Novel strategies to enhance vaccine immunity in neonatal livestock (NEOVACC)

Infectious diseases of livestock continue to cause a major financial impact globally, threatening food security and public health.

Disease control measures comprise a combination of biosecurity with both preventative and therapeutic treatments. However, vaccination represents the most highly cost-effective tool to prevent, manage and even eradicate diseases.

Young animals are particularly susceptible to infectious diseases since they possess a naïve adaptive immune system. The mammalian immune system has evolved so that neonates acquire maternally-derived antibodies (MDA) through the ingestion of colostrum and milk. This provides passive immunity but MDA wane and are lost after weaning. It is therefore critical to immunise young animals to ensure active immunity is in place. However, MDA can interfere with vaccination leaving young animals susceptible to infection. There is therefore a need for new vaccine strategies to enhance immune responses in neonatal animals with MDA.

NEOVACC is a major international collaborative project evaluating novel strategies designed to enhance the effectiveness of vaccines in neonatal animals with MDA. We are focussing on bovine respiratory syncytial virus (BRSV) and porcine reproductive and respiratory syndrome virus (PRRSV) as they cause two major endemic viral diseases in cattle and pigs. In both these infections, MDA interfere with neonatal vaccination leading to high vulnerability at the time of weaning.

Aims and objectives

The project combines complementary expertise in veterinary medicine, virology, immunology, protein engineering and vaccinology from six leading institutions and is structured with three complementary work-packages (WP):

WP1: Designing BSRV immunogens to exploit differences in antibody repertoires between adult and neonatal cattle.

We will identify epitopes on the pre-fusion (preF) protein of BRSV that are distinctly targeted by neonatal and adult antibody repertoires. Epitope-scaffold antigens will be anchored on N-nanorings, that are immunogenic carriers easy to produce in bacteria at low cost. These will be evaluated as vaccine candidates in calves with MDA.

WP2: A DNA vaccine-based approach against PRRSV to counteract MDA interference.

We will generate DNA vaccines where PRRSV antigens are fused to antigen-presenting cell targeting moieties that we have shown enhance immunogenicity. We will then test if a targeted DNA prime/modified live PRRSV vaccine boost vaccine strategy enhances cell mediated and antibody responses and increases vaccine efficacy in MDA+ piglets.

WP3: Engineering immune checkpoint inhibitors to enhance neonatal responses to vaccination.

Immune checkpoints are natural regulators of the immune system, crucial for maintaining self-tolerance and reducing immunopathological responses. Immune checkpoint inhibitors are highly effective cancer immunotherapeutics and are emerging as a novel class of adjuvants for prophylactic immunization. We will evaluate whether genetically engineering a modified live PRRSV vaccine to express peptide-based ICIs will potentiate vaccine responses of piglets resulting in enhanced protection.

Outputs and impact

We will develop and test tools and technologies for producing improved vaccines for two respiratory viral pathogens responsible for huge economic losses in the global pig and cattle industries.

Current PRRSV and BRSV vaccines are weakly immunogenic and are affected by the presence of MDA. Efficacy is limited to a reduction in clinical disease rather than preventing infection. These imperfect vaccines do not suppress the circulation of virus and rather drive immune escape. Break-through infections occur in the face of vaccination, leading to disease and the requirement for antibiotics to treat secondary infections.

Whilst the project will focus on these two diseases, the novel approaches employed to design vaccine antigens, to deliver DNA encoded antigens in a targeted manner to augment B cell responses, and to potentiate responses through immune checkpoint inhibition may be broadly applied, including to human clinical settings.