Differential Patterns of Infection and Disease with P. falciparum and P. vivax in Young Papua New Guinean Children

BACKGROUND: Where P. vivax and P. falciparum occur in the same population, the peak burden of P. vivax infection and illness is often concentrated in younger age groups. Experiences from malaria therapy patients indicate that immunity is acquired faster to P. vivax than to P. falciparum challenge. There is however little prospective data on the comparative risk of infection and disease from both species in young children living in co-endemic areas. METHODOLOGY/PRINCIPAL FINDINGS: A cohort of 264 Papua New Guinean children aged 1-3 years (at enrolment) were actively followed-up for Plasmodium infection and febrile illness for 16 months. Infection status was determined by light microscopy and PCR every 8 weeks and at each febrile episode. A generalised estimating equation (GEE) approach was used to analyse both prevalence of infection and incidence of clinical episodes. A more pronounced rise in prevalence of P. falciparum compared to P. vivax infection was evident with increasing age. Although the overall incidence of clinical episodes was comparable (P. falciparum: 2.56, P. vivax 2.46 episodes / child / yr), P. falciparum and P. vivax infectious episodes showed strong but opposing age trends: P. falciparum incidence increased until the age of 30 months with little change thereafter, but incidence of P. vivax decreased significantly with age throughout the entire age range. For P. falciparum, both prevalence and incidence of P. falciparum showed marked seasonality, whereas only P. vivax incidence but not prevalence decreased in the dry season. CONCLUSIONS/SIGNIFICANCE: Under high, perennial exposure, children in PNG begin acquiring significant clinical immunity, characterized by an increasing ability to control parasite densities below the pyrogenic threshold to P. vivax, but not to P. falciparum, in the 2(nd) and 3(rd) year of life. The ability to relapse from long-lasting liver-stages restricts the seasonal variation in prevalence of P. vivax infections

CCR5 Haplotypes and Mother-to-Child HIV Transmission in Malawi

CCR5 and CCR2 gene polymorphisms (SNPs) have been associated with protection against HIV transmission in adults and with delayed progression to AIDS. The CCR5 Delta32 deletion and SNP -2459G are associated with reduced expression of the CCR5 protein.We investigated the association between infant CCR2/CCR5 diplotype and HIV mother to child transmission (MTCT) in Malawi. Blood samples from infants (n = 552) of HIV positive women who received nevirapine were genotyped using a post-PCR multiplex ligase detection reaction and haplotypes were identified based on 8 CCR2/CCR5 SNPs and the open reading frame 32 base pair deletion. Following verification of Hardy-Weinberg equilibrium, log linear regression was performed to examine the association between mutations and MTCT. Overall, protection against MTCT was weakly associated with two CCR5 SNPs, -2459G (Risk ratio [RR], 0.78; confidence interval [CI], 0.54-1.12), and the linked CCR5 -2135T (RR, 0.78; CI, 0.54-1.13). No child carried the CCR5 Delta32 SNP. Maternal Viral Load (MVL) was found to be an effect measure modifier. Among mothers with low MVL, statistically significant protection against MTCT was observed for -2459G (RR, 0.50; CI, 0.27-0.91), and -2135T (RR, 0.51; CI, 0.28-0.92). Statistically significant protection was not found at high MVL.Results from this study suggest that CCR5 SNPs -2459G and -2135T associated with reduced receptor expression protect against MTCT of HIV at low MVLs, whereas high MVLs may over-ride differences in coreceptor availability

Risk ratio modification of MTCT by MVL

*<p>Non carriers of the SNP were denoted as − − and carriers as ++/+−.</p>†<p>The risk ratio (RR) was calculated from log linear regression, where non carriers (− −) were the referent.</p

Effect Measure Modification by MVL.

<p>Carriers of CCR5 -2459G and -2135T with low MVL were protected from MTCT, whereas carriers of -2459G and -2135T with high MVL demonstrated no change in susceptibility to MTCT.</p

Sensitivity analyses for SNP association with MTCT at different time points of follow-up

†<p>The risk ratio (RR) was calculated from log linear regression, where non carriers (− −) were the referent.</p

Imputation Results for 5 imputations (N = 529 per imputation)

†<p>The risk ratio (RR) was calculated from log linear regression, where non carriers (− −) were the referent.</p

Haplotype Frequencies.

<p>Infant haplotype frequencies were calculated for all eligible births.</p

CCR2/CCR5 Haplotypes and abridged phylogenetic tree.

<p>Haplotypes were constructed based on the evolution of linked CCR2 and CCR5 mutations, including a valine to isoleucine substitution at codon 64 in the CCR2b gene (CCR2-64I), CCR5 mutations -2733A→G, -2554 G→T, -2459A→G, -2135C→T, -2132C→T, -2086A→G, -1835C→T, and the delta-32 deletion in the open reading frame of CCR5 (CCR5-ORF).</p

Association between Haplotype/SNP and MTCT

*<p>Non carriers of the haplotype or SNP were denoted as − − and carriers as ++/+−.</p>†<p>The risk ratio (RR) was calculated from log linear regression, where non carriers (− −) were the referent. Maternal CD4 count, maternal age, and mode of delivery were not significantly associated with the SNPs/haplotypes or MTCT. Maternal viral load was significantly associated with MTCT but was not associated with SNPs or haplotypes. Therefore, these covariates were not included as confounders in the regression models.</p