Sarah J. Cox

Longevity of antibody and cytokine responses following vaccination with high potency emergency FMD vaccines.

The ability of high potency emergency foot-and-mouth disease (FMD) vaccines to promote sustainable immune responses in sheep and pigs following a single application was examined. All vaccine formulations induced a rapid seroconversion in both species, as expected, which was maintained at near peak titres for up to 6 months in sheep and 7 months in pigs. The Montanide ISA 206 formulation gave the best results in sheep. Vaccinated pigs challenged with homologous FMDV were protected from disease at 7 months post vaccination. Systemic levels of cytokines IL-6, IL-8, and in some pigs IL-12, increased following vaccination and were often maintained at an increased level for the duration of the trials. These initial results suggest that high potency vaccines may promote longer lasting immunity than the conventional lower potency vaccines in ruminants and a comparable response in pigs. Results indicate that in an outbreak situation, should emergency vaccination be done with these high potency vaccines, protection should be conferred for a long enough period for the outbreak to be brought under control without the need to revaccinate. Given the increased interval for re-vaccination the use of high potency vaccines for routine prophylactic campaigns could provide a more cost-effective and efficient means of maintaining herd immunity and is an area thus worthy of further examination.

Further studies on the early protective responses of pigs following immunisation with high potency foot and mouth disease vaccine

The ability of an emergency oil adjuvanted foot-and-mouth disease (FMD) vaccine to elicit early protective immunity in pigs against direct contact homologous challenge was examined. All vaccinates showed reduced viraemia and shedding of FMDV, and certain animals were protected, showing no clinical signs. IL-6, IL-8 and IL-12 were consistently detected in challenged animals that had been vaccinated. Other cytokines--IL-1, IL-2, TNF, TGF and interferons--were not detected. This demonstrates that the vaccine did not induce a systemic inflammatory response, nor a systemic elevation of T lymphocyte activity. Although the IL-6 and IL-8 did not relate to protection, IL-12 production was highest in the protected vaccinated pigs. Thus, the induction of monocytic cell activity, demonstrable by the production of IL-6, IL-8 and IL-12, appears to play a critical role in FMDV emergency vaccine induction of the innate immune defences which relate to early protection against FMD. The possible modes of defence in which such cytokine activity would be involved are discussed.

Experimental evaluation of foot-and-mouth disease vaccines for emergency use in ruminants and pigs: a review

Changes to foot-and-mouth disease (FMD) control policies since 2001 mean that emergency vaccination must be considered more readily as a control measure in the future. Since field application of vaccine for emergency use has only rarely been applied, the effectiveness of single dose administration, as a control measure in an outbreak situation, is poorly understood. In this review we consider all the available experimental data from studies utilizing either experimental or readily available, commercially produced vaccines, in order to assess their likely effectiveness as an additional means of controlling FMD transmission and spread in an emergency. Overall it is concluded that such vaccines offer an additional and valuable means of FMD control for both ruminants and pigs. They are able to reduce clinical disease, sub-clinical infection and excretion and onward transmission of virus. However, to be most effective, vaccination should be rapidly applied to give maximum opportunity for immunity to develop. We also identify areas for future research and emphasize the importance of vaccine efficacy studies in providing data for models that can help to predict the efficacy of differing FMD control strategies.

A DNA vaccination regime including protein boost and electroporation protects cattle against foot-and-mouth disease

Protection against foot-and-mouth disease (FMD) using DNA technology has been documented for sheep and pigs but not for the highly susceptible species of cattle. Twenty-five Holstein Friesian cross-bred cattle were vaccinated twice, 21 days apart, with a DNA vaccine containing the capsid coding region (P1) along with the non-structural proteins 2A, 3C and 3D (pcDNA3.1/P1-2A3C3D) of O(1) Kaufbeuren alone or coated onto PLG (d,l-lactide-co-glycolide) microparticles. In some pcDNA3.1/P1-2A3C3D was also combined with an adjuvant plasmid expressing bovine granulocyte macrophage colony stimulating factor (GM-CSF). DNA vaccinations were administered intramuscularly with, or without, the use of electroporation and at 42 days post primary vaccination cattle received a protein boost of 146S FMD virus (FMDV) antigen and non-structural protein 3D. For comparison, four cattle were vaccinated with a conventional FMD vaccine and two more included as unvaccinated controls. Apart from those immunised with PLG microparticles all cattle were challenged with 10(5) TCID(50) cattle adapted O(1) Lausanne FMDV virus at day 93 post primary vaccination. All DNA vaccinated cattle regardless of regime developed good humoral and cell mediated responses prior to challenge. The best overall virus neutralising antibody, IFN-γ and clinical protection (75%) were seen in the cattle whereby the DNA was delivered by electroporation. In contrast, only 25% of cattle vaccinated with the DNA vaccine without electroporation were clinically protected. The addition of GM-CSF in combination with electroporation further improved the efficacy of the vaccine, as demonstrated from the reduction of clinical disease and virus excretions in nasal swabs. We thus demonstrate for the first time that cattle can be clinically protected against FMDV challenge following a DNA prime-protein boost strategy, and particularly when DNA vaccine is combined with GM-CSF and delivered by electroporation.

Foot-and-mouth disease marker vaccine: Cattle protection with a partial VP1 G–H loop deleted virus antigen

Contrary to the dogma that the VP1 G-H loop is essential for FMD vaccine efficacy, it has been previously shown that foot-and-mouth disease 146s antigen containing heterologous VP1 G-H loops confers complete protection in pigs and cattle. Moreover, serological evaluation of cattle vaccinated with an antigen lacking a large proportion of the VP1 G-H loop indicated that these animals should be protected against infection with FMD. Absence of this loop provides opportunity for the development of an FMD negative marker vaccine, allowing infection to be detected by antibodies against this missing region. Cattle vaccinated with this negative marker vaccine were fully protected following virus challenge 28 days post vaccination as determined by the absence of generalised lesions on their feet. Furthermore, use of our improved differentiation ELISA identified animals exposed to infection as early as 7 days post-challenge. We thus demonstrate, for the first time, the ability of this FMD negative marker vaccine to fully protect cattle from experimental challenge and rapidly distinguish animals that are subsequently exposed to infection.

Longevity of protection in cattle following immunisation with emergency FMD A22 serotype vaccine from the UK strategic reserve

To determine the longevity of protective immunity following a single administration of emergency vaccine, and establish whether the immune response could be enhanced by increasing the antigen payload even further, cattle were vaccinated with an A22 Iraq vaccine containing either 1x antigen payload (field dose) or 5x antigen payload. Six months post-immunisation all cattle received a homologous virus challenge. The magnitude of the virus neutralising antibody response elicited was consistent with the response to similarly formulated A serotype vaccines with a PD(50) greater than 32. All the vaccinated cattle, regardless of antigen payload, were protected from clinical disease following challenge although some cattle in both groups became sub-clinically infected. We conclude that immunisation with a single inoculation of vaccine from the UK emergency reserve can protect cattle from clinical disease for at least 6 months post-vaccination and that a boost may be unnecessary in an outbreak situation. Some animals may become sub-clinically infected but this is likely to be dependent on the severity of challenge. The study confirmed that a booster at 21 days post-vaccination was not necessary to maintain a cell-mediated response in cattle for 6 months. No increased benefits were recognised by increasing the antigen payload of this vaccine 5x.

The effect of vaccination on undetected persistence of foot-and-mouth disease virus in cattle herds and sheep flocks.

The importance of carrier animals (those in whom virus persists after recovery from disease or acute infection) and their potential role in the spread of disease remain open questions within foot-and-mouth disease epidemiology. Using simple probabilistic models we attempt to quantify the effect of emergency vaccination--and especially the time of application--on the likely number of such animals, using data from challenge experiments on both cattle and sheep to determine the probability of persistence in diseased and subclinically infected animals. We show that the number of persistently infected animals in a group is predominantly determined by the number of animals initially infected on premises--the high variability of which ultimately limits the accuracy of any predictions of carrier numbers based upon transmission models. Furthermore, results suggest that, within a cattle herd, carrier numbers may be increased if challenge occurs shortly after vaccination. We show that the quality of inspection is the principal factor influencing whether or not carrier herds occur and that, by reducing clinical signs, the application of vaccination in regularly checked stock also results in an increase in undetected persistently infected animals. Where clinical detection would be poor regardless of the use of vaccination (i.e. particularly in sheep), vaccination will result in a reduction in the probability of a group containing undetected carriers: otherwise there is a benefit only if vaccination is applied sufficiently far in advance of any challenge. The implications of the results for serosurveillance are discussed, including the requisite test sensitivity and practices for successful implementation.

IL-6 production following vaccination in pigs—An additional immune response parameter for assessing FMD vaccine efficacy?

Foot-and-mouth disease vaccine potency testing involving live virus challenge can be problematical in pigs. Alternative methods of assessing vaccine efficacy are therefore desirable. Here we investigate the link between IL-6 in blood at time of challenge and protection against challenge by carrying out statistical analyses utilising data from six separate potency tests performed in swine with the aim of assessing whether IL-6 could be exploited as an additional parameter for confirming vaccine efficacy in pigs. These analyses confirmed that systemic IL-6 levels increased when the administered vaccine dose increased and that the odds of protection against challenge increased as IL-6 levels increased. The link between increased protection and increased antibody was reaffirmed and a significant link between IL-6 levels and antibody levels was shown. We therefore conclude that quantifying the levels of IL-6 in serum could provide additional means of qualifying whether a vaccine will afford clinical protection or not in pigs, in the absence of an actual challenge, and thus offer the possibility of improved vaccine potency testing in pigs both in terms of animal welfare as well as cost.