Strain-Specific Duffy Binding Protein Antibodies Correlate with Protection against Infection with Homologous Compared to Heterologous Plasmodium vivax Strains in Papua New Guinean Children

Abstract

Individuals repeatedly infected with malaria acquire protection from infection and disease; immunity is thought to be primarily antibody-mediated and directed to blood-stage infection. Merozoite surface proteins involved in the invasion of host erythrocytes are likely targets of protective antibodies. We hypothesized that Papua New Guinean children (n ‫؍‬ 206) who acquire high antibody levels to two Plasmodium vivax merozoite proteins, Duffy binding protein region II (PvDBPII) and the 19-kDa C-terminal region of P. vivax merozoite surface protein 1 (PvMSP1 19 ), would have a delay in the time to reinfection following treatment to clear all blood-stage malaria infections. Ninety-four percent of the children were reinfected with P. vivax during biweekly follow-ups for 6 months. Since PvDBPII is polymorphic, we examined whether individuals acquired strain-specific immunity to PvDBPII. Children with high antibody levels to a prevalent PvDBPII allele (O) were associated with a delay in the time to reinfection with the same variant of P. vivax by 25% compared to parasites expressing other PvDBPII alleles (age-adjusted hazard ratio, 0.75 [95% confidence interval, 0.56 to 1.00 by Cox regression]) and 39% lower incidence density parasitemia (P ‫؍‬ 0.01). Two other prevalent alleles (AH and P) showed a similar trend of 16% and 18% protection, respectively, against parasites with the same PvDBPII allele and reduced incidence density parasitemia. Antibodies directed to PvDBPII PNG-P and -O were both associated with a 21 to 26% reduction in the risk of P. vivax infections with higher levels of parasitemia (>150 parasites/l), respectively. There was no association with high antibody levels to PvMSP1 19 and a delay in the time to P. vivax reinfection. Thus, anti-PvDBPII antibodies are associated with strain-specific immunity to P. vivax and support the use of PvDBPII for a vaccine against P. vivax.

Immunological markers of Plasmodium vivax exposure and immunity: a systematic review and meta-analysis

“…The full texts of these 162 studies were examined to determine whether they complied with eligibility criteria: 114 did not meet the inclusion criteria (see Additional file 3), 7 fulfilled the inclusion and quality criteria (Figure 1), and 41 studies potentially met inclusion and quality criteria. The authors of the 41 studies that potentially met inclusion and quality criteria were contacted, yielding a further 11 studies that met inclusion and quality criteria, providing a total of 18 studies that were included in the review [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] (Figure 1). Details of these 18 studies are shown in Table 1.…”

Antibody Responses and Avidity of Naturally Acquired Anti-Plasmodium vivax Duffy Binding Protein (PvDBP) Antibodies in Individuals from an Area with Unstable Malaria Transmission

“…Antibody responses to PvDBP have been shown in endemic populations of P. vivax infection in Papua New Guinea, [23][24][25] Brazil, [26][27][28] and Colombia. 29 In addition, different studies suggested that stronger humoral and cellular immune responses to PvDBP-II develop progressively with increasing age, 22,24,29,30 showing a boosting effect that was likely because of repeated exposures to the infection.…”

Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein

“…In addition, antibodies that engage the dimer interface and/or receptor binding residues of DBL domains are potently neutralizing (9,18,19,31). Polymorphisms in DBP and the presence of multiple strains in endemic regions present unique challenges (32)(33)(34). Analysis of 676 bp within DBP-II revealed 127 polymorphic sites with nucleotide diversity varying between 0.006 and 0.0109, resulting in 193 haplotypes (35).…”

“…Analysis of 676 bp within DBP-II revealed 127 polymorphic sites with nucleotide diversity varying between 0.006 and 0.0109, resulting in 193 haplotypes (35). These factors induce strain-specific protection rather than strain-transcending immunity, which leaves individuals susceptible to continued infection and disease (6,9,17,32,33,36).…”