No abstract

Vaccines are one of the most important tools available to prevent and reduce the incidence of infectious diseases in cattle. Despite their availability and widespread use to combat many important pathogens impacting cattle, several of these products demonstrate variable efficacy and safety in the field, require multiple doses, or are unstable under field conditions. Recently, nanoparticle-based vaccine platforms (nanovaccines) have emerged as promising alternatives to more traditional vaccine platforms. In particular, polymer-based nanovaccines provide sustained release of antigen payloads, stabilize such payloads, and induce enhanced antibod- and cell-mediated immune responses, both systemically and locally. To improve vaccine administrative strategies and efficacy, they can be formulated to contain multiple antigenic payloads and have the ability to protect fragile proteins from degradation. Nanovaccines are also stable at room temperature, minimizing the need for cold chain storage. Nanoparticle platforms can be synthesized for targeted delivery through intranasal, aerosol, or oral administration to induce desired mucosal immunity. In recent years, several nanovaccine platforms have emerged, based on biodegradable and biocompatible polymers, liposomes, and virus-like particles. While most nanovaccine candidates have not yet advanced beyond testing in rodent models, a growing number have shown promise for use against cattle infectious diseases. This review will highlight recent advancements in polymeric nanovaccine development and the mechanisms by which nanovaccines may interact with the bovine immune system. We will also discuss the positive implications of nanovaccines use for combating several important viral and bacterial disease syndromes and consider important future directions for nanovaccine development in beef and dairy cattle.

Human respiratory syncytial virus (HRSV) is a leading cause of severe acute lower respiratory tract (LRT) disease in young children worldwide. Currently, there is no approved vaccine for HRSV. Bovine RSV (BRSV) is closely related to HRSV and is the cause of severe acute LRT disease in young cattle. A neonatal calf model presents an opportunity to test HRSV vaccines and study a naturally susceptible host-pathogen interaction similar to HRSV infection. We tested the efficacy of a polyanhydride nanoparticle-vaccine (nanovaccine) encapsulating the post-fusion F and G proteins from BRSV and CpG adjuvant in neonatal calves with maternally-derived antibodies (MDA). A prime-boost immunization of neonatal calves with the BRSV post-fusion F/G CpG nanovaccine induced clinical protection in the presence of MDA. Vaccinated calves developed moderate or no clinical symptoms and were mostly protected from virus-associated lung pathology compared to unvaccinated controls. Calves that received a mucosal/systemic nanovaccine immunization had complete virological protection against BRSV infection in the lungs, which correlated with BRSV-specific immune responses in the bronchoalveolar lavage. Vaccination with the nanovaccine induced anamnestic BRSV-specific IgA titers in the lungs and systemic T cell responses with BRSV-specific CD4+ T cell proliferation and antigen-specific IL-17 and IFNγ secretion. Overall, the BRSV post-fusion F/G CpG nanovaccine is a promising candidate for further studies to protect neonatal calves and infants from RSV infection.

Human respiratory syncytial virus (HRSV) is a leading cause of death in young children and there are no FDA approved vaccines. Bovine RSV (BRSV) is antigenically similar to HRSV, and the neonatal calf model is useful for evaluation of HRSV vaccines. Here, we determined the efficacy of a polyanhydride-based nanovaccine encapsulating the BRSV post-fusion F and G glycoproteins and CpG, delivered prime-boost via heterologous (intranasal/subcutaneous) or homologous (intranasal/intranasal) immunization in the calf model. We compared the performance of the nanovaccine regimens to a modified-live BRSV vaccine, and to non-vaccinated calves. Calves receiving nanovaccine via either prime-boost regimen exhibited clinical and virological protection compared to non-vaccinated calves. The heterologous nanovaccine regimen induced both virus-specific cellular immunity and mucosal IgA, and induced similar clinical, virological and pathological protection as the commercial modified-live vaccine. Principal component analysis identified BRSV-specific humoral and cellular responses as important correlates of protection. The BRSV-F/G CpG nanovaccine is a promising candidate vaccine to reduce RSV disease burden in humans and animals.

Objective: Previously, immunization with a single intranasal dose of a BRSV post-fusion F/G nanovaccine resulted in partial protection from a BRSV challenge (McGill et al. 2019, McGill et al. 2018). Knowledge gained from these previous studies was used to optimize the vaccine by incorporating CpG-ODN and to investigate the impact of mucosal vs. systemic vaccination routes. In this study a prime-boost immunization regimen was used. Method: 36 neonatal, mixed-sex, Holstein calves were divided into 6 groups. Group 1 received a heterologous regime with saline and group 2 a homologous boost of the ‘empty’ nanovaccine CPG. Groups 3 and 4 received a homologous mucosal regime of the nanovaccine ± CpG, while groups 5 and 6 received a heterologous regime of the nanovaccine ± CpG. Vaccine-induced responses were monitored and 6 weeks after boost, all calves were challenged with BRSV. Nasopharyngeal swabs were collected for viral shedding and calves monitored for clinical signs and euthanized on day 7 after infection. Lungs were scored for gross pathology. Blood, nasal secretions and lung tissue samples were analyzed for BRSV specific immune responses. Results: Unvaccinated controls and CpG-only nanovaccine controls developed lung pathology consistent with a severe BRSV infection. We observed no evidence of vaccine enhanced disease in any vaccinated group. Calves that received the homologous vaccination of the nanovaccine + CPG had significantly less lung pathology and viral burden in the lungs compared to control calves. Conclusions: These results indicate that an intranasal homologous vaccination regimen with the post-fusion F/G + CpG nanovaccine has the capacity to reduce BRSV disease in neonatal calves with preexisting maternal antibodies.