scholarly journals Allelic variants of full-length VAR2CSA, the placental malaria vaccine candidate, differ in antigenicity and receptor binding affinity

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jonathan P. Renn ◽  
Justin Y. A. Doritchamou ◽  
Bergeline C. Nguemwo Tentokam ◽  
Robert D. Morrison ◽  
Matthew V. Cowles ◽  
...  
Keyword(s):  
Protective Immunity ◽  
Antigenic Variation ◽  
Placental Malaria ◽  
Surface Protein ◽  
Adverse Outcomes ◽  
Full Length ◽  
Clinical Presentations ◽  
Allelic Differences ◽  
Malaria Vaccine Candidate ◽  
Specific Reactivity

AbstractPlasmodium falciparum-infected erythrocytes (IE) sequester in the placenta via surface protein VAR2CSA, which binds chondroitin sulfate A (CSA) expressed on the syncytiotrophoblast surface, causing placental malaria (PM) and severe adverse outcomes in mothers and their offspring. VAR2CSA belongs to the PfEMP1 variant surface antigen family; PfEMP1 proteins mediate IE adhesion and facilitate parasite immunoevasion through antigenic variation. Here we produced deglycosylated (native-like) and glycosylated versions of seven recombinant full-length VAR2CSA ectodomains and compared them for antigenicity and adhesiveness. All VAR2CSA recombinants bound CSA with nanomolar affinity, and plasma from Malian pregnant women demonstrated antigen-specific reactivity that increased with gravidity and trimester. However, allelic and glycosylation variants differed in their affinity to CSA and their serum reactivities. Deglycosylated proteins (native-like) showed higher CSA affinity than glycosylated proteins for all variants except NF54. Further, the gravidity-related increase in serum VAR2CSA reactivity (correlates with acquisition of protective immunity) was absent with the deglycosylated form of atypical M200101 VAR2CSA with an extended C-terminal region. Our findings indicate significant inter-allelic differences in adhesion and seroreactivity that may contribute to the heterogeneity of clinical presentations, which could have implications for vaccine design.

scholarly journals A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates

2021 ◽  
Author(s):  
Justin Y.A. Doritchamou ◽  
Jonathan P. Renn ◽  
Bethany Jenkins ◽  
Michal Fried ◽  
Patrick E. Duffy
Keyword(s):  
Surface Antigen ◽  
Neutralizing Antibodies ◽  
Placental Malaria ◽  
Neutralizing Antibody ◽  
Cross Reactivity ◽  
Full Length ◽  
Broadly Neutralizing Antibodies ◽  
Protective Antibodies ◽  
Broadly Neutralizing Antibody ◽  
Specific Reactivity

Placental malaria (PM) is a deadly syndrome most frequent and severe in first pregnancies. PM results from accumulation of Plasmodium falciparum (Pf)-infected erythrocytes (IE) that express the surface antigen VAR2CSA and bind to chondroitin sulfate A (CSA) in the placenta. Women become PM-resistant over successive pregnancies as they develop anti adhesion and anti-VAR2CSA antibodies, supporting VAR2CSA as the leading PM-vaccine candidate. However, the first VAR2CSA subunit vaccines failed to induce broadly neutralizing antibody and it is still unclear whether naturally acquired protective antibodies target variant or conserved epitopes. This is crucial to determine whether effective vaccines will require incorporation of many or only a single VAR2CSA allele. Here, IgG from multigravidae was sequentially purified on five full-length VAR2CSA ectodomain variants, thereby depleting IgG reactivity to each. The five VAR2CSA variants purified ~0.7% of total IgG and yielded both strain-transcending and strain-specific reactivity to VAR2CSA and IE-surface antigen. IgG purified on the first VAR2CSA antigen displayed broad cross-reactivity to both recombinant and native VAR2CSA variants, and inhibited binding of all isolates to CSA. IgG remaining after depletion on all variants showed significantly reduced binding-inhibition activity compared to initial total IgG. These findings demonstrate that a single VAR2CSA ectodomain variant displays neutralizing epitopes shared by multiple parasites, including maternal isolates, and suggest that a broadly effective PM-vaccine can be achieved with a limited number of VAR2CSA variants.

scholarly journals CD4+ T Lymphocytes from Calves Immunized withAnaplasma marginale Major Surface Protein 1 (MSP1), a Heteromeric Complex of MSP1a and MSP1b, Preferentially Recognize the MSP1a Carboxyl Terminus That Is Conserved among Strains

2001 ◽  
Vol 69 (11) ◽  
pp. 6853-6862 ◽  
Author(s):  
Wendy C. Brown ◽  
Guy H. Palmer ◽  
Harris A. Lewin ◽  
Travis C. McGuire
Keyword(s):  
T Lymphocytes ◽  
T Lymphocyte ◽  
Protective Immunity ◽  
B Lymphocyte ◽  
Surface Protein ◽  
Specific Response ◽  
Major Surface Protein ◽  
Ifn Γ ◽  
Major Surface ◽  
Lymphocyte Responses

ABSTRACT Native major surface protein 1 (MSP1) of the ehrlichial pathogenAnaplasma marginale induces protective immunity in calves challenged with homologous and heterologous strains. MSP1 is a heteromeric complex of a single MSP1a protein covalently associated with MSP1b polypeptides, of which at least two (designated MSP1F1 and MSP1F3) in the Florida strain are expressed. Immunization with recombinant MSP1a and MSP1b alone or in combination fails to provide protection. The protective immunity in calves immunized with native MSP1 is associated with the development of opsonizing and neutralizing antibodies, but CD4+ T-lymphocyte responses have not been evaluated. CD4+ T lymphocytes participate in protective immunity to ehrlichial pathogens through production of gamma interferon (IFN-γ), which promotes switching to high-affinity immunoglobulin G (IgG) and activation of phagocytic cells to produce nitric oxide. Thus, an effective vaccine for A. marginaleand related organisms should contain both T- and B-lymphocyte epitopes that induce a strong memory response that can be recalled upon challenge with homologous and heterologous strains. This study was designed to determine the relative contributions of MSP1a and MSP1b proteins, which contain both variant and conserved amino acid sequences, in stimulating memory CD4+ T-lymphocyte responses in calves immunized with native MSP1. Peripheral blood mononuclear cells and CD4+ T-cell lines from MSP1-immunized calves proliferated vigorously in response to the immunizing strain (Florida) and heterologous strains of A. marginale. The conserved MSP1-specific response was preferentially directed to the carboxyl-terminal region of MSP1a, which stimulated high levels of IFN-γ production by CD4+ T cells. In contrast, there was either weak or no recognition of MSP1b proteins. Paradoxically, all calves developed high titers of IgG antibodies to both MSP1a and MSP1b polypeptides. These findings suggest that in calves immunized with MSP1 heteromeric complex, MSP1a-specific T lymphocytes may provide help to MSP1b-specific B lymphocytes. The data provide a basis for determining whether selected MSP1a CD4+ T-lymphocyte epitopes and selected MSP1a and MSP1b B-lymphocyte epitopes presented on the same molecule can stimulate a protective immune response.

Evaluation of DNA vaccine encoding BCSP31 surface protein of Brucella abortus for protective immunity

2018 ◽  
Vol 125 ◽  
pp. 514-520 ◽  
Author(s):  
Waqar Imtiaz ◽  
Ahrar Khan ◽  
Shafia Tehseen Gul ◽  
Muhammad Saqib ◽  
Muhammad Kashif Saleemi ◽  
...  
Keyword(s):  
Dna Vaccine ◽  
Brucella Abortus ◽  
Protective Immunity ◽  
Surface Protein

scholarly journals Infant sex modifies associations between placental malaria and risk of malaria in infancy

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Abel Kakuru ◽  
Michelle E. Roh ◽  
Richard Kajubi ◽  
Teddy Ochieng ◽  
John Ategeka ◽  
...  
Keyword(s):  
Malaria Incidence ◽  
Placental Malaria ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Adverse Outcomes ◽  
Adjusted Incidence Rate ◽  
Causal Mediation Analysis ◽  
Infant Sex ◽  
Adjusted Incidence

Abstract Background Placental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM. Methods Data from a birth cohort of 656 infants born to HIV-uninfected mothers randomised to IPTp with dihydroartemisinin–piperaquine (DP) or Sulfadoxine–pyrimethamine (SP) was analysed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (> 0–20% high powered fields [HPFs] with pigment), or severe past PM (> 20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM. Results There were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00–1.71, p = 0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89–1.83, p = 0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45–3.25, p < 0.001), but not female infants (aIRR 0.74, 95% CI 0.46–1.20, p = 0.22). There were no significant associations between active PM or mild-moderate past PM and malaria incidence in male or female infants. Male infants born to mothers given IPTp with DP had significantly less malaria in infancy than males born to mothers given SP, and 89.7% of this effect was mediated through prevention of PM. Conclusion PM may have more severe consequences for male infants, and interventions which reduce PM could mitigate these sex-specific adverse outcomes. More research is needed to better understand this sex-bias between PM and infant malaria risk. Trial registration ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622

scholarly journals Association between Protection against Clinical Malaria and Antibodies to Merozoite Surface Antigens in an Area of Hyperendemicity in Myanmar: Complementarity between Responses to Merozoite Surface Protein 3 and the 220-Kilodalton Glutamate-Rich Protein

2004 ◽  
Vol 72 (1) ◽  
pp. 247-252 ◽  
Author(s):  
Soe Soe ◽  
Michael Theisen ◽  
Christian Roussilhon ◽  
Khin-Saw- Aye ◽  
Pierre Druilhe
Keyword(s):  
Protective Immunity ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Clinical Malaria ◽  
Strong Response ◽  
Vaccine Candidates ◽  
Follow Up Study ◽  
Merozoite Surface Protein 1 ◽  
Complementary Effect

ABSTRACT We performed a longitudinal clinical and parasitological follow-up study in OoDo, a village in southeast Asia in which malaria is hyperendemic, in order to assess the association between protection against malaria attacks and antibodies to three currently evaluated vaccine candidates, merozoite surface protein 1 (MSP1), MSP3, and the 220-kDa glutamate-rich protein (GLURP) from Plasmodium falciparum. Our results showed that the levels of cytophilic immunoglobulin G3 (IgG3) antibodies against conserved regions of MSP3 and GLURP were significantly correlated with protection against clinical P. falciparum malaria. In contrast, the levels of noncytophilic IgG4 antibodies against GLURP increased with the number of malaria attacks. Furthermore, we observed a complementary effect of the MSP3- and GLURP-specific IgG3 antibodies in relation to malaria protection. In the individuals that did not respond to one of the antigens, a strong response to the other antigen was consistently detected and was associated with protection, suggesting that induction of antibodies against both MSP3 and GLURP could be important for the development of protective immunity. The complementarity of the responses to the two main targets of antibody-dependent cellular inhibition identified to date provides the first rational basis for combining these two antigens in a hybrid vaccine formulation.

scholarly journals The Plasmodium falciparum circumsporozoite protein produced in Lactococcus lactis is pure and stable

2019 ◽  
Vol 295 (2) ◽  
pp. 403-414 ◽  
Author(s):  
Susheel K. Singh ◽  
Jordan Plieskatt ◽  
Bishwanath Kumar Chourasia ◽  
Vandana Singh ◽  
Judith M. Bolscher ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Lactococcus Lactis ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Expression System ◽  
Surface Protein ◽  
Circumsporozoite Protein ◽  
Full Length

The Plasmodium falciparum circumsporozoite protein (PfCSP) is a sporozoite surface protein whose role in sporozoite motility and cell invasion has made it the leading candidate for a pre-erythrocytic malaria vaccine. However, production of high yields of soluble recombinant PfCSP, including its extensive NANP and NVDP repeats, has proven problematic. Here, we report on the development and characterization of a secreted, soluble, and stable full-length PfCSP (containing 4 NVDP and 38 NANP repeats) produced in the Lactococcus lactis expression system. The recombinant full-length PfCSP, denoted PfCSP4/38, was produced initially with a histidine tag and purified by a simple two-step procedure. Importantly, the recombinant PfCSP4/38 retained a conformational epitope for antibodies as confirmed by both in vivo and in vitro characterizations. We characterized this complex protein by HPLC, light scattering, MS analysis, differential scanning fluorimetry, CD, SDS-PAGE, and immunoblotting with conformation-dependent and -independent mAbs, which confirmed it to be both pure and soluble. Moreover, we found that the recombinant protein is stable at both frozen and elevated-temperature storage conditions. When we used L. lactis–derived PfCSP4/38 to immunize mice, it elicited high levels of functional antibodies that had the capacity to modify sporozoite motility in vitro. We concluded that the reported yield, purity, results of biophysical analyses, and stability of PfCSP4/38 warrant further consideration of using the L. lactis system for the production of circumsporozoite proteins for preclinical and clinical applications in malaria vaccine development.

scholarly journals Effect of Plasmodium yoelii Exposure on Vaccination with the 19-Kilodalton Carboxyl Terminus of Merozoite Surface Protein 1 and Vice Versa and Implications for the Application of a Human Malaria Vaccine

2008 ◽  
Vol 77 (2) ◽  
pp. 817-824 ◽  
Author(s):  
Jiraprapa Wipasa ◽  
Huji Xu ◽  
Xueqin Liu ◽  
Chakrit Hirunpetcharat ◽  
Anthony Stowers ◽  
...  
Keyword(s):  
Malaria Vaccine ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Plasmodium Yoelii ◽  
Natural Immunity ◽  
Vaccine Response ◽  
Malaria Vaccine Candidate ◽  
Current Infection ◽  
Antibody Specificities ◽  
Original Antigenic Sin

ABSTRACT It is well known that exposure to one antigen can modulate the immune responses that develop following exposure to closely related antigens. It is also known that the composition of the repertoire can be skewed to favor epitopes shared between a current infection and a preceding one, a phenomenon referred to as “original antigenic sin.” It was of interest, therefore, to investigate the antibody response that develops following exposure to the malaria vaccine candidate homologue Plasmodium yoelii MSP119 in mice that had previously experienced malaria infection and vice versa. In this study, preexposure of mice to Plasmodium yoelii elicited native anti-MSP119 antibody responses, which could be boosted by vaccination with recombinant MSP119. Likewise, infection of MSP119-primed mice with P. yoelii led to an increase of anti-MSP119 antibodies. However, this increase was at the expense of antibodies to parasite determinants other than MSP119. This change in the balance of antibody specificities significantly affected the ability of mice to withstand a subsequent infection. These data have particular relevance to the possible outcome of malaria vaccination for those situations where the vaccine response is suboptimal and suggest that suboptimal vaccination may in fact render the ultimate acquisition of natural immunity more difficult.

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