Biology subjects

March, R.

Publications and source records attributed to March, R..

8 recordsLinked to original sources

bioRxiv2024

Efficacy of a new multivalent vaccine for the control of bovine respiratory disease (BRD) in commercial fattening units

Bovine respiratory disease (BRD) is the most common cause of morbidity and mortality in cattle. The effects of BRD are most marked during the first weeks after arrival in calf-rearing units. Vaccination is a tool that can help to control the disease by reducing both the incidence itself and the massive use of antibiotics. Recently, a new multivalent vaccine (DIVENCE(R)), containing live gE/tk double-gene deleted BoHV-1, live-attenuated BRSV, inactivated PI3, BVDV-1 recombinant protein and BVDV-2 recombinant protein, has been designed to protect cattle against the main viral pathogens associated with BRD. The aim of this study was to demonstrate the efficacy of DIVENCE(R) against BRD in field conditions. A total of 360 animals from three different batches were included in the study: one batch of 108 Holstein-Friesian males (Farm 1), another batch of 99 Holstein-Friesian males (Farm 2), and 153 Belgian-Blue cross males and females (Farm 3). On each feedlot, a single batch of animals was included in the study, with a mean age of approx. ten weeks (73.4{+/-}0.6 days). On the vaccination day (Day 0 of the study; D0), calves from the same batch were randomly distributed between the two study groups. The vaccinated group (n=183) received the DIVENCE(R) vaccine and the control group (n=177) received a placebo injection of phosphate-buffered saline (PBS) solution. Both groups were given two intramuscular doses (2 mL/dose) of the corresponding product three weeks apart. All animals were monitored during the entire fattening period (approx. 9 months) after vaccination to assess the incidence, severity, and morbidity of BRD as well as administered treatments and feed performance. Overall, vaccinated animals had significantly (p<0.004) lower morbidity than controls, with only 49 out of the 183 vaccinated calves (26.78%) presenting at least one episode of respiratory disease (RD), versus 73 out of the 177 control calves (41.24%). Thus, a reduction of 35.1% in morbidity was observed in the vaccinated animals. In terms of RD cases, vaccinated animals had a significantly (p<0.001) lower number of cases than control animals, with only 66 cases reported in the 183 vaccinated calves (0.36 cases/calf) versus 110 cases in the 177 control calves (0.62 cases/calf). A reduction of 42% in cases was observed in the vaccinated animals. During the study follow-up, a BRSV outbreak was reported in one of the farms (Farm 1) on Day 23, just two days after the second dose. The vaccinated group had significantly (p<0.02) lower morbidity (11 animals out of 54; 20.4%) and severity (score of 1.70) compared to the control group (29 animals out of 54; 53.70% and score of 2.11). Overall, vaccinated animals needed significantly (p=0.01) fewer antimicrobial treatments (at least one due to RD) than controls. Furthermore, vaccinated animals presented numerically higher average daily weight gain (p=0.07) and significantly higher carcass weight (p=0.01) than controls, at 35.78 g/day and 6.58 kg, respectively. Vaccination with DIVENCE(R) at the beginning of the fattening period decreased the incidence and morbidity of BRD following a BRSV outbreak only two days after the primary vaccination scheme. Additionally, the incidence and morbidity of BRD throughout the entire fattening period was reduced in the vaccinated animals. Thus, DIVENCE(R) can improve economic outcomes in fattening units by reducing antibiotic treatments and enhancing performance.

immunology↗

bioRxiv2024

Fetal protection against bovine viral diarrhea virus types 1 and 2 after vaccination of the dam with the DIVENCE vaccine

The aim of this study was to demonstrate the efficacy of DIVENCE, a vaccine against BVDV types 1 and 2 (BVDV-1 and BVDV-2) transplacental infection, following a booster regimen in heifers. Calves of two-to-three months of age were given two intramuscular doses three weeks apart and a booster vaccine six months later. Efficacy was evaluated by means of a challenge with virulent BVDV-1 or BVDV-2 administered via the intranasal route at 85 days of gestation. Clinical signs, serology, viral shedding, WBC count and viremia were monitored after the challenge. Sixty-six days post-challenge, the fetuses were assessed for BVDV to detect transplacental infection. The results demonstrate a reduction in hyperthermia, leukopenia, viral shedding, and viremia in vaccinated animals post-challenge with BVDV-1 and BVDV-2. Most importantly, DIVENCE administered prior to breeding protected 94% of the fetuses against BVDV transplacental infection overall across both challenge trials (BVDV-1 and BVDV-2).

immunology↗

bioRxiv2024

Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer

Deciphering the structural variation across tumour genomes is crucial to determine the events driving tumour progression and better understand tumour adaptation and evolution. High grade serous ovarian cancer (HGSOC) is an exemplar tumour type showing extreme, but poorly characterised structural diversity. We comprehensively describe the mutational landscape driving HGSOC, exploiting a large (N=324), deeply whole genome sequenced dataset. We reveal two divergent evolutionary trajectories, affecting patient survival and involving differing genomic environments. One involves homologous recombination repair deficiency (HRD) while the other is dominated by whole genome duplication (WGD) with frequent chromothripsis, breakage-fusion-bridges and extra-chromosomal DNA. These trajectories contribute to structural variation hotspots, containing novel candidate driver genes with significantly altered expression. While structural variation predominantly drives tumorigenesis, we also find high mtDNA mutation loads associated with shorter patient survival, and acting in combination with alterations in the nuclear genome to impact prognosis and suggesting new strategies for patient stratification.

cancer biology↗

bioRxiv2023

Immunogenicity and safety in pigs of PHH-1V, a SARS-CoV-2 RBD fusion heterodimer vaccine candidate

The continuing high global incidence of COVID-19 and the undervaccinated status of billions of persons strongly motivate the development of a new generation of efficacious vaccines. We have developed an adjuvanted vaccine candidate, PHH-1V, based on a protein comprising the receptor binding domain (RBD) of the Beta variant of SARS-CoV-2 fused in tandem with the equivalent domain of the Alpha variant, with its immunogenicity, safety and efficacy previously demonstrated in mouse models. In the present study, we immunized pigs with different doses of PHH-1V in a prime-and-boost scheme showing PHH-1V to exhibit an excellent safety profile in pigs and to produce a solid RBD-specific humoral response with neutralising antibodies to 7 distinct SARS-CoV-2 variants of concern, with the induction of a significant IFN{gamma}+ T-cell response. We conclude that PHH-1V is safe and elicits a robust immune response to SARS-CoV-2 in pigs, a large animal preclinical model.

immunology↗

bioRxiv2022

Preclinical efficacy, safety, and immunogenicity of PHH-1V, a second-generation COVID-19 vaccine, in non-human primates

SARS-CoV-2 emerged in December 2019 and quickly spread worldwide, continuously striking with an unpredictable evolution. Despite the success in vaccine production and mass vaccination programmes, the situation is not still completely controlled, and therefore accessible second-generation vaccines are required to mitigate the pandemic. We previously developed an adjuvanted vaccine candidate coded PHH-1V, based on a heterodimer fusion protein comprising the RBD domain of two SARS-CoV-2 variants. Here, we report data on the efficacy, safety, and immunogenicity of PHH-1V in cynomolgus macaques. PHH-1V prime-boost vaccination induces high levels of RBD-specific IgG binding and neutralising antibodies against several SARS-CoV-2 variants, as well as a balanced Th1/Th2 cellular immune response. Remarkably, PHH-1V vaccination prevents SARS-CoV-2 replication in the lower respiratory tract and significantly reduces viral load in the upper respiratory tract after an experimental infection. These results highlight the potential use of the PHH-1V vaccine in humans, currently undergoing Phase III clinical trials.

immunology↗

bioRxiv2021

Preclinical efficacy, safety, and immunogenicity of PHH-1V, a second-generation COVID-19 vaccine candidate based on a novel recombinant RBD fusion heterodimer of SARS-CoV-2.

Current C0VID-19 vaccines have been associated with a decline in infection rates, prevention of severe disease and a decrease in mortality rates. However, SARS-CoV-2 variants are continuously evolving, and development of new accessible COVID-19 vaccines is essential to mitigate the pandemic. Here, we present data on preclinical studies in mice of a receptor-binding domain (RBD)-based recombinant protein vaccine (PHH-1V) consisting of an RBD fusion heterodimer comprising the B.1.351 and B.1.1.7 SARS-CoV-2 variants formulated in SQBA adjuvant, an oil-in-water emulsion. A prime-boost immunisation with PHH-1V in BALB/c and K18-hACE2 mice induced a CD4+ and CD8+ T cell response and RBD-binding antibodies with neutralising activity against several variants, and also showed a good tolerability profile. Significantly, RBD fusion heterodimer vaccination conferred 100% efficacy, preventing mortality in SARS-CoV-2 infected K18-hACE2 mice, but also reducing Beta, Delta and Omicron infection in lower respiratory airways. These findings demonstrate the feasibility of this recombinant vaccine strategy.

immunology↗

bioRxiv2020

Surveying the contribution of rare variants to the genetic architecture of human disease through exome sequencing of 177,882 UK Biobank participants

The UK Biobank (UKB) represents an unprecedented population-based study of 502,543 participants with detailed phenotypic data and linkage to medical records. While the release of genotyping array data for this cohort has bolstered genomic discovery for common variants, the contribution of rare variants to this broad phenotype collection remains relatively unknown. Here, we use exome sequencing data from 177,882 UKB participants to evaluate the association between rare protein-coding variants with 10,533 binary and 1,419 quantitative phenotypes. We performed both a variant-level phenome-wide association study (PheWAS) and a gene-level collapsing analysis-based PheWAS tailored to detecting the aggregate contribution of rare variants. The latter revealed 911 statistically significant gene-phenotype relationships, with a median odds ratio of 15.7 for binary traits. Among the binary trait associations identified using collapsing analysis, 83% were undetectable using single variant association tests, emphasizing the power of collapsing analysis to detect signal in the setting of high allelic heterogeneity. As a whole, these genotype-phenotype associations were significantly enriched for loss-of-function mediated traits and currently approved drug targets. Using these results, we summarise the contribution of rare variants to common diseases in the context of the UKB phenome and provide an example of how novel gene-phenotype associations can aid in therapeutic target prioritisation.

genomics↗

bioRxiv2020

Structural variants at the BRCA1/2 loci are a common source of homologous repair deficiency in high grade serous ovarian carcinoma

Around half of high grade serous ovarian carcinomas (HGSOC) show homologous recombination repair deficiency (HRD), often caused by germline or somatic single nucleotide variant (SNV) mutations or small indels disrupting BRCA1/2. We have uniformly processed the largest collection of whole genome sequencing (WGS) data from HGSOC samples to date (N=205), comprehensively characterising the somatic mutational landscape, and expression at the BRCA1/2 loci. We discover that large structural variants (SV) are a frequent but unappreciated source of BRCA1/2 disruption in these tumours. Somatic structural variation at these loci is dominated by multi-megabase deletions that span the entirety of BRCA1 (median = 4.9Mb) or BRCA2 (median = 6.2Mb), independently affecting a substantial proportion of patients (16%) in addition to those affected by damaging germline or somatic short variants, within the BRCA1/2 coding sequences (24%). In common with previous studies, we show that the presence of damaging somatic SNVs or short indels in BRCA1 (OR=10, 95% CI 1.8-103, p=0.002, adj p=0.027 and BRCA2 (OR=17, 95% CI 2.1-816), p=0.002, adj.p=0.021) was found to influence HRD. For the first time we also study the compound effect of SV and SNV or short indel mutations at both loci, demonstrating that SVs often contribute to compound deficiencies involving SNVs or indels, with large somatic deletions contributing to these compound deficiencies in 15/205 (7%) of samples. Notably the strongest risk of HRD (OR=19 (2.4-896), p=6.6x10-3, adj P=8.5x10-3) is generated by combined large deletions at BRCA1 and BRCA2 in the absence of SNVs or indels, affecting 3% of patients. Overall, we show that HRD is a complex phenotype in HGSOC tumours, affected by the patterns of shorter variants such as SNVs and indels, SVs, methylation and expression seen at multiple loci, and we construct a successful (ROC AUC = 0.75) predictive model of HRD using such variables. In addition, HRD impacts patient survival when conferred by mechanisms other than through the well-understood short variants at BRCA1/2, currently exploited in the clinic. These results alter our understanding of the mutational landscape at the BRCA1/2 loci in highly rearranged tumours, and increase the number of patients predicted to benefit from therapies exploiting HRD in tumours such as PARP inhibition.

cancer biology↗