Increased risk of low birth weight in women with placental malaria associated with P. falciparum VAR2CSA clade

Abstract

Pregnancy associated malaria (PAM) causes adverse pregnancy and birth outcomes owing to Plasmodium falciparum accumulation in the placenta. Placental accumulation is mediated by P. falciparum protein VAR2CSA, a leading PAM-specific vaccine target. The extent of its antigen diversity and impact on clinical outcomes remain poorly understood. Through amplicon deep-sequencing placental malaria samples from women in Malawi and Benin, we assessed sequence diversity of VAR2CSA’s ID1-DBL2x region, containing putative vaccine targets and estimated associations of specific clades with adverse birth outcomes. Overall, var2csa diversity was high and haplotypes subdivided into five clades, the largest two defined by homology to parasites strains, 3D7 or FCR3. Across both cohorts, compared to women infected with only FCR3-like variants, women infected with only 3D7-like variants delivered infants with lower birthweight (difference: −267.99 g; 95% Confidence Interval [CI]: −466.43 g,−69.55 g) and higher odds of low birthweight (<2500 g) (Odds Ratio [OR] 5.41; 95% CI:0.99,29.52) and small-for-gestational-age (OR: 3.65; 95% CI: 1.01,13.38). In two distinct malaria-endemic African settings, parasites harboring 3D7-like variants of VAR2CSA were associated with worse birth outcomes, supporting differential effects of infection with specific parasite strains. The immense diversity coupled with differential clinical effects of this diversity suggest that an effective VAR2CSA-based vaccine may require multivalent activity.

Matched Placental and Circulating Plasmodium falciparum Parasites are Genetically Homologous at the var2csa ID1-DBL2X Locus by Deep Sequencing

“…31 Mother and newborn demographic and clinical data were recorded 31 and are shown in Supplemental P. falciparum samples. The placental samples used in this study have been previously sequenced by Patel et al, 21 (Genbank accession numbers MF061812-MF061963). Perfused placental blood sampling was performed as described elsewhere, with precautions to minimize contamination with peripheral maternal blood.…”

“…In our previous study of placental parasites in Benin, we found 57 distinct placental haplotypes in 56 pregnant women. 21 Furthermore, most women were infected with more than one haplotype, with a mean number of variants per woman of 1.88 (range: 1-7). 21 Given its sequence diversity, the var2csa gene could serve as a marker to distinguish parasite haplotypes in the different compartments in the context of polyclonal infections.…”

Ultrafast laser writing quill effect in low loss waveguide fabrication regime

“…Kazansky et al suggested quill effect arises from pulse front tilt (PFT) of the writing beam [1], which is supported by following works [3][4][5] and is improved by Salter et al by proving that both PFT and time-invariant focal asymmetry may give rise to quill effect [6]. So far all prior works predominately focused on quill effect arising in laser irradiated regions in fused silica that exhibited damage-like textures and were written well above low-loss-waveguide (LLW) writing regime [1][2][3][4][5][6][7][8][9]. In that damage-resulting writing regime and material, quill effect was clearly visible under a transmission mode microscope but this fabrication regime is not particularly useful for function photonic components.…”

“…Quill effect [1], which manifests as a change in material modification by reversing the writing direction of ultrafast laser direct writing, has been actively studied over the last decade since it was reported by Poumellec et al [2]. Kazansky et al suggested quill effect arises from pulse front tilt (PFT) of the writing beam [1], which is supported by following works [3][4][5] and is improved by Salter et al by proving that both PFT and time-invariant focal asymmetry may give rise to quill effect [6]. So far all prior works predominately focused on quill effect arising in laser irradiated regions in fused silica that exhibited damage-like textures and were written well above low-loss-waveguide (LLW) writing regime [1][2][3][4][5][6][7][8][9].…”

Detection of low-density Plasmodium falciparum infections using amplicon deep sequencing

“…Amplicon analysis in Plasmodium has been adapted to multiple sequencing platforms depending on the desired cost, sample size, and sequence length [3,[9][10][11]. Because of this high resolution and flexibility, amplicon-based methods have been utilized in a range of applications, including studies of allele-specific vaccine efficacy [1], disease severity [10], clearance rate [12], within-host competition [13], relapse rate [9], drug resistance [5][6][7], host selection [8], and population structure [8,14]. Amplicon sequencing has high sensitivity for the detection of minority parasite lineages within an infection, and is of particular interest in longitudinal studies that track intra-host dynamics [3,4].…”