Browsing by Author "Holder, A. A."

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Antibody specificities of children living in a malaria endemic area to inhibitory and blocking epitopes on MSP-119 of Plasmodium falciparum
(Elsevier, 2009) Omosun, Y. O.; Adoro, S.; Anumudu, C. I.; Odaibo, A. B.; Uthiapibull, C.; Holder, A. A.; Nwagwu, M.; Nwuba, R. I.
Merozoite surface protein-119 (MSP-119) specific antibodies which include processing inhibitory, blocking and neutral antibodies have been identified in individuals exposed to Plasmodium falciparum. Here we intend to look at the effect of single and multiple amino acid substitutions of MSP-119 on the recognition by polyclonal antibodies from children living in Igbo-Ora, Nigeria. This would provide us with information on the possibility of eliciting mainly processing inhibitory antibodies with a recombinant MSP-119 vaccine. Blood was collected from children in the rainy season and binding of anti-MSP-119 antibodies to modified mutants of MSP-119 was analysed by ELISA. The MSP-119 mutant proteins with single substitutions at positions 22 (Leu→Arg), 43 (Glu→Leu) and 53 (Asn→Arg) and the MSP-119 mutant protein with multiple substitutions at positions 27 + 31 + 34 + 43 (Glu→Tyr, Leu→Arg, Tyr→Ser, Glu→Leu); which had inhibitory epitopes; had the highest recognition. Children recognised both sets of mutants with different age groups having different recognition levels. The percentage of malaria positive individuals (32–80%) with antibodies that bound to the mutants MSP-119 containing epitopes that recognise only processing inhibitory and not blocking antibodies, were significantly different from those with antibodies that did not bind to these mutants (21–28%). The amino acid substitutions that abolished the binding of blocking antibodies without affecting the binding of inhibitory antibodies are of particular interest in the design of MSP-119 based malaria vaccines. Although these MSP-119 mutants have not been found in natural population, their recognition by polyclonal antibodies from humans naturally infected with malaria is very promising for the future use of MSP-119 mutants in the design of a malaria vaccine.
Antibody specificities of children living in a malaria endemic area to inhibitory and blocking epitopes on MSP-119 of Plasmodium falciparum
(Elsevier, 2009) Omosun, Y. O.; Adoro, S.; Anumudu, C. I.; Odaibo, A. B.; Uthiapibull, C.; Holder, A. A.; Nwagwu, M.; Nwuba, R. I.
Merozoite surface protein-119 (MSP-119) specific antibodies which include processing inhibitory, blocking and neutral antibodies have been identified in individuals exposed to Plasmodium falciparum. Here we intend to look at the effect of single and multiple amino acid substitutions of MSP-119 on the recognition by polyclonal antibodies from children living in Igbo-Ora, Nigeria. This would provide us with information on the possibility of eliciting mainly processing inhibitory antibodies with a recombinant MSP-119 vaccine. Blood was collected from children in the rainy season and binding of anti-MSP-119 antibodies to modified mutants of MSP-119 was analysed by ELISA. The MSP-119 mutant proteins with single substitutions at positions 22 (Leu→Arg), 43 (Glu→Leu) and 53 (Asn→Arg) and the MSP-119 mutant protein with multiple substitutions at positions 27 + 31 + 34 + 43 (Glu→Tyr, Leu→Arg, Tyr→Ser, Glu→Leu); which had inhibitory epitopes; had the highest recognition. Children recognised both sets of mutants with different age groups having different recognition levels. The percentage of malaria positive individuals (32–80%) with antibodies that bound to the mutants MSP-119 containing epitopes that recognise only processing inhibitory and not blocking antibodies, were significantly different from those with antibodies that did not bind to these mutants (21–28%). The amino acid substitutions that abolished the binding of blocking antibodies without affecting the binding of inhibitory antibodies are of particular interest in the design of MSP-119 based malaria vaccines. Although these MSP-119 mutants have not been found in natural population, their recognition by polyclonal antibodies from humans naturally infected with malaria is very promising for the future use of MSP-119 mutants in the design of a malaria vaccine.
Cellular responses to modified Plasmodium falciparum MSP 119 antigens in individuals previously exposed to natural malaria infection
(Springer, 2009) Okafor, C. M. F.; Anumudu, C. I.; Omosun, Y. O.; Uthaipibull, C.; Ayede, I.; Awobode, H. O.; Odaibo, A. B.; Langhorne, J.; Holder, A. A.; Nwuba, R. I.; Troye-Blomberg, M.
Background: MSP1 processing-inhibitory antibodies bind to epitopes on the 19 kDa C-terminal region of the Plasmodium falciparum merozoite surface protein 1 (MSP119), inhibiting erythrocyte invasion. Blocking antibodies also bind to this antigen but prevent inhibitory antibodies binding, allowing invasion to proceed. Recombinant MSP119 had been modified previously to allow inhibitory but not blocking antibodies to continue to bind. Immunization with these modified proteins, therefore, has the potential to induce more effective protective antibodies. However, it was unclear whether the modification of MSP119 would affect critical T-cell responses to epitopes in this antigen. Methods: The cellular responses to wild-type MSP119 and a panel of modified MSP119 antigens were measured using an in-vitro assay for two groups of individuals: the first were malaria-naïve and the second had been naturally exposed to Plasmodium falciparum infection. The cellular responses to the modified proteins were examined using cells from malaria-exposed infants and adults. Results: Interestingly, stimulation indices (SI) for responses induced by some of the modified proteins were at least two-fold higher than those elicited by the wild-type MSP119. A protein with four amino acid substitutions (Glu27→Tyr, Leu31→Arg, Tyr34→Ser and Glu43→Leu) had the highest stimulation index (SI up to 360) and induced large responses in 64% of the samples that had significant cellular responses to the modified proteins.
Fine specificity of anti MSP 119 antibodies an multiplicity of Plasmodium falciparum merozoite protein 1 types in individuals in Nigeria with submicroscopic infection
(Springer, 2010) Ngoundou-Landji, J.; Nwuba, R. I.; Anumudu, C. I.; Odaibo, A. B.; Matando Mayo, W. D.; Awobode, H. O.; Okafor, C. M.; Morenikeji, O. A.; Asinobi, A.; Nwagwu, M.; Holder, A. A.; Ntoumi, F.
Background: The absence of antibodies specific for the 19 kDa C-terminal domain of merozoite surface protein 1 (MSP119) has been associated with high-density malaria parasitaemia in African populations. The hypothesis that a high prevalence and/or level of anti-MSP119 antibodies that may inhibit erythrocyte invasion would be present in apparently healthy individuals who harbour a sub-microscopic malaria infection was tested in this study. Methods: Plasma samples were collected from residents in a region in Nigeria hyperendemic for malaria, who had no detectable parasitaemia by microscopy. Using a competition-based enzyme-linked-immunosorbent assay with two invasion-inhibitory monoclonal antibodies (mAbs) 12.10 and 12.8, the levels and prevalence of specific antibodies were measured. The minimum multiplicity of infection was determined using PCR. The prevalence of anaemia was also measured. Results: Plasma samples from 85% of individuals contained antibodies that bound to MSP119. The inhibition of mAb 12.10 binding was strongly correlated with the prevalence (Spearman correlation test, p < 0.0001) and mean titre of anti-MSP119 antibodies (Spearman correlation test, p < 0.001) in the samples. Comparing samples from individuals with multiple infection (group M) and single infection (Group S), group M contained a higher (p = 0.04) prevalence of anti-MSP119 antibodies that competed with mAb 12.10. Using a logistic regression model, it was found that the presence of antibodies competitive with mAb 12.10 was affected negatively by anaemia (p = 0.0016) and positively by the carriage of multiple parasite genotypes (p = 0.04). Conclusions: In the search for correlates of protection against malaria, which will be essential to evaluate clinical trials of malaria vaccines based on MSP1, this study examines some potential assays and the factors that need to taken into account during their evaluation, using samples from individuals naturally exposed to malaria infection.
The human immune response to Plasmodium falciparum includes both antibodies that inhibit merozoite surface protein 1 secondary processing and blocking antibodies
(American Society for Microbiology, 2002-09) Nwuba, R. I.; Sodeinde, O.; Anumudu, C. I.; Omosun, Y. O.; Odaibo, A. B.; Holder, A. A.; Nwagwu, M.
Malaria merozoite surface protein 1 (MSP1) is cleaved in an essential step during erythrocyte invasion. The responses of children to natural malaria infection included antibodies that inhibit this cleavage and others that block the binding of these inhibitory antibodies. There was no correlation between the titer of the antibody to the 19-kDa fragment of MSP1 and its inhibitory activity. These findings have implications for the design of MSP1-based vaccines.
Specificities of antibodies to Plasmodium falciparum merozoite surface protein (MSP)-1 19
(2002) Nwuba, R. I.; Adoro, S. A.; Anumudu, C. I.; Odaibo, A. B.; Omosun, Y.; Holder, A. A.; Nwagwu, M.
In a survey of children living in South Western Nigeria, plasma levels of anti-MSP119 antibodies were not associated with patent parasitemia. Anti-MSP119 antibody titres correlated positively with age, indicating that development of antibodies to MSP119 may depend on long-term exposure to parasites. Using competitive ELISA, 82% of the samples inhibited the binding of processing-inhibitory monoclonal antibodies (mAb) 12.8 and 12.10 to immobilized recombinant MSP119. The binding of mAb 12.8 in the presence of 18% of these samples .was reduced to less than 10%. This suggest that these samples contain polyc1onal antibodies that have a similar binding specificity to that of mAb 12..S, which recognizes an epitope located in the first epidermal growth factor domain of MSP119. Our data provide useful leads for the design of an MSP119-based vaccine.
Total immunoglobulin G and IgG1 subclass levels specific for the MSP-119 of Plasmodium falciparum are different in individuals with either processing-inhibitory, blocking or neutral antibodies
(Faculty of Medicine, Makerere University, 2010) Omosun, Y. O.; Adoro, S.; Anumudu, C. I.; Odaibo, A.; Holder, A. A.; Nwagwu, M.; Nwuba, R. I.
Background: Some MSP-119 specific antibodies that inhibit merozoite invasion also inhibit the secondary processing of MSP-1. However the binding of these inhibitory antibodies can be blocked by another group of antibodies, called blocking antibodies, which recognize adjacent or overlapping epitopes, but themselves have no effect on either MSP-1 processing or merozoite invasion. These antibodies have been reported to be present in individuals living in a malaria endemic area. Methods: Blood samples were obtained from children shown to have processing inhibitory, blocking, and neutral antibodies in a previous study. Enzyme linked immunosorbent assay (ELISA), was used to determine the total IgG, IgM and IgG subtypes. Results: There was a significant difference in anti-MSP-119 IgG, while there was no significant difference in the anti-MSP-119 IgM. Only anti MSP-119 IgG1, amongst the IgG subtypes was significantly different between the groups. Conclusion: This study shows that antibodies against MSP-1 are different not only in specificity and function but also in the amount of total IgG and IgG subtype produced.
Variation in the relationship between anti-MSP-119 antibody response and age in children infected with Plasmodium falciparum during the dry and rainy seasons
(Elsevier, 2005) Omosun, Y. O.; Anumudu, C. I.; Adoro, S.; Odaibo, A. B.; Sodeinde, O.; Holder, A. A.; Nwagwu, M.; Nwuba, R. I.
Malaria remains a major parasitic disease in Africa, with 300–500 million new infections each year. There is therefore an urgent need for the development of new effective measures, including vaccines. Plasmodium falciparum merozoite surface protein-119 (MSP-119) is a prime candidate for a blood-stage malaria vaccine. Blood samples were collected from children aged 10 days to 15 years in the months of January–March (N=351) and October–November (N=369) corresponding to the dry and rainy seasons, respectively. P. falciparum infection was determined by microscopy and enzyme linked immunosorbent assay (ELISA) was used to determine the total IgG and IgG subclasses. There was a significant increase in the mean anti-MSP-119 antibody titre in the dry season (p < 0.05), compared to the rainy season. A significantly positive correlation between the anti-MSP-119 antibody titre and parasite density (p < 0.01, r = 0.138) was observed. In the rainy season, unlike in the dry season, P. falciparum positive children had higher anti-MSP-119 antibody titres than P. falciparum negative children and this difference was significant (p < 0.05). When all individuals were grouped together, the anti-MSP-119 antibody titre increased with age in both seasons (r = 0.186 and 0.002), this increase was more apparent in the dry season. However, when the study population was divided into P. falciparum positive and negative groups, it was observed that in the rainy season, there was a negative correlation between anti-MSP-119 titre and age in P. falciparum positive individuals, while those who were P. falciparum negative had a positive correlation between anti-MSP-119 titre and age. Analysis of anti-MSP-119 IgG subclass showed that IgG1 and IgG3 mean titres were highest in both the dry and rainy seasons with an increase in the mean antibody titres for IgG1, IgG2 and IgG3 in the rainy season. In the dry season there was a positive correlation between IgG1, IgG2, and IgG3 titres with age, while IgG4 was negative, whereas in the rainy season there was a positive correlation between IgG2 and IgG4 (non-cytophilic antibodies) with age and a negative correlation for IgG1 and IgG3 (cytophilic antibodies) with age. Seasonal differences in the level of MSP-119 IgG subclass titres were observed for P. falciparum negative and positive individuals. Only samples, which were positive for IgG2 and IgG4, showed positive correlation between parasitemia and total IgG. The incidence of P. falciparum infection, which increases during the rainy season, might be an important determinant of anti-MSP-119 antibody levels in children living in Igbo-Ora and the results point to the fact that non-cytophilic antibodies to MSP-119 in children might be associated with an increase in total IgG and parasitemia.