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Cited by 75Malaria Research and ControlBlood groups and transfusionHemoglobinopathies and Related Disorders

The role of Plasmodium falciparum variant surface antigens in protective immunity and vaccine development

Open access
Hviid, Lars·2010·Human Vaccines
DOI 10.4161/hv.6.1.9602
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Abstract

There is substantial immuno-epidemiological evidence that the parasite-encoded, so-called variant surface antigens (VSAs), such as PfEMP1 on the surface of infected erythrocytes (IEs) are important-in some cases probably decisive determinants of clinical outcome of P. falciparum malaria. The evidence is increasingly being underpinned by specific molecular understanding of the pathogenic processes involved. Pregnancy-associated malaria (PAM) caused by placenta-sequestering IEs expressing the PfEMP1 variant VAR2CSA is a particularly striking example of this. These findings have raised hopes that development of PfEMP1-based vaccines to protect specifically against severe malaria syndromes-in particular PAM-is feasible. This review summarizes the evidence that VSAs are important targets of NAI, discusses why VSA-based vaccines might be feasible despite the extensive intra- and interclonal variation of VSAs, and how vaccines based on this type of antigens fit into the current global strategy to reduce, eliminate and eventually eradicate the burden of malaria.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that *Plasmodium falciparum* variant surface antigens, especially PfEMP1, are central targets of naturally acquired immunity and that vaccines based on “critical” VSAs—particularly VAR2CSA for pregnancy-associated malaria and certain PfEMP1 variants for severe childhood malaria—are feasible. Such VSA-based vaccines could reduce severe morbidity and mortality but are unlikely to interrupt transmission and would be complementary rather than eradication tools.

Key findings

  • VSA-specific antibodies are central to naturally acquired immunity: severe malaria is associated with VSA_SM variants that many young exposed children already recognize, whereas VSA_UM from uncomplicated malaria are less recognized; protection from severe malaria appears after few disease episodes (probably well under ten), before protection from uncomplicated disease and asymptomatic parasitemia.
  • Pregnancy-associated malaria is caused by placenta-sequestering infected erythrocytes expressing VAR2CSA; primigravidae lack VSA_PAM/VAR2CSA-specific antibodies, antibody levels increase with parity, and VSA_PAM-specific IgG correlates with protection from maternal anemia, prematurity, and low birth weight. VAR2CSA is less interclonally variable and has shared epitopes, making it the leading VSA vaccine candidate.
  • VSA appearance in vivo is non-random: in vitro switching is estimated at approximately 2% per generation; experimental infection initially showed diverse *var* gene expression followed by focusing on Group A genes within a couple of parasite multiplication cycles. VSA-based vaccines might have major impact on morbidity and mortality, but limited impact on transmission; untreated nonimmune case mortality may be as high as 25–50%, while endemic-area case fatality is probably well below 1%.

Methods

  • Narrative review; no primary data collection. It synthesizes published immuno-epidemiological, molecular, serological, and longitudinal evidence on *P. falciparum* VSAs/PfEMP1.
  • Main analysis is an interpretive synthesis linking VSA expression, antibody acquisition, disease severity, pregnancy-associated malaria, and vaccine prospects; no systematic review or meta-analysis is described.

Limitations

  • Stated: understanding of which PfEMP1 variants are involved, their receptors, epitopes, and interclonal variability is “fragmentary”; longitudinal evidence for the EMR hierarchy is limited; antibody decline is difficult to assess; and receptor-specificity results from recombinant proteins should be interpreted with caution.
  • Stated: VSA-based vaccines may have limited impact on parasite transmission and cannot be the main tool to eliminate or eradicate malaria.
  • Evident: as a narrative review, it relies on cited studies and does not provide new primary data or a systematic search/quality assessment.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.4161/hv.6.1.9602

Cites

87 of 87 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 68 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Pregnant women are much more at risk of P. falciparum malaria than their non-pregnant peers.

    “Although pregnant woman are much more at risk of P. falciparum malaria than their non-pregnant peers, this susceptibility is highly parity-dependent (decreases with increasing parity).12”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • Premisecitation

    Levels of VSA PAM/VAR2CSA-specific antibodies are highly dependent on parity (increase with increasing parity).

    “The finding that levels of VSA PAM /VAR2CSA-specific antibodies are also highly dependent on parity (increase with increasing parity) suggest that the two phenomena are related.35,49,50,52”
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  • Premisecitation

    P. falciparum-exposed men, nulligravidae, and children do not possess antibodies that can recognize the VSA expressed by placental infected erythrocytes (VSA PAM/VAR2CSA).

    “Perhaps more convincingly, P. falciparum-exposed men, nulligravidae, and children do not possess antibodies that can recognize the VSA expressed by placental IEs (VSA PAM /VAR2CSA), 33,35,49,50”
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  • Interpretationreasoning

    Parasite-encoded variant surface antigens expressed on the surface of infected erythrocytes are of decisive importance to P. falciparum malaria pathogenesis and clinical outcome.

    “These inferences fit well with evidence that the parasite-encoded so-called variant surface antigens (VSAs), which are expressed on the surface of infected erythrocytes (IEs), are of decisive importance to P. falciparum malaria pathogenesis and clinical outcome, and are all-important targets of NAI.”
    Quote in the paperSubstantial claim
  • Premisecitation

    P. falciparum parasites insert electron-dense knobs in the surface membrane of the erythrocytes they infect.

    “P. falciparum parasites insert electron-dense knobs in the surface membrane of the erythrocytes they infect.5,6”
    Quote in the paperSubstantial claim0 of 2 sources checked
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  • May combine two claims. 14
  • Classified as probably not a substantial claim. 2

  • May combine two claims.

    Interpretationreasoning

    Parasites with the placenta-sequestering adhesion phenotype do not appear in non-pregnant individuals-that it is incompatible with their survival in a non-pregnant host.

    “The peculiar adhesion phenotype of placenta-sequestering IEs (see above) suggests that parasites that have this phenotype do not appear in non-pregnant individuals-that it is incompatible with their survival in a non-pregnant host.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Young children remain at high risk of malaria until they acquire their own protective immunity, which takes several years even in areas of intense transmission.

    “Young children are therefore at high risk of malaria until they have acquired their own protective immunity, which takes several years even in areas of intense transmission.4”
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  • May combine two claims.

    Interpretationnone given

    NAI-dependent protection from malaria-related mortality and severe morbidity is achieved earlier than protection from uncomplicated disease, which in turn precedes control over sub-clinical and asymptomatic parasitemia.

    “Importantly, NAI-dependent protection from malaria-related mortality and severe morbidity is achieved earlier than protection from uncomplicated disease, which in turn precedes control over sub-clinical and asymptomatic parasitemia (which is probably never fully achieved).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PAM is characterized by a selective accumulation of infected erythrocytes in the placenta, where they bind to CSA but not to receptors otherwise very commonly used by infected erythrocytes from non-pregnant individuals (e.g., CD36).

    “PAM is characterized by a selective accumulation of IEs in the placenta, where they bind to CSA but not to receptors otherwise very commonly used by IEs from non-pregnant individuals (e.g., CD36).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Such vaccines could potentially have a major impact on the burden of malaria, by preventing parasites from expressing these particular VSAs, and thereby markedly reducing morbidity.

    “Such vaccines could potentially have a major impact on the burden of malaria, by preventing parasites from expressing these particular VSAs, and thereby markedly reducing morbidity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    VSAs and in particular PfEMP1 appear to be the main targets of the NAI, which is acquired during childhood, and which largely restricts mortality and morbidity to small children (apart from PAM).

    “VSAsand in particular to PfEMP1-appear to be the main targets of the NAI, which is acquired during childhood, and which largely restricts mortality and morbidity to small children (apart from PAM, which constitutes an exception, but an exception that further illustrates the importance of PfEMP1-specific immunity).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In many endemic areas, acquisition of NAI means that only a small minority of infections become symptomatic, and an even smaller fraction results in severe or fatal disease-the case fatality rate is probably well below 1%.

    “This is in sharp contrast to the situation in many endemic areas, where acquisition of NAI means that only a small minority of infections become symptomatic, and an even smaller fraction results in severe or fatal disease-the case fatality rate is probably well below 1%.71”
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    Premisecitation

    There is only limited longitudinal evidence of this, but cross-sectional serological and var gene transcription evidence is consistent with this idea.

    “There is only limited, longitudinal evidence of this, 8,9 but cross-sectional serological and var gene transcription evidence is certainly consistent with this idea.[55][56][57][66][67][68]”
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  • May combine two claims.

    Premisecitation

    Severe malaria mainly occurs early in life and it appears to require only few disease episodes (probably well under ten) to acquire protection from severe malaria.

    “This would explain why severe malaria mainly occurs early in life and why it appears to require only few disease episodes (probably well under ten) to acquire protection from severe malaria, 58,59”
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  • May combine two claims.

    Premisecitation

    VAR2CSA contains several DBL domains with specificity for CSA, suggesting that biologically relevant adhesion to CSA involves a critical combination of multiple domains.

    “VAR2CSA contains several DBL domains with specificity for CSA, suggesting that biologically relevant adhesion to CSA involves a critical combination of multiple domains.38,39”
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  • May combine two claims.

    Interpretationreasoning

    Mortality and severe morbidity appears to be caused mainly by parasites expressing a subset of VSAs that exhibit limited interclonal diversity, to which protective immunity is rapidly acquired following exposure.

    “Furthermore, mortality and severe morbidity appears to be caused mainly by parasites expressing a subset of VSAs that exhibit limited interclonal diversity, to which protective immunity is rapidly acquired following exposure.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    VSA-based vaccines would be extremely useful complementary tools in any effort to reduce the burden of malaria.

    “However, such vaccines would be extremely useful complementary tools in any effort to reduce the burden of malaria.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Many fewer P. falciparum-exposed children possess antibodies recognizing VSAs expressed by infected erythrocytes from children with uncomplicated malaria (VSA UM), and levels are generally lower.

    “In contrast, many fewer such children possess antibodies recognizing VSAs expressed by IEs from children with uncomplicated malaria (VSA UM ), and levels are generally lower.[55][56][57]”
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  • May combine two claims.

    Interpretationreasoning

    Severe disease is caused by parasites expressing VSA SM with substantial interclonal similarity, and which dominate early in life and among those with little or no pre-existing immunity.

    “These findings suggest that severe disease is caused by parasites expressing VSA SM with substantial interclonal similarity, and which dominate early in life and among those with little or no pre-existing immunity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Conserved patterns and structures are emerging at a rapid pace, and will assist in the development of PfEMP1-based vaccines aimed specifically at reducing malaria-related childhood mortality and severe morbidity.

    “Nevertheless, conserved patterns and structures are emerging at a rapid pace, and will assist in the development of PfEMP1-based vaccines aimed specifically at reducing malaria-related childhood mortality and severe morbidity.[86][87][88]”
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15 of 15

  • The paper relies on this without support.

    In the absence of treatment, P. falciparum infection is highly likely to progress to severe and life-threatening disease in a nonimmune patient.

    “In the absence of treatment, P. falciparum infection is highly likely to progress to severe and life-threatening disease in a nonimmune patient.”

  • The paper relies on this without support.

    The mortality rate of untreated nonimmune P. falciparum infection may be as high as 25-50%.

    “Although the associated mortality rate is not known, the limited historic evidence that exists indicates that it may be as high as 25-50%.”

  • The authors state this as an assumption.

    EMR varies among VSAs for a given host at a given time, as well as among hosts for a given VSA, leading to an EMR hierarchy of VSAs.

    “The EMR can safely be assumed to vary among VSAs for a given host at a given time, as well as among hosts for a given VSA, leading to an EMR hierarchy of VSAs.”

  • The authors state this as an assumption.

    The immune system focuses on the dominant VSA, whereas minor sub-populations expressing other VSAs are largely ignored.

    “For the sequential change in the EMR hierarchy to operate in the manner outlined above, it must be assumed that the immune system focuses on the dominant VSA, whereas minor sub-populations expressing other VSAs are largely ignored.”

  • The authors state this as an assumption.

    The level of antibodies with specificity for any given VSA declines fairly rapidly as soon as all parasites expressing it are eradicated from the body.

    “The chronicity and gradual drop in virulence and parasitemia would similarly seem to require that the level of antibodies with specificity for any given variant declines fairly rapidly as soon as all parasites expressing it are eradicated from the body.”

  • The authors state this as an assumption.

    The VSA repertoire is vast.

    “despite the assumed vast repertoire of VSAs.”

  • The paper relies on this without support.

    PAM is a major cause of maternal and perinatal morbidity and mortality.

    “PAM is a major cause of maternal and perinatal morbidity and mortality.”

  • The paper relies on this without support.

    Multigravid women are resistant to PAM.

    “multigravid women (who are resistant to PAM)”

  • The paper relies on this without support.

    The main protective mechanism of VAR2CSA-specific antibodies is to block the sequestration of infected erythrocytes in the placenta.

    “the main protective mechanism of these antibodies is to block the sequestration of IEs in the placenta”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Research works printed but not linked: 7

  1. Staalsoe T, Hamad AA, Hviid L, Elhassan IM, Arnot DE, Theander TG. In vivo switching between variant surface antigens in human Plasmodium falci- parum infection. J Infect Dis 2002; 186:719-22.
  2. Fried M, Duffy PE. Adherence of Plasmodium fal- ciparum to chondroitin sulphate A in the human placenta. Science 1996; 272:1502-4.
  3. Barfod L, Bernasconi N, Dahlbäck M, Jarrosay D, Andersen PH, Salanti A, et al. Human pregnancy- associated malaria-specific B cells target polymor- phic, conformational epitopes in VAR2CSA. Mol Microbiol 2007; 63:335-47.
  4. Andersen P, Nielsen MA, Resende M, Rask TS, Dahlbäck M, Theander T, et al. Structural insights into epitopes in the pregnancy-associated malaria protein VAR2CSA. PLoS Pathog 2008; 4:42.
  5. Dahlbäck M, Rask TS, Andersen PH, Nielsen MA, Tuikue-Ndam NG, Resende M, et al. Epitope map- ping and topographic analysis of VAR2CSA DBL3X involved in Plasmodium falciparum placental seques- tration. PLoS Pathog 2006; 2:124.
  6. Staalsoe T, Megnekou R, Fievet N, Ricke CH, Zornig HD, Leke R, et al. Acquisition and decay of antibod- ies to pregnancy-associated variant antigens on the surface of Plasmodium falciparum infected erythro- cytes that are associated with protection against pla- cental parasitemia. J Infect Dis 2001; 184:618-26.
  7. Greenwood BM, Marsh K, Snow R. Why do some children develop severe malaria? Parasitol Today 1991; 7:277-81.

Cited by

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Related

Authors
Hviid, L.
Affiliations
University of Copenhagen (DK)
Corresponding author
Hviid, Lars
ORCID
Hviid, Lars
Venue
Human Vaccines
Publisher
Informa UK Limited
Published
2010-01
Volume
6
Issue
1
Pages
84-89
ISSN
  • 1554-8600 (ISSN-L)
  • 1554-8619
DOI
10.4161/hv.6.1.9602
OpenAlex
W1968977714
Semantic Scholar
dc513318281ff8d3efc1926a47582886b155f0ad
Cited by
75
References
87
Citations by year
2025: 2 · 2024: 1 · 2022: 3 · 2020: 4 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 9 · 2015: 3 · 2014: 9 · 2013: 13 · 2012: 11
FWCI
1.80
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Vaccines (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Health Sciences › Medicine › Hematology › Blood groups and transfusion
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
Keywords
Plasmodium falciparum, variant surface antigens, PfEMP1, VAR2CSA, malaria in pregnancy, protective immunity, malaria vaccine, severe malaria, antigenic variation, malaria eradication
MeSH terms
Antigens, Protozoan, Antigens, Surface, Female, Humans, Plasmodium falciparum, Pregnancy, Pregnancy Complications, Infectious, Protozoan Proteins, Malaria, Falciparum, Malaria Vaccines

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