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Antibody Correlates of Protection from Clinical Plasmodium falciparum Malaria in an Area of Low and Unstable Malaria Transmission.

ABSTRACT: Immune correlates of protection against clinical malaria are difficult to ascertain in low-transmission areas because of the limited number of malaria cases. We collected blood samples from 5,753 individuals in a Kenyan highland area, ascertained malaria incidence in this population over the next 6 years, and then compared antibody responses to 11 Plasmodium falciparum vaccine candidate antigens in individuals who did versus did not develop clinical malaria in a nested case-control study (154 cases and 462 controls). Individuals were matched by age and village. Antigens tested included circumsporozoite protein (CSP), liver-stage antigen (LSA)-1, apical membrane antigen-1 FVO and 3D7 strains, erythrocyte-binding antigen-175, erythrocyte-binding protein-2, merozoite surface protein (MSP)-1 FVO and 3D7 strains, MSP-3, and glutamate-rich protein (GLURP) N-terminal non-repetitive (R0) and C-terminal repetitive (R2) regions. After adjustment for potential confounding factors, the presence of antibodies to LSA-1, GLURP-R2, or GLURP-R0 was associated with decreased odds of developing clinical malaria (odds ratio [OR], [95% CI] 0.56 [0.36-0.89], 0.56 [0.36-0.87], and 0.77 [0.43-1.02], respectively). Levels of antibodies to LSA-1, GLURP-R2, and CSP were associated with decreased odds of developing clinical malaria (OR [95% CI]; 0.61 [0.41-0.89], 0.60 [0.43-0.84], and 0.49 [0.24-0.99], for every 10-fold increase in antibody levels, respectively). The presence of antibodies to CSP, GLURP-R0, GLURP-R2, and LSA-1 combined best-predicted protection from clinical malaria. Antibodies to CSP, GLURP-R0, GLURP-R2, and LSA-1 are associated with protection against clinical malaria in a low-transmission setting. Vaccines containing these antigens should be evaluated in low malaria transmission areas.

SUBMITTER: Hamre KES

PROVIDER: S-EPMC7695051 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Malaria transmission in Latin America is generally hypoendemic and unstable, with Plasmodium vivax as the most prevalent species. However, only a few studies have been carried out in areas with low and unstable transmission, whereas the clinical profile of malaria has been broadly described in hyperendemic areas. The pattern of clinical manifestations and laboratory findings in low to moderate endemic areas of Colombia is reported here.A passive surveillance study was conducted between 2011 and 2013 involving 1,328 patients with Plasmodium falciparum, P. vivax or mixed malaria infections attending malaria points-of-care of four malaria endemic-areas with distinct transmission intensities and parasite distribution. Trained physicians recorded clinical symptoms and signs as well as socio-demographic characteristics of study participants. Haematological, biochemical and urine tests were performed at the time of diagnosis.Out of 1,328 cases, 673 (50.7%) were caused by P. vivax; 650 (48.9%) were due to P. falciparum; and five (0.4%) patients had mixed infections (P. falciparum/P. vivax). Most patients (92.5%) presented with uncomplicated malaria characterized by fever, chills, headache, sweating, myalgia/arthralgia and parasitaemia ≤ 20,000 parasites/μL. Fever, tachycardia, pallor and abdominal pain on palpation were more frequent in P. falciparum patients, whereas mild hepatomegaly and splenomegaly were mostly observed with P. vivax. Non-severe anaemia (Hb 7.0-10.9 g/dL) was observed in 20% of the subjects, whereas severe anaemia (Hb < 7.0 g/dL) was present in four patients. Half of the patients presented thrombocytopaenia regardless of parasite species. Leukopaenia, neutrophilia and monocytosis were frequently observed in patients infected with P. falciparum. Mild-to-moderate biochemical alterations were present in ~25% of the patients, particularly abnormal bilirubin in those with P. falciparum and abnormal transaminases in P. vivax malaria patients. Proteinuria was present in ~50% of the patients regardless of parasite species, whereas haemoglobinuria was more common in P. vivax infections. Only 7.5% of the cases were classified as clinically severe malaria, caused by both P. vivax and P. falciparum.The high prevalence of uncomplicated malaria associated with moderate parasitaemia suggests the importance of timely diagnosis and effective treatment and encourages new activities to further decrease complicated malaria cases and mortality.

Project description:Understanding naturally acquired immunity to infections caused by Plasmodia in different malaria endemicity settings is needed for better vaccine designs and for exploring antibody responses as a proxy marker of malaria transmission intensity. This study investigated the sero-epidemiology of malaria along the international border between China and Myanmar, where malaria elimination action plans are in place. This study recruited 233 P. vivax and 156 P. falciparum infected subjects with acute malaria at the malaria clinics and hospitals. In addition, 93 and 67 healthy individuals from the same endemic region or from non-endemic region, respectively, were used as controls. Acute malaria infections were identified by microscopy. Anti-recombinant PfMSP119 and PvMSP119 antibody levels were measured by ELISA. Antibody responses to respective MSP119 were detected in 50.9% and 78.2% patients with acute P. vivax and P. falciparum infections, respectively. There were cross-reacting antibodies in Plasmodium patients against these two recombinant proteins, though we could not exclude the possibility of submicroscopic mixed-species infections. IgG1, IgG3 and IgG4 were the major subclasses. Interestingly, 43.2% of the healthy endemic population also had antibodies against PfMSP119, whereas only 3.9% of this population had antibodies against PvMSP119. Higher antibody levels were correlated with age and parasite density, but not with season, gender or malaria history. Both total IgG and individual IgG subclasses underwent substantial declines during the convalescent period in three months. This study demonstrated that individuals in a hypoendemic area with coexistence of P. vivax and P. falciparum can mount rapid antibody responses against both PfMSP119 and PvMSP119. The significantly higher proportion of responders to PfMSP119 in the healthy endemic population indicates higher prevalence of P. falciparum in the recent past. Specific antibodies against PvMSP119 could serve as a marker of recent exposure to P. vivax in epidemiological studies.

Project description:Prevalence and levels of antibodies to multiple Plasmodium falciparum antigens show promise as tools for estimating malaria exposure. In a highland area of Kenya with unstable transmission, we assessed the presence and levels of antibodies to 12 pre-erythrocytic and blood-stage P. falciparum antigens by multiplex cytometric bead assay or ELISA in 604 individuals in August 2007, with follow-up testing in this cohort in April 2008, April 2009, and May 2010. Four hundred individuals were tested at all four time points. During this period, the only substantial malaria incidence occurred from April to August 2009. Antibody prevalence in adults was high at all time points (> 70%) for apical membrane antigen 1, erythrocyte-binding antigen 175, erythrocyte-binding protein-2, glutamate rich protein (GLURP)-R2, merozoite surface protein (MSP) 1 (19), MSP-1 (42), and liver-stage antigen-1; moderate (30-70%) for GLURP-R0, MSP-3, and thrombospondin-related adhesive protein; and low (< 30%) for SE and circumsporozoite protein (CSP). Changes in community-wide malaria exposure were best reflected in decreasing antibody levels overtime for highly immunogenic antigens, and in antibody seroprevalence overtime for the less-immunogenic antigens. Over the 3 years, antibody levels to all antigens except CSP and schizont extract (SE) decreased in an age-dependent manner. Prevalence and levels of antibodies to all antigens except CSP and SE increased with age. Increases in antibody prevalence and levels to CSP and SE coincided with increases in community-wide malaria incidence. Antibody levels to multiple P. falciparum antigens decrease in the absence of consistent transmission. Multiplex assays that assess both the presence and level of antibodies to multiple pre-erythrocytic and blood-stage P. falciparum antigens may provide the most useful estimates of past and recent malaria transmission in areas of unstable transmission and could be useful tools in malaria control and elimination campaigns.

Project description:The incidence of malaria in Sri Lanka has significantly declined in recent years. Similar trends were seen in Kataragama, a known malaria endemic location within the southern province of the country, over the past five years. This is a descriptive study of anti-malarial antibody levels and selected host genetic mutations in residents of Kataragama, under low malaria transmission conditions.Sera were collected from 1,011 individuals residing in Kataragama and anti-malarial antibodies and total IgE levels were measured by a standardized ELISA technique. Host DNA was extracted and used for genotyping of selected SNPs in known genes associated with malaria. The antibody levels were analysed in relation to the past history of malaria (during past 10?years), age, sex, the location of residence within Kataragama and selected host genetic markers.A significant increase in antibodies against Plasmodium falciparum antigens AMA1, MSP2, NANP and Plasmodium vivax antigen MSP1 in individuals with past history of malaria were observed when compared to those who did not. A marked increase of anti-MSP1(Pf) and anti-AMA1(Pv) was also evident in individuals between 45-59?years (when compared to other age groups). Allele frequencies for two SNPs in genes that code for IL-13 and TRIM-5 were found to be significantly different between those who have experienced one or more malaria attacks within past 10?years and those who did not. When antibody levels were classified into a low-high binary trait, significant associations were found with four SNPs for anti-AMA1(Pf); two SNPs for anti-MSP1(Pf); eight SNPs for anti-NANP(Pf); three SNPs for anti-AMA1(Pv); seven SNPs for anti-MSP1(Pv); and nine SNPs for total IgE. Eleven of these SNPs with significant associations with anti-malarial antibody levels were found to be non-synonymous.Evidence is suggestive of an age-acquired immunity in this study population in spite of low malaria transmission levels. Several SNPs were in linkage disequilibrium and had a significant association with elevated antibody levels, suggesting that these host genetic mutations might have an individual or collective effect on inducing or/and maintaining high anti-malarial antibody levels.

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Project description:IntroductionSolomon Islands is intensifying national efforts to achieve malaria elimination. A long history of indoor spraying with residual insecticides, combined recently with distribution of long lasting insecticidal nets and artemether-lumefantrine therapy, has been implemented in Solomon Islands. The impact of these interventions on local endemicity of Plasmodium spp. is unknown.MethodsIn 2012, a cross-sectional survey of 3501 residents of all ages was conducted in Ngella, Central Islands Province, Solomon Islands. Prevalence of Plasmodium falciparum, P. vivax, P. ovale and P. malariae was assessed by quantitative PCR (qPCR) and light microscopy (LM). Presence of gametocytes was determined by reverse transcription quantitative PCR (RT-qPCR).ResultsBy qPCR, 468 Plasmodium spp. infections were detected (prevalence = 13.4%; 463 P. vivax, five mixed P. falciparum/P. vivax, no P. ovale or P. malariae) versus 130 by LM (prevalence = 3.7%; 126 P. vivax, three P. falciparum and one P. falciparum/P. vivax). The prevalence of P. vivax infection varied significantly among villages (range 3.0-38.5%, p<0.001) and across age groups (5.3-25.9%, p<0.001). Of 468 P. vivax infections, 72.9% were sub-microscopic, 84.5% afebrile and 60.0% were both sub-microscopic and afebrile. Local residency, low education level of the household head and living in a household with at least one other P. vivax infected individual increased the risk of P. vivax infection. Overall, 23.5% of P. vivax infections had concurrent gametocytaemia. Of all P. vivax positive samples, 29.2% were polyclonal by MS16 and msp1F3 genotyping. All five P. falciparum infections were detected in residents of the same village, carried the same msp2 allele and four were positive for P. falciparum gametocytes.ConclusionP. vivax infection remains endemic in Ngella, with the majority of cases afebrile and below the detection limit of LM. P. falciparum has nearly disappeared, but the risk of re-introductions and outbreaks due to travel to nearby islands with higher malaria endemicity remains.

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Antibody Correlates of Protection from Clinical Plasmodium falciparum Malaria in an Area of Low and Unstable Malaria Transmission.

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