Clinical efficacy and long-term immunogenicity of an early triple dose regimen of SARS-CoV-2 mRNA vaccination in cancer patients.

INTRODUCTION: Three doses of SARS-CoV-2 mRNA vaccines have been recommended for cancer patients to reduce the risk of severe disease. Anti-neoplastic treatment, such as chemotherapy, may affect long-term vaccine immunogenicity. METHOD: Patients with solid or haematological cancer were recruited from 2 hospitals between July 2021 and March 2022. Humoral response was evaluated using GenScript cPASS surrogate virus neutralisation assays. Clinical outcomes were obtained from medical records and national mandatory-reporting databases. RESULTS: A total of 273 patients were recruited, with 40 having haematological malignancies and the rest solid tumours. Among the participants, 204 (74.7%) were receiving active cancer therapy, including 98 (35.9%) undergoing systemic chemotherapy and the rest targeted therapy or immunotherapy. All patients were seronegative at baseline. Seroconversion rates after receiving 1, 2 and 3 doses of SARS-CoV-2 mRNA vaccination were 35.2%, 79.4% and 92.4%, respectively. After 3 doses, patients on active treatment for haematological malignancies had lower antibodies (57.3%±46.2) when compared to patients on immunotherapy (94.1%±9.56, P<0.05) and chemotherapy (92.8%±18.1, P<0.05). SARS-CoV-2 infection was reported in 77 (28.2%) patients, of which 18 were severe. No patient receiving a third dose within 90 days of the second dose experienced severe infection. CONCLUSION: This study demonstrates the benefit of early administration of the third dose among cancer patients.

Genomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy.

Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genomewide association studies (GWAS) from two clinical cohorts treated with MTAs (Cancer and Leukemia Group B (CALGB) 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1 ; e.g., rs74497159, ßCALGB 40101 per allele log hazard ratio (95% confidence interval (CI)) = 0.591 (0.254-0.928), ßCALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334-1.053); PMETA  = 3.62 × 10-7 ) were the most highly ranked associations based on P values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in induced pluripotent stem cell-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.

A Pharmacogenetic Prediction Model of Progression-Free Survival in Breast Cancer using Genome-Wide Genotyping Data from CALGB 40502 (Alliance).

Genome-wide genotyping data are increasingly available for pharmacogenetic association studies, but application of these data for development of prediction models is limited. Prediction methods, such as elastic net regularization, have recently been applied to genetic studies but only limitedly to pharmacogenetic outcomes. An elastic net was applied to a pharmacogenetic study of progression-free survival (PFS) of 468 patients with advanced breast cancer in a clinical trial of paclitaxel, nab-paclitaxel, and ixabepilone. A final model included 13 single nucleotide polymorphisms (SNPs) in addition to clinical covariates (prior taxane status, hormone receptor status, disease-free interval, and presence of visceral metastases) with an area under the curve (AUC) integrated over time of 0.81, an increase compared to an AUC of 0.64 for a model with clinical covariates alone. This model may be of value in predicting PFS with microtubule targeting agents and may inform reverse translational studies to understand differential response to these drugs.

Effects of imposed defocus of opposite sign on temporal gene expression patterns of BMP4 and BMP7 in chick RPE.

This study investigated the effects of imposed optical defocus on the expression patterns of bone morphogenetic protein 4 and 7 (BMP4, BMP7) in chick retinal pigment epithelium (RPE), as indicators of roles in postnatal eye growth regulation. BMP4 and BMP7 gene and protein expression patterns were characterized for retina, RPE and choroid tissues of young normal White-Leghorn chickens. The effects of short-term (2 and 48 h) exposure to monocular +10 and -10 diopter (D) lenses on RPE gene expression of BMP4 and BMP7 were also examined. Tissues from both treated and fellow eyes as well as from eyes of age-matched untreated birds were included in the latter experiment. Of ocular tissues comprising the posterior wall of the chick eye, RPE showed the highest expression of BMP4 and BMP7 mRNA, compared to retina and choroid. Western blots and immunohistochemistry confirmed the expression of BMP4 and BMP7 protein in all layers - retina, RPE, choroid and sclera. With imposed defocus, both BMP4 and BMP7 showed bidirectional changes in expression in RPE, however, with different temporal patterns. With +10 D lenses, BMP4 gene expression was up-regulated after both 2 and 48 h of treatment, while BMP7 expression was up-regulated only after 48 h of lens wear. With -10 D lenses, both BMP4 and BMP7 showed down-regulation of gene expression for both 2 and 48 h treatment durations. With the -10 D lens treatment applied for 48 h, gene expression for both BMP4 and BMP7 was also down-regulated in contralateral fellows of treated eyes compared to eyes of untreated chicks. The rapid changes in gene expression in chick RPE observed for both BMP4 and BMP7, up or down according to the sign of imposed optical defocus, resemble similar trends reported for BMP2. Further studies are needed to confirm the roles of BMPs as ocular growth modulators, as suggested by these data. The data also suggest a role for the RPE as a conduit for relaying growth modulatory retinal signals.

Learning new meanings for old words: effects of semantic relatedness.

Changes to our everyday activities mean that adult language users need to learn new meanings for previously unambiguous words. For example, we need to learn that a "tweet" is not only the sound a bird makes, but also a short message on a social networking site. In these experiments, adult participants learned new fictional meanings for words with a single dominant meaning (e.g., "ant") by reading paragraphs that described these novel meanings. Explicit recall of these meanings was significantly better when there was a strong semantic relationship between the novel meaning and the existing meaning. This relatedness effect emerged after relatively brief exposure to the meanings (experiment 1), but it persisted when training was extended across 7 days (experiment 2) and when semantically demanding tasks were used during this extended training (experiment 3). A lexical decision task was used to assess the impact of learning on online recognition. In Experiment 3, participants responded more quickly to words whose new meaning was semantically related than to those with an unrelated meaning. This result is consistent with earlier studies showing an effect of meaning relatedness on lexical decision, and it indicates that these newly acquired meanings become integrated with participants' preexisting knowledge about the meanings of words.

Influenza H5N1 and H1N1 virus replication and innate immune responses in bronchial epithelial cells are influenced by the state of differentiation.

Influenza H5N1 virus continues to be enzootic in poultry and transmits zoonotically to humans. Although a swine-origin H1N1 virus has emerged to become pandemic, its virulence for humans remains modest in comparison to that seen in zoonotic H5N1 disease. As human respiratory epithelium is the primary target cells for influenza viruses, elucidating the viral tropism and host innate immune responses of influenza H5N1 virus in human bronchial epithelium may help to understand the pathogenesis. Here we established primary culture of undifferentiated and well differentiated normal human bronchial epithelial (NHBE) cells and infected with highly pathogenic influenza H5N1 virus (A/Vietnam/3046/2004) and a seasonal influenza H1N1 virus (A/Hong Kong/54/1998), the viral replication kinetics and cytokine and chemokine responses were compared by qPCR and ELISA. We found that the in vitro culture of the well differentiated NHBE cells acquired the physiological properties of normal human bronchi tissue which express high level of alpha2-6-linked sialic acid receptors and human airway trypsin-like (HAT) protease, in contrast to the low expression in the non-differentiated NHBE cells. When compared to H1N1 virus, the H5N1 virus replicated more efficiently and induced a stronger type I interferon response in the undifferentiated NHBE cells. In contrast, in well differentiated cultures, H5N1 virus replication was less efficient and elicited a lower interferon-beta response in comparison with H1N1 virus. Our data suggest that the differentiation of bronchial epithelial cells has a major influence in cells' permissiveness to human H1N1 and avian H5N1 viruses and the host innate immune responses. The reduced virus replication efficiency partially accounts for the lower interferon-beta responses in influenza H5N1 virus infected well differentiated NHBE cells. Since influenza infection in the bronchial epithelium will lead to tissue damage and associate with the epithelium regeneration, the data generated from the undifferentiated NHBE cultures may also be relevant to disease pathogenesis.

Tropism and innate host responses of the 2009 pandemic H1N1 influenza virus in ex vivo and in vitro cultures of human conjunctiva and respiratory tract.

The novel pandemic influenza H1N1 (H1N1pdm) virus of swine origin causes mild disease but occasionally leads to acute respiratory distress syndrome and death. It is important to understand the pathogenesis of this new disease in humans. We compared the virus tropism and host-responses elicited by pandemic H1N1pdm and seasonal H1N1 influenza viruses in ex vivo cultures of human conjunctiva, nasopharynx, bronchus, and lung, as well as in vitro cultures of human nasopharyngeal, bronchial, and alveolar epithelial cells. We found comparable replication and host-responses in seasonal and pandemic H1N1 viruses. However, pandemic H1N1pdm virus differs from seasonal H1N1 influenza virus in its ability to replicate in human conjunctiva, suggesting subtle differences in its receptor-binding profile and highlighting the potential role of the conjunctiva as an additional route of infection with H1N1pdm. A greater viral replication competence in bronchial epithelium at 33 degrees C may also contribute to the slight increase in virulence of the pandemic influenza virus. In contrast with highly pathogenic influenza H5N1 virus, pandemic H1N1pdm does not differ from seasonal influenza virus in its intrinsic capacity for cytokine dysregulation. Collectively, these results suggest that pandemic H1N1pdm virus differs in modest but subtle ways from seasonal H1N1 virus in its intrinsic virulence for humans, which is in accord with the epidemiology of the pandemic to date. These findings are therefore relevant for understanding transmission and therapy.

Influenza H5N1 virus infection of polarized human alveolar epithelial cells and lung microvascular endothelial cells.

BACKGROUND: Highly pathogenic avian influenza (HPAI) H5N1 virus is entrenched in poultry in Asia and Africa and continues to infect humans zoonotically causing acute respiratory disease syndrome and death. There is evidence that the virus may sometimes spread beyond respiratory tract to cause disseminated infection. The primary target cell for HPAI H5N1 virus in human lung is the alveolar epithelial cell. Alveolar epithelium and its adjacent lung microvascular endothelium form host barriers to the initiation of infection and dissemination of influenza H5N1 infection in humans. These are polarized cells and the polarity of influenza virus entry and egress as well as the secretion of cytokines and chemokines from the virus infected cells are likely to be central to the pathogenesis of human H5N1 disease. AIM: To study influenza A (H5N1) virus replication and host innate immune responses in polarized primary human alveolar epithelial cells and lung microvascular endothelial cells and its relevance to the pathogenesis of human H5N1 disease. METHODS: We use an in vitro model of polarized primary human alveolar epithelial cells and lung microvascular endothelial cells grown in transwell culture inserts to compare infection with influenza A subtype H1N1 and H5N1 viruses via the apical or basolateral surfaces. RESULTS: We demonstrate that both influenza H1N1 and H5N1 viruses efficiently infect alveolar epithelial cells from both apical and basolateral surface of the epithelium but release of newly formed virus is mainly from the apical side of the epithelium. In contrast, influenza H5N1 virus, but not H1N1 virus, efficiently infected polarized microvascular endothelial cells from both apical and basolateral aspects. This provides a mechanistic explanation for how H5N1 virus may infect the lung from systemic circulation. Epidemiological evidence has implicated ingestion of virus-contaminated foods as the source of infection in some instances and our data suggests that viremia, secondary to, for example, gastro-intestinal infection, can potentially lead to infection of the lung. HPAI H5N1 virus was a more potent inducer of cytokines (e.g. IP-10, RANTES, IL-6) in comparison to H1N1 virus in alveolar epithelial cells, and these virus-induced chemokines were secreted onto both the apical and basolateral aspects of the polarized alveolar epithelium. CONCLUSION: The predilection of viruses for different routes of entry and egress from the infected cell is important in understanding the pathogenesis of influenza H5N1 infection and may help unravel the pathogenesis of human H5N1 disease.