Antibody responses to the full-length VAR2CSA and its DBL domains in Cameroonian children and teenagers

Additional file 2. IgG levels to VAR2CSA domains in 10–15 year old Cameroonian girls living in Ngali II and Ntouessong villages. IgG levels to VAR2CSA DBL domains and full-length protein (FV2) were measured in 11–15 year old girls residing in Ngali II and Ntouessong villages. DBL1 domain was from 3D7 strain and all the other proteins from FCR3 parasite strain. Median MFI and Inter-Quartile Range (IQR) are plotted

Antibody response to var2csa in pregnant Cameroonian women

Ph.D. University of Hawaii at Manoa 2013.Includes bibliographical references.Women are highly susceptible to malaria during pregnancy, because parasites express the VAR2CSA-adhesin that facilitates the binding of infected erythrocytes to placental syncytotrophoblasts, resulting in a condition known as placental malaria. Currently, vaccines to prevent placental malaria are being developed; however, testing vaccines for pregnant women will be challenging in the absence of serological assays that predict protection. This study sought to identify correlates of protection for placental malaria. Plasma from women with ≥ 3 pregnancies were evaluated, allowing us to delineate fine immunologic differences between placental malaria-positive and-negative women. First, we evaluated naturally acquired immunity to a recombinant protein, ID1-ID2a that contains the minimal sequence of VAR2CSA required for binding to the placenta. Our results showed that antibodies to ID1-ID2a were not associated with protection from placental malaria. Next, we employed a multi-assay approach and compared immune responses to full length and different VAR2CSA domains in 24 assays. Data showed that women in their 3rd and 4th pregnancies residing in a low transmission areas were acquiring immunity, and had lower antibody levels to VAR2CSA, recognized fewer VAR2CSA domains, and had lower avidity antibodies to VAR2CSA; whereas, women with ≥5 pregnancies were likely to have malaria only if they had low avidity IgG to VAR2CSA. Multivariate regression models and recursive partitioning methods resulted in Younden index of 0.39 and 0.45, respectively. Since models with different combinations of assays resulted in similar predictive power, it is likely that more than one correlate of protection exists depending on a woman's age, gravidity, exposure to VAR2CSA and antibodies to other malarial antigens. Lastly, we measured how long immunity to VAR2CSA persists. Antibody half-life estimates ranged from 4 years to a lifetime in multigravidae; but, antibodies to VAR2CSA in primigravidae were short lived, averaging less than a year. Thus, a single pregnancy is not sufficient to generate long-lived memory B cells. Knowing what assays correlate with protection and how long after vaccination protective immunity persists is imperative for development of a vaccine

Influence of intermittent preventive treatment on antibodies to VAR2CSA in pregnant Cameroonian women

Intermittent preventive treatment (IPT) and insecticide-treated bed nets are the standard of care for preventing malaria in pregnant women. Since these preventive measures reduce exposure to malaria, their influence on the antibody (Ab) response to the parasite antigen VAR2CSA was evaluated in pregnant Cameroonian women exposed to holoendemic malaria. Ab levels to full-length VAR2CSA (FV2), variants of the six Duffy binding like (DBL) domains, and proportion of high avidity Ab to FV2 were measured longitudinally in 92 women before and 147 women after IPT. As predicted, reduced exposure interfered with acquisition of Ab in primigravidae, with 71% primigravidae being seronegative to FV2 at delivery. Use of IPT for > 13 weeks by multigravidae resulted in 26% of women being seronegative at delivery and a significant reduction in Ab levels to FV2, DBL5, DBL6, proportion of high avidity Ab to FV2, and number of variants recognized. Thus, in women using IPT important immune responses were not acquired by primigravidae and reduced in a portion of multigravidae, especially women with one to two previous pregnancies. Longitudinal data from individual multigravidae on IPT suggest that lower Ab levels most likely resulted from lack of boosting of the VAR2CSA response and not from a short-lived Ab response

Comparison of the specificity of antibodies to VAR2CSA in Cameroonian multigravidae with and without placental malaria:a retrospective case-control study

BACKGROUND: Antibodies (Ab) to VAR2CSA prevent Plasmodium falciparum-infected erythrocytes from sequestrating in the placenta, i.e., prevent placental malaria (PM). The specificity of Ab to VAR2CSA associated with absence of PM is unknown. Accordingly, differences in the specificity of Ab to VAR2CSA were compared between multigravidae with and without PM who had Ab to VAR2CSA. METHODS: In a retrospective case–control study, plasma collected from Cameroonian multigravidae with (n = 96) and without (n = 324) PM were screened in 21 assays that measured antibody levels to full length VAR2CSA (FV2), individual VAR2CSA DBL domains, VAR2CSA domains from different genetic backgrounds (variants), as well as proportion of high avidity Ab to FV2. RESULTS: Multigravidae with and without PM had similar levels of Ab to FV2, the six VAR2CSA DBL domains and different variants, while the proportion of high avidity Ab to FV2 was significantly higher in women without PM at delivery (p = 0.0030) compared to women with PM. In a logistic regression model adjusted for gravidity and age, the percentage of high avidity Ab to FV2 was associated with reduced likelihood of PM in multigravidae. A 5 % increase in proportion of high avidity Ab to FV2 was associated with a nearly 15 % lower likelihood of PM. CONCLUSION: Ab avidity to FV2 may be an important indicator of immunity to PM. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12936-015-1023-6) contains supplementary material, which is available to authorized users

Boletín de Segovia: Número 133 - 1913 noviembre 5

Copia digital. Madrid : Ministerio de Cultura. Subdirección General de Coordinación Bibliotecaria, 200

MOESM2 of Comparison of the specificity of antibodies to VAR2CSA in Cameroonian multigravidae with and without placental malaria: a retrospective case–control study

Additional file 2. Testing mouse anti-human monoclonal antibodies for cross-reactivity (median fluorescent intensities tabulated)

The Antibody Response of Pregnant Cameroonian Women to VAR2CSA ID1-ID2a, a Small Recombinant Protein Containing the CSA-Binding Site

<div><p>In pregnant women, <i>Plasmodium falciparum</i>-infected erythrocytes expressing the VAR2CSA antigen bind to chondroitin sulfate A in the placenta causing placental malaria. The binding site of VAR2CSA is present in the ID1-ID2a region. This study sought to determine if pregnant Cameroonian women naturally acquire antibodies to ID1-ID2a and if antibodies to ID1-ID2a correlate with absence of placental malaria at delivery. Antibody levels to full-length VAR2CSA and ID1-ID2a were measured in plasma samples from 745 pregnant Cameroonian women, 144 Cameroonian men, and 66 US subjects. IgM levels and IgG avidity to ID1-ID2a were also determined. As expected, antibodies to ID1-ID2a were absent in US controls. Although pregnant Cameroonian women developed increasing levels of antibodies to full-length VAR2CSA during pregnancy, no increase in either IgM or IgG to ID1-ID2a was observed. Surprisingly, no differences in antibody levels to ID1-ID2a were detected between Cameroonian men and pregnant women. For example, in rural settings only 8–9% of males had antibodies to full-length VAR2CSA, but 90–96% had antibodies to ID1-ID2a. In addition, no significant difference in the avidity of IgG to ID1-ID2a was found between pregnant women and Cameroonian men, and no correlation between antibody levels at delivery and absence of placental malaria was found. Thus, the response to ID1-ID2a was not pregnancy specific, but predominantly against cross-reactivity epitopes, which may have been induced by other PfEMP1 antigens, malarial antigens, or microbes. Currently, ID1-ID2a is a leading vaccine candidate, since it binds to the CSA with the same affinity as the full-length molecule and elicits binding-inhibitory antibodies in animals. Further studies are needed to determine if the presence of naturally acquired cross-reactive antibodies in women living in malaria endemic countries will alter the response to ID1-ID2a following vaccination with ID1-ID2a.</p></div

IgM levels to FV2 and ID1-ID2a in Cameroonian women.

<p>IgM levels to FV2 and ID1-ID2a (3D7 and FCR3) were measured in plasma collected at first smear-positive visit and the following visit approximately one month later from women living in <b>A</b>) city of Yaoundé (PG n = 17, MG n = 26) and <b>B</b>) village of Ngali II (PG n = 21, MG n = 33). No statistically significant differences in IgM levels to either ID1-ID2a or FV2 were observed between PG and MG in both locations (all p values>0.05). Since the beads were coupled at saturation, it appears that both PG and MG produced higher IgM levels to FV2 compared to ID1-ID2a 3D7 (both locations p-values <0.001). Yaoundé PG and MG produced higher IgM levels to FV2 compared to ID1-ID2a FCR3 (p<0.05). Small ♀- PG, big ♀- MG. Median MFI and IQR are plotted.</p

Impact of HIV-1 infection on the IGF-1 axis and angiogenic factors in pregnant Cameroonian women receiving antiretroviral therapy.

Although mother-to-child transmission of HIV has dramatically declined, the number of in utero HIV-exposed, uninfected infants is on the increase. HIV-exposed infants are at an increased risk of mortality, morbidity and slower early growth than their non-HIV exposed counterparts. Maternal HIV increases the risk of having preterm deliveries, intrauterine growth restriction and low birth weight babies. However, the mechanism underlying dysregulation of fetal growth in HIV-infected pregnant women is unknown. We sought to determine whether maternal HIV is associated with dysregulation of the insulin-like growth factor (IGF) axis, some angiogenic factors or other related biomarkers that regulate fetal growth. A total of 102 normotensive pregnant women were enrolled in a small cross-sectional study. Amongst these were thirty-one HIV-1 positive women receiving combination antiretroviral therapy (cART) (Mean age: 30.0 ± 5.1 years; % on ART: 83.9%; median plasma viral load: 683 copies/ml; median CD4 count: 350 cells/ul) and 71 HIV uninfected women (mean age: 27.3 ± 5.8) recruited at delivery. A panel of biomarkers including IGF1 and IGF binding proteins (IGFBP1, IGFBP3), angiopoietins (ANG) 1 and 2, matrix metalloproteinases (MMP) 2 and 9, and galectin 13, was measured in plasma collected from the placental intervillous space. The levels of IGF1, IGFBP1, ANG1, ANG2, MMP2, MMP9 and Gal-13 were not affected by maternal HIV, even when adjusted for maternal factors in linear regression models (all p>0.05). It was observed that HIV-infection in pregnancy did not significantly affect key markers of the IGF axis and angiogenic factors. If anything, it did not affect women. These findings highlight the importance of the use of ART during pregnancy, which maintains factors necessary for fetal development closer to those of healthy women. However, decrease in IGF1 levels might be exacerbated in women con-infected with HIV and malaria