence, and MSP-2 infections compared to infants with normal haemoglobin. PCV levels, and the incidence of febrile episodes both with and without parasitaemia were also similar. In contrast to the sickle cell trait, the TNF alpha promotor polymorphism appeared not to have any protective effect on malaria in this study, and its importance in other unspecified fever-causing diseases in this population needs further investigation.

Heritability and segregation analysis of immune responses to specific malaria antigens in Papua New Guinea.

Familial patterns of inheritance of immune responses to specific Plasmodium falciparum antigens were studied in 214 adults in an area of Papua New Guinea highly endemic for malaria. Preliminary variance component analysis indicated familial aggregation in both humoral and cellular immune responses against the ring-infected erythrocyte surface antigen (RESA) and the FC27 allele of the Merozoite surface antigen 2 (MSA-2). Including a term for sharing houses in the models affected only the antibody response to RESA. Segregation analysis of the antibody responses against RESA indicated inheritance via a multifactorial model and analysis of the proliferation response suggested a possible recessive major gene. The best fitting models for the immune responses against MSA-2 (FC27) postulated dominant major gene inheritance. We found no significant associations between HLA class I or II alleles and these two antigens in this population. Although there was evidence of familial aggregation of antibody responses to MSA-2 (3D7), the segregation analysis failed to identify a mode of inheritance. There was little or no heritability of either humoral or cellular immune responses against the NANP repeats of the Circumsporozoite protein (NANP), the synthetic malaria vaccine SPf66, or a preparation of MSA-2 (3D7) from which the repetitive part was deleted (MSA-2 (d3D7)). Although it is often difficult to separate genetic effects from the effects of living in the same environment, it appears that some immune responses against certain malaria antigens may be partly influenced by genetic factors.