Acquisition of Antibodies against Plasmodium falciparum Merozoites and Malaria Immunity in Young Children and the Influence of Age, Force of Infection, and Magnitude of Response

Individuals in areas ofPlasmodium falciparumendemicity develop immunity to malaria after repeated exposure. Knowledge of the acquisition and nature of protective immune responses toP. falciparumis presently limited, particularly for young children. We examined antibodies (IgM, IgG, and IgG subclasses) to merozoite antigens and their relationship to the prospective risk of malaria in children 1 to 4 years of age in a region of malaria endemicity in Papua New Guinea. IgG, IgG1, and IgG3 responses generally increased with age, were higher in children with active infection, and reflected geographic heterogeneity in malaria transmission. Antigenic properties, rather than host factors, appeared to be the main determinant of the type of IgG subclass produced. High antibody levels were not associated with protection from malaria; in contrast, they were typically associated with an increased risk of malaria. Adjustment for malaria exposure, using a novel molecular measure of the force of infection byP. falciparum, accounted for much of the increased risk, suggesting that the antibodies were markers of higher exposure toP. falciparum. Comparisons between antibodies in this cohort of young children and in a longitudinal cohort of older children suggested that the lack of protective association was explained by lower antibody levels among young children and that there is a threshold level of antibodies required for protection from malaria. Our results suggest that in populations with low immunity, such as young children, antibodies to merozoite antigens may act as biomarkers of malaria exposure and that, with increasing exposure and responses of higher magnitude, antibodies may act as biomarkers of protective immunity.

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Contrasting Patterns of Serologic and Functional Antibody Dynamics to Plasmodium falciparum Antigens in a Kenyan Birth Cohort

Clinical and Vaccine Immunology ◽

10.1128/cvi.00452-15 ◽

2015 ◽

Vol 23 (2) ◽

pp. 104-116 ◽

Cited By ~ 12

Author(s):

Arlene E. Dent ◽

Indu Malhotra ◽

Xuelie Wang ◽

Denise Babineau ◽

Kee Thai Yeo ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Cord Blood ◽

Natural Infection ◽

Surface Protein ◽

Merozoite Surface Protein ◽

In Utero ◽

Content Type ◽

Malaria Exposure ◽

Increased Risk ◽

Functional Antibodies

ABSTRACTIgG antibodies toPlasmodium falciparumare transferred from the maternal to fetal circulation during pregnancy, wane after birth, and are subsequently acquired in response to natural infection. We examined the dynamics of malaria antibody responses of 84 Kenyan infants from birth to 36 months of age by (i) serology, (ii) variant surface antigen (VSA) assay, (iii) growth inhibitory activity (GIA), and (iv) invasion inhibition assays (IIA) specific for merozoite surface protein 1 (MSP1) and sialic acid-dependent invasion pathway. Maternal antibodies in each of these four categories were detected in cord blood and decreased to their lowest level by approximately 6 months of age. Serologic antibodies to 3 preerythrocytic and 10 blood-stage antigens subsequently increased, reaching peak prevalence by 36 months. In contrast, antibodies measured by VSA, GIA, and IIA remained low even up to 36 months. Infants sensitized toP. falciparum in utero, defined by cord blood lymphocyte recall responses to malaria antigens, acquired antimalarial antibodies at the same rate as those who were not sensitizedin utero, indicating that fetal exposure to malaria antigens did not affect subsequent infant antimalarial responses. Infants with detectable serologic antibodies at 12 months of age had an increased risk ofP. falciparuminfection during the subsequent 24 months. We conclude that serologic measures of antimalarial antibodies in children 36 months of age or younger represent biomarkers of malaria exposure rather than protection and that functional antibodies develop after 36 months of age in this population.

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Changes in Antigen-Specific Cytokine and Chemokine Responses to Plasmodium falciparum Antigens in a Highland Area of Kenya after a Prolonged Absence of Malaria Exposure

Infection and Immunity ◽

10.1128/iai.01924-14 ◽

2014 ◽

Vol 82 (9) ◽

pp. 3775-3782 ◽

Cited By ~ 6

Author(s):

Lyticia A. Ochola ◽

Cyrus Ayieko ◽

Lily Kisia ◽

Ng'wena G. Magak ◽

Estela Shabani ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Severe Disease ◽

Clinical Malaria ◽

Necrosis Factor Alpha ◽

Content Type ◽

Highland Area ◽

Cytokine Responses ◽

Increased Risk ◽

Tnf Α ◽

Ifn Γ

ABSTRACTIndividuals naturally exposed toPlasmodium falciparumlose clinical immunity after a prolonged lack of exposure.P. falciparumantigen-specific cytokine responses have been associated with protection from clinical malaria, but the longevity ofP. falciparumantigen-specific cytokine responses in the absence of exposure is not well characterized. A highland area of Kenya with low and unstable malaria transmission provided an opportunity to study this question. The levels of antigen-specific cytokines and chemokines associated in previous studies with protection from clinical malaria (gamma interferon [IFN-γ], interleukin-10 [IL-10], and tumor necrosis factor alpha [TNF-α]), with increased risk of clinical malaria (IL-6), or with pathogenesis of severe disease in malaria (IL-5 and RANTES) were assessed by cytometric bead assay in April 2008, October 2008, and April 2009 in 100 children and adults. During the 1-year study period, none had an episode of clinicalP. falciparummalaria. Two patterns of cytokine responses emerged, with some variation by antigen: a decrease at 6 months (IFN-γ and IL-5) or at both 6 and 12 months (IL-10 and TNF-α) or no change over time (IL-6 and RANTES). These findings document thatP. falciparumantigen-specific cytokine responses associated in prior studies with protection from malaria (IFN-γ, TNF-α, and IL-10) decrease significantly in the absence ofP. falciparumexposure, whereas those associated with increased risk of malaria (IL-6) do not. The study findings provide a strong rationale for future studies of antigen-specific IFN-γ, TNF-α, and IL-10 responses as biomarkers of increased population-level susceptibility to malaria after prolonged lack ofP. falciparumexposure.

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Antibodies to Peptides in Semiconserved Domains of RIFINs and STEVORs Correlate with Malaria Exposure

mSphere ◽

10.1128/msphere.00097-19 ◽

2019 ◽

Vol 4 (2) ◽

Cited By ~ 9

Author(s):

Albert E. Zhou ◽

Andrea A. Berry ◽

Jason A. Bailey ◽

Andrew Pike ◽

Antoine Dara ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Severe Malaria ◽

Surface Antigen ◽

Immune Evasion ◽

Clinical Malaria ◽

Malaria Episode ◽

Natural Immunity ◽

Content Type ◽

Variant Surface Antigen ◽

Malaria Exposure

ABSTRACT The repetitive interspersed family (RIFIN) and the subtelomeric variable open reading frame (STEVOR) family represent two of three major Plasmodium falciparum variant surface antigen families involved in malaria pathogenesis and immune evasion and are potential targets in the development of natural immunity. Protein and peptide microarrays populated with RIFINs and STEVORs associated with severe malaria vulnerability in Malian children were probed with adult and pediatric sera to identify epitopes that reflect malaria exposure. Adult sera recognized and reacted with greater intensity to all STEVOR proteins than pediatric sera did. Serorecognition of and seroreactivity to peptides within the semiconserved domain of STEVORs increased with age and seasonal malaria exposure, while serorecognition and seroreactivity increased for the semiconserved and second hypervariable domains of RIFINs only with age. Serologic responses to RIFIN and STEVOR peptides within the semiconserved domains may play a role in natural immunity to severe malaria. IMPORTANCE Malaria, an infectious disease caused by the parasite Plasmodium falciparum, causes nearly 435,000 deaths annually worldwide. RIFINs and STEVORs are two variant surface antigen families that are involved in malaria pathogenesis and immune evasion. Recent work has shown that a lack of humoral immunity to these proteins is associated with severe malaria vulnerability in Malian children. This is the first study to have compared serologic responses of children and adults to RIFINs and STEVORs in settings of malaria endemicity and to examine such serologic responses before and after a clinical malaria episode. Using microarrays, we determined that the semiconserved domains in these two parasite variant surface antigen families harbor peptides whose seroreactivity reflects malaria exposure. A similar approach has the potential to illuminate the role of variant surface antigens in the development of natural immunity to clinical malaria. Potential vaccines for severe malaria should include consideration of peptides within the semiconserved domains of RIFINs and STEVORs.

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Analysis of Antibodies to Newly Described Plasmodium falciparum Merozoite Antigens Supports MSPDBL2 as a Predicted Target of Naturally Acquired Immunity

Infection and Immunity ◽

10.1128/iai.00301-13 ◽

2013 ◽

Vol 81 (10) ◽

pp. 3835-3842 ◽

Cited By ~ 20

Author(s):

Kevin K. A. Tetteh ◽

Faith H. A. Osier ◽

Ali Salanti ◽

Gathoni Kamuyu ◽

Laura Drought ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Risk Ratio ◽

Statistical Significance ◽

Clinical Malaria ◽

Content Type ◽

Type Antigen ◽

Falciparum Merozoite ◽

Merozoite Antigens ◽

Allelic Type

ABSTRACTProspective studies continue to identify malaria parasite genes with particular patterns of polymorphism which indicate they may be under immune selection, and the encoded proteins require investigation. Sixteen new recombinant protein reagents were designed to characterize three such polymorphic proteins expressed inPlasmodium falciparumschizonts and merozoites: MSPDBL1 (also termed MSP3.4) and MSPDBL2 (MSP3.8), which possess Duffy binding-like (DBL) domains, and SURFIN4.2, encoded by a member of the surface-associated interspersed (surf) multigene family. After testing the antigenicities of these reagents by murine immunization and parasite immunofluorescence, we analyzed naturally acquired antibody responses to the antigens in two cohorts in coastal Kenya in which the parasite was endemic (Chonyi [n= 497] and Ngerenya [n= 461]). As expected, the prevalence and levels of serum antibodies increased with age. We then investigated correlations with subsequent risk of clinical malaria among children <11 years of age during 6 months follow-up surveillance. Antibodies to the polymorphic central region of MSPDBL2 were associated with reduced risk of malaria in both cohorts, with statistical significance remaining for the 3D7 allelic type after adjustment for individuals' ages in years and antibody reactivity to whole-schizont extract (Chonyi, risk ratio, 0.51, and 95% confidence interval [CI], 0.28 to 0.93; Ngerenya, risk ratio, 0.38, and 95% CI, 0.18 to 0.82). For the MSPDBL1 Palo Alto allelic-type antigen, there was a protective association in one cohort (Ngerenya, risk ratio, 0.53, and 95% CI, 0.32 to 0.89), whereas the other antigens showed no protective associations after adjustment. These findings support the prediction that antibodies to the polymorphic region of MSPDBL2 contribute to protective immunity.

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Associations between Aminoquinoline Resistance Genotypes and Clinical Presentations of Plasmodium falciparum Infection in Uganda

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00721-20 ◽

2020 ◽

Vol 64 (10) ◽

Author(s):

Gloria Cuu ◽

Victor Asua ◽

Stephen Tukwasibwe ◽

Sam L. Nsobya ◽

Ann Nanteza ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Severe Malaria ◽

Case Control Study ◽

Case Control ◽

Content Type ◽

Parasite Fitness ◽

Symptomatic Malaria ◽

Clinical Presentations ◽

Increased Risk ◽

Control Study

ABSTRACT Mutations that mediate resistance of Plasmodium falciparum to aminoquinoline antimalarials are selected by prior drug use and may alter parasite fitness, but associations with clinical presentations are uncertain. We evaluated genotypes in samples from a case-control study of determinants of severe malaria in Ugandan children 4 months to 10 years of age. We studied 274 cases with severe malaria matched by age and geography to 275 uncomplicated malaria controls and 179 asymptomatic parasitemic controls. The overall prevalence of mutations of interest (considering mixed results as mutant) was 67.0% for PfCRT K76T, 8.5% for PfMDR1 N86Y, 71.5% for PfMDR1 Y184F, and 14.7% for PfMDR1 D1246Y. Compared to asymptomatic controls, the odds of mutant PfCRT 76T were lower for uncomplicated (odds ratio, 0.42 [95% confidence interval, 0.24 to 0.72]; P < 0.001) or severe (0.56 [0.32 to 0.97]; P = 0.031) malaria; the odds of mutant PfMDR1 86Y were lower for uncomplicated (0.33 [0.16 to 0.65]; P < 0.001) or severe (0.21 [0.09 to 0.45]; P < 0.001) malaria; and the odds of mutant PfMDR1 1246Y were higher for uncomplicated (1.83 [0.90 to 3.98]; P = 0.076) or severe (2.06 [1.01 to 4.55]; P = 0.033) malaria. The odds of mutant PfMDR1 184F were lower in severe than asymptomatic (0.59 [0.37 to 0.92]; P = 0.016) or uncomplicated (0.61 [0.41 to 0.90]; P = 0.009) malaria. Overall, the PfCRT 76T and PfMDR1 86Y mutations were associated with decreased risk of symptomatic malaria, PfMDR1 1246Y was associated with increased risk of symptomatic malaria, and PfMDR1 184F was associated with decreased risk of severe malaria. These results offer insights into parasite genotypes in children with different presentations, although the basis for the identified associations is likely complex.

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Characteristic Age Distribution of Plasmodium vivax Infections after Malaria Elimination on Aneityum Island, Vanuatu

Infection and Immunity ◽

10.1128/iai.00931-13 ◽

2013 ◽

Vol 82 (1) ◽

pp. 243-252 ◽

Cited By ~ 27

Author(s):

Akira Kaneko ◽

Luis F. Chaves ◽

George Taleo ◽

Morris Kalkoa ◽

Rie Isozumi ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Malaria Elimination ◽

Gene Pool ◽

Age Distribution ◽

Age Groups ◽

Antibody Responses ◽

The Other ◽

Content Type ◽

Younger Age ◽

Antibody Levels

ABSTRACTResurgence is a major concern after malaria elimination. After the initiation of the elimination program on Aneityum Island in 1991, microscopy showed thatPlasmodium falciparumdisappeared immediately, whereasP. vivaxdisappeared from 1996 onward, untilP. vivaxcases were reported in January 2002. By conducting malariometric surveys of the entire population of Aneityum, we investigated the age distribution of individuals with parasites during this epidemic in the context of antimalarial antibody levels and parasite antigen diversity. In July 2002,P. vivaxinfections were detected by microscopy in 22/759 individuals: 20/298 born after the beginning of the elimination program in 1991, 2/126 born between 1982 and 1991, and none of 335 born before 1982. PCR increased the number of infections detected to 77, distributed among all age groups. Prevalences were 12.1%, 16.7%, and 6.0%, respectively (P< 0.001). In November, a similar age pattern was found, but with fewer infections: 6/746 and 39/741 individuals were found to be infected by microscopy and PCR, respectively. The frequencies of antibody responses toP. vivaxwere significantly higher in individuals born before 1991 than in younger age groups and were similar to those on Malakula Island, an area of endemicity. Remarkably low antigen diversity (h, 0.15) ofP. vivaxinfections was observed on Aneityum compared with the other islands (h, 0.89 to 1.0). AP. vivaxresurgence was observed among children and teenagers on Aneityum, an age distribution similar to those before elimination and on islands whereP. vivaxis endemic, suggesting that in the absence of significant exposure, immunity may persist, limiting infection levels in adults. The limited parasite gene pool on islands may contribute to this protection.

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Identification of Protective B-Cell Epitopes within the Novel Malaria Vaccine Candidate Plasmodium falciparum Schizont Egress Antigen 1

Clinical and Vaccine Immunology ◽

10.1128/cvi.00068-17 ◽

2017 ◽

Vol 24 (7) ◽

Cited By ~ 4

Author(s):

Christina E. Nixon ◽

Sangshin Park ◽

Sunthorn Pond-Tor ◽

Dipak Raj ◽

Lynn E. Lambert ◽

...

Keyword(s):

Plasmodium Falciparum ◽

B Cell ◽

The Novel ◽

B Cell Epitopes ◽

Content Type ◽

Peptide Microarrays ◽

Malaria Vaccine Candidate ◽

Antibody Levels ◽

Longitudinal Treatment ◽

The Relationship

ABSTRACT Naturally acquired antibodies to Plasmodium falciparum schizont egress antigen 1 (PfSEA-1A) are associated with protection against severe malaria in children. Vaccination of mice with SEA-1A from Plasmodium berghei (PbSEA-1A) decreases parasitemia and prolongs survival following P. berghei ANKA challenge. To enhance the immunogenicity of PfSEA-1A, we identified five linear B-cell epitopes using peptide microarrays probed with antisera from nonhuman primates vaccinated with recombinant PfSEA-1A (rPfSEA-1A). We evaluated the relationship between epitope-specific antibody levels and protection from parasitemia in a longitudinal treatment-reinfection cohort in western Kenya. Antibodies to three epitopes were associated with 16 to 17% decreased parasitemia over an 18-week high transmission season. We are currently designing immunogens to enhance antibody responses to these three epitopes.

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Acquired Antibodies to Merozoite Antigens in Children from Uganda with Uncomplicated or Severe Plasmodium falciparum Malaria

Clinical and Vaccine Immunology ◽

10.1128/cvi.00156-13 ◽

2013 ◽

Vol 20 (8) ◽

pp. 1170-1180 ◽

Cited By ~ 9

Author(s):

Hodan Ahmed Ismail ◽

Ulf Ribacke ◽

Linda Reiling ◽

Johan Normark ◽

Tom Egwang ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Uncomplicated Malaria ◽

Severe Disease ◽

Plasmodium Falciparum Malaria ◽

Antibody Responses ◽

Enzyme Linked Immunosorbent Assay ◽

Content Type ◽

Apical Membrane Antigen 1 ◽

Merozoite Antigens ◽

Erythrocyte Binding

ABSTRACTMalaria can present itself as an uncomplicated or severe disease. We have here studied the quantity and quality of antibody responses against merozoite antigens, as well as multiplicity of infection (MOI), in children from Uganda. We found higher levels of IgG antibodies toward erythrocyte-binding antigen EBA181, MSP2 ofPlasmodium falciparum3D7 and FC27 (MSP2-3D7/FC27), and apical membrane antigen 1 (AMA1) in patients with uncomplicated malaria by enzyme-linked immunosorbent assay (ELISA) but no differences against EBA140, EBA175, MSP1, and reticulocyte-binding protein homologues Rh2 and Rh4 or for IgM against MSP2-3D7/FC27.Patients with uncomplicated malaria were also shown to have higher antibody affinities for AMA1 by surface plasmon resonance (SPR). Decreased invasion of two clinicalP. falciparumisolates in the presence of patient plasma correlated with lower initial parasitemia in the patients, in contrast to comparisons of parasitemia to ELISA values or antibody affinities, which did not show any correlations. Analysis of the heterogeneity of the infections revealed a higher MOI in patients with uncomplicated disease, with theP. falciparumK1 MSP1 (MSP1-K1) and MSP2-3D7 being the most discriminative allelic markers. Higher MOIs also correlated positively with higher antibody levels in several of the ELISAs. In conclusion, certain antibody responses and MOIs were associated with differences between uncomplicated and severe malaria. When different assays were combined, some antibodies, like those against AMA1, seemed particularly discriminative. However, only decreased invasion correlated with initial parasitemia in the patient, signaling the importance of functional assays in understanding development of immunity against malaria and in evaluating vaccine candidates.

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Merozoite Antigens of Plasmodium falciparum Elicit Strain-Transcending Opsonizing Immunity

Infection and Immunity ◽

10.1128/iai.00145-16 ◽

2016 ◽

Vol 84 (8) ◽

pp. 2175-2184 ◽

Cited By ~ 25

Author(s):

Danika L. Hill ◽

Danny W. Wilson ◽

Natalia G. Sampaio ◽

Emily M. Eriksson ◽

Victoria Ryg-Cornejo ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Vaccine Development ◽

Field Isolate ◽

Field Studies ◽

Content Type ◽

Merozoite Antigens ◽

Transgenic Parasites ◽

Highly Correlated ◽

Immunological Assays ◽

Parasite Strains

It is unclear whether naturally acquired immunity toPlasmodium falciparumresults from the acquisition of antibodies to multiple, diverse antigens or to fewer, highly conserved antigens. Moreover, the specific antibody functions required for malaria immunity are unknown, and hence informative immunological assays are urgently needed to address these knowledge gaps and guide vaccine development. In this study, we investigated whether merozoite-opsonizing antibodies are associated with protection from malaria in a strain-specific or strain-transcending manner by using a novel field isolate and an immune plasma-matched cohort from Papua New Guinea with our validated assay of merozoite phagocytosis. Highly correlated opsonization responses were observed across the 15 parasite strains tested, as were strong associations with protection (composite phagocytosis score across all strains in children uninfected at baseline: hazard ratio of 0.15, 95% confidence interval of 0.04 to 0.63). Opsonizing antibodies had a strong strain-transcending component, and the opsonization of transgenic parasites deficient for MSP3, MSP6, MSPDBL1, orP. falciparumMSP1-19 (PfMSP1-19) was similar to that of wild-type parasites. We have provided the first evidence that merozoite opsonization is predominantly strain transcending, and the highly consistent associations with protection against diverse parasite strains strongly supports the use of merozoite opsonization as a correlate of immunity for field studies and vaccine trials. These results demonstrate that conserved domains within merozoite antigens targeted by opsonization generate strain-transcending immune responses and represent promising vaccine candidates.

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Loss of Humoral and Cellular Immunity to Invasive Nontyphoidal Salmonella during Current or Convalescent Plasmodium falciparum Infection in Malawian Children

Clinical and Vaccine Immunology ◽

10.1128/cvi.00057-17 ◽

2017 ◽

Vol 24 (7) ◽

Cited By ~ 5

Author(s):

Tonney S. Nyirenda ◽

James T. Nyirenda ◽

Dumizulu L. Tembo ◽

Janet Storm ◽

Queen Dube ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Cellular Immunity ◽

Bactericidal Activity ◽

Health Centre ◽

Complement C3 ◽

Content Type ◽

Humoral And Cellular Immunity ◽

Increased Risk ◽

Serovar Typhimurium ◽

Malaria Episodes

ABSTRACT Invasive nontyphoidal Salmonella (iNTS) infections are commonly associated with Plasmodium falciparum infections, but the immunologic basis for this linkage is poorly understood. We hypothesized that P. falciparum infection compromises the humoral and cellular immunity of the host to NTS, which increases the susceptibility of the host to iNTS infection. We prospectively recruited children aged between 6 and 60 months at a Community Health Centre in Blantyre, Malawi, and allocated them to the following groups; febrile with uncomplicated malaria, febrile malaria negative, and nonfebrile malaria negative. Levels of Salmonella enterica serovar Typhimurium-specific serum bactericidal activity (SBA) and whole-blood bactericidal activity (WBBA), complement C3 deposition, and neutrophil respiratory burst activity (NRBA) were measured. Levels of SBA with respect to S. Typhimurium were reduced in febrile P. falciparum-infected children (median, −0.20 log10 [interquartile range {IQR}, −1.85, 0.32]) compared to nonfebrile malaria-negative children (median, −1.42 log10 [IQR, −2.0, −0.47], P = 0.052). In relation to SBA, C3 deposition on S. Typhimurium was significantly reduced in febrile P. falciparum-infected children (median, 7.5% [IQR, 4.1, 15.0]) compared to nonfebrile malaria-negative children (median, 29% [IQR, 11.8, 48.0], P = 0.048). WBBA with respect to S. Typhimurium was significantly reduced in febrile P. falciparum-infected children (median, 0.25 log10 [IQR, −0.73, 1.13], P = 0.0001) compared to nonfebrile malaria-negative children (median, −1.0 log10 [IQR, −1.68, −0.16]). In relation to WBBA, S. Typhimurium-specific NRBA was reduced in febrile P. falciparum-infected children (median, 8.8% [IQR, 3.7, 20], P = 0.0001) compared to nonfebrile malaria-negative children (median, 40.5% [IQR, 33, 65.8]). P. falciparum infection impairs humoral and cellular immunity to S. Typhimurium in children during malaria episodes, which may explain the increased risk of iNTS observed in children from settings of malaria endemicity. The mechanisms underlying humoral immunity impairment are incompletely understood and should be explored further.

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