IgG Responses to the Plasmodium falciparum Antigen VAR2CSA in Colombia Are Restricted to Pregnancy and Are Not Induced by Exposure to Plasmodium vivax

Lopez-Perez, Mary; Larsen, Mads Delbo; Bayarri‐Olmos, Rafael; Ampomah, Paulina; Stevenson, Liz; Arévalo‐Herrera, Myriam; Herrera, Sócrates; Hviid, Lars

doi:10.1128/iai.00136-18

Cited by 23 publications

(32 citation statements)

References 57 publications

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“…We included studies that collectively examined a broad range of antibody responses, including to the surface of pRBC isolates from infected placentas, to CSAbinding pRBC strains, and to recombinant VAR2CSA antigens. With respect to the antigens examined, parasite isolates differed in their geographical origin and recombinant antigens varied by allele, domain boundary, and expression system (Additional file 6), potentially impacting variation in antibody reactivity between studies [83,84]. Importantly, the influence of the global genetic diversity of the var2csa gene on antibody reactivity, and consequently, vaccine development, has not been adequately determined [84].…”

Section: Discussionmentioning

confidence: 99%

Pregnancy-specific malarial immunity and risk of malaria in pregnancy and adverse birth outcomes: a systematic review

Cutts

Agius

Lin

et al. 2020

BMC Med

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Background: In endemic areas, pregnant women are highly susceptible to Plasmodium falciparum malaria characterized by the accumulation of parasitized red blood cells (pRBC) in the placenta. In subsequent pregnancies, women develop protective immunity to pregnancy-associated malaria and this has been hypothesized to be due to the acquisition of antibodies to the parasite variant surface antigen VAR2CSA. In this systematic review we provide the first synthesis of the association between antibodies to pregnancy-specific P. falciparum antigens and pregnancy and birth outcomes. Methods: We conducted a systematic review and meta-analysis of population-based studies (published up to 07 June 2019) of pregnant women living in P. falciparum endemic areas that examined antibody responses to pregnancy-specific P. falciparum antigens and outcomes including placental malaria, low birthweight, preterm birth, peripheral parasitaemia, maternal anaemia, and severe malaria. Results: We searched 6 databases and identified 33 studies (30 from Africa) that met predetermined inclusion and quality criteria: 16 studies contributed estimates in a format enabling inclusion in meta-analysis and 17 were included in narrative form only. Estimates were mostly from cross-sectional data (10 studies) and were heterogeneous in terms of magnitude and direction of effect. Included studies varied in terms of antigens tested, methodology used to measure antibody responses, and epidemiological setting. Antibody responses to pregnancyspecific pRBC and VAR2CSA antigens, measured at delivery, were associated with placental malaria (9 studies) and may therefore represent markers of infection, rather than correlates of protection. Antibody responses to pregnancy-specific pRBC, but not recombinant VAR2CSA antigens, were associated with trends towards protection from low birthweight (5 studies). Conclusions: Whilst antibody responses to several antigens were positively associated with the presence of placental and peripheral infections, this review did not identify evidence that any specific antibody response is associated with protection from pregnancy-associated malaria across multiple populations. Further prospective cohort studies using standardized laboratory methods to examine responses to a broad range of antigens in different epidemiological settings and throughout the gestational period, will be necessary to identify and prioritize pregnancy-specific P. falciparum antigens to advance the development of vaccines and serosurveillance tools targeting pregnant women.

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Section: Discussionmentioning

confidence: 99%

Pregnancy-specific malarial immunity and risk of malaria in pregnancy and adverse birth outcomes: a systematic review

Cutts

Agius

Lin

et al. 2020

BMC Med

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“…The full-length ectodomain of the VAR2CSA-type PfEMP1 IT4VAR04 (FV2) was produced in ExpiCHO-S cells as a recombinant C-terminal histidine-tagged protein, as described elsewhere (20).…”

Section: Methodsmentioning

confidence: 99%

Evasion of Classical Complement Pathway Activation on Plasmodium falciparum-Infected Erythrocytes Opsonized by PfEMP1-Specific IgG

et al. 2019

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Members of the PfEMP1 protein family are expressed on the surface of P. falciparum-infected erythrocytes (IEs), where they contribute to the pathogenesis of malaria and are important targets of acquired immunity. Although the PfEMP1-specific antibody response is dominated by the opsonizing and complement-fixing subclasses IgG1 and IgG3, activation of the classical complement pathway by antibody-opsonized IEs does not appear to be a major immune effector mechanism. To study the molecular background for this, we used ELISA and flow cytometry to assess activation of the classical component pathway by recombinant and native PfEMP1 antigen opsonized by polyclonal and monoclonal PfEMP1-specific human IgG. Polyclonal IgG specific for VAR2CSA-type PfEMP1 purified from a pool of human immune plasma efficiently activated the classical complement pathway when bound to recombinant PfEMP1 in ELISA. In contrast, no activation of complement could be detected by flow cytometry when the same IgG preparation was used to opsonize IEs expressing the corresponding native PfEMP1 antigen. After engineering of a VAR2CSA-specific monoclonal antibody to facilitate its on-target hexamerization, complement activation was detectable in an ELISA optimized for uniform orientation of the immobilized antigen. In contrast, the antibody remained unable to activate complement when bound to native VAR2CSA on IEs. Our data suggest that the display of PfEMP1 proteins on IEs is optimized to prevent activation of the classical complement pathway, and thus represents a hitherto unappreciated parasite strategy to evade acquired immunity to malaria.

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“…This topological difference in surface-expressed VAR2CSA by the two parasites was independent of the densities of IE surface knobs, which were similar between the isolates (37). PAM1.4 is a human monoclonal antibody which is specific for an unknown conformational epitope in full-length VAR2CSA (38)(39)(40). It is therefore possible that differential folding of VAR2CSA on NF54 and FCR3 may lead to a difference in PAM1.4 epitopes displayed by the two parasites.…”

Section: Discussionmentioning

confidence: 85%

Functional Antibodies against Placental Malaria Parasites Are Variant Dependent and Differ by Geographic Region

et al. 2019

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During pregnancy, Plasmodium falciparum-infected erythrocytes (IE) accumulate in the intervillous spaces of the placenta by binding to chondroitin sulfate A (CSA) and elicit inflammatory responses that are associated with poor pregnancy outcomes. Primigravidae lack immunity to IE that sequester in the placenta and thus are susceptible to placental malaria (PM). Women become resistant to PM over successive pregnancies as antibodies to placental IE are acquired. Here, we assayed plasma collected at delivery from Malian and Tanzanian women of different parities for total antibody levels against recombinant VAR2CSA antigens (FCR3 allele), and for surface reactivity and binding inhibition and opsonizing functional activities against IE using two CSA-binding laboratory isolates (FCR3 and NF54). Overall, antibody reactivity to VAR2CSA recombinant proteins and to CSA-binding IE was higher in multigravidae than in primigravidae. However, plasma from Malian gravid women reacted more strongly with FCR3 whereas Tanzanian plasma preferentially reacted with NF54. Further, acquisition of functional antibodies was variant dependent: binding inhibition of P. falciparum strain NF54 (P < 0.001) but not of the strain FCR3 increased significantly with parity, while only opsonizing activity against FCR3 (P < 0.001) increased significantly with parity. In addition, opsonizing and binding inhibition activities of plasma of multigravidae were significantly correlated in assays of FCR3 (r = 0.4, P = 0.01) but not of NF54 isolates; functional activities did not correlate in plasma from primigravidae. These data suggest that IE surface-expressed epitopes involved in each functional activity differ among P. falciparum strains. Consequently, geographic bias in circulating strains may impact antibody functions. Our study has implications for the development of PM vaccines aiming to achieve broad protection against various parasite strains.

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IgG Responses to the Plasmodium falciparum Antigen VAR2CSA in Colombia Are Restricted to Pregnancy and Are Not Induced by Exposure to Plasmodium vivax

Cited by 23 publications

References 57 publications

Pregnancy-specific malarial immunity and risk of malaria in pregnancy and adverse birth outcomes: a systematic review

Pregnancy-specific malarial immunity and risk of malaria in pregnancy and adverse birth outcomes: a systematic review

Evasion of Classical Complement Pathway Activation on Plasmodium falciparum-Infected Erythrocytes Opsonized by PfEMP1-Specific IgG

Functional Antibodies against Placental Malaria Parasites Are Variant Dependent and Differ by Geographic Region

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