Abstract
Malaria risk is highly heterogeneous. Understanding village and household-level spatial heterogeneity of malaria risk can support a transition to spatially targeted interventions for malaria ...elimination. This analysis uses data from cross-sectional prevalence surveys conducted in 2014 and 2016 in two villages (Megiar and Mirap) in Papua New Guinea. Generalised additive modelling was used to characterise spatial heterogeneity of malaria risk and investigate the contribution of individual, household and environmental-level risk factors. Following a period of declining malaria prevalence, the prevalence of
P. falciparum
increased from 11.4 to 19.1% in Megiar and 12.3 to 28.3% in Mirap between 2014 and 2016, with focal hotspots observed in these villages in 2014 and expanding in 2016. Prevalence of
P. vivax
was similar in both years (20.6% and 18.3% in Megiar, 22.1% and 23.4% in Mirap) and spatial risk heterogeneity was less apparent compared to
P. falciparum
. Within-village hotspots varied by
Plasmodium
species across time and between villages. In Megiar, the adjusted odds ratio (AOR) of infection could be partially explained by household factors that increase risk of vector exposure, such as collecting outdoor surface water as a main source of water. In Mirap, increased AOR overlapped with proximity to densely vegetated areas of the village. The identification of household and environmental factors associated with increased spatial risk may serve as useful indicators of transmission hotspots and inform the development of tailored approaches for malaria control.
...a cost-effectiveness analysis of repellent distribution in the context of a large-scale malaria control and elimination programme was conducted in order to inform policy. Methods Ethics This trial ...is registered in the Australian New Zealand Clinical Trials Registry (ACTRN12616001434482; approved retrospectively 14 October 2016) and was approved by the Ethics Review Committee on Medical Research involving Human Subjects, Department of Medical Research, Ministry of Health and Sports, Myanmar Government (#21/Ethics/2015; extended approval #Ethics/DMR/2016/020), and the Alfred Hospital, Melbourne, Australia (95/15). ...the repellent was provided in plain unbranded tubes, and the investigators registered the trial after completion of fieldwork (but prior to the commencement of data analysis) to minimise public disclosure. In order to determine the number of repellent tubes required to supply a village across the study, the respective village authority provided the village population size, and the number of tubes needed to be stocked was estimated by the in-country study team (2 tubes per person initially and an additional 20%–30% of this total allocation for the VHV-led repellent replacement).
Background. Antibodies targeting blood stage antigens are important in protection against malaria, but the principle targets remain unclear. Erythrocyte-binding antigens (EBAs) are important ...erythrocyte invasion ligands used by merozoites and may be targets of protective immunity, but there are limited data examining their potential importance. Methods. We examined antibodies among 206 Papua New Guinean children who were treated with antimalarials at enrolment and observed prospectively for 6 months for reinfection and malaria. Immunoglobulin (Ig) G, IgG subclasses, and IgM to different regions of EBA175, EBA140, and EBA181 expressed as recombinant proteins were assessed in comparison with several other merozoite antigens. Results. High levels of IgG to each of the EBAs were strongly associated with protection from symptomatic malaria and high density parasitemia, but not with risk of reinfection per se. The predominant IgG subclasses were either IgG1 or IgG3, depending on the antigen. The predominance of IgG1 versus IgG3 reflected structural features of specific regions of the proteins. IgG3 was most strongly associated with protection, even for those antigens that had an IgG1 predominant response. Conclusions. The EBAs appear important targets of acquired protective immunity. These findings support their further development as vaccine candidates.
During pregnancy, immunoglobulin G (IgG) is transferred from the mother to the fetus, providing protection from disease in early infancy. Plasmodium falciparum infections may reduce maternofetal ...antibody transfer efficiency, but mechanisms remain unclear.
Mother-cord paired serum samples collected at delivery from Papua New Guinea (PNG) and the Thailand-Myanmar Border Area (TMBA) were tested for IgG1 and IgG3 to four P. falciparum antigens and measles antigen, as well as total serum IgG. Multivariable linear regression was conducted to assess the association of peripheral P. falciparum infection during pregnancy or placental P. falciparum infection assessed at delivery with maternofetal antibody transfer efficiency. Path analysis assessed the extent to which associations between P. falciparum infection and antibody transfer were mediated by gestational age at delivery or levels of maternal total serum IgG.
Maternofetal antibody transfer efficiency of IgG1 and IgG3 was lower in PNG compared to TMBA (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.88 to 0.09, median of -0.20 log2 units). Placental P. falciparum infections were associated with substantially lower maternofetal antibody transfer efficiency in PNG primigravid women (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.62 to -0.10, median of -0.36 log2 units), but not multigravid women. The lower antibody transfer efficiency amongst primigravid women with placental infection was only partially mediated by gestational age at delivery (proportion indirect effect ranged from 0% to 18%), whereas no mediation effects of maternal total serum IgG were observed.
Primigravid women may be at risk of impaired maternofetal antibody transport with placental P. falciparum infection. Direct effects of P. falciparum on the placenta, rather than earlier gestational age and elevated serum IgG, are likely responsible for the majority of the reduction in maternofetal antibody transfer efficiency with placental infection.
2·6 million stillbirths occur annually worldwide. The association between malaria in pregnancy and stillbirth has yet to be comprehensively quantified. We aimed to quantify the association between ...malaria in pregnancy and stillbirth, and to assess the influence of malaria endemicity on the association.
We did a systematic review of the association between confirmed malaria in pregnancy and stillbirth. We included population-based cross-sectional, cohort, or case-control studies (in which cases were stillbirths or perinatal deaths), and randomised controlled trials of malaria in pregnancy interventions, identified before Feb 28, 2017. We excluded studies in which malaria in pregnancy was not confirmed by PCR, light microscopy, rapid diagnostic test, or histology. The primary outcome was stillbirth. We pooled estimates of the association between malaria in pregnancy and stillbirth using meta-analysis. We used meta-regression to assess the influence of endemicity. The study protocol is registered with PROSPERO, protocol number CRD42016038742.
We included 59 studies of 995 records identified, consisting of 141 415 women and 3387 stillbirths. Plasmodium falciparum malaria detected at delivery in peripheral samples increased the odds of stillbirth (odds ratio OR 1·81 95% CI 1·42–2·30; I2=26·1%; 34 estimates), as did P falciparum detected in placental samples (OR 1·95 1·48–2·57; I2=33·6%; 31 estimates). P falciparum malaria detected and treated during pregnancy was also associated with stillbirth, but to a lesser extent (OR 1·47 95% CI 1·13–1·92; 19 estimates). Plasmodium vivax malaria increased the odds of stillbirth when detected at delivery (2·81 0·77–10·22; three estimates), but not when detected and treated during pregnancy (1·09 0·76–1·57; four estimates). The association between P falciparum malaria in pregnancy and stillbirth was two times greater in areas of low-to-intermediate endemicity than in areas of high endemicity (ratio of ORs 1·96 95% CI 1·34–2·89). Assuming all women with malaria are still parasitaemic at delivery, an estimated 20% of the 1 059 700 stillbirths in malaria-endemic sub-Saharan Africa are attributed to P falciparum malaria in pregnancy; the population attributable fraction decreases to 12%, assuming all women with malaria are treated during pregnancy.
P falciparum and P vivax malaria in pregnancy both increase stillbirth risk. The risk of malaria-associated stillbirth is likely to increase as endemicity declines. There is a pressing need for context-appropriate, evidence-based interventions for malaria in pregnancy in low-endemicity settings.
Australian Commonwealth Government, National Health and Medical Research Council, Australian Research Council.
Acquired antibodies are important in human immunity to malaria, but key targets remain largely unknown. Plasmodium falciparum reticulocyte-binding-homologue-4 (PfRh4) is important for invasion of ...human erythrocytes and may therefore be a target of protective immunity.
IgG and IgG subclass-specific responses against different regions of PfRh4 were determined in a longitudinal cohort of 206 children in Papua New Guinea (PNG). Human PfRh4 antibodies were tested for functional invasion-inhibitory activity, and expression of PfRh4 by P. falciparum isolates and sequence polymorphisms were determined.
Antibodies to PfRh4 were acquired by children exposed to P. falciparum malaria, were predominantly comprised of IgG1 and IgG3 subclasses, and were associated with increasing age and active parasitemia. High levels of antibodies, particularly IgG3, were strongly predictive of protection against clinical malaria and high-density parasitemia. Human affinity-purified antibodies to the binding region of PfRh4 effectively inhibited erythrocyte invasion by P. falciparum merozoites and antibody levels in protected children were at functionally-active concentrations. Although expression of PfRh4 can vary, PfRh4 protein was expressed by most isolates derived from the cohort and showed limited sequence polymorphism.
Evidence suggests that PfRh4 is a target of antibodies that contribute to protective immunity to malaria by inhibiting erythrocyte invasion and preventing high density parasitemia. These findings advance our understanding of the targets and mechanisms of human immunity and evaluating the potential of PfRh4 as a component of candidate malaria vaccines.
Understanding the targets and mechanisms of human immunity to malaria is important for advancing the development of highly efficacious vaccines and serological tools for malaria surveillance. The ...PfRH5 and PfRipr proteins form a complex on the surface of P. falciparum merozoites that is essential for invasion of erythrocytes and are vaccine candidates. We determined IgG subclass responses to these proteins among malaria-exposed individuals in Papua New Guinea and their association with protection from malaria in a longitudinal cohort of children. Cytophilic subclasses, IgG1 and IgG3, were predominant with limited IgG2 and IgG4, and IgG subclass-specific responses were higher in older children and those with active infection. High IgG3 to PfRH5 and PfRipr were significantly and strongly associated with reduced risk of malaria after adjusting for potential confounding factors, whereas associations for IgG1 responses were generally weaker and not statistically significant. Results further indicated that malaria exposure leads to the co-acquisition of IgG1 and IgG3 to PfRH5 and PfRipr, as well as to other PfRH invasion ligands, PfRH2 and PfRH4. These findings suggest that IgG3 responses to PfRH5 and PfRipr may play a significant role in mediating naturally-acquired immunity and support their potential as vaccine candidates and their use as antibody biomarkers of immunity.
Malaria in pregnancy is preventable and contributes significantly to the estimated 5.5 million stillbirths and neonatal deaths that occur annually. The contribution of malaria in pregnancy in areas ...of low transmission has not been quantified, and the roles of maternal anaemia, small-for-gestational-age status, and preterm birth in mediating the effect of malaria in pregnancy on stillbirth and neonatal death are poorly elucidated.
We analysed observational data routinely collected at antenatal clinics on the Thai-Myanmar border (1986-2015). We used Cox regression and sequential mediation analysis to determine the effect of falciparum and vivax malaria in pregnancy on antepartum (death in utero) and intrapartum (death during labour) stillbirth and neonatal mortality as well as mediation through maternal anaemia, preterm birth, and small-for-gestational-age status.
Of 61,836 women, 9350 (15%) had malaria in pregnancy, and 526 (0.8%) had stillbirths. In a sub-set of 9090 live born singletons followed from birth there were 153 (1.7%) neonatal deaths. The hazard of antepartum stillbirth increased 2.24-fold 95% confidence interval: 1.47, 3.41 following falciparum malaria (42% mediated through small-for-gestational-age status and anaemia), driven by symptomatic falciparum malaria (hazard ratio, HR: 2.99 1.83, 4.89) rather than asymptomatic falciparum malaria (HR: 1.35 0.61, 2.96). The hazard of antepartum stillbirth increased 2.21-fold 1.12, 4.33 following symptomatic vivax malaria (24% mediated through small-for-gestational-age status and anaemia) but not asymptomatic vivax malaria (HR: 0.54 0.20, 1.45). There was no association between falciparum or vivax malaria in pregnancy and intrapartum stillbirth (falciparum HR: 1.03 0.58, 1.83; vivax HR: 1.18 0.66, 2.11). Falciparum and vivax malaria in pregnancy increased the hazard of neonatal death 2.55-fold 1.54, 4.22 and 1.98-fold 1.10, 3.57, respectively (40% and 50%, respectively, mediated through small-for-gestational-age status and preterm birth).
Prevention of malaria in pregnancy, new and existing interventions to prevent small-for-gestational-age status and maternal anaemia, and improved capacity for managing preterm and small-for-gestational-age newborns will reduce the number of malaria-associated stillbirths and neonatal deaths in malaria-endemic areas.
Most deaths from severe falciparum malaria occur within 24 h of presentation to a hospital. Intravenous (i.v.) artesunate is the first-line treatment for severe falciparum malaria, but its efficacy ...may be compromised by delayed parasitological responses. In patients with severe malaria, the life-saving benefit of the artemisinin derivatives is their ability to clear circulating parasites rapidly, before they can sequester and obstruct the microcirculation. To evaluate the dosing of i.v. artesunate for the treatment of artemisinin-sensitive and reduced ring stage sensitivity to artemisinin severe falciparum malaria infections, Bayesian pharmacokinetic-pharmacodynamic modeling of data from 94 patients with severe malaria (80 children from Africa and 14 adults from Southeast Asia) was performed. Assuming that delayed parasite clearance reflects a loss of ring stage sensitivity to artemisinin derivatives, the median (95% credible interval) percentage of patients clearing ≥99% of parasites within 24 h (PC24≥99%) for standard (2.4 mg/kg body weight i.v. artesunate at 0 and 12 h) and simplified (4 mg/kg i.v. artesunate at 0 h) regimens was 65% (52.5% to 74.5%) versus 44% (25% to 61.5%) for adults, 62% (51.5% to 74.5%) versus 39% (20.5% to 58.5%) for larger children (≥20 kg), and 60% (48.5% to 70%) versus 36% (20% to 53.5%) for smaller children (<20 kg). The upper limit of the credible intervals for all regimens was below a PC24≥99% of 80%, a threshold achieved on average in clinical studies of severe falciparum malaria infections. In severe falciparum malaria caused by parasites with reduced ring stage susceptibility to artemisinin, parasite clearance is predicted to be slower with both the currently recommended and proposed simplified i.v. artesunate dosing regimens.
Cervical cancer screening is vital for its prevention. Adherence is a crucial indicator that implies the individual willingness to take cervical cancer screening. We aimed to estimate the global and ...regional adherence rates of cervical cancer screening in 2019 and identify its associated factors among general women.
We searched studies in PubMed, Web of Science, Embase, China National Knowledge Infrastructure, Wanfang Database, ProQuest theses database and Google Web, without a lower time limit and until 23 June, 2021. Survey studies were considered eligible if they investigated cervical cancer screening adherence among general women, with data on sample size, the number of adherent subjects, and/or adherence rate. Random-effects were used to pool the odds ratios (ORs) of associated factors of adherence. Using modelling analysis, we estimated 2019 overall and age-specific adherence rates at the global and regional levels in women aged 20-69 years.
Eight thousand two hundred ninety records were identified, and 153 articles were included. Being married (vs not married: OR, 1.34; 95% confidence interval CI: 1.23-1.46), higher educational attainment (higher than high school vs less than high school: OR, 1.44; 95% CI: 1.35-1.53), having healthcare (OR, 1.64; 95% CI: 1.43-1.88), former smoking (OR, 1.20; 95% CI: 1.07-1.34), physical activity (OR, 1.19; 95% CI: 1.05-1.36), parity (OR, 1.07; 95% CI: 1.01-1.12), and chronic disease (OR, 1.17; 95% CI: 1.04-1.32) were associated with better adherence, whereas obesity (vs normal: OR, 0.85; 95% CI: 0.74-0.97) and current smoking (vs former/never: OR, 0.64; 95% CI: 0.54-0.76) were associated with worse adherence. In 2019, the adherence was at 33.66% (95% CI: 23.34-39.30%) worldwide, and was higher in high-income countries (HICs) (75.66, 95% CI: 66.74-82.81%) than in low and middle-income countries (LMICs) (24.91, 95% CI: 14.30-30.24%). It varied across regions, the highest in the European region (65.36, 95% CI: 55.40-74.19%), but the lowest in the African region (5.28, 95% CI: 3.43-8.03%).
Cervical cancer screening adherence remained low globally, exhibiting geographical discrepancy with HICs higher than LMICs. Further implementations of screening programs should comprehensively consider the local economy, social benefits, and demographic structure to adapt delivery for vulnerable or underserved women to boost screening adherence.
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