Progress and new horizons toward a VAR2CSA-based placental malaria vaccine

Doritchamou, Justin; Suurbaar, Jennifer; Ndam, Nicaise Tuikue

doi:10.1080/14760584.2021.1878029

Cited by 14 publications

(14 citation statements)

References 114 publications

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“…Our data support the idea that one VAR2CSA variant might induce antibody with broad functional activity, acknowledging the challenges in developing a full-length VAR2CSA-based vaccine (reviewed in Doritchamou et al, 2021 ), including the possibility that non-functional epitopes may interfere with the optimal functional antibody response. It is also possible that the flanking flexible arm composed of DBL5ɛ–6ɛ or DBL5ɛ–7ɛ (in some cases) may play a role in masking functional epitopes on the core (NTS-ID3) structure of VAR2CSA ( Doritchamou et al, 2019 ; Ma et al, 2021 ).…”

Section: Discussionsupporting

confidence: 79%

“…Both trial teams reported that VAR2CSA subunit vaccines were safe, immunogenic and induced functional anti-adhesion antibodies in malaria-naive and malaria-exposed women ( Mordmüller et al, 2019 ; Sirima et al, 2020 ). However, functional activity was primarily against homologous parasites (same VAR2CSA sequence as vaccine) and low or absent against heterologous parasites ( Sirima et al, 2020 ), suggesting the vaccine antigen failed to display functional epitopes shared across multiple P. falciparum variants (reviewed in Doritchamou et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Doritchamou

Renn

Jenkins

et al. 2022

eLife

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Placental malaria (PM) is a deadly syndrome most frequent and severe in first pregnancies. PM results from accumulation of Plasmodium falciparum-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 known that naturally acquired antibodies target both variant-specific and conserved epitopes. It is crucial to determine whether effective vaccines will require incorporation of many or only a single VAR2CSA variants. 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. In two independent antibody purification/depletion experiments with permutated order of VAR2CSA variants, 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 conserved epitopes that are targeted by neutralizing (or binding-inhibitory) antibodies shared by multiple parasite strains, including maternal isolates. This suggests that a broadly effective PM-vaccine can be achieved with a limited number of VAR2CSA variants.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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

Doritchamou

Renn

Jenkins

et al. 2022

eLife

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“…Vaccines to prevent pregnancy-associated malaria is also another option. As the search for an effective candidate continues [ 68 ], such vaccines could target adolescent girls before their first pregnancy. Whether these vaccines would be sufficient on their own or need to be supported by additional interventions such as treated nets needs to be explored.…”

Section: Discussionmentioning

confidence: 99%

Trends of malaria infection in pregnancy in Ghana over the past two decades: a review

Osarfo

Ampofo

Tagbor

2022

Malar J

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Background There has been a global decline in malaria transmission over the past decade. However, not much is known of the impact of this observation on the burden of malaria infection in pregnancy in endemic regions including Ghana. A narrative review was undertaken to help describe trends in malaria infection in pregnancy in Ghana. Among others, such information is important in showing any progress made in malaria in pregnancy control. Methods To describe trends in pregnancy-associated malaria infection in Ghana, a search and review of literature reporting data on the prevalence of asymptomatic Plasmodium falciparum infection in pregnancy was conducted. Results Thirty-six (36) studies, conducted over 1994–2019, were included in the review. In the northern savannah zone with largely seasonal malaria transmission, prevalence appeared to reduce from about 50–60% in 1994–2010 to 13–26% by 2019. In the middle transitional/forest zone, where transmission is perennial with peaks in the rainy season, prevalence apparently reduced from 60% in the late 1990 s to about 5–20% by 2018. In the coastal savannah area, there was apparent reduction from 28 to 35% in 2003–2010 to 5–11% by 2018–2019. The burden of malaria infection in pregnancy continues to be highest among teenagers and younger-aged pregnant women and paucigravidae. Conclusions There appears to be a decline in asymptomatic parasite prevalence in pregnancy in Ghana though this has not been uniform across the different transmission zones. The greatest declines were noticeably in urban settings. Submicroscopic parasitaemia remains a challenge for control efforts. Further studies are needed to evaluate the impact of the reduced parasite prevalence on maternal anaemia and low birthweight and to assess the local burden of submicroscopic parasitaemia in relation to pregnancy outcomes.

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“…Notably, most of the binding-inhibition activity to CSA-binding parasites was depleted on the first variant (NF54) and the resulting IgG purified on NF54 demonstrated straintranscending blocking activity to all isolates tested in this study. This finding suggests that one VAR2CSA variant might induce antibody with broadly neutralizing activity, acknowledging the challenges in developing a full-length vaccine (reviewed in (Doritchamou et al, 2021)), including the possibility that non-functional epitopes may interfere with the optimal functional antibody response. It is also possible that the flanking flexible arm composed of DBL5ɛ-6ɛ or DBL5ɛ-7ɛ (in some cases) may play a role in masking functional epitopes on the core (NTS-ID3) structure of VAR2CSA (Doritchamou et al, 2019;Ma et al, 2021).…”

Section: Discussionmentioning

confidence: 80%

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

Doritchamou

Renn

Jenkins

et al. 2021

Preprint

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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.

show abstract

Progress and new horizons toward a VAR2CSA-based placental malaria vaccine

Cited by 14 publications

References 114 publications

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

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

Trends of malaria infection in pregnancy in Ghana over the past two decades: a review

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

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