Nonsecretor Histo-blood Group Antigen Phenotype Is Associated With Reduced Risk of Clinical Rotavirus Vaccine Failure in Malawian Infants

Background Histo–blood group antigen (HBGA) Lewis/secretor phenotypes predict genotype-specific susceptibility to rotavirus gastroenteritis (RVGE). We tested the hypothesis that nonsecretor/Lewis-negative phenotype leads to reduced vaccine take and lower clinical protection following vaccination with G1P[8] rotavirus vaccine (RV1) in Malawian infants Methods A cohort study recruited infants receiving RV1 at age 6 and 10 weeks. HBGA phenotype was determined by salivary enzyme-linked immunosorbent assay (ELISA). RV1 vaccine virus shedding was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in stool collected on alternate days for 10 days post-immunization. Plasma rotavirus–specific immunoglobulin A was determined by ELISA pre- and post-immunization. In a case-control study, HBGA phenotype distribution was compared between RV1-vaccinated infants with RVGE and 1:1 age-matched community controls. Rotavirus genotype was determined by RT-PCR. Results In 202 cohort participants, neither overall vaccine virus fecal shedding nor seroconversion differed by HBGA phenotype. In 238 case-control infants, nonsecretor phenotype was less common in infants with clinical vaccine failure (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.20–0.75). Nonsecretor phenotype was less common in infants with P[8] RVGE (OR, 0.12; 95% CI, 0.03–0.50) and P[4] RVGE (OR, 0.17; 95% CI, 0.04–0.75). Lewis-negative phenotype was more common in infants with P[6] RVGE (OR, 3.2; 95% CI, 1.4–7.2). Conclusions Nonsecretor phenotype was associated with reduced risk of rotavirus vaccine failure. There was no significant association between HBGA phenotype and vaccine take. These data refute the hypothesis that high prevalence of nonsecretor/Lewis-negative phenotypes contributes to lower rotavirus vaccine effectiveness in Malawi

Antigenic Complementarity in the Origins of Autoimmunity: A General Theory Illustrated With a Case Study of Idiopathic Thrombocytopenia Purpura

We describe a novel, testable theory of autoimmunity, outline novel predictions made by the theory, and illustrate its application to unravelling the possible causes of idiopathic thrombocytopenia purpura (ITP). Pairs of stereochemically complementary antigens induce complementary immune responses (antibody or T-cell) that create loss of regulation and civil war within the immune system itself. Antibodies attack antibodies creating circulating immune complexes; T-cells attack T-cells creating perivascular cuffing. This immunological civil war abrogates the self-nonself distinction. If at least one of the complementary antigens mimics a self antigen, then this unregulated immune response will target host tissues as well. Data demonstrating that complementary antigens are found in some animal models of autoimmunity and may be present in various human diseases, especially ITP, are reviewed. Specific mechanisms for preventing autoimmunity or suppressing existing autoimmunity are derived from the theory, and critical tests proposed. Finally, we argue that Koch's postulates are inadequate for establishing disease causation for multiple-antigen diseases and discuss the possibility that current research has failed to elucidate the causes of human autoimmune diseases because we are using the wrong criteria

Evaluation of Pneumococcal Serotyping of Nasopharyngeal-Carriage Isolates by Latex Agglutination, Whole-Genome Sequencing (PneumoCaT), and DNA Microarray in a High-Pneumococcal-Carriage-Prevalence Population in Malawi.

Accurate assessment of the serotype distribution associated with pneumococcal colonization and disease is essential for evaluating and formulating pneumococcal vaccines and for informing vaccine policy. For this reason, we evaluated the concordance between pneumococcal serotyping results by latex agglutination, whole-genome sequencing (WGS) with PneumoCaT, and DNA microarray for samples from community carriage surveillance in Blantyre, Malawi. Nasopharyngeal swabs were collected according to WHO recommendations between 2015 and 2017 by using stratified random sampling among study populations. Participants included healthy children 3 to 6 years old (vaccinated with the 13-valent pneumococcal conjugate vaccine [PCV13] as part of the Expanded Program on Immunization [EPI]), healthy children 5 to 10 years old (age-ineligible for PCV13), and HIV-infected adults (18 to 40 years old) on antiretroviral therapy (ART). For phenotypic serotyping, we used a 13-valent latex kit (Statens Serum Institut [SSI], Denmark). For genomic serotyping, we applied the PneumoCaT pipeline to whole-genome sequence libraries. For molecular serotyping by microarray, we used the BUGS Bioscience Senti-SP microarray. A total of 1,347 samples were analyzed. Concordance was 90.7% (95% confidence interval [CI], 89.0 to 92.2%) between latex agglutination and PneumoCaT, 95.2% (95% CI, 93.9 to 96.3%) between latex agglutination and the microarray, and 96.6% (95% CI, 95.5 to 97.5%) between the microarray and PneumoCaT. By detecting additional vaccine serotype (VT) pneumococci carried at low relative abundances (median, 8%), the microarray increased VT detection by 31.5% over that by latex serotyping. To conclude, all three serotyping methods were highly concordant in identifying dominant serotypes. Latex serotyping is accurate in identifying vaccine serotypes and requires the least expertise and resources for field implementation and analysis. However, WGS, which adds population structure, and microarray, which adds multiple-serotype carriage, should be considered at regional reference laboratories for investigating the importance of vaccine serotypes at low relative abundances in transmission and disease

Evaluation of pneumococcal serotyping in nasopharyngeal carriage isolates by latex agglutination, whole genome sequencing (PneumoCaT) and DNA microarray in a high pneumococcal carriage prevalence population in Malawi

BACKGROUND: Accurate assessment of the serotype distribution associated with pneumococcal colonization and disease is essential for the evaluation and formulation of pneumococcal vaccines and informing vaccine policy. METHODS: We evaluated pneumococcal serotyping concordance between latex agglutination, PneumoCaT by whole genome sequencing (WGS) and DNA microarray using samples from community carriage surveillance in Blantyre, Malawi. Nasopharyngeal swabs were collected, following WHO recommendations, between 2015 and 2017, using stratified random sampling among study populations. Participants included healthy children 3–6 years old (PCV13 vaccinated as part of EPI), healthy children 5–10 years (age-ineligible for PCV13), and HIV-infected adults (18–40yrs) on ART. For phenotypic serotyping we used a 13-valent latex kit (SSI, Denmark). For genomic serotyping we applied PneumoCaT pipeline to whole genome sequence libraries. For molecular serotyping by microarray we used the BUGS Bioscience Senti-SP microarray. RESULTS: 1347 samples were analysed. Concordance was 90.7% (95% CI: 89.0–92.2) between latex and PneumoCaT; 95.2% (93.9–96.3) between latex and microarray; and 96.6% (95.5–97.5) between microarray and PneumoCaT. By detecting additional vaccine serotype (VT) pneumococcus carried at low relative abundance (median 8%), microarray increased VT detection by 31.5% compared to latex serotyping. CONCLUSION: All three serotyping methods were highly concordant in identifying dominant serotypes. Latex serotyping is accurate in identifying vaccine-serotypes and requires the least expertise and resources for field-implementation and analysis. However, WGS, which adds population structure, and microarray, which adds multiple-serotype carriage, should be considered at regional reference laboratories while investigating the importance of VT in low relative abundance in transmission and disease

Hepatitis B vaccination impact and the unmet need for antiviral treatment in Blantyre, Malawi

BACKGROUND: Hepatitis B is the leading cause of cirrhosis and liver cancer in sub-Saharan Africa. To reduce hepatitis-associated mortality, antiviral treatment programmes are needed. We estimated prevalence, vaccine impact and need for antiviral treatment in Blantyre, Malawi to inform an effective public health response. METHODS: We conducted a household study in Blantyre in 2016-2018. We selected individuals from a census using random sampling and estimated age-sex-standardised HBsAg seroprevalence. Impact of infant hepatitis B vaccination, which began in 2002, was estimated by binomial log-linear regression comparing individuals born before and after vaccine implementation. In HBsAg-positive adults, eligibility for antiviral therapy was assessed. RESULTS: Of 97,386 censused individuals, 6,073 (median age 18 years; 56.7% female) were sampled. HBsAg seroprevalence was 5.1% (95% CI 4.3-6.1) among adults and 0.3% (0.1-0.6) among children born after vaccine introduction. Estimated vaccine impact was 95.8% (70.3-99.4). Of HBsAg-positive adults, 26% were HIV-positive. Among HIV-negative individuals, 3%, 6% and 9% were eligible for hepatitis B treatment by WHO, European and American hepatology association criteria, respectively. CONCLUSIONS: Infant HBV vaccination has been highly effective in reducing HBsAg prevalence in urban Malawi. Up to 9% of HBsAg-positive HIV-negative adults are eligible, but have an unmet need, for antiviral therapy

Perceptual Other-Race Training Reduces Implicit Racial Bias

Background: Implicit racial bias denotes socio-cognitive attitudes towards other-race groups that are exempt from conscious awareness. In parallel, other-race faces are more difficult to differentiate relative to own-race faces – the ‘‘Other-Race Effect.’ ’ To examine the relationship between these two biases, we trained Caucasian subjects to better individuate other-race faces and measured implicit racial bias for those faces both before and after training. Methodology/Principal Findings: Two groups of Caucasian subjects were exposed equally to the same African American faces in a training protocol run over 5 sessions. In the individuation condition, subjects learned to discriminate between African American faces. In the categorization condition, subjects learned to categorize faces as African American or not. For both conditions, both pre- and post-training we measured the Other-Race Effect using old-new recognition and implicit racial biases using a novel implicit social measure – the ‘‘Affective Lexical Priming Score’ ’ (ALPS). Subjects in the individuation condition, but not in the categorization condition, showed improved discrimination of African American faces with training. Concomitantly, subjects in the individuation condition, but not the categorization condition, showed a reduction in their ALPS. Critically, for the individuation condition only, the degree to which an individual subject’s ALPS decreased was significantly correlated with the degree of improvement that subject showed in their ability to differentiate African American faces

Co-option of Liver Vessels and Not Sprouting Angiogenesis Drives Acquired Sorafenib Resistance in Hepatocellular Carcinoma.

Background The anti-angiogenic Sorafenib is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC). However, acquired resistance limits its efficacy. An emerging theory to explain intrinsic resistance to other anti-angiogenic drugs is 'vessel co-option,' ie, the ability of tumors to hijack the existing vasculature in organs such as the lungs or liver, thus limiting the need for sprouting angiogenesis. Vessel co-option has not been evaluated as a potential mechanism for acquired resistance to anti-angiogenic agents.Methods To study sorafenib resistance mechanisms, we used an orthotopic human HCC model (n = 4-11 per group), where tumor cells are tagged with a secreted protein biomarker to monitor disease burden and response to therapy. Histopathology, vessel perfusion assessed by contrast-enhanced ultrasound, and miRNA sequencing and quantitative real-time polymerase chain reaction were used to monitor changes in tumor biology.Results While sorafenib initially inhibited angiogenesis and stabilized tumor growth, no angiogenic 'rebound' effect was observed during development of resistance unless therapy was stopped. Instead, resistant tumors became more locally infiltrative, which facilitated extensive incorporation of liver parenchyma and the co-option of liver-associated vessels. Up to 75% (±10.9%) of total vessels were provided by vessel co-option in resistant tumors relative to 23.3% (±10.3%) in untreated controls. miRNA sequencing implicated pro-invasive signaling and epithelial-to-mesenchymal-like transition during resistance development while functional imaging further supported a shift from angiogenesis to vessel co-option.Conclusions This is the first documentation of vessel co-option as a mechanism of acquired resistance to anti-angiogenic therapy and could have important implications including the potential therapeutic benefits of targeting vessel co-option in conjunction with vascular endothelial growth factor receptor signaling

The Universal One-Loop Effective Action

We present the universal one-loop effective action for all operators of dimension up to six obtained by integrating out massive, non-degenerate multiplets. Our general expression may be applied to loops of heavy fermions or bosons, and has been checked against partial results available in the literature. The broad applicability of this approach simplifies one-loop matching from an ultraviolet model to a lower-energy effective field theory (EFT), a procedure which is now reduced to the evaluation of a combination of matrices in our universal expression, without any loop integrals to evaluate. We illustrate the relationship of our results to the Standard Model (SM) EFT, using as an example the supersymmetric stop and sbottom squark Lagrangian and extracting from our universal expression the Wilson coefficients of dimension-six operators composed of SM fields.Comment: 30 pages, v2 contains additional comments and corrects typos, version accepted for publication in JHE