Vaccine Safety and Efficacy Evaluation of a Recombinant Bovine Respiratory Syncytial Virus (BRSV) with Deletion of the SH Gene and Subunit Vaccines Based On Recombinant Human RSV Proteins: N-nanorings, P and M2-1, in Calves with Maternal Antibodies

Abstract

The development of safe and effective vaccines against both bovine and human respiratory syncytial viruses (BRSV, HRSV) to be used in the presence of RSV-specific maternally-derived antibodies (MDA) remains a high priority in human and veterinary medicine. Herein, we present safety and efficacy results from a virulent BRSV challenge of calves with MDA, which were immunized with one of three vaccine candidates that allow serological differentiation of infected from vaccinated animals (DIVA): an SH gene-deleted recombinant BRSV (ΔSHrBRSV), and two subunit (SU) formulations based on HRSV-P, -M2-1, and -N recombinant proteins displaying BRSV-F and -G epitopes, adjuvanted by either oil emulsion (Montanide ISA71VG, SUMont) or immunostimulating complex matrices (AbISCO-300, SUAbis). Whereas all control animals developed severe respiratory disease and shed high levels of virus following BRSV challenge, ΔSHrBRSV-immunized calves demonstrated almost complete clinical and virological protection five weeks after a single intranasal vaccination. Although mucosal vaccination with ΔSHrBRSV failed to induce a detectable immunological response, there was a rapid and strong anamnestic mucosal BRSV-specific IgA, virus neutralizing antibody and local T cell response following challenge with virulent BRSV. Calves immunized twice intramuscularly, three weeks apart with SUMont were also well protected two weeks after boost. The protection was not as pronounced as that in ΔSHrBRSV-immunized animals, but superior to those immunized twice subcutaneously three weeks apart with SUAbis. Antibody responses induced by the subunit vaccines were non-neutralizing and not directed against BRSV F or G proteins. When formulated as SUMont but not as SUAbis, the HRSV N, P and M2-1 proteins induced strong systemic cross-protective cell-mediated immune responses detectable already after priming. ΔSHrBRSV and SUMont are two promising DIVA-compatible vaccines, apparently inducing protection by different immune responses that were influenced by vaccine-composition, immunization route and regimen.

Partial Attenuation of Respiratory Syncytial Virus with a Deletion of a Small Hydrophobic Gene Is Associated with Elevated Interleukin-1β Responses

“…In the current study, we demonstrated that RSV ⌬SH protected against viral challenge in the mouse model. A recent study has demonstrated that a bRSV ⌬SH vaccine is highly protective in infant calves, even in the presence of maternal antibody (29), and a live attenuated RSV ⌬SH vaccine with additional point mutations (Medi-559) has been shown to be safe and immunogenic in clinical trials in children (30). Data from chimpanzee studies (31), which showed moderate attenuation, suggest SH alone would be insufficient for a safe live vaccine, though it has been shown to be highly effective in cattle (29).…”

“…A recent study has demonstrated that a bRSV ⌬SH vaccine is highly protective in infant calves, even in the presence of maternal antibody (29), and a live attenuated RSV ⌬SH vaccine with additional point mutations (Medi-559) has been shown to be safe and immunogenic in clinical trials in children (30). Data from chimpanzee studies (31), which showed moderate attenuation, suggest SH alone would be insufficient for a safe live vaccine, though it has been shown to be highly effective in cattle (29). While addition of ⌬SH to other temperature-sensitive vaccines had a marginal effect (32,33) on attenuation, we speculate that SH has an immunomodulatory function and that its deletion as part of a live attenuated RSV vaccine design would be beneficial.…”

A multifaceted approach to RSV vaccination

“…This phenomenon needs to be taken into account since most of the preclinical studies to test/validate prototype vaccines for maternal immunization have used na€ ıve dams for vaccination. 9,30,31 In our study, the vaccine-induced protection of the litter was evidenced only later (4 weeks after birth), when waning of maternal immunity is more evident, in contrast to testing it on or close to the day of delivery, when most of the animals are fully protected independent of the vaccination status. Overall, this data strongly supports the idea that we must use a different set of conditions for testing prototype RSV vaccines in order to find a successful vaccine for vaccination during pregnancy.…”

RSV N-nanorings fused to palivizumab-targeted neutralizing epitope as a nanoparticle RSV vaccine

“…In a previous attempt to design chimeric N-nanorings fused to bovine FsII, we failed to generate anti-F antibodies in calves, strongly suggesting that bovine FsII was not correctly exposed. 25 In the present study, we fused an extended human FsII either at the N-terminus (Nter) or on the top of the β-hairpin located between G106 and K107 residues (G106) of N. Indeed, the two FsII-fused N protein constructs (N-FsII) were able to form soluble nanorings. These N-FsII-nanorings were efficiently recognized by either monoclonal antibodies specific for FsII, sera of F-immunized mice or palivizumab.…”

“…23 In calves, N-nanorings alone or co-administered with RSV P and M2-1 proteins, provide strong cellular immunity and significant but partial protection against virus replication and clinical symptoms upon bovine RSV challenge. 24,25 Importantly, we did not record signs of pulmonary disease exacerbation upon challenge of vaccinated mice or calves. 23,24 …”