Natural immunity to malaria preferentially targets the endothelial protein C receptor-binding regions of PfEMP1s.

Antibody responses to variant surface antigens (VSAs) produced by the malaria parasite Plasmodium falciparum may contribute to age-related natural immunity to severe malaria. One VSA family, P. falciparum erythrocyte membrane protein-1 (PfEMP1), includes a subset of proteins that binds endothelial protein C receptor (EPCR) in human hosts and potentially disrupts the regulation of inflammatory responses, which may lead to the development of severe malaria. We probed peptide microarrays containing segments spanning five PfEMP1 EPCR-binding domain variants with sera from 10 Malian adults and 10 children to determine the differences between adult and pediatric immune responses. We defined serorecognized peptides and amino acid residues as those that elicited a significantly higher antibody response than malaria-naïve controls. We aimed to identify regions consistently serorecognized among adults but not among children across PfEMP1 variants, potentially indicating regions that drive the development of immunity to severe malaria. Adult sera consistently demonstrated broader and more intense serologic responses to constitutive PfEMP1 peptides than pediatric sera, including peptides in EPCR-binding domains. Both adults and children serorecognized a significantly higher proportion of EPCR-binding peptides than peptides that do not directly participate in receptor binding, indicating a preferential development of serologic responses at functional residues. Over the course of a single malaria transmission season, pediatric serological responses increased between the start and the peak of the season, but waned as the transmission season ended. IMPORTANCE Severe malaria and death related to malaria disproportionately affect sub-Saharan children under 5 years of age, commonly manifesting as cerebral malaria and/or severe malarial anemia. In contrast, adults in malaria-endemic regions tend to experience asymptomatic or mild disease. Our findings indicate that natural immunity to malaria targets specific regions within the EPCR-binding domain, particularly peptides containing EPCR-binding residues. Epitopes containing these residues may be promising targets for vaccines or therapeutics directed against severe malaria. Our approach provides insight into the development of natural immunity to a binding target linked to severe malaria by characterizing an "adult-like" response as recognizing a proportion of epitopes within the PfEMP1 protein, particularly regions that mediate EPCR binding. This "adult-like" response likely requires multiple years of malaria exposure, as increases in pediatric serologic response over a single malaria transmission season do not appear significant.

Effect of Test and Treat on clinical outcomes in Nigeria: A national retrospective study.

BACKGROUND: In Nigeria, results from the pilot of the Test and Treat strategy showed higher loss to follow up (LTFU) among people living with HIV compared to before its implementation. The aim of this evaluation was to assess the effects of antiretroviral therapy (ART) initiation within 14 days on LTFU at 12 months and viral suppression. METHODS: We conducted a retrospective cohort study using routinely collected de-identified patient-level data hosted on the Nigeria National Data Repository from 1,007 facilities. The study population included people living with HIV age ≥15. We used multivariable Cox proportional frailty hazard models to assess time to LTFU comparing ART initiation strategy and multivariable log-binomial regression for viral suppression. RESULTS: Overall, 26,937 (38.13%) were LTFU at 12 months. Among individuals initiated within 14 days, 38.4% were LTFU by 12 months compared to 35.4% for individuals initiated >14 days (p<0.001). In the adjusted analysis, individuals who were initiated ≤14 days after HIV diagnosis had a higher hazard of being LTFU (aHR 1.15, 95% CI 1.10-1.20) than individuals initiated after 14 days of HIV diagnosis. Among individuals with viral load results, 86.2% were virally suppressed. The adjusted risk ratio for viral suppression among individuals who were initiated ≤14 days compared to >14 days was not statistically significant. CONCLUSION: LTFU was higher among individuals who were initiated within 14 days compared to greater than 14 days after HIV diagnosis. There was no difference for viral suppression. The provision of early tailored interventions to support newly diagnosed people living may contribute to reducing LTFU.

Prevalence of HIV drug resistance in Nigeria: results from a cross-sectional, population-based survey of Nigerian adults with unsuppressed viral load.

BACKGROUND: HIV drug resistance (HIVDR) surveillance is an important tool to monitor threats to progress towards epidemic control. The characterization of HIVDR in Nigeria at the national level is needed to inform both clinical decisions and population-level HIV policy strategies. This study uses data obtained from the Nigeria HIV/AIDS Indicator and Impact Survey (NAIIS) to describe the prevalence and distribution of HIVDR in Nigeria. METHODS: NAIIS was a cross-sectional, population-based survey of households throughout Nigeria in 2018. NAIIS was designed to provide estimates of HIV prevalence and related health indicators from a nationally representative sample. The study population included participants aged 15-64 years who tested positive for HIV, had a viral load at least 1000 copies/ml, and had available HIV drug resistance genotypes. HIV isolates were genotyped to detect drug resistance mutations. Individual characteristics of study participants associated with HIVDR were identified using a weighted multivariable logistic regression model. RESULTS: Of 1355 respondents with available HIV genotypes, 293 (19%) had evidence of drug-resistant mutations (DRMs) that conferred resistance to at least one antiretroviral drug. The majority of DRMs observed conferred resistance to NNRTIs (17.6%) and NRTIs (11.2%). HIVDR was associated with being ART-experienced, longer duration on ART, and lower CD4+ count but not sociodemographic characteristics. CONCLUSION: The population level DRM prevalence in Nigeria was consistent with what would be expected in a mature HIV treatment landscape. The continued roll out of dolutegravir-anchored regimens should mitigate the impact of NNRTI resistance on population viral load suppression and progress towards epidemic control.