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

Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality.

peer reviewedDespite advances in COVID-19 management, identifying patients evolving toward death remains challenging. To identify early predictors of mortality within 60 days of symptom onset (DSO), we performed immunovirological assessments on plasma from 279 individuals. On samples collected at DSO11 in a discovery cohort, high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA), low receptor binding domain–specific immunoglobulin G and antibody-dependent cellular cytotoxicity, and elevated cytokines and tissue injury markers were strongly associated with mortality, including in patients on mechanical ventilation. A three-variable model of vRNA, with predefined adjustment by age and sex, robustly identified patients with fatal outcome (adjusted hazard ratio for log-transformed vRNA = 3.5). This model remained robust in independent validation and confirmation cohorts. Since plasma vRNA’s predictive accuracy was maintained at earlier time points, its quantitation can help us understand disease heterogeneity and identify patients who may benefit from new therapies

Antigenicity of the Mu (B.1.621) and A.2.5 SARS-CoV-2 Spikes

The rapid emergence of SARS-CoV-2 variants is fueling the recent waves of the COVID-19 pandemic. Here, we assessed ACE2 binding and antigenicity of Mu (B.1.621) and A.2.5 Spikes. Both these variants carry some mutations shared by other emerging variants. Some of the pivotal mutations such as N501Y and E484K in the receptor-binding domain (RBD) detected in B.1.1.7 (Alpha), B.1.351 (Beta) and P.1 (Gamma) are now present within the Mu variant. Similarly, the L452R mutation of B.1.617.2 (Delta) variant is present in A.2.5. In this study, we observed that these Spike variants bound better to the ACE2 receptor in a temperature-dependent manner. Pseudoviral particles bearing the Spike of Mu were similarly neutralized by plasma from vaccinated individuals than those carrying the Beta (B.1.351) and Delta (B.1.617.2) Spikes. Altogether, our results indicate the importance of measuring critical parameters such as ACE2 interaction, plasma recognition and neutralization ability of each emerging variant

SARS-CoV-2 Spike Expression at the Surface of Infected Primary Human Airway Epithelial Cells

Different serological assays were rapidly generated to study humoral responses against the SARS-CoV-2 Spike glycoprotein. Due to the intrinsic difficulty of working with SARS-CoV-2 authentic virus, most serological assays use recombinant forms of the Spike glycoprotein or its receptor binding domain (RBD). Cell-based assays expressing different forms of the Spike, as well as pseudoviral assays, are also widely used. To evaluate whether these assays recapitulate findings generated when the Spike is expressed in its physiological context (at the surface of the infected primary cells), we developed an intracellular staining against the SARS-CoV-2 nucleocapsid (N) to distinguish infected from uninfected cells. Human airway epithelial cells (pAECs) were infected with authentic SARS-CoV-2 D614G or Alpha variants. We observed robust cell-surface expression of the SARS-CoV-2 Spike at the surface of the infected pAECs using the conformational-independent anti-S2 CV3-25 antibody. The infected cells were also readily recognized by plasma from convalescent and vaccinated individuals and correlated with several serological assays. This suggests that the antigenicity of the Spike present at the surface of the infected primary cells is maintained in serological assays involving expression of the native full-length Spike

Multivariate predictors of malarial infection at double bleed time points diagnosed by light microscopy.

<p>GEE-model based estimates with semi-robust confidence intervals.</p><p>OR: Odds ratio. CI₉₅: 95% confidence intervals</p>1<p>Comparison level: Iliata 1. ² Comparison level: January. ³ Average bed net usage as continuous variable. ⁴Per g/dl increase.</p

Age dependence of risk of malarial illness: Effect of age at start of 8/9 weeks follow-up period on incidence of malarial illness with different parasite cut-offs.

<p>GEE model based estimates and semi-robust standard errors for age categories. Fitted lines: best fitting 1^st, 2^nd or 3^rd degree polynomials of age as continuous variable.</p

Association of personal bed net use on risk of malarial infections and disease.

<p>Closes circles: univariate estimates, open triangle: adjusted for age and time trends, closed diamonds: age, time and village adjusted, open squares: estimates from best fitting model (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009047#pone-0009047-t001" target="_blank">Table 1</a> & <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009047#pone-0009047-t002" target="_blank">2</a>). All estimates from GEE model with semi-robust standard errors.</p

Prevalence of malaria at regular cross-sectional surveys: A) first samples only, B) double bleed samples 24 hrs apart, C) study retention profile.

<p>Prevalence of malaria at regular cross-sectional surveys: A) first samples only, B) double bleed samples 24 hrs apart, C) study retention profile.</p

Multivariate predictors of malarial infection at double bleed time points as diagnosed by post-PCR LDR-FMA assay.

<p>GEE-model based estimates with semi-robust confidence intervals.</p><p>OR: Odds ratio. CI₉₅: 95% confidence intervals</p>1<p>Comparison level: Iliata 1. ² Comparison level: January. ³ Average bed net usage as continuous variable. ⁴Per g/dl increase</p

Incidence of <i>P. falciparum</i> and <i>P. vivax</i> clinical episodes with different parasitaemia threshold for individual 8/9 weekly intervals.

<p>Incidence of <i>P. falciparum</i> and <i>P. vivax</i> clinical episodes with different parasitaemia threshold for individual 8/9 weekly intervals.</p