Validation of open-path dual-comb spectroscopy against an O2 background: erratum.

This erratum corrects errors that appear in Opt. Express31, 5042 (2023).10.1364/OE.480301.

Chemical tools to define and manipulate interferon-inducible Ubl protease USP18.

Ubiquitin-specific protease 18 (USP18) is a multifunctional cysteine protease primarily responsible for deconjugating interferon-inducible ubiquitin-like (Ubl) modifier ISG15 from protein substrates. Here, we report the design and synthesis of activity-based probes (ABPs) capable of selectively detecting USP18 activity over other ISG15 cross-reactive deubiquitinases (DUBs) by incorporating unnatural amino acids into the C-terminal tail of ISG15. Combining with a ubiquitin-based DUB ABP, the selective USP18 ABP is employed in a chemoproteomic screening platform to identify and assess inhibitors of DUBs including USP18. We further demonstrate that USP18 ABPs can be utilized to profile differential activities of USP18 in lung cancer cell lines, providing a strategy that will help define the activity-related landscape of USP18 in different disease states and unravel important (de)ISGylation-dependent biological processes.

COVID-19 vaccines and adverse events of special interest: A multinational Global Vaccine Data Network (GVDN) cohort study of 99 million vaccinated individuals.

BACKGROUND: The Global COVID Vaccine Safety (GCoVS) Project, established in 2021 under the multinational Global Vaccine Data Network™ (GVDN®), facilitates comprehensive assessment of vaccine safety. This study aimed to evaluate the risk of adverse events of special interest (AESI) following COVID-19 vaccination from 10 sites across eight countries. METHODS: Using a common protocol, this observational cohort study compared observed with expected rates of 13 selected AESI across neurological, haematological, and cardiac outcomes. Expected rates were obtained by participating sites using pre-COVID-19 vaccination healthcare data stratified by age and sex. Observed rates were reported from the same healthcare datasets since COVID-19 vaccination program rollout. AESI occurring up to 42 days following vaccination with mRNA (BNT162b2 and mRNA-1273) and adenovirus-vector (ChAdOx1) vaccines were included in the primary analysis. Risks were assessed using observed versus expected (OE) ratios with 95 % confidence intervals. Prioritised potential safety signals were those with lower bound of the 95 % confidence interval (LBCI) greater than 1.5. RESULTS: Participants included 99,068,901 vaccinated individuals. In total, 183,559,462 doses of BNT162b2, 36,178,442 doses of mRNA-1273, and 23,093,399 doses of ChAdOx1 were administered across participating sites in the study period. Risk periods following homologous vaccination schedules contributed 23,168,335 person-years of follow-up. OE ratios with LBCI > 1.5 were observed for Guillain-Barré syndrome (2.49, 95 % CI: 2.15, 2.87) and cerebral venous sinus thrombosis (3.23, 95 % CI: 2.51, 4.09) following the first dose of ChAdOx1 vaccine. Acute disseminated encephalomyelitis showed an OE ratio of 3.78 (95 % CI: 1.52, 7.78) following the first dose of mRNA-1273 vaccine. The OE ratios for myocarditis and pericarditis following BNT162b2, mRNA-1273, and ChAdOx1 were significantly increased with LBCIs > 1.5. CONCLUSION: This multi-country analysis confirmed pre-established safety signals for myocarditis, pericarditis, Guillain-Barré syndrome, and cerebral venous sinus thrombosis. Other potential safety signals that require further investigation were identified.

Maintaining a whole blood-centered transfusion improves survival in hemorrhagic resuscitation.

BACKGROUND: Whole blood (WB) transfusion has been shown to improve mortality in trauma resuscitation. The optimal ratio of packed red blood cells (pRBC) to WB in emergent transfusion has not been determined. We hypothesized that a low pRBC/WB transfusion ratio is associated with improved survival in trauma patients. METHODS: We analyzed the 2021 Trauma Quality Improvement Program (TQIP) database to identify patients who underwent emergent surgery for hemorrhage control and were transfused within 4 hours of hospital arrival, excluding transfers or deaths in the emergency department. We stratified patients based on pRBC/WB ratios. The primary outcome was mortality at 24 hours. Logistic regression was performed to estimate odds of mortality among ratio groups compared with WB alone, adjusting for injury severity, time to intervention, and demographics. RESULTS: Our cohort included 17,562 patients; of those, 13,678 patients had only pRBC transfused and were excluded. Fresh frozen plasma/pRBC ratio was balanced in all groups. Among those who received WB (n = 3,884), there was a significant increase in 24-hour mortality with higher pRBC/WB ratios (WB alone 5.2%, 1:1 10.9%, 2:1 11.8%, 3:1 14.9%, 4:1 20.9%, 5:1 34.1%, p = 0.0001). Using empirical cutpoint estimation, we identified a 3:1 ratio or less as an optimal cutoff point. Adjusted odds ratios of 24-hour mortality for 4:1 and 5:1 groups were 2.85 (95% confidence interval [CI], 1.19-6.81) and 2.89 (95% CI, 1.29-6.49), respectively. Adjusted hazard ratios of 24-hour mortality were 2.83 (95% CI, 1.18-6.77) for 3:1 ratio, 3.67 (95% CI, 1.57-8.57) for 4:1 ratio, and 1.97 (95% CI, 0.91-4.23) for 5:1 ratio. CONCLUSION: Our analysis shows that higher pRBC/WB ratios at 4 hours diminished survival benefits of WB in trauma resuscitation. Further efforts should emphasize this relationship to optimize trauma resuscitation protocols. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Background malaria incidence and parasitemia during the three-dose RTS,S/AS01 vaccination series do not reduce magnitude of antibody response nor efficacy against the first case of malaria.

BACKGROUND: RTS,S/AS01 has been recommended by WHO for widespread implementation in medium to high malaria transmission settings. Previous analyses have noted lower vaccine efficacies in higher transmission settings, possibly due to the more rapid development of naturally acquired immunity in the control group. METHODS: To investigate a reduced immune response to vaccination as a potential mechanism behind lower efficacy in high transmission areas, we examine initial vaccine antibody (anti-CSP IgG) response and vaccine efficacy against the first case of malaria (to exclude the effect of naturally acquired immunity) using data from three study areas (Kintampo, Ghana; Lilongwe, Malawi; Lambaréné, Gabon) from the 2009-2014 phase III trial (NCT00866619). Our key exposures are parasitemia during the vaccination series and background malaria incidence. We calculate vaccine efficacy (one minus hazard ratio) using a cox-proportional hazards model and allowing for the time-varying effect of RTS,S/AS01. RESULTS: We find that antibody responses to the primary three-dose vaccination series were higher in Ghana than in Malawi and Gabon, but that neither antibody levels nor vaccine efficacy against the first case of malaria varied by background incidence or parasitemia during the primary vaccination series. CONCLUSIONS: We find that vaccine efficacy is unrelated to infections during vaccination. Contributing to a conflicting literature, our results suggest that vaccine efficacy is also unrelated to infections before vaccination, meaning that control-group immunity is likely a major reason for lower efficacy in high transmission settings, not reduced immune responses to RTS,S/AS01. This may be reassuring for implementation in high transmission settings, though further studies are needed.

Social Determinants of Health among Older Adults with Dementia in Urban and Rural Areas.

BACKGROUND: Social determinants of health (SDOH) may influence health in people living with dementia. Little is known about SDOH differences in urban compared to rural dwelling people living with dementia. OBJECTIVES: To explore urban-rural differences in SDOH in people living with mild cognitive impairment (MCI) and dementia. DESIGN: Descriptive study. SETTING/PARTICIPANTS: People ≥55 years with MCI or dementia empaneled to Community Internal Medicine at Mayo Clinic (Rochester, MN, USA) who completed SDOH questions between June 1, 2019 and June 30, 2021 were included. MEASUREMENTS: SDOH questions addressed education, depression, alcohol use, financial strain, food insecurity, physical activity, social connections, stress and transportation. SDOH data were compared by location based on Rural-Urban Commuting Areas Codes. RESULTS: Of 3552 persons with MCI (n=1495) or dementia (n=2057), 62% lived in urban areas, 19% in large rural, 10% in small rural and 9% in isolated areas. Approximately 60% were physically inactive, 20% socially isolated and 30% had stress concerns. Rural patients experienced greater financial strain (p=0.003). CONCLUSION: Social isolation, stress and physical inactivity are common in people living with MCI and dementia across urban and rural areas. Targeted interventions to improve physical and psychosocial health could have great impact in this population.

Radiology reporting of incidental osteoporotic vertebral fragility fractures present on CT studies: results of UK national re-audit.

AIM: To describe a UK-wide re-audit of the 2019 Royal College of Radiologists (RCR) audit evaluating patient-related data and organisational infrastructure in the radiological reporting of vertebral fragility fractures (VFFs) on computed tomography (CT) studies and to assess the impact of a series of RCR interventions, initiated to raise VFF awareness, on reporting practice and outcomes. MATERIALS AND METHODS: Patient specific and organisational questionnaires largely replicated those utilised in 2019. The patient questionnaire involved retrospective analysis of between 50 and 100 consecutive, non-traumatic CT studies which included the thoracolumbar spine. All RCR radiology audit leads were invited to participate. Data collection commenced from 1 April 2022. RESULTS: Data were supplied by 129/194 (67%) departments. One thousand five hundred and eighty-six of 7,316 patients (21.7%) had a VFF on auditor review. Overall improvements were demonstrated in key initial/provisional reporting results; comment on spine/bone (93.2%, 14.4% improvement, p<0.0002); fracture severity assessment (34.7%, 8.5% improvement, p=0.0007); use of recommended terminology (67.8%, 7.5% improvement, p=0.0034); recommendations for further management (11.7%, 9.1% improvement, p<0.0002). CONCLUSIONS: The 2022 national re-audit confirms improvements in diagnostic performance and practice in VFF reporting. Continuing work is required to build on this improvement and to further embed best practice.

Family-systems interventions for families of people with an intellectual disability or who are autistic: a systematic review.

BACKGROUND: Family-systems interventions have been proposed as one way of supporting families of people with an intellectual disability (ID) or who are autistic. This systematic review aimed to summarise what family-systems interventions have been studied with this population, what evidence there is for their effectiveness and families' experiences of the interventions. METHODS: The review was preregistered on PROSPERO (CRD42022297516). We searched five electronic databases, identified 6908 records and screened 72 full texts. Study quality was evaluated using the Mixed Methods Appraisal Tool, and a narrative synthesis was used. RESULTS: We identified 13 eligible articles with 292 participating families. Most studies reported positive effects of the interventions on wellbeing and family relationships, and families reported positive experiences. However, research quality was poor and there are no any sufficiently powered randomised controlled trials demonstrating family-systems interventions' effectiveness for this population. CONCLUSIONS: There is a need for higher-quality research to establish whether family-systems interventions are beneficial for families of people who have an ID or who are autistic.

Amyloid-ß (Aß) immunotherapy induced microhemorrhages are associated with activated perivascular macrophages and peripheral monocyte recruitment in Alzheimer's disease mice.

BACKGROUND: Amyloid-related imaging abnormalities (ARIA) have been identified as the most common and serious adverse events resulting from pathological changes in the cerebral vasculature during several recent anti-amyloid-ß (Aß) immunotherapy trials. However, the precise cellular and molecular mechanisms underlying how amyloid immunotherapy enhances cerebral amyloid angiopathy (CAA)-mediated alterations in vascular permeability and microhemorrhages are not currently understood. Interestingly, brain perivascular macrophages have been implicated in regulating CAA deposition and cerebrovascular function however, further investigations are required to understand how perivascular macrophages play a role in enhancing CAA-related vascular permeability and microhemorrhages associated with amyloid immunotherapy. METHODS: In this study, we examined immune responses induced by amyloid-targeting antibodies and CAA-induced microhemorrhages using histology and gene expression analyses in Alzheimer's disease (AD) mouse models and primary culture systems. RESULTS: In the present study, we demonstrate that anti-Aß (3D6) immunotherapy leads to the formation of an antibody immune complex with vascular amyloid deposits and induces the activation of CD169+ perivascular macrophages. We show that macrophages activated by antibody mediated Fc receptor signaling have increased expression of inflammatory signaling and extracellular matrix remodeling genes such as Timp1 and MMP9 in vitro and confirm these key findings in vivo. Finally, we demonstrate enhanced vascular permeability of plasma proteins and recruitment of inflammatory monocytes around vascular amyloid deposits, which are associated with hemosiderin deposits from cerebral microhemorrhages, suggesting the multidimensional roles of activated perivascular macrophages in response to Aß immunotherapy. CONCLUSIONS: In summary, our study establishes a connection between Aß antibodies engaged at CAA deposits, the activation of perivascular macrophages, and the upregulation of genes involved in vascular permeability. However, the implications of this phenomenon on the susceptibility to microhemorrhages remain to be fully elucidated. Further investigations are warranted to determine the precise role of CD169 + perivascular macrophages in enhancing CAA-mediated vascular permeability, extravasation of plasma proteins, and infiltration of immune cells associated with microhemorrhages.

Open-path dual-comb spectroscopy of methane and VOC emissions from an unconventional oil well development in Northern Colorado.

We present results from a field study monitoring methane and volatile organic compound emissions near an unconventional oil well development in Northern Colorado from September 2019 to May 2020 using a mid-infrared dual-comb spectrometer. This instrument allowed quantification of methane, ethane, and propane in a single measurement with high time resolution and integrated path sampling. Using ethane and propane as tracer gases for methane from oil and gas activity, we observed emissions during the drilling, hydraulic fracturing, millout, and flowback phases of well development. Large emissions were seen in drilling and millout phases and emissions decreased to background levels during the flowback phase. Ethane/methane and propane/methane ratios varied widely throughout the observations.

XeF2 Coordination Complexes of the [BrO2]+ Cation, [O2Br(FXeF)n][AsF6] (n = 1, 2) and [O2Br(FXeF)2][SbF6]; Their Syntheses and Structural Characterizations.

The syntheses and structural characterizations of the first XeF2 coordination complexes of the [BrO2]+ cation are described. The reactions of [BrO2][PnF6] (Pn = As, Sb) with XeF2 in anhydrous HF solvent yield the salts [O2Br(FXeF)n][AsF6] (n = 1, 2) and [O2Br(FXeF)2][SbF6], which were characterized by low-temperature (LT) Raman spectroscopy and single-crystal X-ray diffraction (SCXRD). The XeF2 ligands and [PnF6]- coordinate to the Lewis acidic [BrO2]+ cation through primarily electrostatic BrV---FXe σ-hole bonds that result from coordination of the F atoms into regions of high positive electrostatic potential on the Br(V) atom and have bond trajectories that avoid the stereoactive valence electron lone-pair of Br(V). The complexes and their structural characterizations by LT Raman spectroscopy and SCXRD significantly extend the coordination chemistry of Br(V) and provide rare examples of a noble-gas difluoride coordinated to a strong oxidant main-group Lewis acid center.

Mortality by Admission Diagnosis in Children 1-60 Months of Age Admitted to a Tertiary Care Government Hospital in Malawi.

Diagnosis-specific mortality is a measure of pediatric healthcare quality that has been incompletely studied in sub-Saharan African hospitals. Identifying the mortality rates of multiple conditions at the same hospital may allow leaders to better target areas for intervention. In this secondary analysis of routinely collected data, we investigated hospital mortality by admission diagnosis in children aged 1-60 months admitted to a tertiary care government referral hospital in Malawi between October 2017 and June 2020. The mortality rate by diagnosis was calculated as the number of deaths among children admitted with a diagnosis divided by the number of children admitted with the same diagnosis. There were 24,452 admitted children eligible for analysis. Discharge disposition was recorded in 94.2% of patients, and 4.0% (N = 977) died in the hospital. The most frequent diagnoses among admissions and deaths were pneumonia/bronchiolitis, malaria, and sepsis. The highest mortality rates by diagnosis were found in surgical conditions (16.1%; 95% CI: 12.0-20.3), malnutrition (15.8%; 95% CI: 13.6-18.0), and congenital heart disease (14.5%; 95% CI: 9.9-19.2). Diagnoses with the highest mortality rates were alike in their need for significant human and material resources for medical care. Improving mortality in this population will require sustained capacity building in conjunction with targeted quality improvement initiatives against both common and deadly diseases.

Malaria Transmission Intensity and Parasitemia during the Three-Dose RTS,S/AS01 Vaccination Series do not Reduce Magnitude of Antibody Response nor Efficacy Against the First Case of Malaria.

Background: RTS,S/AS01 has been recommended by WHO for widespread implementation in medium to high malaria transmission settings. Previous analyses have noted lower vaccine efficacies in higher transmission settings, possibly due to the more rapid development of naturally acquired immunity in the control group. Methods: To investigate a reduced immune response to vaccination as a potential mechanism behind lower efficacy in high transmission areas, we examine initial vaccine antibody (anti-CSP IgG) response and vaccine efficacy against the first case of malaria to exclude the delayed malaria effect using data from three study areas (Kintampo, Ghana; Lilongwe, Malawi; Lambaréné, Gabon) from the 2009-2014 phase III trial (NCT00866619). Our key exposures are parasitemia during the vaccination series and malaria transmission intensity. We calculate vaccine efficacy (one minus hazard ratio) using a cox-proportional hazards model and allowing for the time-varying effect of RTS,S/AS01. Results: We find that antibody responses to the primary three-dose vaccination series were higher in Ghana than in Malawi and Gabon, but that neither antibody levels nor vaccine efficacy against the first case of malaria varied by transmission intensity or parasitemia during the primary vaccination series. Conclusions: We find that vaccine efficacy is unrelated to infections during vaccination. Contributing to a conflicting literature, our results suggest that vaccine efficacy is also unrelated to infections before vaccination, meaning that delayed malaria is likely the main reason for lower efficacy in high transmission settings, not reduced immune responses. This may be reassuring for implementation in high transmission settings, though further studies are needed.

Leaky barriers to gene sharing between locally co-existing coagulase-negative Staphylococcus species.

Coagulase-negative Staphylococcus (CoNS) are opportunistic pathogens implicated in many human and animal infections. The evolutionary history of CoNS remains obscure because of the historical lack of recognition for their clinical importance and poor taxonomic sampling. Here, we sequenced the genomes of 191 CoNS isolates representing 15 species sampled from diseased animals diagnosed in a veterinary diagnostic laboratory. We found that CoNS are important reservoirs of diverse phages, plasmids and mobilizable genes encoding antimicrobial resistance, heavy metal resistance, and virulence. Frequent exchange of DNA between certain donor-recipient partners suggests that specific lineages act as hubs of gene sharing. We also detected frequent recombination between CoNS regardless of their animal host species, indicating that ecological barriers to horizontal gene transfer can be surmounted in co-circulating lineages. Our findings reveal frequent but structured patterns of transfer that exist within and between CoNS species, which are driven by their overlapping ecology and geographical proximity.

The genomic landscape of familial glioma.

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3, and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.

Comparison of radiographic scoring systems for assessment of bone healing after tibial plateau leveling osteotomy in dogs.

Introduction: Accurate radiographic assessment of bone healing is vital in determining both clinical treatment and for assessing interventions aimed at the promotion of bone healing. Several scoring systems have been used to evaluate osteotomy changes following tibial plateau leveling osteotomy (TPLO). The goal of this study was to compare the ability of five radiographic scoring systems to identify changes in bone healing following TPLO over time (Aim I), and to evaluate the influence of limb positioning on TPLO osteotomy scoring (Aim II). Materials and methods: Phase I-A randomized, blinded, prospective study was conducted using similarly positioned postoperative TPLO radiographs from seven dogs taken immediately postoperatively, 6-weeks, and 8-weeks postoperatively. Ten reviewers assessed the radiographs, and five different scoring systems were tested for each set including three previously published ones, a Visual Analog Score (VAS), and a subjective 11-point scale. For each system, responses for 6-week postoperative were compared to 8-week postoperative. Scores were judged as correct (=showing an increase in score), incorrect (=decrease in score), or unchanged (=same score). Phase II-An international group of 39 reviewers was asked to score radiographs from three dogs, taken in different positions, using the VAS grading system. Scores were averaged and comparisons were made for each set. Results: Phase I-The VAS system identified the greatest number of sets correctly (76%), with the least unchanged scores (15%), and 9% incorrect scores. Phase II-All three patients had an increase in the average difference between VAS-scores for differently positioned radiographs compared to similarly positioned radiographs. The magnitude of change between different positions far exceeded the magnitude of comparison of the similarly positioned radiographs from the 6- and 8-week time point. Discussion/Conclusion: The VAS system appears to be the most appropriate of the tested systems to identify small changes in bone healing. In addition, the positioning of postoperative TPLO radiographs makes a substantial difference in the healing score that is assigned. Care must be undertaken when performing postoperative radiographs in both the clinical and research setting to ensure accurate assessment of bone healing.

Validation of open-path dual-comb spectroscopy against an O2 background.

Dual-comb spectroscopy measures greenhouse gas concentrations over kilometers of open air with high precision. However, the accuracy of these outdoor spectra is challenging to disentangle from the absorption model and the fluctuating, heterogenous concentrations over these paths. Relative to greenhouse gases, O2 concentrations are well-known and evenly mixed throughout the atmosphere. Assuming a constant O2 background, we can use O2 concentration measurements to evaluate the consistency of open-path dual-comb spectroscopy with laboratory-derived absorption models. To this end, we construct a dual-comb spectrometer spanning 1240 nm to 1700nm, which measures O2 absorption features in addition to CO2 and CH4. O2 concentration measurements across a 560 m round-trip outdoor path reach 0.1% precision in 10 minutes. Over seven days of shifting meteorology and spectrometer conditions, the measured O2 has -0.07% mean bias, and 90% of the measurements are within 0.4% of the expected hemisphere-average concentration. The excursions of up to 0.4% seem to track outdoor temperature and humidity, suggesting that accuracy may be limited by the O2 absorption model or by water interference. This simultaneous O2, CO2, and CH4 spectrometer will be useful for measuring accurate CO2 mole fractions over vertical or many-kilometer open-air paths, where the air density varies.

Glatiramer Acetate Complexed with CpG as Intratumoral Immunotherapy in Combination with Anti-PD-1.

CpG oligodeoxynucleotides are toll-like receptor 9 agonists capable of inducing potent pro-inflammatory immune responses. Although CpG oligodeoxynucleotides have shown promising antitumor effects, their systemic activity can trigger immune-related toxicity, limiting therapeutic application. We previously identified glatiramer acetate (GA), a cationic polypeptide approved for the treatment of relapsing-remitting multiple sclerosis, as an intratumoral delivery agent capable of complexing with CpG, thereby pinning it to the injection site and limiting systemic exposure. Here, we investigated whether the combination of CpG or GA-CpG polyplexes and intraperitoneal anti-PD-1 therapy would result in synergistic efficacy in AT84 and CT26 murine syngeneic models of head and neck and colon cancers, respectively. In both AT84 and CT26 tumor models, intratumoral CpG or GA-CpG treatment similarly suppressed tumor growth, but the efficacy was not amplified with anti-PD-1. Nevertheless, combination treatment increased cytotoxic T cell, helper T cell, and natural killer cell infiltration into AT84 tumors. Surprisingly, the combination of intratumoral GA and intraperitoneal anti-PD-1 treatment resulted in elevated systemic GM-CSF and IL-2 cytokine levels and demonstrated synergistic antitumor effects in the CT26 mouse tumor model. Moreover, tumors that responded most significantly to anti-PD-1 plus GA treatment showed increased markers of infiltration of CD4+ T cells and natural killer cells. Combinations of intratumoral GA or GA-CpG polyplexes with anti-PD-1 treatment warrant further investigation as combination cancer immunotherapy strategies.

Genome Sequencing of Methicillin-Resistant and Methicillin-Susceptible Mammaliicoccus sciuri from Diseased Animals.

Mammaliicoccus sciuri (previously Staphylococcus sciuri) is a frequent colonizer of mammals. We report the draft genomes of a methicillin-resistant strain (2254A) isolated from an armadillo and a methicillin-susceptible strain (6942A) from a cow. Genomes were sequenced using long-read Nanopore sequencing.

Malaria Transmission Intensity Likely Modifies RTS, S/AS01 Efficacy Due to a Rebound Effect in Ghana, Malawi, and Gabon.

BACKGROUND: RTS,S/AS01 is the first malaria vaccine to be approved and recommended for widespread implementation by the World Health Organization (WHO). Trials reported lower vaccine efficacies in higher-incidence sites, potentially due to a "rebound" in malaria cases in vaccinated children. When naturally acquired protection in the control group rises and vaccine protection in the vaccinated wanes concurrently, malaria incidence can become greater in the vaccinated than in the control group, resulting in negative vaccine efficacies. METHODS: Using data from the 2009-2014 phase III trial (NCT00866619) in Lilongwe, Malawi; Kintampo, Ghana; and Lambaréné, Gabon, we evaluate this hypothesis by estimating malaria incidence in each vaccine group over time and in varying transmission settings. After estimating transmission intensities using ecological variables, we fit models with 3-way interactions between vaccination, time, and transmission intensity. RESULTS: Over time, incidence decreased in the control group and increased in the vaccine group. Three-dose efficacy in the lowest-transmission-intensity group (0.25 cases per person-year [CPPY]) decreased from 88.2% to 15.0% over 4.5 years, compared with 81.6% to -27.7% in the highest-transmission-intensity group (3 CPPY). CONCLUSIONS: These findings suggest that interventions, including the fourth RTS,S dose, that protect vaccinated individuals during the potential rebound period should be implemented for high-transmission settings.