Antibodies to the Plasmodium falciparum Antigens Circumsporozoite Protein, Thrombospondin-Related Adhesive Protein, and Liver-Stage Antigen 1 Vary by Ages of Subjects and by Season in a Highland Area of Kenya

ABSTRACT Immunoglobulin G (IgG) antibodies to three vaccine candidate preerythrocytic Plasmodium falciparum antigens were evaluated in children and adults in an epidemic-prone highland area of Kenya during rainy (high-transmission) and dry (low-transmission) seasons. The frequencies and median levels of IgG antibodies to circumsporozoite protein (CSP) and thrombospondin-related adhesive protein (TRAP) were compared to the frequencies and median levels of IgG antibodies to liver-stage antigen 1 (LSA-1) reported previously. The frequencies and median levels of IgG antibodies to CSP and TRAP were similar in children and adults in the rainy season, but they were lower in children than in adults in the dry season. The frequencies and median levels of antibodies to LSA-1 were lower in children than in adults in both the rainy and dry seasons. Antibodies to CSP and LSA-1 were primarily members of the IgG1 and IgG3 subclasses, while antibodies to TRAP were primarily members of the IgG3 and IgG4 subclasses. In a treatment-reinfection study following dry season testing, antibodies to TRAP were associated with a trend toward protection from infection in children (P = 0.051) but not in adults. Antibodies to LSA-1 and CSP did not correlate with protection in children or adults. In this highland area of Kenya with unstable transmission, IgG antibodies to preerythrocytic P. falciparum antigens vary in subjects by age and season, and the protective effects of these antibodies against infection may be different in adults and children.

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Faculty Opinions recommendation of Antibodies to the Plasmodium falciparum antigens circumsporozoite protein, thrombospondin-related adhesive protein, and liver-stage antigen 1 vary by ages of subjects and by season in a highland area of Kenya.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.719352138.793500854 ◽

2014 ◽

Author(s):

James Beeson

Keyword(s):

Plasmodium Falciparum ◽

Circumsporozoite Protein ◽

Liver Stage ◽

Highland Area ◽

Adhesive Protein

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Gamma Interferon Responses to Plasmodium falciparum Liver-Stage Antigen 1 and Thrombospondin-Related Adhesive Protein and Their Relationship to Age, Transmission Intensity, and Protection against Malaria

Infection and Immunity ◽

10.1128/iai.72.9.5135-5142.2004 ◽

2004 ◽

Vol 72 (9) ◽

pp. 5135-5142 ◽

Cited By ~ 39

Author(s):

Chandy C. John ◽

Ann M. Moormann ◽

Peter O. Sumba ◽

Ayub V. Ofulla ◽

Daniel C. Pregibon ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Clinical Malaria ◽

Gamma Interferon ◽

Transmission Intensity ◽

Liver Stage ◽

Adhesive Protein ◽

Transmission Area ◽

Ifn Γ ◽

Stable Transmission ◽

Unstable Transmission

ABSTRACT Gamma interferon (IFN-γ) responses to the Plasmodium falciparum antigens liver-stage antigen 1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) are thought to be important in protection against malaria. Optimal methods of testing and the effects of age and transmission intensity on these responses are unknown. IFN-γ responses to LSA-1 and TRAP peptides were assessed by the enzyme-linked immunospot assay (ELISPOT) and enzyme-linked immunosorbent assay (ELISA) in children and adults from areas of stable and unstable malaria transmission in Kenya. Adults in the areas of stable and unstable transmission had similar frequencies and levels of IFN-γ responses to LSA-1 and TRAP as determined by ELISPOT and ELISA. In contrast, IFN-γ responses to the LSA-1 T3 peptide (assessed by ELISPOT) and to any LSA-1 peptide (assessed by ELISA) were less frequent in children in the area of unstable transmission than in children in the area of stable transmission. IFN-γ responses to LSA-1 were more frequently detected by ELISA than by ELISPOT in the stable-transmission area. IFN-γ responses detected by ELISA and ELISPOT did not correlate with each other. In children in the stable-transmission area, IFN-γ responses to LSA-1 peptides assessed by ELISA, but not by ELISPOT, were associated with protection against clinical malaria and anemia. IFN-γ responses to LSA-1 appear to require repeated P. falciparum exposure and/or increased age and, as measured by ELISA, are associated with protection against clinical malaria and anemia.

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Antibody responses to repetitive epitopes of the circumsporozoite protein, liver stage antigen-1, and merozoite surface protein-2 in infants residing in a Plasmodium falciparum-hyperendemic area of western Kenya. XIII. Asembo Bay Cohort Project.

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.2002.66.7 ◽

2002 ◽

Vol 66 (1) ◽

pp. 7-12 ◽

Cited By ~ 21

Author(s):

Z Zhou ◽

B L Nahlen ◽

A A Lal ◽

O H Branch ◽

L Xiao ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Surface Protein ◽

Merozoite Surface Protein ◽

Antibody Responses ◽

Circumsporozoite Protein ◽

Western Kenya ◽

Liver Stage ◽

Hyperendemic Area

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Pre-erythrocytic antibody profiles induced by controlled human malaria infections in healthy volunteers under chloroquine prophylaxis

Scientific Reports ◽

10.1038/srep03549 ◽

2013 ◽

Vol 3 (1) ◽

Cited By ~ 55

Author(s):

Philip L. Felgner ◽

Meta Roestenberg ◽

Li Liang ◽

Christopher Hung ◽

Aarti Jain ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Life Cycle ◽

Healthy Volunteers ◽

Protective Immunity ◽

Circumsporozoite Protein ◽

Blood Stage ◽

Asexual Blood Stage ◽

Liver Stage ◽

Human Malaria ◽

Life Cycle Stages

Abstract Complete sterile protection to Plasmodium falciparum (Pf) infection mediated by pre-erythrocytic immunity can be experimentally induced under chloroquine prophylaxis, through immunization with sporozoites from infected mosquitoes' bites (CPS protocol). To characterize the profile of CPS induced antibody (Ab) responses, we developed a proteome microarray containing 809 Pf antigens showing a distinct Ab profile with recognition of antigens expressed in pre-erythrocytic life-cycle stages. In contrast, plasma from naturally exposed semi-immune individuals from Kenya was skewed toward antibody reactivity against asexual blood stage antigens. CPS-immunized and semi-immune individuals generated antibodies against 192 and 202 Pf antigens, respectively, but only 60 antigens overlapped between the two groups. Although the number of reactive antigens varied between the CPS-immunized individuals, all volunteers reacted strongly against the pre-erythrocytic antigens circumsporozoite protein (CSP) and liver stage antigen 1 (LSA1). Well classified merozoite and erythrocytic antigens were strongly reactive in semi-immune individuals but lacking in the CPS immunized group. These data show that the antibody profile of CPS-immunized and semi-immune groups have quite distinct profiles reflecting their protective immunity; antibodies from CPS immunized individuals react strongly against pre-erythrocytic while semi-immune individuals mainly react against erythrocytic antigens.

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Protective effects of combining monoclonal antibodies and vaccines against the Plasmodium falciparum circumsporozoite protein

PLoS Pathogens ◽

10.1371/journal.ppat.1010133 ◽

2021 ◽

Vol 17 (12) ◽

pp. e1010133

Author(s):

Lawrence T. Wang ◽

Lais S. Pereira ◽

Patience K. Kiyuka ◽

Arne Schön ◽

Neville K. Kisalu ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Monoclonal Antibodies ◽

Polyclonal Antibodies ◽

Passive Transfer ◽

Circumsporozoite Protein ◽

Protective Effects ◽

Repeat Region ◽

Human Mabs ◽

Additional Protection

Combinations of monoclonal antibodies (mAbs) against different epitopes on the same antigen synergistically neutralize many viruses. However, there are limited studies assessing whether combining human mAbs against distinct regions of the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) enhances in vivo protection against malaria compared to each mAb alone or whether passive transfer of PfCSP mAbs would improve protection following vaccination against PfCSP. Here, we isolated a panel of human mAbs against the subdominant C-terminal domain of PfCSP (C-CSP) from a volunteer immunized with radiation-attenuated Pf sporozoites. These C-CSP-specific mAbs had limited binding to sporozoites in vitro that was increased by combination with neutralizing human “repeat” mAbs against the NPDP/NVDP/NANP tetrapeptides in the central repeat region of PfCSP. Nevertheless, passive transfer of repeat- and C-CSP-specific mAb combinations did not provide enhanced protection against in vivo sporozoite challenge compared to repeat mAbs alone. Furthermore, combining potent repeat-specific mAbs (CIS43, L9, and 317) that respectively target the three tetrapeptides (NPDP/NVDP/NANP) did not provide additional protection against in vivo sporozoite challenge. However, administration of either CIS43, L9, or 317 (but not C-CSP-specific mAbs) to mice that had been immunized with R21, a PfCSP-based virus-like particle vaccine that induces polyclonal antibodies against the repeat region and C-CSP, provided enhanced protection against sporozoite challenge when compared to vaccine or mAbs alone. Collectively, this study shows that while combining mAbs against the repeat and C-terminal regions of PfCSP provide no additional protection in vivo, repeat mAbs do provide increased protection when combined with vaccine-induced polyclonal antibodies. These data should inform the implementation of PfCSP human mAbs alone or following vaccination to prevent malaria infection.

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STABILITY OF INTERFERON-γ AND INTERLEUKIN-10 RESPONSES TO PLASMODIUM FALCIPARUM LIVER STAGE ANTIGEN-1 AND THROMBOSPONDIN-RELATED ADHESIVE PROTEIN IN RESIDENTS OF A MALARIA HOLOENDEMIC AREA

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.2006.74.585 ◽

2006 ◽

Vol 74 (4) ◽

pp. 585-590 ◽

Cited By ~ 13

Author(s):

ANN M. MOORMANN ◽

PETER ODADA SUMBA ◽

CHANDY C. JOHN ◽

JAMES W. KAZURA ◽

PAULA EMBURY ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Interleukin 10 ◽

Interferon Γ ◽

Liver Stage ◽

Adhesive Protein

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#63: Antibodies to Peptides Representing Plasmodium falciparum Circumsporozoite Protein Reflect Acquisition of Naturally Acquired Immunity in Malian Adults and Children

Journal of the Pediatric Infectious Diseases Society ◽

10.1093/jpids/piaa170.032 ◽

2021 ◽

Vol 10 (Supplement_1) ◽

pp. S10-S12

Author(s):

DeAnna J Friedman-Klabanoff ◽

Mark A Travassos ◽

Sonia Agrawal ◽

Amed Ouattara ◽

Andrew Pike ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Small Sample Size ◽

Small Sample ◽

Circumsporozoite Protein ◽

Rank Test ◽

Effective Vaccine ◽

Repeat Region ◽

Junctional Region ◽

C Terminus ◽

Adults And Children

Abstract Background An effective vaccine against Plasmodium falciparum, the most common and deadly cause of malaria, is a global priority. Circumsporozoite protein (CSP) is a major P. falciparum vaccine target. Previously recognized CSP epitopes include the immunodominant NANP repeat region, the conserved junction between Region 1 (R1) and the NANP repeats, and the polymorphic Th2R and Th3R in the C-terminus. RTS,S, the most advanced vaccine to date, contains 19 NANP repeats and the C-terminus from the 3D7 parasite clone. CSP-specific monoclonal antibodies to the R1-NANP junctional region showed potent neutralizing activity in vitro and in vivo and are therefore under development for immunoprophylaxis. However, little is known about naturally acquired humoral immunity to precise and diverse epitopes along the CSP sequence, especially in the R1-NANP junctional region. Our goal was to use novel high-throughput tools to examine immunity to diverse CSP epitopes. Methods We probed sera from 10 adults and 10 children from Bandiagara, Mali, a region with intense, seasonal malaria transmission, on a diversity-reflecting peptide microarray. This microarray included 73 CSP variants from reference genomes and field-derived genomic data represented as 16 amino acid (aa) peptides with 12 aa overlap. We used a sliding window-based average smoothing procedure to determine log2 transformed signal intensities (SI) at each aa position. SI and serorecognition, defined as SI >2.5 standard deviations above the mean SI of malaria-naïve controls, were compared. We used the Wilcoxon rank-sum test for comparisons between adults and children and the Wilcoxon signed-rank test for matched comparisons of children over the malaria season, with the Benjamini-Hochberg procedure to control the false discovery rate. Results Adult sera recognized more variants than children at 313 of the 401 positions along CSP, including areas of the R1-NANP junctional region, the NANP repeat region, and the C-terminal Th2R and Th3R epitopes. Adults had higher SI than children to variants in known epitopes, including the R1-NANP junctional region and NANP, but not to a large portion of the 3D7 sequence of Th2R. Across the malaria season, children did not recognize significantly more variants at any one position. However, children had higher SI mid-season when compared with pre-season at a few small epitopes in the R1-NANP junctional region and Th2R. No significant differences existed between SI at any position when comparing post- to mid- or pre-season. Conclusions We identified precise CSP epitopes where serologic responses differed between adults and children and in children over a malaria season in Bandiagara. Adults showed responses to more variants and higher antibody responses at the R1-NANP junctional region and the NANP repeat region, but not to the 3D7 variant sequence in the Th2R epitope, which is included in RTS,S. Children acquired some short-lived immunity to the R1-NANP junctional region and a Th2R epitope during the season but not the NANP repeat region. Our limitations included a small sample size. Next steps include differentiation of immunodominant from protective responses in a larger study with longitudinal infection surveillance data.

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