18 research outputs found
Cellular responses to modified Plasmodium falciparum MSP119 antigens in individuals previously exposed to natural malaria infection
<p>Abstract</p> <p>Background</p> <p>MSP1 processing-inhibitory antibodies bind to epitopes on the 19 kDa C-terminal region of the <it>Plasmodium falciparum </it>merozoite surface protein 1 (MSP1<sub>19</sub>), inhibiting erythrocyte invasion. Blocking antibodies also bind to this antigen but prevent inhibitory antibodies binding, allowing invasion to proceed. Recombinant MSP1<sub>19 </sub>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 MSP1<sub>19 </sub>would affect critical T-cell responses to epitopes in this antigen.</p> <p>Methods</p> <p>The cellular responses to wild-type MSP1<sub>19 </sub>and a panel of modified MSP1<sub>19 </sub>antigens were measured using an <it>in-vitro </it>assay for two groups of individuals: the first were malaria-naïve and the second had been naturally exposed to <it>Plasmodium falciparum </it>infection. The cellular responses to the modified proteins were examined using cells from malaria-exposed infants and adults.</p> <p>Results</p> <p>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 MSP1<sub>19</sub>. 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.</p> <p>Conclusion</p> <p>This study suggests that specific MSP1<sub>19 </sub>variants that have been engineered to improve their antigenicity for inhibitory antibodies, retain T-cell epitopes and the ability to induce cellular responses. These proteins are candidates for the development of MSP1-based malaria vaccines.</p
Epidemiological factors that promote the development of severe malaria anaemia in children in Ibadan
Background: Effective control and management of severe malaria cases depends on a clear understanding of the local epidemiologicalfactors and specific clinical manifestations of the disease in the different endemic regions.
Objectives: To determine the prevalence of severe malaria and epidemiological factors that affect the development of malaria anaemia.
Methods: A cross-sectional survey was carried out among children below 5 years of age, at the Adeoyo State Maternity Hospital,Ibadan, Nigeria. Questionnaires and case histories were taken from patients clinically diagnosed of malaria.Thus, 372 volunteers wererecruited into the study from the 3131 paediatric cases that reported over the10-week period to the out-patient department (OPD) ofthe hospital. 229 (61.6%) of the recruited volunteers presented with fever (>37.5 oC) at consultation.These had malaria parasite andPCV tests done.
Results: Clinical diagnosis was confirmed microscopically in 78% (290/372) for Plasmodium infection using thick film slides.Anaemia (PC
The Human Immune Response to Plasmodium falciparum Includes Both Antibodies That Inhibit Merozoite Surface Protein 1 Secondary Processing and Blocking Antibodies
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
Factors influencing the induction of high affinity antibodies to Plasmodium falciparum merozoite antigens and how affinity changes over time
Understanding the functional characteristics of naturally acquired antibodies against P. falciparum merozoite antigens is crucial for determining the protective functions of antibodies. Affinity (measured as kd) of naturally acquired antibodies against two key targets of acquired immunity, EBA175 and PfRh2, was determined using Surface Plasmon Resonance (SPR) in a longitudinal survey in Nigeria. A majority of the participants, 79% and 67%, maintained stable antibody affinities to EBA175 and PfRh2, respectively, over time. In about 10% of the individuals, there was a reciprocal interaction with a reduction over time in antibody affinity for PfRh2 and an increase for EBA175. In general, PfRh2 elicited antibodies with higher affinity compared to EBA175. Individuals with higher exposure to malaria produced antibodies with higher affinity to both antigens. Younger individuals (5-15 years) produced comparable or higher affinity antibodies than adults (>15 years) against EBA175, but not for PfRh2. Correlation between total IgG (ELISA) and affinity varied between individuals, but PfRh2 elicited antibodies with a higher correlation in a majority of the participants. There was also a correlation between antibody inhibition of erythrocyte invasion by merozoites and PfRh2 affinity. This work gives new insights into the generation and maintenance of antibody affinity over time
Subclass responses and their half-lives for antibodies against EBA175 and PfRh2 in naturally acquired immunity against Plasmodium falciparum malaria
Background: Plasmodium falciparum EBA175 and PfRh2 belong to two main families involved in parasite invasion, and both are potential vaccine candidates. Current knowledge is limited regarding which target antigens and subclasses of antibodies are actually important for protection, and how naturally acquired immunity is achieved. Methods: Repeated blood samples were collected from individuals in Nigeria over a period of almost one year. ELISA was used to analyse subclasses of IgG responses. Results: For both EBA175 (region III-V) and (a fragment of) PfRh2, the dominant antibody responses consisted of IgG1 and IgG3 followed by IgG2, while for PfRh2 there was also a relatively prominent response for IgG4. High levels of IgG1, IgG2 and IgG3 for EBA175 and total IgG for PfRh2 correlated significantly with a lower parasitaemia during the study period. Children with HbAS had higher levels of some subclasses compared to children with HbAA, while in adults the pattern was the opposite. The half-lives of IgG2 and IgG4 against EBA175 were clearly shorter than those for IgG1 and IgG3. Conclusion: EBA175 and PfRh2 are potential targets for protective antibodies since both correlated with lower parasitaemia. The shorter half-lives for IgG2 and IgG4 might explain why these subclasses are often considered less important in protection against malaria. Triggering the right subclass responses could be of critical importance in a successful vaccine. Further studies are needed to evaluate the role of haemoglobin polymorphisms and their malaria protective effects in this process
Cytokine profiles and antibody responses to Plasmodium falciparum malaria infection in individuals living in Ibadan, southwest Nigeria
Background: The ability of the host immune system to efficiently
clear Plasmodium falciparum parasites during a malaria infection
depends on the type of immune response mounted by the host. Study
design: In a cross-sectional study, we investigated the cellular-and
antibody responses in individuals with P. falciparum infection, in an
attempt to identify immunological signs indicative of the development
of natural immunity against malaria in Ibadan, Nigeria. Levels of
IL-10, IL-12(p70), IFN-γ, and IgM, IgG and IgG1-4 subclasses in
the serum of 36 symptomatic children with microscopically confirmed
malaria parasitaemia and 54 asymptomatic controls were analysed by
ELISA. Results: IFN-γ and IL-10 were significantly higher in the
symptomatic children (p=0.009, p=0.025 respectively) than in the
asymptomatic controls but no differences were seen for IL-12(p70).
Estimated higher ratios of IFN-γ/IL-10 and IFN-γ/IL-12 were
also observed in the symptomatic children while the asymptomatic
controls had higher IL-12/IL-10 ratio. The mean concentration levels of
anti-P. falciparum IgG1, IgG2, IgG3 antibodies were statistically
significantly higher in the individuals >5 years of age than <5
years while anti-P. falciparum IgG3 antibodies were notably low in
<5 years category. Children <5 years had higher IgM antibodies
than IgG and the expression of IgG subclasses increased with age.
Conclusion: Taken together, malaria infection is on a delicate balance
of pro- and anti-inflammatory cytokines. The higher levels of
IFN-γ seen in the symptomatic children (<6months) may be
instrumental in immune-protection against malaria by limiting parasite
replication. The observed variations in immunoglobulin subclass levels
were age-dependent and exposure-related
Acquisition, maintenance and adaptation of invasion inhibitory antibodies against Plasmodium falciparum invasion ligands involved in immune evasion
Erythrocyte-binding antigens (EBAs) and P. falciparum reticulocyte-binding homologue proteins (PfRhs) are two important protein families that can vary in expression and utilization by P. falciparum to evade inhibitory antibodies. We evaluated antibodies at repeated time-points among individuals living in an endemic region in Nigeria over almost one year against these vaccine candidates. Antibody levels against EBA140, EBA175, EBA181, PfRh2, PfRh4, and MSP2, were measured by ELISA. We also used parasites with disrupted EBA140, EBA175 and EBA181 genes to show that all these were targets of invasion inhibitory antibodies. However, antigenic targets of inhibitory antibodies were not stable and changed substantially over time in most individuals, independent of age. Antibodies levels measured by ELISA also varied within and between individuals over time and the antibodies against EBA181, PfRh2 and MSP2 declined more rapidly in younger individuals (15 years) compared with older (>15). The breadth of high antibody responses over time was more influenced by age than by the frequency of infection. High antibody levels were associated with a more stable invasion inhibitory response, which could indicate that during the long process of formation of immunity, many changes not only in levels but also in functional responses are needed. This is an important finding in understanding natural immunity against malaria, which is essential for making an efficacious vaccine
Fine specificity of anti-MSP1<sub>19 </sub>antibodies and multiplicity of <it>Plasmodium falciparum </it>Merozoite Surface Protein 1 types in individuals in Nigeria with sub-microscopic infection
Abstract 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 19 antibodies (Spearman correlation test, p 19 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.</p