Maternally-derived Antibodies to Schizont Egress Antigen-1 and Protection of Infants From Severe Malaria

Abstract

Background: In holoendemic areas, children suffer the most from Plasmodium falciparum malaria, yet newborns and young infants express a relative resistance to both infection and severe malarial disease (SM). This relative resistance has been ascribed to maternally-derived anti-parasite immunoglobulin G; however, the targets of these protective antibodies remain elusive.

Methods: We enrolled 647 newborns at birth from a malaria-holoendemic region of Tanzania. We collected cord blood, measured antibodies to Plasmodium falciparum Schizont Egress Antigen-1 (PfSEA-1), and related these antibodies to the risk of severe malaria in the first year of life. In addition, we vaccinated female mice with PbSEA-1, mated them, and challenged their pups with P. berghei ANKA parasites to assess the impact of maternal PbSEA-1 vaccination on newborns' resistance to malaria.

Results: Children with high cord-blood anti-PfSEA-1 antibody levels had 51.4% fewer cases of SM compared to individuals with lower anti-PfSEA-1 levels over 12 months of follow-up (P = .03). In 3 trials, pups born to PbSEA-1-vaccinated dams had significantly lower parasitemia and longer survival following a P. berghei challenge compared to pups born to control dams.

Conclusions: We demonstrate that maternally-derived, cord-blood anti-PfSEA-1 antibodies predict decreased risk of SM in infants and vaccination of mice with PbSEA-1 prior to pregnancy protects their offspring from lethal P. berghei challenge. These results identify, for the first time, a parasite-specific target of maternal antibodies that protect infants from SM and suggest that vaccination of pregnant women with PfSEA-1 may afford a survival advantage to their offspring.

Keywords: cord blood; malaria; maternal antibodies; vaccine.

Figure 1.

Anti–PfSEA-1 antibody levels are highly correlated in maternal peripheral, placental, and cord-blood compartments. Anti–PfSEA-1 IgG levels were measured by bead-based assays in paired samples from maternal peripheral (n = 581), placental (n = 615), and cord-blood (n = 647) plasma. Abbreviation: PfSEA-1, Plasmodium falciparum Schizont Egress Antigen-1.

Figure 2.

Incidence of severe malaria in Tanzanian children from birth to 12 months of age, dichotomized into those with the highest 10% (n = 64) and lowest 90% (n = 583) levels of anti–PfSEA-1 IgG in cord blood. Bars represent the incidence of severe malaria after adjustment for age, age², parity, average prior parasitemia, and repeated measures within individuals in GEE models. Error bars represent SEM. (A) Total IgG anti–PfSEA-1. (B) IgG₁ anti–PfSEA-1. Abbreviations: GEE, generalized estimating equation; IgG; PfSEA-1, Plasmodium falciparum Schizont Egress Antigen-1; SEM, standard error of the mean.

Figure 3.

Vaccination of female BALB/cJ mice with rPbSEA-1A protects their pups from challenge with P. berghei ANKA. Antibody responses of rPbSEA-1A assayed by bead-based endpoint titration ELISA in vaccinated female mice and their offspring in the (A) first, (D) second, and (G) third trials. The bars represent mean fluorescence; the error bars represent SEMs. Black bars represent anti–rPbSEA-1A IgG responses in female adult mice immunized with rPbSEA-1A or adjuvant alone. The white bars represent anti–rPbSEA-1A IgG responses in their pups. (B) In the first trial, pups born to control dams (Control Litters #1 and #2, total n = 10) had 8.4-fold higher parasitemia on day 9 post-challenge compared to pups born to the PbSEA-1A vaccinated dam (n = 5), who produced high-titer anti–PbSEA-1 antibodies (PbSEA-1 Litter #1, P < .002). Error bars represent SEMs. (C) In the first trial, BALB/cJ pups born to the vaccinated dam who produced high-titer anti–PbSEA-1A (PbSEA-1 Litter #1, n = 5) had 1.67-fold longer median survival times compared to pups born to control dams (Control Litters #1 and #2, total n = 10, P < .001). (E) In the second trial, BALB/cJ pups born to the control dam (Control Litter, n = 4) had 4.8-fold higher parasitemia on day 9 post-challenge (and a 170-fold higher parasitemia on day 17, the day of maximal parasitemia difference) compared to pups born to the 2 PbSEA-1A–vaccinated dams (PbSEA-1 Litters #1 and #2, n = 10, P < .005). Error bars represent SEMs. (F) In the second trial, BALB/cJ pups born to the vaccinated dams had 1.36-fold longer median survival times compared to pups born to the control dam (P < .003). (H) In the third trial, BALB/cJ pups born to the control dam had 27-fold higher parasitemia on day 9 post-challenge compared to pups born to the PbSEA-1A–vaccinated dam (P < .0001). Error bars represent SEMs. (I) In the third trial, BALB/cJ pups born to the vaccinated dam had 1.47-fold longer median survival times compared to pups born to the control dam (P < .001). Abbreviations: IgG, immunoglobulin G; ELISA, enzyme linked immunosorbent assay; PbSEA-1, Plasmodium berghei Schizont Egress Antigen-1; PfSEA-1, Plasmodium falciparum Schizont Egress Antigen-1; SEM, standard error of the mean.