Understanding the mechanisms that maintain protective antibody levels after immunisation is important for vaccine design. In this study, we have determined the kinetics of plasma and memory B cells detectable in the blood of cattle immunised with model T-dependent or T-independent antigens. Immunisation with the T-D antigen resulted in an expansion of TNP-specific plasma cells post-TNP primary and booster immunisations, which was associated with increased titres of TNP-specific IgG antibodies. Although no TNP-specific memory B cells were detected in the T-D group following the primary immunisation, we detected an increase in the number of TNP-specific memory B cells post-TNP boost. In contrast, no TNP-specific plasma or memory B cells were detected after primary or secondary immunisation with the T-I antigen. We then investigated if immunisation with a third party antigen (tetanus toxin fragment C, TTC) would result in a bystander stimulation and increase the number of TNP-specific plasma and memory B cells in the T-D and/or T-I group. TTC immunisation in the T-D group resulted in a small increase in the number of TNP-specific plasma cells post-TTC primary immunisation and boost, and in an increase in the number of TNP-specific memory B cells post-TTC boost. This bystander effect was not observed in the animals previously immunised with the T-I antigen. In conclusion, the present study characterised for the first time the B cell response in cattle to immunisation with T-D and T-I antigens and showed that bystander stimulation of an established T-D B cell memory response may occur in cattle.

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Foot and mouth disease virus causes a livestock disease of significant global socio-economic importance. Advances in its control and eradication depend critically on improvements in vaccine efficacy, which can be best achieved by better understanding the complex within-host immunodynamic response to inoculation. We present a detailed and empirically parametrised dynamical mathematical model of the hypothesised immune response in cattle, and explore its behaviour with reference to a variety of experimental observations relating to foot and mouth immunology. The model system is able to qualitatively account for the observed responses during in-vivo experiments, and we use it to gain insight into the incompletely understood effect of single and repeat inoculations of differing dosage using vaccine formulations of different structural stability.

Foot-and-mouth disease virus (FMDV) is a highly contagious viral disease. Antibodies are pivotal in providing protection against FMDV infection. Serological protection against one FMDV serotype does not confer interserotype protection. However, some historical data have shown that interserotype protection can be induced following sequential FMDV challenge with multiple FMDV serotypes. In this study, we have investigated the kinetics of the FMDV-specific antibody-secreting cell (ASC) response following homologous and heterologous inactivated FMDV vaccination regimes. We have demonstrated that the kinetics of the B cell response are similar for all four FMDV serotypes tested following a homologous FMDV vaccination regime. When a heterologous vaccination regime was used with the sequential inoculation of three different inactivated FMDV serotypes (O, A, and Asia1 serotypes) a B cell response to FMDV SAT1 and serotype C was induced. The studies also revealed that the local lymphoid tissue had detectable FMDV-specific ASCs in the absence of circulating FMDV-specific ASCs, indicating the presence of short-lived ASCs, a hallmark of a T-independent 2 (TI-2) antigenic response to inactivated FMDV capsid.IMPORTANCE We have demonstrated the development of intraserotype response following a sequential vaccination regime of four different FMDV serotypes. We have found indication of short-lived ASCs in the local lymphoid tissue, further evidence of a TI-2 response to FMDV. KEYWORDS B cell, FMDV, T-independent, viral immunology F oot-and-mouth disease virus (FMDV) is a highly contagious pathogen that has a large socioeconomic impact upon countries in which the virus is endemic. Studies of cattle and mice have shown that protection from the virus is largely mediated by antibodies (1). One of the main approaches to FMD control is through vaccination with inactivated FMDV antigen in formulation with adjuvants (2). However, the current inactivated FMDV vaccines are unable to induce long duration of immunity in cattle; regular repeated immunizations are required to maintain protective antibody titers (1).It is generally considered that serological protection against one FMDV serotype does not confer interserotype protection and may not, in some cases, confer intraserotype protection, given the antigenic variation seen within some serotypes (1). We have recently shown that intraserotype protection is possible within the FMDV O serotype using a heterologous FMDV challenge model following a single vaccination with inactivated FMDV (3). Indeed, Cottral and Gailiunas were able to demonstrate that after three rounds of challenge with multiple FMDV serotypes, the animals were resistant to further FMDV challenges (4). These animals had clearly developed cross-

Antibodies play a pivotal role against viral infection, and maintenance of protection is dependent on plasma and memory B-cells. Understanding antigen-specific B-cell responses in cattle is essential to inform future vaccine design. We have previously defined T-cell-dependent and -independent B-cell responses in cattle, as a prelude to investigating foot-and-mouth-disease-virus (FMDV)-specific B-cell responses. In this study, we have used an FMDV O-serotype vaccination (O1-Manisa or O SKR) and live-virus challenge (FMDV O SKR) to investigate the homologous and heterologous B-cell response in cattle following both vaccination and live-virus challenge. The FMDV O-serotype vaccines were able to induce a cross-reactive plasma-cell response, specific for both O1-Manisa and O SKR, post-vaccination. Post-FMDV O SKR live-virus challenge, the heterologous O1-Manisa vaccination provided cross-protection against O SKR challenge and cross-reactive O SKR-specific plasma cells were induced. However, vaccination and live-virus challenge were not able to induce a detectable FMDV O-serotype-specific memory B-cell response in any of the cattle. The aim of new FMDV vaccines should be to induce memory responses and increased duration of immunity in cattle.