Targeting pregnant women to monitor malaria transmission
Targeting pregnant women to monitor malaria transmission
To develop a robust and sensitive serological test for pregnant women at antenatal clinics that can be used to monitor trends of malaria transmission in the community.
Principal Investigator (PI)
Summary of findings
Publication: "Changing Trends in P.falciparum Burden, Immunity, and Disease in Pregnancy" published in The New England Journal of Medicine, 22 October 2015
RATIONALE: The current focus on malaria elimination requires new metrics for malaria transmission intensity, as traditional approaches became logistically complex in contexts of low malaria burden.Malaria-specific antibodies detectable for no more than 6 months following last Plasmodium falciparum infection (i.e. the last high-transmission season) have been suggested as sensitive markers to provide actionable information for malaria elimination activities. Pregnancy-specific antibodies against VAR2CSA (the parasite antigen that binds to Chondroitin Sulphate A in the placenta), have the potential to provide a precise estimation of recent exposure (one pregnancy). Moreover, malaria prevalence in pregnant women was shown to strongly correlate with prevalence of infection detected in children. Overall, these characteristics led us to hypothesize that detection of anti-VAR2CSA antibodies in pregnant women, who are easily accessible through antenatal care clinics (ANCs), could constitute a useful field-deployable approach for malaria surveillance. With this project we aimed at developing a VAR2CSA-based serological assay that could provide information about trends of malaria transmission in different phases of malaria elimination activities.
METHODS: We used a Luminex-based quantitative suspension immunoassay to test 46 peptides covering both conserved and semi-conserved regions of VAR2CSA, three recombinant proteins (DBL3x, DBL5ε, DBL6ε), and non-pregnancy specific malaria antigens from the merozoite (AMA1, MSP119) and the circumsporozoite (CSP). To select antigens with sero-surveillance potential for malaria, IgGs were measured in plasmas, either cryopreserved or eluted from blood spotted onto filter paper, from malaria-exposed pregnant women (Benin [n=864], Gabon [n=131], Mozambique [n=847], Kenya [n=297] and Tanzania [n=31]) and from non-exposed individuals (Spain, [n=203]) recruited between 2003 and 2012. Moreover, the effect of parity and the impact of intermittent preventive treatment during pregnancy (IPTp) on antibodies, were assessed.
RESULTS: We first excluded 21 out of 49 VAR2CSA-derived antigens, which were poorly recognized by plasmas from Mozambican pregnant women with high IgGs against VAR2CSA (native protein in CS2; n=106) or recognized by men from Mozambique (n=102) or Spanish individuals (n=100). From the 28 antigens selected (25 peptides and three recombinant proteins), two peptides were not associated with the expected increase of IgG responses at delivery in women who had a P. falciparum infection during pregnancy (n=49), compared to uninfected women (n=190). IgG levels and seroprevalences against five of the remaining 23 peptides were able to mirror changes of malaria prevalence in Mozambican pregnant women at delivery (n=616; qPCR prevalence of 27% in 2003/4, 2% in 2010 and 6% in 2012), as well as clinical malaria cases from 2003/4 to 2012 in children under five years of age observed at the Manhiça District Hospital (South Mozambique). Seroprevalence against two of the five peptides reflected the pattern of malaria burden in HIV-uninfected women from Benin (n=864, qPCR=41%), Gabon (n=131, qPCR=10%) and Mozambique (n=485, qPCR=6%) during 2010-2012. All pregnant women living in an area from Tanzania where no malaria infection was observed by microscopy (n=31) as well as pregnant women from Barcelona (n=49) were seronegative against the selected peptides. Moreover, IgG levels and seroprevalences against one of the peptides were associated with reductions in exposure to P. falciparum in HIV-uninfected pregnant women who received IPTp with mefloquine compared to those who received IPTp with sulfadoxine-pyrimethamine. In contrast to VAR2CSA recombinant domains, antibodies against the five selected peptides were not observed to increase with parity of the pregnant women, suggesting that antibody responses against peptides were not maintained during successive pregnancies. In HIV-infected women, IgG levels and seroprevalences against one of selected peptides detected differences in the burden of P. falciparum infection among Kenyan (n=297, PCRpw=8%) and Mozambican pregnant women (n=362, PCRpw=3%), but reductions of exposure associated with the use of IPTp with mefloquine compared with placebo were not detected.
CONCLUSION: The pregnancy-specific serology against VAR2CSA-derived peptides provides information on exposure to P falciparum during one pregnancy. IgG levels and seroprevalences against two VAR2CSA peptides were able to detect temporal changes in malaria trends among pregnant women as well as in pediatric malaria admissions, the burden of infection in different settings and the absence of transmission. Moreover, antibodies against one peptide detected the impact of interventions during pregnancy to reduce the parasite prevalence in HIV-uninfected women. This sero-surveillance tool could be used in pregnant women attending ANCs to provide programmatic information about recent changes in the intensity of malaria transmission, as well as to monitor the absence of transmission resulting from elimination activities.