A Recombinant BCG Vaccine Is Safe and Immunogenic in Neonatal Calves and Reduces the Clinical Disease Caused by the Respiratory Syncytial Virus

Abstract

The human respiratory syncytial virus (hRSV) constitutes a major health burden, causing millions of hospitalizations in children under five years old worldwide due to acute lower respiratory tract infections. Despite decades of research, licensed vaccines to prevent hRSV are not available. Development of vaccines against hRSV targeting young infants requires ruling out potential vaccine-enhanced disease presentations. To achieve this goal, vaccine testing in proper animal models is essential. A recombinant BCG vaccine that expresses the Nucleoprotein of hRSV (rBCG-N-hRSV) protects mice against hRSV infection, eliciting humoral and cellular immune protection. Further, this vaccine was shown to be safe and immunogenic in human adult volunteers. Here, we evaluated the safety, immunogenicity, and protective efficacy of the rBCG-N-hRSV vaccine in a neonatal bovine RSV calf infection model. Newborn, colostrum-replete Holstein calves were either vaccinated with rBCG-N-hRSV, WT-BCG, or left unvaccinated, and then inoculated via aerosol challenge with bRSV strain 375. Vaccination with rBCG-N-hRSV was safe and well-tolerated, with no systemic adverse effects. There was no evidence of vaccine-enhanced disease following bRSV challenge of rBCG-N-hRSV vaccinated animals, suggesting that the vaccine is safe for use in neonates. Vaccination increased virus-specific IgA and virus-neutralization activity in nasal fluid and increased the proliferation of virus- and BCG-specific CD4+ and CD8+ T cells in PBMCs and lymph nodes at 7dpi. Furthermore, rBCG-N-hRSV vaccinated calves developed reduced clinical disease as compared to unvaccinated control calves, although neither pathology nor viral burden were significantly reduced in the lungs. These results suggest that the rBCG-N-hRSV vaccine is safe in neonatal calves and induces protective humoral and cellular immunity against this respiratory virus. These data from a newborn animal model provide further support to the notion that this vaccine approach could be considered as a candidate for infant immunization against RSV.

The Role of Nucleoprotein in Immunity to Human Negative-Stranded RNA Viruses—Not Just Another Brick in the Viral Nucleocapsid

“…Further, this vaccine was shown to be safe and immunogenic in human adult volunteers. In the model of neonatal calves, this type of immunization increased virus-specific IgA and virus-neutralization activity in nasal fluid and increased the proliferation of virus- and BCG-specific CD4+ and CD8+ T cells in lymph nodes supporting the notion that this vaccine approach could be considered as a candidate for infant immunization against RSV [ 201 ]. RSV may induce an inappropriate Th2-type immune response, which causes severe pulmonary inflammation.…”

“…Given the extensively accepted safety and immunogenicity profile of the bacillus Calmette–Guérin (BCG) vaccine in newborns, the vaccine based on the recombinant BCG expressing NP of RSV (rBCG-N-hRSV) is intended for direct use on neonates to prevent severe hRSV infection [ 201 ]. A phase I clinical trial rBCG-N-hRSV vaccine showed that the vaccine was safe; serum IgG antibodies directed against M. bovis and the N-protein of RSV increased after vaccination, as well as the cellular response, consisting of IFN-γ and IL-2 production against PPD and the N-protein.…”

Use of Thoracic Ultrasonography to Improve Disease Detection in Experimental BRD Infection

“…Briefly, randomly selected samples, ~0.5 g each, lesioned and non-lesioned lung tissues were collected from two separate lung lobes each calf and stored in RNAlater (ThermoFisher). RNA was then isolated and pooled from the separate locations (lesioned samples pooled together, non-lesioned lung tissues pooled together) using Trizol Reagent (Life Technologies) and then cleaned up using a Qiagen RNeasy isolation column, as described ( 14 ). Nasal swabs samples were collected from the upper nasal cavity of BRSV infected calves on days 0, 3, 7, 10, and 14 after infection.…”

FeedingSaccharomyces cerevisiaefermentation products lessens the severity of a viral–bacterial coinfection in preweaned calves

“…Twenty-seven, 1- to 2-d-old Holstein × Angus calves (12 males and 15 females) were enrolled in the trial. A statistical power analysis was performed for sample size estimation based upon published results (including our own; Castrucci et al, 1996 , 1998 ; Nickell et al, 2016 ; Guerra-Maupome et al, 2019 ; Mahmoud et al, 2020 ; Wheat et al, 2020 ; Díaz et al, 2021 ) for in vivo innate immunostimulant activity in cattle. Given a medium effect size (following Cohen’s criteria, Cohen, 1988 ), an α = 0.05, and power = 0.7, the projected samples size to measure a significant effect of SCFP supplementation on gross lung pathology scores (in challenge studies, Mann–Whitney test) was n = 12, calculated using the G*Power 3.1 software.…”