Efficacy and Safety of a Recombinant Plant-Based Adjuvanted Covid-19 Vaccine.

BACKGROUND: Coronavirus-like particles (CoVLP) that are produced in plants and display the prefusion spike glycoprotein of the original strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are combined with an adjuvant (Adjuvant System 03 [AS03]) to form the candidate vaccine. METHODS: In this phase 3, multinational, randomized, placebo-controlled trial conducted at 85 centers, we assigned adults (≥18 years of age) in a 1:1 ratio to receive two intramuscular injections of the CoVLP+AS03 vaccine or placebo 21 days apart. The primary objective of the trial was to determine the efficacy of the CoVLP+AS03 vaccine in preventing symptomatic coronavirus disease 2019 (Covid-19) beginning at least 7 days after the second injection, with the analysis performed after the detection of at least 160 cases. RESULTS: A total of 24,141 volunteers participated in the trial; the median age of the participants was 29 years. Covid-19 was confirmed by polymerase-chain-reaction assay in 165 participants in the intention-to-treat population; all viral samples that could be sequenced contained variants of the original strain. Vaccine efficacy was 69.5% (95% confidence interval [CI], 56.7 to 78.8) against any symptomatic Covid-19 caused by five variants that were identified by sequencing. In a post hoc analysis, vaccine efficacy was 78.8% (95% CI, 55.8 to 90.8) against moderate-to-severe disease and 74.0% (95% CI, 62.1 to 82.5) among the participants who were seronegative at baseline. No severe cases of Covid-19 occurred in the vaccine group, in which the median viral load for breakthrough cases was lower than that in the placebo group by a factor of more than 100. Solicited adverse events were mostly mild or moderate and transient and were more frequent in the vaccine group than in the placebo group; local adverse events occurred in 92.3% and 45.5% of participants, respectively, and systemic adverse events in 87.3% and 65.0%. The incidence of unsolicited adverse events was similar in the two groups up to 21 days after each dose (22.7% and 20.4%) and from day 43 through day 201 (4.2% and 4.0%). CONCLUSIONS: The CoVLP+AS03 vaccine was effective in preventing Covid-19 caused by a spectrum of variants, with efficacy ranging from 69.5% against symptomatic infection to 78.8% against moderate-to-severe disease. (Funded by Medicago; ClinicalTrials.gov number, NCT04636697.).

Characterization of QoI-Fungicide Resistance in Cercospora Isolates Associated with Cercospora Leaf Blight of Soybean from the Southern United States.

Cercospora leaf blight (CLB) of soybean, caused by Cercospora cf. flagellaris, C. kikuchii, and C. cf. sigesbeckiae, is an economically important disease in the southern United States. Cultivar resistance to CLB is inconsistent; therefore, fungicides in the quinone outside inhibitor (QoI) class have been relied on to manage the disease. Approximately 620 isolates from plants exhibiting CLB were collected between 2018 and 2021 from 19 locations in eight southern states. A novel polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay based on two genes, calmodulin and histone h3, was developed to differentiate between the dominant species of Cercospora, C. cf. flagellaris, and C. cf. sigesbeckiae. A multilocus phylogenetic analysis of actin, calmodulin, histone h3, ITS rDNA, and transcription elongation factor 1-α was used to confirm PCR-RFLP results and identify remaining isolates. Approximately 80% of the isolates collected were identified as C. cf. flagellaris, while 15% classified as C. cf. sigesbeckiae, 2% as C. kikuchii, and 3% as previously unreported Cercospora species associated with CLB in the United States. PCR-RFLP of cytochrome b (cytb) identified QoI-resistance conferred by the G143A substitution. Approximately 64 to 83% of isolates were determined to be QoI-resistant, and all contained the G143A substitution. Results of discriminatory dose assays using azoxystrobin (1 ppm) were 100% consistent with PCR-RFLP results. To our knowledge, this constitutes the first report of QoI resistance in CLB pathogen populations from Alabama, Arkansas, Kentucky, Mississippi, Missouri, Tennessee, and Texas. In areas where high frequencies of resistance have been identified, QoI fungicides should be avoided, and fungicide products with alternative modes-of-action should be utilized in the absence of CLB-resistant soybean cultivars.

An increase in glycoprotein concentration on extracellular virions dramatically alters vaccinia virus infectivity and pathogenesis without impacting immunogenicity.

The extracellular virion (EV) form of Orthopoxviruses is required for cell-to-cell spread and pathogenesis, and is the target of neutralizing antibodies in the protective immune response. EV have a double envelope that contains several unique proteins that are involved in its intracellular envelopment and/or subsequent infectivity. One of these, F13, is involved in both EV formation and infectivity. Here, we report that replacement of vaccinia virus F13L with the molluscum contagiosum virus homolog, MC021L, results in the production of EV particles with significantly increased levels of EV glycoproteins, which correlate with a small plaque phenotype. Using a novel fluorescence-activated virion sorting assay to isolate EV populations based on glycoprotein content we determine that EV containing either higher or lower levels of glycoproteins are less infectious, suggesting that there is an optimal concentration of glycoproteins in the outer envelope that is required for maximal infectivity of EV. This optimal glycoprotein concentration was required for lethality and induction of pathology in a cutaneous model of animal infection, but was not required for induction of a protective immune response. Therefore, our results demonstrate that there is a sensitive balance between glycoprotein incorporation, infectivity, and pathogenesis, and that manipulation of EV glycoprotein levels can produce vaccine vectors in which pathologic side effects are attenuated without a marked diminution in induction of protective immunity.

Bearded or smooth? Awns improve yield when wheat experiences heat stress during grain fill in the southeastern United States.

The presence or absence of awns-whether wheat heads are 'bearded' or 'smooth' - is the most visible phenotype distinguishing wheat cultivars. Previous studies suggest that awns may improve yields in heat or water-stressed environments, but the exact contribution of awns to yield differences remains unclear. Here we leverage historical phenotypic, genotypic, and climate data for wheat (Triticum aestivum) to estimate the yield effects of awns under different environmental conditions over a 12-year period in the southeastern USA. Lines were classified as awned or awnless based on sequence data, and observed heading dates were used to associate grain fill periods of each line in each environment with climatic data and grain yield. In most environments, awn suppression was associated with higher yields, but awns were associated with better performance in heat-stressed environments more common at southern locations. Wheat breeders in environments where awns are only beneficial in some years may consider selection for awned lines to reduce year-to-year yield variability, and with an eye towards future climates.

Profiling of Fusarium head blight resistance QTL haplotypes through molecular markers, genotyping-by-sequencing, and machine learning.

KEY MESSAGE: Marker-assisted selection is important for cultivar development. We propose a system where a training population genotyped for QTL and genome-wide markers may predict QTL haplotypes in early development germplasm. Breeders screen germplasm with molecular markers to identify and select individuals that have desirable haplotypes. The objective of this research was to investigate whether QTL haplotypes can be accurately predicted using SNPs derived by genotyping-by-sequencing (GBS). In the SunGrains program during 2020 (SG20) and 2021 (SG21), 1,536 and 2,352 lines submitted for GBS were genotyped with markers linked to the Fusarium head blight QTL: Qfhb.nc-1A, Qfhb.vt-1B, Fhb1, and Qfhb.nc-4A. In parallel, data were compiled from the 2011-2020 Southern Uniform Winter Wheat Scab Nursery (SUWWSN), which had been screened for the same QTL, sequenced via GBS, and phenotyped for: visual Fusarium severity rating (SEV), percent Fusarium damaged kernels (FDK), deoxynivalenol content (DON), plant height, and heading date. Three machine learning models were evaluated: random forest, k-nearest neighbors, and gradient boosting machine. Data were randomly partitioned into training-testing splits. The QTL haplotype and 100 most correlated GBS SNPs were used for training and tuning of each model. Trained machine learning models were used to predict QTL haplotypes in the testing partition of SG20, SG21, and the total SUWWSN. Mean disease ratings for the observed and predicted QTL haplotypes were compared in the SUWWSN. For all models trained using the SG20 and SG21, the observed Fhb1 haplotype estimated group means for SEV, FDK, DON, plant height, and heading date in the SUWWSN were not significantly different from any of the predicted Fhb1 calls. This indicated that machine learning may be utilized in breeding programs to accurately predict QTL haplotypes in earlier generations.

Rapid and specific detection of intact viral particles using functionalized microslit silicon membranes as a fouling-based sensor.

The COVID-19 pandemic demonstrated the public health benefits of reliable and accessible point-of-care (POC) diagnostic tests for viral infections. Despite the rapid development of gold-standard reverse transcription polymerase chain reaction (RT-PCR) assays for SARS-CoV-2 only weeks into the pandemic, global demand created logistical challenges that delayed access to testing for months and helped fuel the spread of COVID-19. Additionally, the extreme sensitivity of RT-PCR had a costly downside as the tests could not differentiate between patients with active infection and those who were no longer infectious but still shedding viral genomes. To address these issues for the future, we propose a novel membrane-based sensor that only detects intact virions. The sensor combines affinity and size based detection on a membrane-based sensor and does not require external power to operate or read. Specifically, the presence of intact virions, but not viral debris, fouls the membrane and triggers a macroscopically visible hydraulic switch after injection of a 40 µL sample with a pipette. The device, which we call the µSiM-DX (microfluidic device featuring a silicon membrane for diagnostics), features a biotin-coated microslit membrane with pores ∼2-3× larger than the intact virus. Streptavidin-conjugated antibody recognizing viral surface proteins are incubated with the sample for ∼1 hour prior to injection into the device, and positive/negative results are obtained within ten seconds of sample injection. Proof-of-principle tests have been performed using preparations of vaccinia virus. After optimizing slit pore sizes and porous membrane area, the fouling-based sensor exhibits 100% specificity and 97% sensitivity for vaccinia virus (n = 62). Moreover, the dynamic range of the sensor extends at least from 105.9 virions per mL to 1010.4 virions per mL covering the range of mean viral loads in symptomatic COVID-19 patients (105.6-107 RNA copies per mL). Forthcoming work will test the ability of our sensor to perform similarly in biological fluids and with SARS-CoV-2, to fully test the potential of a membrane fouling-based sensor to serve as a PCR-free alternative for POC containment efforts in the spread of infectious disease.

Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, virus-like particle influenza vaccine in adults (18-64 years) and older adults (≥65 years): two multicentre, randomised phase 3 trials.

BACKGROUND: Seasonal influenza remains a substantial public health threat despite the availability of egg-derived and other vaccines. Plant-based manufacturing might address some of the limitations of current vaccines. We describe two phase 3 efficacy studies of a recombinant quadrivalent virus-like particle (QVLP) influenza vaccine manufactured in plants, one in adults aged 18-64 years (the 18-64 study) and one in older people aged 65 years and older (the 65-plus study). METHODS: We did two randomised, observer-blind, multinational studies in the northern hemisphere in the 2017-18 (the 18-64 study) and 2018-19 (the 65-plus study) influenza seasons. The 18-64 study was done at 73 sites and the 65-plus study was done at 104 sites, both across Asia, Europe, and North America. In the 18-64 study, inclusion criteria were body-mass index less than 40 kg/m2; age 18-64 years at screening visit; and good health. In the 65-plus study, inclusion criteria were body-mass index of maximum 35 kg/m2; aged 65 years or older at screening visit; not living in a rehabilitation centre or care home; and no acute or evolving medical problems. Participants in the 18-64 study were randomly assigned (1:1) to receive either QVLP vaccine (30 µg haemagglutinin per strain) or placebo. Participants in the 65-plus study were randomly assigned (1:1) to receive QVLP vaccine (30 µg haemagglutinin per strain) or quadrivalent inactivated vaccine (QIV; 15 µg haemagglutinin per strain). The primary outcome in the 18-64 study was absolute vaccine efficacy to prevent laboratory-confirmed, respiratory illness caused by antigenically matched influenza strains. The primary outcome in the 65-plus study was relative vaccine efficacy to prevent laboratory-confirmed influenza-like illness caused by any influenza strain. The primary analyses were done in the per-protocol population and safety was assessed in all participants who received the assigned treatment. These studies are registered with ClinicalTrials.gov (18-64 study NCT03301051; 65-plus study NCT03739112). FINDINGS: In the 18-64 study, between Aug 30, 2017, and Jan 15, 2018, 10 160 participants were randomly assigned to receive either QVLP vaccine (5077 participants) or placebo (5083 participants). The per-protocol population consisted of 4814 participants in the QVLP group and 4812 in the placebo group. The study did not meet its primary endpoint of 70% absolute vaccine efficacy for the QVLP vaccine (35·1% [95% CI 17·9 to 48·7]) against respiratory illness caused by matched strains. 55 (1·1%) of 5064 participants in the QVLP group versus 51 (1·0%) of 5072 in the placebo group had a serious adverse event. Four (0·1%) and six [0·1%] participants had severe treatment-related treatment-emergent adverse events. In the 65-plus study, between Sept 18, 2018, and Feb 22, 2019, 12 794 participants were randomly assigned to receive either QVLP vaccine (6396 participants) or QIV (6398 participants). The per-protocol population consisted of 5996 participants in the QVLP group and 6026 in the QIV group. The study met its primary non-inferiority endpoint with a relative vaccine efficacy of the QVLP vaccine for the prevention of influenza-like illness caused by any strain of 8·8% (-16·7 to 28·7). 263 (4·1%) of 6352 participants in the QVLP group versus 266 (4·2%) of 6366 in the QIV group had serious adverse events (one [<0·1%] vs two [<0·1%] were considered treatment-related); one (<0·1%) versus three (<0·1%) participants had severe treatment-related treatment-emergent adverse events. INTERPRETATION: These efficacy studies are the first large-scale studies of any plant-derived human vaccine. Together, they show that the plant-derived QVLP vaccine can provide substantial protection against respiratory illness and influenza-like illness caused by influenza viruses in adults. QVLP vaccine was well tolerated and no major safety signal arose in participants who received QVLP vaccine across the two studies. FUNDING: Medicago.

The Molluscum Contagiosum Gene MC021L Partially Compensates for the Loss of Its Vaccinia Virus Homolog, F13L.

Orthopoxviruses produce two antigenically distinct infectious enveloped virions termed intracellular mature virions and extracellular virions (EV). EV have an additional membrane compared to intracellular mature virions due to a wrapping process at the trans-Golgi network and are required for cell-to-cell spread and pathogenesis. Specific to the EV membrane are a number of proteins highly conserved among orthopoxviruses, including F13, which is required for the efficient wrapping of intracellular mature virions to produce EV and which plays a role in EV entry. The distantly related molluscipoxvirus, molluscum contagiosum virus, is predicted to encode several vaccinia virus homologs of EV-specific proteins, including the homolog of F13L, MC021L. To study the function of MC021, we replaced the F13L open reading frame in vaccinia virus with an epitope-tagged version of MC021L. The resulting virus (vMC021L-HA) had a small-plaque phenotype compared to vF13L-HA but larger than vΔF13L. The localization of MC021-HA was markedly different from that of F13-HA in infected cells, but MC021-HA was still incorporated in the EV membrane. Similar to F13-HA, MC021-HA was capable of interacting with both A33 and B5. Although MC021-HA expression did not fully restore plaque size, vMC021L-HA produced amounts of EV similar to those produced by vF13L-HA, suggesting that MC021 retained some of the functionality of F13. Further analysis revealed that EV produced from vMC021L-HA exhibit a marked reduction in target cell binding and an increase in dissolution, both of which correlated with a small-plaque phenotype.IMPORTANCE The vaccinia virus extracellular virion protein F13 is required for the production and release of infectious extracellular virus, which in turn is essential for the subsequent spread and pathogenesis of orthopoxviruses. Molluscum contagiosum virus infects millions of people worldwide each year, but it is unknown whether EV are produced during infection for spread. Molluscum contagiosum virus contains a homolog of F13L termed MC021L. To study the potential function of this homolog during infection, we utilized vaccinia virus as a surrogate and showed that a vaccinia virus expressing MC021L-HA in place of F13L-HA exhibits a small-plaque phenotype but produces similar levels of EV. These results suggest that MC021-HA can compensate for the loss of F13-HA by facilitating wrapping to produce EV and further delineates the dual role of F13 during infection.

Vaccinia Virus Glycoproteins A33, A34, and B5 Form a Complex for Efficient Endoplasmic Reticulum to trans-Golgi Network Transport.

Orthopoxviruses produce two, antigenically distinct, infectious enveloped virions termed intracellular mature virions and extracellular virions. Extracellular virions are required for cell-to-cell spread and pathogenesis. Specific to the extracellular virion membrane, glycoproteins A33, A34, and B5 are highly conserved among orthopoxviruses and have roles during extracellular virion formation and subsequent infection. B5 is dependent on an interaction with either A33 or A34 for localization to the site of intracellular envelopment and incorporation into the envelope of released extracellular virions. In this report we show that an interaction between A33 and A34 can be detected in infected cells. Furthermore, we show that a three-protein complex between A33, A34, and B5 forms in the endoplasmic reticulum (ER) that disassociates post ER export. Finally, immunofluorescence reveals that coexpression of all three glycoproteins results in their localization to a juxtanuclear region that is presumably the site of intracellular envelopment. These results demonstrate the existence of two previously unidentified interactions: one between A33 and A34 and another simultaneous interaction between all three of the glycoproteins. Furthermore, these results indicate that interactions among A33, A34, and B5 are vital for proper intracellular trafficking and subcellular localization.IMPORTANCE The secondary intracellular envelopment of poxviruses at the trans-Golgi network to release infectious extracellular virus (EV) is essential for their spread and pathogenesis. Viral glycoproteins A33, A34, and B5 are critical for the efficient production of infectious EV and interactions among these proteins are important for their localization and incorporation into the outer extracellular virion membrane. We have uncovered a novel interaction between glycoproteins A33 and A34. Furthermore, we show that B5 can interact with the A33-A34 complex. Our analysis indicates that the three-protein complex has a role in ER exit and proper localization of the three glycoproteins to the intracellular site of wrapping. These results show that a complex set of interactions occur in the secretory pathway of infected cells to ensure proper glycoprotein trafficking and envelope content, which is important for the release of infectious poxvirus virions.

Type I interferon-dependent CCL4 is induced by a cGAS/STING pathway that bypasses viral inhibition and protects infected tissue, independent of viral burden.

Type I interferons (T1-IFN) are critical in the innate immune response, acting upon infected and uninfected cells to initiate an antiviral state by expressing genes that inhibit multiple stages of the lifecycle of many viruses. T1-IFN triggers the production of Interferon-Stimulated Genes (ISGs), activating an antiviral program that reduces virus replication. The importance of the T1-IFN response is highlighted by the evolution of viral evasion strategies to inhibit the production or action of T1-IFN in virus-infected cells. T1-IFN is produced via activation of pathogen sensors within infected cells, a process that is targeted by virus-encoded immunomodulatory molecules. This is probably best exemplified by the prototypic poxvirus, Vaccinia virus (VACV), which uses at least 6 different mechanisms to completely block the production of T1-IFN within infected cells in vitro. Yet, mice lacking aspects of T1-IFN signaling are often more susceptible to infection with many viruses, including VACV, than wild-type mice. How can these opposing findings be rationalized? The cytosolic DNA sensor cGAS has been implicated in immunity to VACV, but has yet to be linked to the production of T1-IFN in response to VACV infection. Indeed, there are two VACV-encoded proteins that effectively prevent cGAS-mediated activation of T1-IFN. We find that the majority of VACV-infected cells in vivo do not produce T1-IFN, but that a small subset of VACV-infected cells in vivo utilize cGAS to sense VACV and produce T1-IFN to protect infected mice. The protective effect of T1-IFN is not mediated via ISG-mediated control of virus replication. Rather, T1-IFN drives increased expression of CCL4, which recruits inflammatory monocytes that constrain the VACV lesion in a virus replication-independent manner by limiting spread within the tissue. Our findings have broad implications in our understanding of pathogen detection and viral evasion in vivo, and highlight a novel immune strategy to protect infected tissue.

Barriers and facilitators to influenza and pneumococcal vaccine hesitancy in rheumatoid arthritis: a qualitative study.

OBJECTIVES: Immunization is an essential component of RA care. Nevertheless, vaccine coverage in RA is suboptimal. Contextual, individual and vaccine-related factors influence vaccine acceptance. However, barriers and facilitators of vaccination in RA are not well defined. The aim of this study was to assess perspectives of RA patients and healthcare professionals (HCPs) involved in RA care of barriers and facilitators regarding influenza and pneumococcal vaccines. METHODS: Eight focus groups (four with RA patients and four with HCPs) and eight semi-structured open-ended individual interviews with vaccine-hesitant RA patients were conducted. Data were audio recorded, transcribed verbatim and imported to MAXQDA software. Analysis using the framework of vaccine hesitancy proposed by the Strategic Advisory Group of Experts on Immunization was conducted. RESULTS: RA patients and HCPs reported common and specific barriers and facilitators to influenza vaccination that included contextual, individual and/or group and vaccine- and/or vaccination-specific factors. A key contextual influence on vaccination was patients' perception of the media, pharmaceutical industry, authorities, scientists and the medical community at large. Among the individual-related influences, experiences with vaccination, knowledge/awareness and beliefs about health and disease prevention were considered to impact vaccine acceptance. Vaccine-related factors including concerns about vaccine side effects such as RA flares, the safety of new formulations, the mechanism of action, access to vaccines and costs associated with vaccination were identified as actionable barriers. CONCLUSION: Acknowledging RA patients' perceived barriers to influenza and pneumococcal vaccination and implementing specific strategies to address them might increase vaccination coverage in this population.

Measuring Multimorbidity: Selecting the Right Instrument for the Purpose and the Data Source.

BACKGROUND: Adults have a higher prevalence of multimorbidity-or having multiple chronic health conditions-than having a single condition in isolation. Researchers, health care providers, and health policymakers find it challenging to decide upon the most appropriate assessment tool from the many available multimorbidity measures. OBJECTIVE: The objective of this study was to describe a broad range of instruments and data sources available to assess multimorbidity and offer guidance about selecting appropriate measures. DESIGN: Instruments were reviewed and guidance developed during a special expert workshop sponsored by the National Institutes of Health on September 25-26, 2018. RESULTS: Workshop participants identified 4 common purposes for multimorbidity measurement as well as the advantages and disadvantages of 5 major data sources: medical records/clinical assessments, administrative claims, public health surveys, patient reports, and electronic health records. Participants surveyed 15 instruments and 2 public health data systems and described characteristics of the measures, validity, and other features that inform tool selection. Guidance on instrument selection includes recommendations to match the purpose of multimorbidity measurement to the measurement approach and instrument, review available data sources, and consider contextual and other related constructs to enhance the overall measurement of multimorbidity. CONCLUSIONS: The accuracy of multimorbidity measurement can be enhanced with appropriate measurement selection, combining data sources and special considerations for fully capturing multimorbidity burden in underrepresented racial/ethnic populations, children, individuals with multiple Adverse Childhood Events and older adults experiencing functional limitations, and other geriatric syndromes. The increased availability of comprehensive electronic health record systems offers new opportunities not available through other data sources.

Genome-wide association mapping of the 'super-soft' kernel texture in white winter wheat.

KEY MESSAGE: The novel super-soft kernel phenotype has the potential to improve wheat processing and flour quality. We identified genomic regions associated with this kernel texture in white winter wheat. Grain hardness is a key determinant of wheat milling and baking quality. The recently discovered 'super-soft' kernel phenotype has the potential to improve wheat processing and flour quality. However, the genetic basis underlying the super-soft trait in wheat is not yet well understood. In this study, we investigated the phenotypic and genotypic structure of the super-soft trait in a collection of 172 advanced soft white winter wheat breeding lines and cultivars adapted to the Pacific Northwest region of the USA. This collection had a continuous distribution for grain hardness index (single-kernel characterization system). Ten super-soft genotypes showed hardness index ≤ 12 including the cultivar Jasper. Over 98,000 SNP markers from genotyping-by-sequencing were used for association mapping (GWAS). The GWAS identified 20 significant markers associated with grain hardness. These significant SNPs corresponded to seven QTL on chromosomes 2B, 3A, 3B, 5A, 6B,7A, and one unaligned chromosome. Two of these QTL, QSKhard.wql-3A and QSKhard.wql-5A, had large effects and distinguished between the normal soft and the super-soft classes. QSKhard.wql-3A and QSKhard.wql-5A reduced the hardness index by 11.7 and 13.1 on average, respectively. The remaining QTL had small effects and reduced grain hardness within the normal soft range. QSKhard.wql-2B, QSKhard.wql-3A, QSKhard.wql-3B, and QSKhard.wql-6B were not previously reported to be in genomic regions of grain hardness-related genes/QTL. The identified super-soft genotypes as well as the SNPs associated with lower grain hardness will be useful to assist breeding for this grain texture trait.

COVID-19 Pandemic Impact on the National Health Care Surveys.

While underscoring the need for timely, nationally representative data in ambulatory, hospital, and long-term-care settings, the COVID-19 pandemic posed many challenges to traditional methods and mechanisms of data collection. To continue generating data from health care and long-term-care providers and establishments in the midst of the COVID-19 pandemic, the National Center for Health Statistics had to modify survey operations for several of its provider-based National Health Care Surveys, including quickly adding survey questions that captured the experiences of providing care during the pandemic. With the aim of providing information that may be useful to other health care data collection systems, this article presents some key challenges that affected data collection activities for these national provider surveys, as well as the measures taken to minimize the disruption in data collection and to optimize the likelihood of disseminating quality data in a timely manner. (Am J Public Health. 2021;111(12):2141-2148. https://doi.org/10.2105/AJPH.2021.306514).

Randomized Trial of 2 Schedules of Meningococcal B Vaccine in Adolescents and Young Adults, Canada1.

Emergency vaccination programs often are needed to control outbreaks of meningococcal disease caused by Neisseria meningitidis serogroup B (MenB) on college campuses. Such campaigns expend multiple campus and public health resources. We conducted a randomized, controlled, multicenter, observer-blinded trial comparing immunogenicity and tolerability of an accelerated vaccine schedule of 0 and 21 days to a longer interval of 0 and 60 days for 4-component MenB vaccine (MenB-4C) in students 17-25 years of age. At day 21 after the first MenB-4C dose, we observed protective human serum bactericidal titers >4 to MenB strains 5/99, H44/76, and NZ 98/254 in 98%-100% of participants. Geometric mean titers increased >22-fold over baseline. At day 180, >95% of participants sustained protective titers regardless of their vaccine schedule. The most common adverse event was injection site pain. An accelerated MenB-4C immunization schedule could be considered for rapid control of campus outbreaks.

A Bivalent Meningococcal B Vaccine in Adolescents and Young Adults.

BACKGROUND: MenB-FHbp is a licensed meningococcal B vaccine targeting factor H-binding protein. Two phase 3 studies assessed the safety of the vaccine and its immunogenicity against diverse strains of group B meningococcus. METHODS: We randomly assigned 3596 adolescents (10 to 18 years of age) to receive MenB-FHbp or hepatitis A virus vaccine and saline and assigned 3304 young adults (18 to 25 years of age) to receive MenB-FHbp or saline at baseline, 2 months, and 6 months. Immunogenicity was assessed in serum bactericidal assays that included human complement (hSBAs). We used 14 meningococcal B test strains that expressed vaccine-heterologous factor H-binding proteins representative of meningococcal B epidemiologic diversity; an hSBA titer of at least 1:4 is the accepted correlate of protection. The five primary end points were the proportion of participants who had an increase in their hSBA titer for each of 4 primary strains by a factor of 4 or more and the proportion of those who had an hSBA titer at least as high as the lower limit of quantitation (1:8 or 1:16) for all 4 strains combined after dose 3. We also assessed the hSBA responses to the primary strains after dose 2; hSBA responses to the 10 additional strains after doses 2 and 3 were assessed in a subgroup of participants only. Safety was assessed in participants who received at least one dose. RESULTS: In the modified intention-to-treat population, the percentage of adolescents who had an increase in the hSBA titer by a factor of 4 or more against each primary strain ranged from 56.0 to 85.3% after dose 2 and from 78.8 to 90.2% after dose 3; the percentages of young adults ranged from 54.6 to 85.6% and 78.9 to 89.7%, after doses 2 and 3, respectively. Composite responses after doses 2 and 3 in adolescents were 53.7% and 82.7%, respectively, and those in young adults were 63.3% and 84.5%, respectively. Responses to the 4 primary strains were predictive of responses to the 10 additional strains. Most of those who received MenB-FHbp reported mild or moderate pain at the vaccination site. CONCLUSIONS: MenB-FHbp elicited bactericidal responses against diverse meningococcal B strains after doses 2 and 3 and was associated with more reactions at the injection site than the hepatitis A virus vaccine and saline. (Funded by Pfizer; ClinicalTrials.gov numbers, NCT01830855 and NCT01352845 ).

The Ectodomain of the Vaccinia Virus Glycoprotein A34 Is Required for Cell Binding by Extracellular Virions and Contains a Large Region Capable of Interaction with Glycoprotein B5.

An interaction between the orthopoxvirus glycoproteins A34 and B5 has been reported. The transmembrane and ectodomain of A34 are sufficient for interaction with B5, localization of B5 to the site of intracellular wrapping, and subsequent incorporation into the envelope of released extracellular virions. Several mutagenic approaches were undertaken to better define the B5 interaction domain on A34. A set of C-terminal truncations in A34 identified residues 1 to 80 as sufficient for interaction with B5. Additional truncations identified residues 80 to 130 of A34 as sufficient for interaction with B5. To better understand the function of this region, a set of recombinant viruses expressing A34 with the full, partial, or no B5 interaction site (residues 1 to 130, 1 to 100, and 1 to 70, respectively) was constructed. All the recombinants expressing truncations of A34 incorporated B5 into extracellular virions but had a small-plaque phenotype similar to that of a virus with the A34R gene deleted (vΔA34R). Further characterization indicated that the small-plaque phenotype exhibited by these viruses is due to a combination of abrogated actin tail formation, reduced cell binding, and a defect in polyanion-induced nonfusogenic dissolution. Taken together, these results suggest that residues 80 to 130 of A34 are not necessary for the proper localization and incorporation of B5 into extracellular virions and, furthermore, that the C-terminal residues of A34 are involved in cell binding and dissolution.IMPORTANCE Previous studies have shown that the vaccinia virus glycoproteins A34 and B5 interact, and in the absence of A34, B5 is mislocalized and not incorporated into extracellular virions. Here, using a transient-transfection assay, residues 80 to 130 of the ectodomain of A34 were determined to be sufficient for interaction with B5. Recombinant viruses expressing A34 with a full, partial, or no B5 interaction site were constructed and characterized. All of the A34 truncations interacted with B5 as predicted by the transient-transfection studies but had a small-plaque phenotype. Further analysis revealed that all of the recombinants incorporated detectable levels of B5 into released virions but were defective in cell binding and extracellular virion (EV) dissolution. This study is the first to directly demonstrate that A34 is involved in cell binding and implicate the ectodomain in this role.

Antineoplastic drugs prescription during visits by adult cancer patients with comorbidities: findings from the 2010-2016 National Ambulatory Medical Care Survey.

PURPOSE: Cancer treatment may be affected by comorbidities; however, studies are limited. The purpose of this study is to examine the frequency of comorbidities at visits by patients with breast, prostate, colorectal, and lung cancer and to estimate frequency of a prescription for antineoplastic drugs being included in the treatment received at visits by patients with cancer and concomitant comorbidities. METHODS: We used nationally representative data on visits to office-based physicians from the 2010-2016 National Ambulatory Medical Care Survey and selected visits by adults with breast, prostate, colorectal, or lung cancer (n = 4,672). Nineteen comorbid conditions were examined. Descriptive statistics were calculated for visits by cancer patients with 0, 1, and ≥ 2 comorbidities. RESULTS: From 2010-2016, a total of 10.2 million physician office visits were made annually by adult patients with breast, prostate, colorectal, or lung cancer. Among US visits by adult patients with breast, prostate, colorectal, or lung cancer, 56.3% were by patients with ≥ 1 comorbidity. Hypertension was the most frequently observed comorbidity (37.7%), followed by hyperlipidemia (19.0%) and diabetes (12.3%). Antineoplastic drugs were prescribed in 33.5% of the visits and prescribed at a lower percentage among visits by cancer patients with COPD (21.3% versus 34.3% of visits by cancer patients without COPD) and heart disease (22.7% versus 34.2% of visits by cancer patients without heart disease). CONCLUSION: Our study provides information about comorbidities in cancer patients being treated by office-based physicians in an ambulatory setting.

Computerized Capability of Office-Based Physicians to Identify Patients Who Need Preventive or Follow-up Care - United States, 2017.

Preventive care or follow-up care have the potential to improve health outcomes, reduce disease in the population, and decrease health care costs in the long-term (1). Approximately one half of persons in the United States receive general recommended preventive services (2,3). Missed physician appointments can hinder the receipt of needed health care (4). With electronic health record (EHR) systems able to improve interaction and communication between patients and providers (5), electronic reminders are used to decrease missed care. These reminders can improve various types of preventive and follow-up care, such as immunizations (6) and cancer screening (7); however, computerized capability must exist to make use of these reminders. To examine this capability among U.S. office-based physicians, data from the National Electronic Health Records Survey (NEHRS) for 2017, the most recent data available, were analyzed. An estimated 64.7% of office-based physicians had computerized capability to identify patients who were due for preventive or follow-up care, with 72.9% of primary care physicians and 71.4% of physicians with an EHR system having this capability compared with surgeons (54.8%), nonprimary care physicians (58.5%), and physicians without an EHR system (23.4%). Having an EHR system is associated with the ability to send electronic reminders to increase receipt of preventive or follow-up care, which has been shown to improve patient health outcomes (8).

Exposure to lead and vaccine-specific IgG titers in South African children participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE): A longitudinal study.

BACKGROUND: While successes have been achieved in reducing global exposure to lead, few studies have investigated the potential health effects of low-level exposure (e.g. blood lead levels [BLLs] below the CDC reference level of 5 µg/dL), particularly among children from low- and middle-income countries. In addition, lead is immunotoxic in animals but human data on immune response to vaccines is limited. Our aim was to determine whether low-level exposure to lead is associated with humoral response to vaccines among rural South African children. METHODS: We used data from the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE), a birth cohort study conducted in Limpopo, South Africa. BLLs were measured in whole blood collected at age 1 year and IgG titers for measles, tetanus and Haemophilus influenzae type B (Hib) were determined at age 3.5 years among 425 fully-vaccinated children. RESULTS: BLLs were low (median = 1.90 µg/dL) and 94% of children had a BLL below 5 µg/dL. Overall, BLLs were associated with higher risks of having IgG titers below the protective limit for tetanus (RR = 1.88 per 10-fold increase; 95%CI = 1.08, 3.24) but not measles (RR = 1.02; 95%CI = 0.26, 3.95) or Hib (RR = 0.96; 95%CI = 0.54, 1.71). BLLs were also associated with low Hib IgG titers among children exposed to HIV in utero and with low measles IgG titers among females. In contrast, the association with measles IgG titers was positive among males. CONCLUSION: Low-level exposure to lead may compromise the humoral response to vaccines. Children exposed to HIV in utero and females may be particularly susceptible.