Vaccination of young calves against respiratory pathogens: Immunological considerations

The neonatal calf is vulnerable to infections and remains at high risk of respiratory disease throughout the first year of life. Bovine respiratory disease is complex, and control relies on a multi-pronged approach to reduce the pathogen challenge, address management-associated risk factors and maximise the resilience of the calf to infection. This article will discuss the immune system of the young calf and how vaccination to optimise immunity in young cattle can maximise their resilience to infection and help to provide the foundations of a healthy, productive life. 

Development of the immune system 

The calf’s immune system develops during the gestation period but continues to mature during the early months of life. By the time a calf is born the innate immune system is largely formed. Macrophages and neutrophils can be detected from around 130 days of gestation; however, a rise in foetal cortisol ahead of parturition suppresses innate immune function for a period following birth.
Gamma delta T cells, in particular, play an important role in the innate immune response at this stage of life. Young calves have high levels of these cells, up to 60 per cent of the total lymphocyte pool, and although their role is not fully clear, it is probable that they have a function in recognising specific pathogen-associated molecular patterns (PAMPs), present on many disease-causing organisms to provide a first-line response to infection.
The cellular components of the adaptive immune system – the B and T lymphocytes – are also present in the foetal calf, but at lower levels than in adult animals. During gestation the foetal environment offers a high level of protection against microbial challenge. This means that calves are typically born ‘agammaglobulinaemic’, with no circulating antibody unless infection has occurred in utero.  Once born, however, the calf’s innate and adaptive immune system must rapidly adapt to deal with exposure to both pathogenic and commensal microbes. Humoral immune responses are initiated – functional levels of endogenous immunoglobulin M (IgM) are detectable in colostrum-deprived calves from eight days after birth, and IgA, IgG1 and IgG2 are present from 16-32 days. Adult levels of circulating antibody are reached at around four months of age. 

Passive immunity in the young calf 

Antibodies transferred from the dam to the calf in colostrum confer passive protection against infection in early life. IgG predominates in cow colostrum, accounting for over 75 per cent of total immunoglobulin, but IgM and IgA are also present. During the first hours of life, macromolecules present in the gut, including immunoglobulins, undergo endocytosis by the enterocytes and pass into the circulation. Uptake of other colostrum constituents, including cytokines, lymphocytes and growth factors, also influences the development of the immune system. Bioactive compounds in colostrum also play a role in the development and maturation of the gut itself. Calves fed colostrum at birth have been shown to have improved intestinal morphology compared to those fed milk alone.
The transfer of molecules across the gut was previously considered to be a passive process, however there is increasing evidence to show that it is influenced by both calf and management factors. Colostrum-feeding protocols can ensure that an appropriate volume of good quality colostrum is fed to every calf in a hygienic and timely manner. Care should also be taken to recognise animals that may be at specific risk of failure of passive transfer due to factors that impact on their ability to absorb IgG even when an appropriate amount of colostrum is fed. Management factors such as cold stress, premature birth, dystocia, and delivery by caesarean section can all directly reduce the ability of the enterocytes to take up antibodies.
Monitoring passive transfer can help to guide colostrum management practices on farm. Guidelines on interpretation of IgG assessment have recently been updated. This change was initiated following a recognition that application of the previous target of serum IgG >10g/L was effective in reducing mortality but did not have the same impact on calf morbidity. In place of this single threshold, the following herd-level targets are now recommended: 

• 40 per cent of calves achieve >25g of IgG/L of serum at 24-48 hours; 
• 30 per cent of calves achieve 18.0-24.9g/L; 
• 20 per cent of calves achieve 10.0-17.9g/L; and
• <10 per cent of calves achieve <10.0g/L. 

Assessment of total IgG does not provide insight into the levels of pathogen-specific antibody titres – each calf begins life with a different maternal antibody profile which is influenced by a wide range of farm-level and calf-level factors. 

Maternally derived antibody and the vaccine response 

The calf is largely dependent on maternally derived antibodies (MDA) for protection against disease for at least the first two to four weeks of life. Early vaccination is used on many farms with the objective of achieving a smooth transition from passive to active immunity, avoiding the immunity gap that can occur at this time.
However, the presence of high levels of MDA can have a negative impact on the vaccine response of young calves. Although the mechanism has not been fully characterised, binding of maternal antibodies to vaccine antigens can interfere with the response to systemic (injectable) vaccines. This inhibits B cell activation and attenuates the initial antibody response to vaccination, meaning that calves vaccinated in the face of vaccine antigen specific-MDA are unlikely to undergo sero-conversion when defined as a four-fold increase in antibody level, however vaccination may still induce a humoral response in addition to a B cell memory response. T cell priming is also recognised to occur following vaccination against respiratory viruses in the face of MDA.
As severe respiratory infections pose a significant threat to young calves, it is desirable that vaccines work in the face of MDA and provide rapid immunity. Studies have shown that live attenuated viral vaccines delivered via the mucosal route induce immunity more consistently in the face of MDA than inactivated or live vaccines delivered by injection.
A study demonstrated that MDA-positive calves vaccinated with a live attenuated intranasal vaccine containing PI-3 and bovine respiratory syncytial virus (BRSV) were protected against challenge with either PI-3 or BRSV at 12 weeks after initial vaccination. Both MDA-positive and MDA-negative vaccinated calves showed a comparable, significant level of reduction of both viral shedding and clinical signs when compared to unvaccinated controls. Seroconversion was also observed in the vaccinated MDA-negative animals and circulating antibody titres were maintained at similar levels following vaccination of the MDA-positive calves.
The efficacy of mucosal vaccines in the face of MDA is due to the presence of lower levels of pathogen-specific maternal antibodies at the mucosal surface where the immune response is initiated compared to SC or IM injection sites. As respiratory viruses initiate infection within the respiratory tract, inducing immunity at the mucosal surfaces can optimise protection against infection: mucosal antibodies block virus entry into cells, whilst cytotoxic T cells kill infected cells. 
Mucosal immunity develops rapidly, but typically provides a shorter duration of immunity than that conferred by systemic administration of injectable vaccines. Follow-up vaccination can extend the duration of immunity against bovine respiratory disease (BRD) pathogens and provide appropriate protection ahead of high-risk periods. In addition to this, immunological priming can be induced by intranasal vaccination of both MDA-negative and MDA-positive calves, which can enhance the serological response to subsequent administration of the same antigens by the injectable route. 

Respiratory vaccination strategies 

An optimised respiratory vaccination strategy should provide calves with enhanced resilience to key pathogens at periods of high risk. On many farms the risk begins early in life, and continues throughout the first year, peaking at times of increased stress such as weaning and housing. Vaccine selection should consider farm level risk. In many instances, administration of a single course of a respiratory vaccine will not provide the duration of protection and pathogen cover required to effectively reduce the risk of disease throughout periods of high challenge. 
An integrated approach, which capitalises on the rapid onset protection against respiratory viruses provided by mucosal vaccines, even in young MDA-positive calves, and the longer-term protection offered by subsequent administration of a full primary course of an injectable vaccine can enhance the resilience of calves to infection and minimise the impact of respiratory disease on health and productivity. 

References available on request.