Does behavior mediate the effect of weather on SARS-CoV-2 transmission? evidence from cell-phone data.

There is growing evidence that weather alters SARS-CoV-2 transmission, but it remains unclear what drives the phenomenon. One prevailing hypothesis is that people spend more time indoors in cooler weather, leading to increased spread of SARS-CoV-2 related to time spent in confined spaces and close contact with others. However, the evidence in support of that hypothesis is limited and, at times, conflicting. We use a mediation framework, and combine daily weather, COVID-19 hospital surveillance, cellphone-based mobility data and building footprints to estimate the relationship between daily indoor and outdoor weather conditions, mobility, and COVID-19 hospitalizations. We quantify the direct health impacts of weather on COVID-19 hospitalizations and the indirect effects of weather via time spent indoors away-from-home on COVID-19 hospitalizations within five Colorado counties between March 4th 2020 and January 31st 2021. We also evaluated the evidence for seasonal effect modification by comparing the results of all-season (using season as a covariate) to season-stratified models. Four weather conditions were associated with both time spent indoors away-from-home and 12-day lagged COVID-19 hospital admissions in one or more season: high minimum temperature (all-season), low maximum temperature (spring), low minimum absolute humidity (winter), and high solar radiation (all-season & winter). In our mediation analyses, we found evidence that changes in 12-day lagged hospital admissions were primarily via the direct effects of weather conditions, rather than via indirect effects by which weather changes time spent indoors away-from-home. Our findings do not support the hypothesis that weather impacted SARS-CoV-2 transmission via changes in mobility patterns during the first year of the pandemic. Rather, weather appears to have impacted SARS-CoV-2 transmission primarily via mechanisms other than human movement. We recommend further analysis of this phenomenon to determine whether these findings generalize to current SARS-CoV-2 transmission dynamics, as well as other seasonal respiratory pathogens.

Does behavior mediate the effect of weather on SARS-CoV-2 transmission? Evidence from cell-phone data.

Background: There is growing evidence that weather alters SARS-CoV-2 transmission, but it remains unclear what drives the phenomenon. One prevailing hypothesis is that people spend more time indoors in cooler weather, leading to increased spread of SARS-CoV-2 related to time spent in confined spaces and close contact with others. However, the evidence in support of that hypothesis is limited and, at times, conflicting. Objectives: We aim to evaluate the extent to which weather impacts COVID-19 via time spent away-from-home in indoor spaces, as compared to a direct effect of weather on COVID-19 hospitalization, independent of mobility. Methods: We use a mediation framework, and combine daily weather, COVID-19 hospital surveillance, cellphone-based mobility data and building footprints to estimate the relationship between daily indoor and outdoor weather conditions, mobility, and COVID-19 hospitalizations. We quantify the direct health impacts of weather on COVID-19 hospitalizations and the indirect effects of weather via time spent indoors away-from-home on COVID-19 hospitalizations within five Colorado counties between March 4th 2020 and January 31st 2021. Results: We found evidence that changes in 12-day lagged hospital admissions were primarily via the direct effects of weather conditions, rather than via indirect effects by which weather changes time spent indoors away-from-home. Sensitivity analyses evaluating time at home as a mediator were consistent with these conclusions. Discussion: Our findings do not support the hypothesis that weather impacted SARS-CoV-2 transmission via changes in mobility patterns during the first year of the pandemic. Rather, weather appears to have impacted SARS-CoV-2 transmission primarily via mechanisms other than human movement. We recommend further analysis of this phenomenon to determine whether these findings generalize to current SARS-CoV-2 transmission dynamics and other seasonal respiratory pathogens.

Plasmodium falciparum infection and disease in infancy associated with increased risk of malaria and anaemia in childhood.

BACKGROUND: Infants under 6 months of age are often excluded from malaria surveillance and observational studies. The impact of malaria during early infancy on health later in childhood remains unknown. METHODS: Infants from two birth cohorts in Malawi were monitored at quarterly intervals and whenever they were ill from birth through 24 months for Plasmodium falciparum infections and clinical malaria. Poisson regression and linear mixed effects models measured the effect of exposure to malaria in infancy on subsequent malaria incidence, weight-for-age z-scores (WAZ), and haemoglobin concentrations after 6 months. RESULTS: Infants with at least one P. falciparum infection during their first 6 months had increased incidence ratio (IRR) of P. falciparum infection (IRR = 1.27, 95% CI, 1.06-1.52) and clinical malaria (IRR = 2.37, 95% CI, 2.02-2.80) compared to infants without infection. Infants with clinical malaria had increased risk of P. falciparum infection incidence between 6 and 24 months (IRR = 1.64, 95% CI, 1.38-1.94) and clinical malaria (IRR = 1.85, 95% CI, 1.48-2.32). Exposure to malaria was associated with lower WAZ over time (p = 0.02) and lower haemoglobin levels than unexposed infants at every time interval (p = 0.02). CONCLUSIONS: Infants experiencing malaria infection or clinical malaria are at increased risk of subsequent infection and disease, have poorer growth, and lower haemoglobin concentrations.

Optimizing next-generation RSV prevention in Mali: A cost-effectiveness analysis of pediatric vaccination, maternal vaccination, and extended half-life monoclonal antibody immunoprophylaxis.

Respiratory syncytial virus (RSV) is the most common cause of early childhood lower respiratory tract infection (LRTI) in low- and middle-income countries (LMICs). Maternal vaccines, birth-dose extended half-life monoclonal antibodies (mAbs), and pediatric vaccines are under development for prevention of respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in young children. We analyzed the health and economic impact of RSV interventions used alone or in combinations in Mali. We modeled age-specific and season-specific risks of RSV LRTI in children through three years, using WHO Preferred Product Characteristics and data generated in Mali. Health outcomes included RSV LRTI cases, hospitalizations, deaths, and disability-adjusted life-years (DALYs). We identified the optimal combination of products across a range of scenarios. We found that mAb delivered at birth could avert 878 DALYs per birth cohort at an incremental cost-effectiveness ratio (ICER) of $597 per DALY averted compared to no intervention if the product were available at $1 per dose. Combining mAb with pediatric vaccine administered at 10/14 weeks, 1947 DALYs would be prevented. The ICER of this combination strategy is $1514 per DALY averted compared to mAb alone. Incorporating parameter uncertainty, mAb alone is likely to be optimal from the societal perspective at efficacy against RSV LRTI above 66%. The optimal strategy was sensitive to economic considerations, including product prices and willingness-to-pay for DALYs. For example, the combination of mAb and pediatric vaccine would be optimal from the government perspective at a willingness-to-pay above $775 per DALY. Maternal vaccine alone or in combination with other interventions was never the optimal strategy, even for high vaccine efficacy. The same was true for pediatric vaccine administered at 6/7 months. At prices comparable to existing vaccine products, extended half-life RSV mAbs would be impactful and efficient components of prevention strategies in LMICs such as Mali.

Etiology, Presentation, and Risk Factors for Diarrheal Syndromes in 3 Sub-Saharan African Countries After the Introduction of Rotavirus Vaccines From the Vaccine Impact on Diarrhea in Africa (VIDA) Study.

BACKGROUND: Diarrheal disease is heterogeneous, including watery diarrhea (WD) and dysentery, some cases of which become persistent diarrhea (PD). Changes in risk over time necessitate updated knowledge of these syndromes in sub-Saharan Africa. METHODS: The Vaccine Impact on Diarrhea in Africa (VIDA) study was an age-stratified, case-control study of moderate-to-severe diarrhea among children <5 years old in The Gambia, Mali, and Kenya (2015-2018). We analyzed cases with follow-up of about 60 days after enrollment to detect PD (lasting ≥14 days), examined the features of WD and dysentery, and examined determinants for progression to and sequelae from PD. Data were compared with those from the Global Enteric Multicenter Study (GEMS) to detect temporal changes. Etiology was assessed from stool samples using pathogen attributable fractions (AFs), and predictors were assessed using χ2 tests or multivariate regression, where appropriate. RESULTS: Among 4606 children with moderate-to-severe diarrhea, 3895 (84.6%) had WD and 711 (15.4%) had dysentery. PD was more frequent among infants (11.3%) than in children 12-23 months (9.9%) or 24-59 months (7.3%), P = .001 and higher in Kenya (15.5%) than in The Gambia (9.3%) or Mali (4.3%), P < .001; the frequencies were similar among children with WD (9.7%) and those with dysentery (9.4%). Compared to children not treated with antibiotics, those who received antibiotics had a lower frequency of PD overall (7.4% vs 10.1%, P = .01), and particularly among those with WD (6.3% vs 10.0%; P = .01) but not among children with dysentery (8.5% vs 11.0%; P = .27). For those with watery PD, Cryptosporidium and norovirus had the highest AFs among infants (0.16 and 0.12, respectively), while Shigella had the highest AF (0.25) in older children. The odds of PD decreased significantly over time in Mali and Kenya while increasing significantly in The Gambia. CONCLUSIONS: The burden of PD endures in sub-Saharan Africa, with nearly 10% of episodes of WD and dysentery becoming persistent.

Community exposures among Colorado adults who tested positive for SARS-CoV-2 -A case-control study, March-December 2021.

OBJECTIVES: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which causes coronavirus disease 2019 (COVID-19), is spread primarily through exposure to respiratory droplets from close contact with an infected person. To inform prevention measures, we conducted a case-control study among Colorado adults to assess the risk of SARS-CoV-2 infection from community exposures. METHODS: Cases were symptomatic Colorado adults (aged ≥18 years) with a positive SARS-CoV-2 test by reverse transcription-polymerase chain reaction (RT-PCR) reported to Colorado's COVID-19 surveillance system. From March 16 to December 23, 2021, cases were randomly selected from surveillance data ≤12 days after their specimen collection date. Cases were matched on age, zip code (urban areas) or region (rural/frontier areas), and specimen collection date with controls randomly selected among persons with a reported negative SARS-CoV-2 test result. Data on close contact and community exposures were obtained from surveillance and a survey administered online. RESULTS: The most common exposure locations among all cases and controls were place of employment, social events, or gatherings and the most frequently reported exposure relationship was co-worker or friend. Cases were more likely than controls to work outside the home (adjusted odds ratio (aOR) 1.18, 95% confidence interval (CI): 1.09-1.28) in industries and occupations related to accommodation and food services, retail sales, and construction. Cases were also more likely than controls to report contact with a non-household member with confirmed or suspected COVID-19 (aOR 1.16, 95% CI: 1.06-1.27). CONCLUSIONS: Understanding the settings and activities associated with a higher risk of SARS-CoV-2 infection is essential for informing prevention measures aimed at reducing the transmission of SARS-CoV-2 and other respiratory diseases. These findings emphasize the risk of community exposure to infected persons and the need for workplace precautions in preventing ongoing transmission.

Artemether-lumefantrine efficacy among adults on antiretroviral therapy in Malawi.

BACKGROUND: When people with human immunodeficiency virus (HIV) infection (PWH) develop malaria, they are at risk of poor anti-malarial treatment efficacy resulting from impairment in the immune response and/or drug-drug interactions that alter anti-malarial metabolism. The therapeutic efficacy of artemether-lumefantrine was evaluated in a cohort of PWH on antiretroviral therapy (ART) and included measurement of day 7 lumefantrine levels in a subset to evaluate for associations between lumefantrine exposure and treatment response. METHODS: Adults living with HIV (≥ 18 years), on ART for ≥ 6 months with undetectable HIV RNA viral load and CD4 count ≥ 250/mm3 were randomized to daily trimethoprim-sulfamethoxazole (TS), weekly chloroquine (CQ) or no prophylaxis. After diagnosis of uncomplicated Plasmodium falciparum malaria, a therapeutic efficacy monitoring was conducted with PCR-correction according to WHO guidelines. The plasma lumefantrine levels on day 7 in 100 episodes of uncomplicated malaria was measured. A frailty proportional hazards model with random effects models to account for clustering examined the relationship between participant characteristics and malaria treatment failure within 28 days. Pearson's Chi-squared test was used to compare lumefantrine concentrations among patients with treatment failure and adequate clinical and parasitological response (ACPR). RESULTS: 411 malaria episodes were observed among 186 participants over 5 years. The unadjusted ACPR rate was 81% (95% CI 77-86). However, after PCR correction to exclude new infections, ACPR rate was 94% (95% CI 92-97). Increasing age and living in Ndirande were associated with decreased hazard of treatment failure. In this population of adults with HIV on ART, 54% (51/94) had levels below a previously defined optimal day 7 lumefantrine level of 200 ng/ml. This occurred more commonly among participants who were receiving an efavirenz-based ART compared to other ART regimens (OR 5.09 [95% CI 1.52-7.9]). Participants who experienced treatment failure had lower day 7 median lumefantrine levels (91 ng/ml [95% CI 48-231]) than participants who experienced ACPR (190 ng/ml [95% CI 101-378], p-value < 0.008). CONCLUSION: Recurrent malaria infections are frequent in this population of PWH on ART. The PCR-adjusted efficacy of AL meets the WHO criteria for acceptable treatment efficacy. Nevertheless, lumefantrine levels tend to be low in this population, particularly in those on efavirenz-based regimens, with lower concentrations associated with more frequent malaria infections following treatment. These results highlight the importance of understanding drug-drug interactions when diseases commonly co-occur.

The Association Between Rainfall, Temperature, and Reported Drinking Water Source: A Multi-Country Analysis.

Climate change may alter access to safe drinking water, with important implications for health. We assessed the relationship between temperature and rainfall and utilization of basic drinking water (BDW) in The Gambia, Mozambique, Pakistan, and Kenya. The outcomes of interest were (a) whether the reported drinking water source used in the past 2 weeks met the World Health Organization definition of BDW and (b) use of a BDW source that was always available. Temperature and precipitation data were compiled from weather stations and satellite data and summarized to account for long- and short-term weather patterns and lags. We utilized random forests and logistic regression to identify key weather variables that predicted outcomes by site and the association between important weather variables and BDW use. Higher temperatures were associated with decreased BDW use at three of four sites and decreased use of BDW that is always available at all four sites. Increasing rainfall, both in the long- and short-term, was associated with increased BDW use in three sites. We found evidence for interactions between household wealth and weather variables at two sites, suggesting lower wealth populations may be more sensitive to weather-driven changes in water access. Changes in temperature and precipitation can alter safe water use in low-resource settings-investigating drivers for these relationships can inform efforts to build climate resilience.

The Association among Malaria in Pregnancy, Neonatal inflammation, and Neurocognitive Development in a Cohort of Malawian Infants.

Malaria in pregnancy (MIP) causes poor birth outcomes, but its impact on neurocognitive development has not been well characterized. Between 2012 and 2014, we enrolled 307 mother-infant pairs and monitored 286 infants for neurocognitive development using the Malawi Developmental Assessment Tool at 6, 12, and 24 months of age. MIP was diagnosed from peripheral blood and placental specimens. Cord blood cytokine levels were assessed for a subset of neonates. Predictors of neurodevelopment were examined using mixed-effect logistic regression for developmental delay. Among the participants, 78 mothers (25.4%) had MIP, and 45 infants (15.7%) experienced severe neurocognitive delay. MIP was not associated with differences in cord blood cytokine levels or neurocognitive development. Preterm birth, low birthweight, increasing maternal education level, and increasing interleukin 6 levels were associated significantly with delay. The results highlight the prevalence of severe delay and a need for broad access to early childhood support in this setting.

Dynamics of the Gut Microbiome in Shigella-Infected Children during the First Two Years of Life.

Shigella continues to be a major contributor to diarrheal illness and dysentery in children younger than 5 years of age in low- and middle-income countries. Strategies for the prevention of shigellosis have focused on enhancing adaptive immunity. The interaction between Shigella and intrinsic host factors, such as the microbiome, remains unknown. We hypothesized that Shigella infection would impact the developing microbial community in infancy and, conversely, that changes in the gastrointestinal microbiome may predispose infections. To test this hypothesis, we characterized the gastrointestinal microbiota in a longitudinal birth cohort from Malawi that was monitored for Shigella infection using 16S rRNA amplicon sequencing. Children with at least one Shigella quantitative polymerase chain reaction (qPCR) positive sample during the first 2 years of life (cases) were compared to uninfected controls that were matched for sex and age. Overall, the microbial species diversity, as measured by the Shannon diversity index, increased over time, regardless of case status. At early time points, the microbial community was dominated by Bifidobacterium longum and Escherichia/Shigella. A greater abundance of Prevotella 9 and Bifidobacterium kashiwanohense was observed at 2 years of age. While no single species was associated with susceptibility to Shigella infection, significant increases in Lachnospiraceae NK4A136 and Fusicatenibacter saccharivorans were observed following Shigella infection. Both taxa are in the family Lachnospiraceae, which are known short-chain fatty acid producers that may improve gut health. Our findings identified temporal changes in the gastrointestinal microbiota associated with Shigella infection in Malawian children and highlight the need to further elucidate the microbial communities associated with disease susceptibility and resolution. IMPORTANCE Shigella causes more than 180 million cases of diarrhea globally, mostly in children living in poor regions. Infection can lead to severe health impairments that reduce quality of life. There is increasing evidence that disruptions in the gut microbiome early in life can influence susceptibility to illnesses. A delayed or impaired reconstitution of the microbiota following infection can further impact overall health. Aiming to improve our understanding of the interaction between Shigella and the developing infant microbiome, we investigated changes in the gut microbiome of Shigella-infected and uninfected children over the course of their first 2 years of life. We identified species that may be involved in recovery from Shigella infection and in driving the microbiota back to homeostasis. These findings support future studies into the elucidation of the interaction between the microbiota and enteric pathogens in young children and into the identification of potential targets for prevention or treatment.

High burden of malaria among Malawian adults on antiretroviral therapy after discontinuing prophylaxis.

OBJECTIVE: Many individuals living with the human immunodeficiency virus (HIV) infection and receiving antiretroviral therapy (ART) reside in areas at high risk for malaria but how malaria affects clinical outcomes is not well described in this population. We evaluated the burden of malaria infection and clinical malaria, and impact on HIV viral load and CD4 + cell count among adults on ART. DESIGN: We recruited Malawian adults on ART who had an undetectable viral load and ≥250 CD4 +  cells/µl to participate in this randomized trial to continue daily trimethoprim-sulfamethoxazole (TS), discontinue daily co-trimoxazole, or switch to weekly chloroquine (CQ). METHODS: We defined clinical malaria as symptoms consistent with malaria and positive blood smear, and malaria infection as Plasmodium falciparum DNA detected from dried blood spots (collected every 4-12 weeks). CD4 + cell count and viral load were measured every 24 weeks. We used Poisson regression and survival analysis to compare the incidence of malaria infection and clinical malaria. Clinicaltrials.gov NCT01650558. RESULTS: Among 1499 participants enrolled, clinical malaria incidence was 21.4/100 person-years of observation (PYO), 2.4/100 PYO and 1.9/100 PYO in the no prophylaxis, TS, and CQ arms, respectively. We identified twelve cases of malaria that led to hospitalization and all individuals recovered. The preventive effect of staying on prophylaxis was approximately 90% compared to no prophylaxis (TS: incidence rate ratio [IRR] 0.11, 95% confidence interval [CI] 0.08, 0.15 and CQ: IRR 0.09, 95% CI 0.06, 0.13). P. falciparum infection prevalence among all visits was 187/1475 (12.7%), 48/1563 (3.1%), and 29/1561 (1.9%) in the no prophylaxis, TS, and CQ arms, respectively. Malaria infection and clinical malaria were not associated with changes in CD4 + cell count or viral load. CONCLUSION: In clinically stable adults living with HIV on ART, clinical malaria was common after chemoprophylaxis stopped. However, neither malaria infection nor clinical illness appeared to affect HIV disease progression.

Modeling the systemic risks of COVID-19 on the wildland firefighting workforce.

Wildfire management in the US relies on a complex nationwide network of shared resources that are allocated based on regional need. While this network bolsters firefighting capacity, it may also provide pathways for transmission of infectious diseases between fire sites. In this manuscript, we review a first attempt at building an epidemiological model adapted to the interconnected fire system, with the aims of supporting prevention and mitigation efforts along with understanding potential impacts to workforce capacity. Specifically, we developed an agent-based model of COVID-19 built on historical wildland fire assignments using detailed dispatch data from 2016-2018, which form a network of firefighters dispersed spatially and temporally across the US. We used this model to simulate SARS-CoV-2 transmission under several intervention scenarios including vaccination and social distancing. We found vaccination and social distancing are effective at reducing transmission at fire incidents. Under a scenario assuming High Compliance with recommended mitigations (including vaccination), infection rates, number of outbreaks, and worker days missed are effectively negligible, suggesting the recommended interventions could successfully mitigate the risk of cascading infections between fires. Under a contrasting Low Compliance scenario, it is possible for cascading outbreaks to emerge leading to relatively high numbers of worker days missed. As the model was built in 2021 before the emergence of the Delta and Omicron variants, the modeled viral parameters and isolation/quarantine policies may have less relevance to 2022, but nevertheless underscore the importance of following basic prevention and mitigation guidance. This work could set the foundation for future modeling efforts focused on mitigating spread of infectious disease at wildland fire incidents to manage both the health of fire personnel and system capacity.

Novel use of online optimization in a mathematical model of COVID-19 to guide the relaxation of pandemic mitigation measures.

Since early 2020, non-pharmaceutical interventions (NPIs)-implemented at varying levels of severity and based on widely-divergent perspectives of risk tolerance-have been the primary means to control SARS-CoV-2 transmission. This paper aims to identify how risk tolerance and vaccination rates impact the rate at which a population can return to pre-pandemic contact behavior. To this end, we developed a novel mathematical model and we used techniques from feedback control to inform data-driven decision-making. We use this model to identify optimal levels of NPIs across geographical regions in order to guarantee that hospitalizations will not exceed given risk tolerance thresholds. Results are shown for the state of Colorado, United States, and they suggest that: coordination in decision-making across regions is essential to maintain the daily number of hospitalizations below the desired limits; increasing risk tolerance can decrease the number of days required to discontinue NPIs, at the cost of an increased number of deaths; and if vaccination uptake is less than 70%, at most levels of risk tolerance, return to pre-pandemic contact behaviors before the early months of 2022 may newly jeopardize the healthcare system. The sooner we can acquire population-level vaccination of greater than 70%, the sooner we can safely return to pre-pandemic behaviors.

School-Based Malaria Screening and Treatment Reduces Plasmodium falciparum Infection and Anemia Prevalence in Two Transmission Settings in Malawi.

BACKGROUND: In areas highly endemic for malaria, Plasmodium falciparum infection prevalence peaks in school-age children, adversely affecting health and education. School-based intermittent preventive treatment reduces this burden but concerns about cost and widespread use of antimalarial drugs limit enthusiasm for this approach. School-based screening and treatment is an attractive alternative. In a prospective cohort study, we evaluated the impact of school-based screening and treatment on the prevalence of P. falciparum infection and anemia in 2 transmission settings. METHODS: We screened 704 students in 4 Malawian primary schools for P. falciparum infection using rapid diagnostic tests (RDTs), and treated students who tested positive with artemether-lumefantrine. We determined P. falciparum infection by microscopy and quantitative polymerase chain reaction (qPCR), and hemoglobin concentrations over 6 weeks in all students. RESULTS: Prevalence of infection by RDT screening was 37% (9%-64% among schools). An additional 9% of students had infections detected by qPCR. Following the intervention, significant reductions in infections were detected by microscopy (adjusted relative reduction [aRR], 48.8%; P < .0001) and qPCR (aRR, 24.5%; P < .0001), and in anemia prevalence (aRR, 30.8%; P = .003). Intervention impact was reduced by infections not detected by RDT and new infections following treatment. CONCLUSIONS: School-based screening and treatment reduced P. falciparum infection and anemia. This approach could be enhanced by repeating screening, using more-sensitive screening tests, and providing longer-acting drugs. CLINICAL TRIALS REGISTRATION: NCT04858087.

Analysis of Recurrent Times-to-Clinical Malaria Episodes and Plasmodium falciparum Parasitemia: A Joint Modeling Approach Applied to a Cohort Data.

Background: Recurrent clinical malaria episodes due to Plasmodium falciparum parasite infection are common in endemic regions. With each infection, acquired immunity develops, making subsequent disease episodes less likely. To capture the effect of acquired immunity to malaria, it may be necessary to model recurrent clinical disease episodes jointly with P. falciparum parasitemia data. A joint model of longitudinal parasitemia and time-to-first clinical malaria episode (single-event joint model) may be inaccurate because acquired immunity is lost when subsequent episodes are excluded. This study's informativeness assessed whether joint modeling of recurrent clinical malaria episodes and parasitemia is more accurate than a single-event joint model where the subsequent episodes are ignored. Methods: The single event joint model comprised Cox Proportional Hazards (PH) sub-model for time-to-first clinical malaria episode and Negative Binomial (NB) mixed-effects sub-model for the longitudinal parasitemia. The recurrent events joint model extends the survival sub-model to a Gamma shared frailty model to include all recurrent clinical episodes. The models were applied to cohort data from Malawi. Simulations were also conducted to assess the performance of the model under different conditions. Results: The recurrent events joint model, which yielded higher hazard ratios of clinical malaria, was more precise and in most cases produced smaller standard errors than the single-event joint model; hazard ratio (HR) = 1.42, [95% confidence interval [CI]: 1.22, 2.03] vs. HR = 1.29, [95% CI:1.60, 2.45] among participants who reported not to use LLINs every night compared to those who used the nets every night; HR = 0.96, [ 95% CI: 0.94, 0.98] vs. HR = 0.81, [95% CI: 0.75, 0.88] for each 1-year increase in participants' age; and HR = 1.36, [95% CI: 1.05, 1.75] vs. HR = 1.10, [95% CI: 0.83, 4.11] for observations during the rainy season compared to the dry season. Conclusion: The recurrent events joint model in this study provides a way of estimating the risk of recurrent clinical malaria in a cohort where the effect of immunity on malaria disease acquired due to P. falciparum parasitemia with aging is captured. The simulation study has shown that if correctly specified, the recurrent events joint model can give risk estimates with low bias.

Repertoire of Naturally Acquired Maternal Antibodies Transferred to Infants for Protection Against Shigellosis.

Shigella is the second leading cause of diarrheal diseases, accounting for >200,000 infections and >50,000 deaths in children under 5 years of age annually worldwide. The incidence of Shigella-induced diarrhea is relatively low during the first year of life and increases substantially, reaching its peak between 11 to 24 months of age. This epidemiological trend hints at an early protective immunity of maternal origin and an increase in disease incidence when maternally acquired immunity wanes. The magnitude, type, antigenic diversity, and antimicrobial activity of maternal antibodies transferred via placenta that can prevent shigellosis during early infancy are not known. To address this knowledge gap, Shigella-specific antibodies directed against the lipopolysaccharide (LPS) and virulence factors (IpaB, IpaC, IpaD, IpaH, and VirG), and antibody-mediated serum bactericidal (SBA) and opsonophagocytic killing antibody (OPKA) activity were measured in maternal and cord blood sera from a longitudinal cohort of mother-infant pairs living in rural Malawi. Protein-specific (very high levels) and Shigella LPS IgG were detected in maternal and cord blood sera; efficiency of placental transfer was 100% and 60%, respectively, and had preferential IgG subclass distribution (protein-specific IgG1 > LPS-specific IgG2). In contrast, SBA and OPKA activity in cord blood was substantially lower as compared to maternal serum and varied among Shigella serotypes. LPS was identified as the primary target of SBA and OPKA activity. Maternal sera had remarkably elevated Shigella flexneri 2a LPS IgM, indicative of recent exposure. Our study revealed a broad repertoire of maternally acquired antibodies in infants living in a Shigella-endemic region and highlights the abundance of protein-specific antibodies and their likely contribution to disease prevention during the first months of life. These results contribute new knowledge on maternal infant immunity and target antigens that can inform the development of vaccines or therapeutics that can extend protection after maternally transferred immunity wanes.

Estimating the Impact of Statewide Policies to Reduce Spread of Severe Acute Respiratory Syndrome Coronavirus 2 in Real Time, Colorado, USA.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic necessitated rapid local public health response, but studies examining the impact of social distancing policies on SARS-CoV-2 transmission have struggled to capture regional-level dynamics. We developed a susceptible-exposed-infected-recovered transmission model, parameterized to Colorado, USA‒specific data, to estimate the impact of coronavirus disease‒related policy measures on mobility and SARS-CoV-2 transmission in real time. During March‒June 2020, we estimated unknown parameter values and generated scenario-based projections of future clinical care needs. Early coronavirus disease policy measures, including a stay-at-home order, were accompanied by substantial decreases in mobility and reduced the effective reproductive number well below 1. When some restrictions were eased in late April, mobility increased to near baseline levels, but transmission remained low (effective reproductive number <1) through early June. Over time, our model parameters were adjusted to more closely reflect reality in Colorado, leading to modest changes in estimates of intervention effects and more conservative long-term projections.

Cost-effectiveness of infant respiratory syncytial virus preventive interventions in Mali: A modeling study to inform policy and investment decisions.

IMPORTANCE: Low- and middle-income countries have a high burden of respiratory syncytial virus lower respiratory tract infections. A monoclonal antibody administered monthly is licensed to prevent these infections, but it is cost-prohibitive for most low- and middle-income countries. Long-acting monoclonal antibodies and maternal vaccines against respiratory syncytial virus are under development. OBJECTIVE: We estimated the likelihood of respiratory syncytial virus preventive interventions (current monoclonal antibody, long-acting monoclonal antibody, and maternal vaccine) being cost-effective in Mali. DESIGN: We modeled age-specific and season-specific risks of respiratory syncytial virus lower respiratory tract infections within monthly cohorts of infants from birth to six months. We parameterized with respiratory syncytial virus data from Malian cohort studies, as well as product efficacy from clinical trials. Integrating parameter uncertainty, we simulated health and economic outcomes for status quo without prevention, intra-seasonal monthly administration of licensed monoclonal antibody, pre-seasonal birth dose administration of a long-acting monoclonal antibody, and maternal vaccination. We then calculated the incremental cost-effectiveness ratio of each intervention compared to status quo from the perspectives of the government, donor, and society. RESULTS: At a price of $3 per dose and from the societal perspective, current monoclonal antibody, long-acting monoclonal antibody, and maternal vaccine would have incremental cost-effectiveness ratios of $4280 (95% CI $1892 to $122,434), $1656 (95% CI $734 to $9091), and $8020 (95% CI $3501 to $47,047) per disability-adjusted life-year averted, respectively. CONCLUSIONS AND RELEVANCE: In Mali, long-acting monoclonal antibody is likely to be cost-effective from both the government and donor perspectives at $3 per dose. Maternal vaccine would need higher efficacy over that measured by a recent trial in order to be considered cost-effective.

Whole-genome analysis of Malawian Plasmodium falciparum isolates identifies possible targets of allele-specific immunity to clinical malaria.

Individuals acquire immunity to clinical malaria after repeated Plasmodium falciparum infections. Immunity to disease is thought to reflect the acquisition of a repertoire of responses to multiple alleles in diverse parasite antigens. In previous studies, we identified polymorphic sites within individual antigens that are associated with parasite immune evasion by examining antigen allele dynamics in individuals followed longitudinally. Here we expand this approach by analyzing genome-wide polymorphisms using whole genome sequence data from 140 parasite isolates representing malaria cases from a longitudinal study in Malawi and identify 25 genes that encode possible targets of naturally acquired immunity that should be validated immunologically and further characterized for their potential as vaccine candidates.

Human Mobility Associated With Risk of Schistosoma japonicum Infection in Sichuan, China.

Urbanization increases human mobility in ways that can alter the transmission of classically rural, vector-borne diseases like schistosomiasis. The impact of human mobility on individual-level Schistosoma risk is poorly characterized. Travel outside endemic areas may protect against infection by reducing exposure opportunities, whereas travel to other endemic regions may increase risk. Using detailed monthly travel- and water-contact surveys from 27 rural communities in Sichuan, China, in 2008, we aimed to describe human mobility and to identify mobility-related predictors of S. japonicum infection. Candidate predictors included timing, frequency, distance, duration, and purpose of recent travel as well as water-contact measures. Random forests machine learning was used to detect key predictors of individual infection status. Logistic regression was used to assess the strength and direction of associations. Key mobility-related predictors include frequent travel and travel during July-both associated with decreased probability of infection and less time engaged in risky water-contact behavior, suggesting travel may remove opportunities for schistosome exposure. The importance of July travel and July water contact suggests a high-risk window for cercarial exposure. The frequency and timing of human movement out of endemic areas should be considered when assessing potential drivers of rural infectious diseases.