Placental Malaria: Tackling variants with antibodies

Antibodies targeting the protein that causes placental malaria can recognise multiple variants of the protein, which may help guide the development of new vaccines to protect pregnant women from malaria.
  1. Elizabeth H Aitken
  2. Stephen J Rogerson  Is a corresponding author
  1. Department of Infectious Diseases, Department of Microbiology and Immunology, at the Doherty Institute, University of Melbourne, Australia

Malaria is a serious, potentially life-threatening disease spread by mosquitoes. Pregnant women are especially at risk, as high densities of the parasite that causes malaria can accumulate in the placenta. This can trigger damaging inflammation in the placenta, which could affect the growth and development of the unborn baby, and even lead to a higher risk of infant death (Walker et al., 2014).

The malaria parasites that infect pregnant women are unique in displaying a protein called VAR2CSA on their surface. When VAR2CSA binds to CSA, a molecule on the surface of placenta cells, it leads to placental malaria. Over successive pregnancies, the body develops immunity against placental malaria by generating antibodies targeting VAR2CSA, and preventing it from attaching to CSA (Salanti et al., 2004). This suggests that VAR2CSA vaccines, which mimic the body’s natural defence mechanisms, may be able to provide some protection against placental malaria.

However, the sequences of the gene that codes for VAR2CSA vary between the different parasite strains (Benavente et al., 2018). Two trial vaccines have so far been developed based on sub-parts of the protein, using different variants of VAR2CSA that included an important CSA-binding domain. And although each vaccine candidate worked well against the variant of the protein used, there was little evidence of protection against other variants (Mordmüller et al., 2019; Sirima et al., 2020). Now, in eLife, Patrick Duffy and colleagues at the US National Institute of Allergy and Infectious Diseases – including Justin Doritchamou as first author – investigated whether an antibody could recognise different versions of the full-length VAR2CSA protein from different parasites (Doritchamou et al., 2022).

Doritchamou et al. first mixed five variants of the VAR2CSA protein (one at a time) with a pooled plasma sample from women who were immune to placental malaria. Each time they mixed a single VAR2CSA variant with the plasma, antibodies that bound to that variant were purified out of the pool and quantified. This revealed that most antibodies had bound to the first two variants, suggesting that antibodies towards the latter variants had already been depleted from the pool because they also recognised the earlier variants.

To confirm that antibodies were cross-protective, the researchers then took the antibodies they had purified using one particular VAR2CSA variant and tested their ability to recognise other variants. This revealed that the antibodies that attached to the first VAR2CSA variant were able to recognise all other tested variants. Cross-recognition was seen using purified proteins or using infected red blood cells expressing the variant.

The fact that naturally acquired antibodies against one version of full-length VAR2CSA also react with other variants implies that exposure to a small number of VAR2CSA variants might be enough to provide protection (Figure 1). This finding differs from the group’s previous results using just domains of VAR2CSA, where antibodies for a specific domain from one variant did not bind to other variants (Doritchamou et al., 2016). This suggests that the important antibody target on the protein may only form when the whole protein folds together. However, VAR2CSA is a large molecule and synthesising the amount of complete protein needed for a vaccine would be challenging, especially if multiple variants are required.

Antibody defence in placental malaria.

Placental malaria is caused by an accumulation of parasite-infected red blood cells (red, circled structures) in the placenta. These infected blood cells have a protein (VAR2CSA) that can attach to the CSA protein (green wavy lines) located on the epithelial layer of the placenta (dark pink) (A). Over successive pregnancies, the body develops antibodies (Y-shaped proteins) against VAR2CSA that can prevent the infected red blood cells from binding. However, the genetic code of VAR2CSA proteins can vary (illustrated as differently coloured parasites in the red blood cells), and effective antibodies would need to recognize multiple variants. Doritchamou et al. mixed placental plasma from immune mothers with individual VAR2CSA variants and quantified the number of antibodies bound to each one (blue). They then showed that antibodies bound to one full-length VAR2CSA variant were also able to recognize other VAR2CSA variants (C) and block their binding to CSA. These antibodies were cross protective (B), suggesting that exposure to just a small number of VAR2CSA proteins may be enough to provide protection from placental malaria.

Additionally, naturally occurring antibodies, which lack an attached sugar called fucose, may be more protective than antibodies induced by a placental malaria vaccine, which have this sugar (Larsen et al., 2021). The reasons for this difference are unclear. Perhaps vaccine formulations that better mimic natural antigen presentation, such as providing the full-length protein, would lead to highly active antibodies without fucose, which would be highly desirable.

There is also the question of when is the best time to administer a vaccine. Ideally, immunisation would start in young, adolescent girls, a strategy commonly used for HPV vaccines to prevent cervical cancer. Such a vaccine roll-out would require detailed and ongoing consultation in communities where the vaccine might be used, but saving the lives of young mothers and their babies should be worth every effort.

References

Article and author information

Author details

  1. Elizabeth H Aitken

    Elizabeth H Aitken is in the Department of Infectious Diseases, Department of Microbiology and Immunology, at the Doherty Institute, University of Melbourne, Australia

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2677-6208
  2. Stephen J Rogerson

    Stephen J Rogerson is in the Department of Infectious Diseases, Department of Microbiology and Immunology, at the Doherty Institute, University of Melbourne, Australia

    For correspondence
    sroger@unimelb.edu.au
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4287-1982

Publication history

  1. Version of Record published:

Copyright

© 2022, Aitken and Rogerson

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 913
    views
  • 109
    downloads
  • 1
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Elizabeth H Aitken
  2. Stephen J Rogerson
(2022)
Placental Malaria: Tackling variants with antibodies
eLife 11:e77751.
https://doi.org/10.7554/eLife.77751

Further reading

    1. Immunology and Inflammation
    Zhiyan Wang, Nore Ojogun ... Mingfang Lu
    Research Article

    The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasing worldwide. Since gut-derived bacterial lipopolysaccharides (LPS) can travel via the portal vein to the liver and play an important role in producing hepatic pathology, it seemed possible that (1) LPS stimulates hepatic cells to accumulate lipid, and (2) inactivating LPS can be preventive. Acyloxyacyl hydrolase (AOAH), the eukaryotic lipase that inactivates LPS and oxidized phospholipids, is produced in the intestine, liver, and other organs. We fed mice either normal chow or a high-fat diet for 28 weeks and found that Aoah-/- mice accumulated more hepatic lipid than did Aoah+/+ mice. In young mice, before increased hepatic fat accumulation was observed, Aoah-/- mouse livers increased their abundance of sterol regulatory element-binding protein 1, and the expression of its target genes that promote fatty acid synthesis. Aoah-/- mice also increased hepatic expression of Cd36 and Fabp3, which mediate fatty acid uptake, and decreased expression of fatty acid-oxidation-related genes Acot2 and Ppara. Our results provide evidence that increasing AOAH abundance in the gut, bloodstream, and/or liver may be an effective strategy for preventing or treating MASLD.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Malika Hale, Kennidy K Takehara ... Marion Pepper
    Research Article

    Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here, we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across three donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.