Characterization of Naturally Acquired Immunity to a Panel of Antigens Expressed in Mature P. falciparum Gametocytes.

INTRODUCTION: Naturally acquired immune responses against antigens expressed on the surface of mature gametocytes develop in individuals living in malaria-endemic areas. Evidence suggests that such anti-gametocyte immunity can block the development of the parasite in the mosquito, thus playing a role in interrupting transmission. A better comprehension of naturally acquired immunity to these gametocyte antigens can aid the development of transmission-blocking vaccines and improve our understanding of the human infectious reservoir. METHODS: Antigens expressed on the surface of mature gametocytes that had not previously been widely studied for evidence of naturally acquired immunity were identified for protein expression alongside Pfs230-C using either the mammalian HEK293E or the wheat germ cell-free expression systems. Where there was sequence variation in the candidate antigens (3D7 vs a clinical isolate PfKE04), both variants were expressed. ELISA was used to assess antibody responses against these antigens, as well as against crude stage V gametocyte extract (GE) and AMA1 using archived plasma samples from individuals recruited to participate in malaria cohort studies. We analyzed antibody levels (estimated from optical density units using a standardized ELISA) and seroprevalence (defined as antibody levels greater than three standard deviations above the mean levels of a pool of malaria naïve sera). We described the dynamics of antibody responses to these antigens by identifying factors predictive of antibody levels using linear regression models. RESULTS: Of the 25 antigens selected, seven antigens were produced successfully as recombinant proteins, with one variant antigen, giving a total of eight proteins for evaluation. Antibodies to the candidate antigens were detectable in the study population (N = 216), with seroprevalence ranging from 37.0% (95% CI: 30.6%, 43.9%) for PSOP1 to 77.8% (95% CI: 71.6%, 83.1%) for G377 (3D7 variant). Responses to AMA1 and GE were more prevalent than those to the gametocyte proteins at 87.9% (95% CI: 82.8%, 91.9%) and 88.3% (95% CI: 83.1%, 92.4%), respectively. Additionally, both antibody levels and breadth of antibody responses were associated with age and concurrent parasitaemia. CONCLUSION: Age and concurrent parasitaemia remain important determinants of naturally acquired immunity to gametocyte antigens. Furthermore, we identify novel candidates for transmission-blocking activity evaluation

Age, Spatial, and Temporal Variations in Hospital Admissions with Malaria in Kilifi County, Kenya: A 25-Year Longitudinal Observational Study

Background Encouraging progress has been seen with reductions in Plasmodium falciparum malaria transmission in some parts of Africa. Reduced transmission might lead to increasing susceptibility to malaria among older children, which has implications for ongoing control strategies. Methods and findings We conducted a longitudinal observational study of children admitted to Kilifi County Hospital in Kenya and linked to data on residence and Insecticide Treated Net (ITN) ownership. This included data from 69,104 children admitted to Kilifi County Hospital aged from 3 months to 13 years between 1st January 1990 and 31st December 2014. The variation in malaria slide positivity among admissions was examined in logistic regression models using the predictors; location of residence, calendar time, child’s age, ITN use and Enhanced Vegetation Index (a proxy for soil moisture). The proportion of malaria slide positive admissions declined from 0.56 with 95% confidence interval (95%CI) 0.54 to 0.58 in 1998 to 0.07 95%CI 0.06 to 0.08 in 2009, but then increased again through to 0.24 95%CI 0.22 to 0.25 in 2014. Older children accounted for most of the increase after 2009 (0.035 95%CI (0.030 to 0.040) among young children compared to 0.22 95%CI 0.21 to 0.23 in older children). There was a non-linear relationship between malaria risk and prevalence of ITN use within a 2km radius of an admitted child’s residence such that the predicted malaria positive fraction varied from ~0.4 to <0.1 as the prevalence of ITN use varied from 20% to 80%. In this observational analysis we were unable to determine the cause of the decline in malaria between 1998 and 2009, which pre-dated the dramatic scale-up in ITN distribution and use. Conclusion Following a period of reduced transmission a cohort of older children emerged who have increased susceptibility to malaria. Further reductions in malaria transmission are needed to mitigate against the increasing burden among older children and universal ITN coverage is a promising strategy to achieve this

Identifying models of HIV care and treatment service delivery in Tanzania, Uganda, and Zambia using cluster analysis and Delphi survey.

BACKGROUND: Organization of HIV care and treatment services, including clinic staffing and services, may shape clinical and financial outcomes, yet there has been little attempt to describe different models of HIV care in sub-Saharan Africa (SSA). Information about the relative benefits and drawbacks of different models could inform the scale-up of antiretroviral therapy (ART) and associated services in resource-limited settings (RLS), especially in light of expanded client populations with country adoption of WHO's test and treat recommendation. METHODS: We characterized task-shifting/task-sharing practices in 19 diverse ART clinics in Tanzania, Uganda, and Zambia and used cluster analysis to identify unique models of service provision. We ran descriptive statistics to explore how the clusters varied by environmental factors and programmatic characteristics. Finally, we employed the Delphi Method to make systematic use of expert opinions to ensure that the cluster variables were meaningful in the context of actual task-shifting of ART services in SSA. RESULTS: The cluster analysis identified three task-shifting/task-sharing models. The main differences across models were the availability of medical doctors, the scope of clinical responsibility assigned to nurses, and the use of lay health care workers. Patterns of healthcare staffing in HIV service delivery were associated with different environmental factors (e.g., health facility levels, urban vs. rural settings) and programme characteristics (e.g., community ART distribution or integrated tuberculosis treatment on-site). CONCLUSIONS: Understanding the relative advantages and disadvantages of different models of care can help national programmes adapt to increased client load, select optimal adherence strategies within decentralized models of care, and identify differentiated models of care for clients to meet the growing needs of long-term ART patients who require more complicated treatment management

Regression model prediction and variability explained by the predictors of the model.

<p>Panel A shows the predicted probability of a positive slide result (<i>y</i>-axis) against the prevalence of ITN use in a 2 km radius around each admitted child’s residence (shaded area represents 95% CI). Panel B shows the pseudo R² of the various variables assessed in the extended model (ITN use around a child’s residence, EVI, age, age–time interaction, time, region, and location). We repeated our analysis using a cut-off of >2,500 parasites per μl. The same patterns were seen—i.e., a pattern of a postdecline increase in MPF among older children (<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002047#pmed.1002047.s006" target="_blank">S6 Fig</a>), and an inverse relationship between MPF and age of malaria (r = −0.63, <i>p</i> < 0.001) and a pattern of protection by community-level ITN use (<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002047#pmed.1002047.s007" target="_blank">S7 Fig</a>). These patterns remained statistically significant.</p

Temporal trends of malaria positive fraction (MPF), age of slide positivity, and mortality among acute admissions.

<p>Panel A shows the temporal trend of MPF. Panel B shows the trends of mean age over time for the slide-positive and slide-negative admissions. Panel C shows the temporal trends of absolute number of deaths, and Panel D shows case fatality rates. Shaded areas in panels A, B, and D represent 95% CIs.</p

Temporal trends of MPF by age and parasite prevalence.

<p>Panels A and B show the temporal trends of MPF in admitted children aged ≤ 1 y old and children aged > 1 y old, respectively; the red line represents the southern region, while the blue line represents the northern region of the creek. Panel C shows all age MPF for randomly selected locations from the southern and northern regions. Panel D shows the age-standardized parasite prevalence (i.e., <i>Plasmodium falciparum</i> parasite rate [PfPR_2-10]) among the trauma cases. Shaded areas in panels A, B, and D represent 95% CIs.</p

Flow diagram of participant numbers.

<p>Participant numbers and reasons for exclusion at each stage are shown.</p

Characteristics of the study population.

<p>Characteristics of the study population.</p