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The investigation of factors associated with susceptibility to severe malaria is best achieved using case-control studies. The presence of a history of severe malaria in controls could affect the quality of their phenotype and study findings and hence should be rigorously determined. Here, we assessed the performance of a qualitative questionnaire to identify a history of cerebral malaria in controls in a case-control study of severe malaria in Mali. We evaluated the archived medical records of 220 children diagnosed with severe diseases at health care centers in rural and urban settings in Mali from 2018 to 2019. Parents of enrolled children were then identified and interviewed using a structured questionnaire by an investigator blinded to the diagnosis. The diagnosis derived from the interview was then compared with the diagnosis from the medical records as the reference diagnosis. The sensitivity and specificity of the questionnaire to detect cerebral malaria in history were, respectively, 84% and 76%. The questionnaire was concordant with the medical record diagnosis in 60% (95% CI: 50-71%) of cases. For other clinical phenotypes of malaria (severe malaria anemia, uncomplicated malaria, and severe malaria anemia concurrent with cerebral malaria), sensitivity and specificity ranged from 42% to 85% and 88% to 96%, respectively. Positive and negative predictive values were, respectively, 75% and 85%. The questionnaire demonstrated suitable sensitivity and specificity to identify cerebral malaria in a participant's history. In sub-Saharan Africa, a region with suboptimal medical record archives, such a tool could be used in case-control studies of severe malaria to select controls.

We used a protein microarray featuring Plasmodium falciparum field variants of a merozoite surface antigen to examine malaria exposure in Malian children with different severe malaria syndromes. Unlike children with cerebral malaria alone or severe malarial anemia alone, those with concurrent cerebral malaria and severe malarial anemia had serologic responses demonstrating a broader prior parasite exposure pattern than matched controls with uncomplicated disease. Comparison of levels of malaria-related cytokines revealed that children with the concurrent phenotype had elevated levels of interleukin (IL)-6, IL-8, and IL-10. Our results suggest that the pathophysiology of this severe subtype is unique and merits further investigation.

Many African countries have reported declines in malaria incidence, attributed to the implementation of control strategies. In Mali, artemisinin-based combination therapy (ACT) was introduced in 2004, and long-lasting insecticide-treated nets (LLINs) have been partially distributed free of charge since 2007. In the Malian town of Bandiagara, a study conducted from 2009 to 2013 showed a stable incidence of malaria compared with 1999, despite the implementation of ACTs and LLINs. Since 2016, seasonal malaria chemoprevention has been scaled up across the country. In addition to these strategies, the population of Bandiagara benefited from indoor residual spray implementation in 2017 and 2018 and continued universal bed net coverage. This study aimed to measure the incidence of malaria in Bandiagara, given this recent scaling up of control strategies. A cohort of 300 children aged 6 months to 15 years was followed up from October 2017 to December 2018. We performed monthly cross-sectional surveys to measure anemia and the prevalence of malaria infection by microscopy. The overall incidence of symptomatic malaria was 0.5 episodes/person-year. Malaria incidence in children up to 5 years old significantly declined since 2012 and since 1999 (incidence rate ratio estimates: 6.7 [95% CI: 4.2-11.4] and 13.5 [95% CI: 8.4-22.7]), respectively. The average prevalence of malaria parasitemia was 6.7%. Malaria incidence was higher in children older than 5 years than in those younger than 5 years, highlighting the need to extend malaria control efforts to these older children.

Minority communities have borne the brunt of COVID-19 disease in the United States. Nonwhites have contracted most of the SARS-CoV-2 infections; COVID-19 mortality rates for Black Americans are more than twice those for whites. Given this, studying the most effective ways to prevent and treat SARS-CoV-2 in these populations should be a research priority, particularly with respect to vaccine trials. Federal guidelines from the National Institutes of Health and Food and Drug Administration emphasize the need for inclusion of minority groups in these trials, but none of the publicly available SARS-CoV-2 vaccine trial protocols requires representative sampling of minorities. This piece emphasizes the importance of adequate inclusion of minority communities in SARS-CoV-2 vaccine trials, and the implications of this inclusion for SARS-CoV-2 vaccine distribution.

As COVID-19 has spread across the globe, quarantines and sheltering-in-place orders have become important public health tools but, as currently implemented, have eroded human rights, particularly for the marginalized, including essential workers, detainees, women, and children. Quarantines and sheltering-in-place orders must include explicit guarantees of human rights protections. We outline protections for the quarantined that communities and governments should strive to guarantee.

Controlled human malaria infection (CHMI) is a powerful tool to evaluate the efficacy of malaria vaccines and pharmacologics. Investigators at the University of Maryland, Baltimore, Center for Vaccine Development (UMB-CVD) pioneered the technique in the 1970s and continue to advance the frontiers of CHMI research. We reviewed the records of 338 malaria-naive volunteers who underwent CHMI at UMB-CVD with Plasmodium falciparum from 1971 until 2017. These 338 volunteers underwent 387 CHMI events, including 60 via intradermal injection or direct venous inoculation (DVI) of purified, cryopreserved sporozoites. No volunteer suffered an unplanned hospitalization or required intravenous therapy related to CHMI. Median prepatency period was longer in challenges using NF54 (9 days) than in those using 7G8 (8 days), P = 0.0006 by the log-rank test. With dose optimization of DVI, the prepatent period did not differ between DVI and mosquito bite challenge (log-rank test, P = 0.66). Polymerase chain reaction (PCR) detected P. falciparum infection 3 days earlier than thick smears ( P < 0.001), and diagnosis by ultrasensitive PCR was associated with less severe symptoms than smear-based diagnosis (39% versus 0%, P = 0.0003). Historical studies with NF54 showed a shorter median prepatency period of 10.3 days than more recent studies (median 11.0 days, P = 0.02) despite significantly lower salivary gland scores in earlier studies, P = 0.0001. The 47-year experience of CHMI at UMB-CVD has led to advancements in sporozoite delivery, diagnostics, and use of heterologous challenge. Additional studies on new challenge strains and genomic data to reflect regional heterogeneity will help advance the use of CHMI as supporting data for vaccine licensure.

In areas of seasonal malaria transmission, the incidence rate of malaria infection is presumed to be near zero at the end of the dry season. Asymptomatic individuals may constitute a major parasite reservoir during this time. We conducted a longitudinal analysis of the spatio-temporal distribution of clinical malaria and asymptomatic parasitemia over time in a Malian town to highlight these malaria transmission dynamics. For a cohort of 300 rural children followed over 2009-2014, periodicity and phase shift between malaria and rainfall were determined by spectral analysis. Spatial risk clusters of clinical episodes or carriage were identified. A nested-case-control study was conducted to assess the parasite carriage factors. Malaria infection persisted over the entire year with seasonal peaks. High transmission periods began 2-3 months after the rains began. A cluster with a low risk of clinical malaria in the town center persisted in high and low transmission periods. Throughout 2009-2014, cluster locations did not vary from year to year. Asymptomatic and gametocyte carriage were persistent, even during low transmission periods. For high transmission periods, the ratio of asymptomatic to clinical cases was approximately 0.5, but was five times higher during low transmission periods. Clinical episodes at previous high transmission periods were a protective factor for asymptomatic carriage, but carrying parasites without symptoms at a previous high transmission period was a risk factor for asymptomatic carriage. Stable malaria transmission was associated with sustained asymptomatic carriage during dry seasons. Control strategies should target persistent low-level parasitemia clusters to interrupt transmission.

Plasmodium vivax was thought to infect only the erythrocytes of Duffy blood group positive people. In the last decade, P. vivax has appeared throughout Africa, both in areas where Duffy positive and negative people live side by side as in Madagascar and Ethiopia and in areas where people are primarily Duffy negative, such as in western Kenya. We performed quantitative polymerase chain reaction on blood samples dried onto filter paper to determine the prevalence of P. vivax and Plasmodium falciparum in a cohort of 300 children (newborn to 6 years of age) in Bandiagara, a Sahelian area of Mali, west Africa, where the people are Duffy negative. We report 1-3 occurrences of P. vivax in each of 25 Duffy-negative children at six time points over two rainy seasons and the beginning of the third season. The prevalence of P. vivax infection was 2.0-2.5% at every time point (June 2009 to June 2010). All children with P. vivax infections were asymptomatic and afebrile, and parasite densities were extremely low. Anemia, however, was the main burden of infection. Plasmodium vivax could become a burden to sub-Saharan Africa, and the evidence of P. vivax existence needs to be taken into consideration in designing malaria control and elimination strategies in Africa.

A community-based immunization coverage survey is the standard way to estimate effective vaccination delivery to a target population in a region. Accompanying serosurveys can provide objective measures of protective immunity against vaccine-preventable diseases but pose considerable challenges with respect to specimen collection and preservation and community compliance. We performed serosurveys coupled to immunization coverage surveys in three administrative districts (woredas) in rural Ethiopia. Critical to the success of this effort were serosurvey equipment and supplies, team composition, and tight coordination with the coverage survey. Application of these techniques to future studies may foster more widespread use of serosurveys to derive more objective assessments of vaccine-derived seroprotection and monitor and compare the performance of immunization services in different districts of a country., (© The American Society of Tropical Medicine and Hygiene.)

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family mediates parasite sequestration in small capillaries through tissue-specific cytoadherence. The best characterized of these proteins is VAR2CSA, which is expressed on the surface of infected erythrocytes that bind to chondroitin sulfate in the placental matrix. Antibodies to VAR2CSA prevent placental cytoadherence and protect against placental malaria. The size and complexity of the VAR2CSA protein pose challenges for vaccine development, but smaller constitutive domains may be suitable for subunit vaccine development. A protein microarray was printed to include five overlapping fragments of the 3D7 VAR2CSA extracellular region. Malian women with a history of at least one pregnancy had antibody recognition of four of these fragments and had stronger reactivity against the two distal fragments than did nulliparous women, children, and men from Mali, suggesting that the C-terminal extracellular VAR2CSA domains are a potential focus of protective immunity. With carefully chosen sera from longitudinal studies of pregnant women, this approach has the potential to identify seroreactive VAR2CSA domains associated with protective immunity against pregnancy-associated malaria., (© The American Society of Tropical Medicine and Hygiene.)

Parasite antigen diversity poses an obstacle to developing an effective malaria vaccine. A protein microarray containing Plasmodium falciparum apical membrane antigen 1 (AMA1, n = 57) and merozoite surface protein 1 19-kD (MSP119, n = 10) variants prevalent at a malaria vaccine testing site in Bandiagara, Mali, was used to assess changes in seroreactivity caused by seasonal and lifetime exposure to malaria. Malian adults had significantly higher magnitude and breadth of seroreactivity to variants of both antigens than did Malian children. Seroreactivity increased over the course of the malaria season in children and adults, but the difference was more dramatic in children. These results help to validate diversity-covering protein microarrays as a promising tool for measuring the breadth of antibody responses to highly variant proteins, and demonstrate the potential of this new tool to help guide the development of malaria vaccines with strain-transcending efficacy., (© The American Society of Tropical Medicine and Hygiene.)