Vaccinating the Young Calf with a Parenteral Adjuvanted Vaccine to Develop a Protective BRSV IgA nasal Response

Objective The purpose of this study was to evaluate the efficacy of an adjuvanted modified live virus (MLV) vaccine in the presence of well-defined maternal passive immunity.Study Description Calves were vaccinated at approximately 1 month of age and challenged ~90 days later when BRSV systemic antibodies were less than 1:4. Clinical signs, nasal secretions and blood samples for virus measurement [polymerase chain reaction (PCR) and virus isolation (VI)] and to measure for mucosal BRSV IgA antibodies were collected and the animals were euthanized and necropsied 8 days post infection. Body temperature and other clinical signs were lower at 6 and 7 days post challenge in the vaccinates. Nasal viral shed was 3–4 times lower in the vaccinated animals as measured by VI and PCR compared to the controls. On day 8 following challenge, animals were necropsied, and lung lobes were scored and tested for virus by PCR and indirect fluorescent assay (IFA). There was a 25-fold reduction in PCR virus detection in vaccinates and two of the vaccinated calves’ lungs were PCR negative. Only 29.4% of vaccinated calves were BRSV positive on IFA testing at necropsy, while 87.5% of control calves were BRSV positive. Vaccinated calves developed a mucosal BRSV IgA response with over 50% of the vaccinated calves having IgA prior to challenge and all vaccinated calves were positive following challenge

Twelve-month observational study of children with cancer in 41 countries during the COVID-19 pandemic

Introduction Childhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality. Methods Prospective cohort study in 109 institutions in 41 countries. Inclusion criteria: children <18 years who were newly diagnosed with or undergoing active treatment for acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, retinoblastoma, Wilms tumour, glioma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, medulloblastoma and neuroblastoma. Of 2327 cases, 2118 patients were included in the study. The primary outcome measure was all-cause mortality at 30 days, 90 days and 12 months. Results All-cause mortality was 3.4% (n=71/2084) at 30-day follow-up, 5.7% (n=113/1969) at 90-day follow-up and 13.0% (n=206/1581) at 12-month follow-up. The median time from diagnosis to multidisciplinary team (MDT) plan was longest in low-income countries (7 days, IQR 3-11). Multivariable analysis revealed several factors associated with 12-month mortality, including low-income (OR 6.99 (95% CI 2.49 to 19.68); p<0.001), lower middle income (OR 3.32 (95% CI 1.96 to 5.61); p<0.001) and upper middle income (OR 3.49 (95% CI 2.02 to 6.03); p<0.001) country status and chemotherapy (OR 0.55 (95% CI 0.36 to 0.86); p=0.008) and immunotherapy (OR 0.27 (95% CI 0.08 to 0.91); p=0.035) within 30 days from MDT plan. Multivariable analysis revealed laboratory-confirmed SARS-CoV-2 infection (OR 5.33 (95% CI 1.19 to 23.84); p=0.029) was associated with 30-day mortality. Conclusions Children with cancer are more likely to die within 30 days if infected with SARS-CoV-2. However, timely treatment reduced odds of death. This report provides crucial information to balance the benefits of providing anticancer therapy against the risks of SARS-CoV-2 infection in children with cancer

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Persistence of replication-incompetent adenovirus in cattle.

<p>Viable recombinant adenovirus inoculated intradermally is only recoverable within three days. Presence of adenovirus rescued from tissue samples of four steers at defined time points was tracked by immunocytometric analysis of HEK-293A cells. Representative data from one steer is shown: A, D, G, J, and M are positive controls at 24 hr., 48 hr., 72 hr., day 7, and day 21, respectively. B, E, H, and K, are skin biopsies taken from the inoculation sites on the neck of the steers at 24 hr., 48 hr., 72 hr., and day 7, respectively, whereas C, F, I, and L, are cognate control skin biopsies taken concurrently from the flank. N and O are draining lymph node and spleen samples, respectively, collected three weeks post-inoculation.</p

Clinical manifestations post-challenge.

<p>A) Mean rectal temperature fluctuation; and B) Mean change ratios of white blood cell counts in the vaccinated and negative control groups post-challenge. Asterisks denote statistically significant differences as compared to the negative controls. *P<0.05; **P<0.01 and ***P<0.001.</p

Validation of B-cell epitopes in the mosaic BVDV antigens.

<p>Authenticity of the adenovirus-expressed novel BVDV mosaic antigens was confirmed by immunocytometric analysis using E2-specific neutralizing monoclonal antibodies 26A and 348 (both neutralize BVDV-1 & 2); bovine anti-BVDV hyper-immune serum (generated by immunizing steers multiple times with BVDV-1 & 2 vaccines followed by boosting with killed diverse BVDV-1 & 2 strains and then challenged with wild type BVDV-1 & 2 strains (The sera have high BVDV-1 & 2 neutralizing titers [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0170425#pone.0170425.ref059" target="_blank">59</a>]); and goat anti-BVDV polyclonal serum generated against multiple wild-type BVDV-1 & 2 strains. A) HEK-293A cells expressing N^proE2^1-3; B) HEK-293A cells expressing NS^2-31; C) HEK-293A cells expressing NS^2-32; and D) HEK-293A cells expressing luciferase.</p

Validation of mosaic antigens using BVDV-specific T-cells.

<p>Authenticity of T-cell epitopes in the mosaic BVDV antigens was validated by proliferation assay using PBMCs from a BVDV-1 & 2 hyper-immune steer [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0170425#pone.0170425.ref059" target="_blank">59</a>]. The data shown is minus background counts from negative control (media alone) treatment. The asterisks denote a statistically significant difference (P<0.01) between the proliferation induced by the N^proE2^1-3, NS^2-31 and the NS^2-32 antigens and both whole killed viruses BVDV-1b and BVDV-2. This outcome is representative of assays conducted using PBMCs from other BVDV immune steers.</p

Mosaic BVDV vaccine induced BVDV-1 specific neutralizing antibodies.

<p>Serum neutralization assays were used to evaluate BVDV-1-specific neutralization titers at A) One-week post-boost; and B) one-week pre-challenge against five BVDV type 1 strains. Mean group titers are represented by the bars. Statistically significant differences between the groups are denoted by asterisks. *P<0.05; **P<0.01.</p

Immunization timeline.

<p>On day -228 pre-challenge, cattle in the treatment group were vaccinated with a cocktail of the recombinant adenoviruses expressing mosaic BVDV antigens (AdBVDV), whereas positive control cattle received a commercial MLV BVDV vaccine. Negative control cattle were inoculated with the recombinant AdLuc. On day -149 pre-challenge, the cattle were boosted with the respective priming inoculum and dose (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0170425#pone.0170425.t001" target="_blank">Table 1</a>). On day 0, all the cattle were challenged by intranasal delivery of a BVDV-1373 using an atomizer. Blood samples were collected on selected days (0, 3, 6, 10, 12, 13 and 15), whereas clinical observations and rectal temperatures were monitored and recorded daily from days 1–15 post-challenge.</p

Virus isolation from calves on day 7 and day 10 post-challenge.

<p>Virus isolation from calves on day 7 and day 10 post-challenge.</p