Can vaccinating sheep reduce the occurrence of caseous lymphadenitis?

PICO question 
Is there a decrease of caseous lymphadenitis in vaccinated sheep compared to unvaccinated sheep? 
Clinical bottom line 
The evidence provided by the studies used is strong (all have been randomised controlled trials), supporting the hypothesis that sheep vaccinated against caseous lymphadenitis (CLA) are less likely to develop the disease when compared to unvaccinated sheep. Vaccination may be a useful tool in the prevention and control of clinical CLA following a risk assessment. 



Group D (vaccine 4):
Toxoid PLD vaccine combined with the polyvalent clostridial vaccine -Clostridium perfringens, Clostridium tetani, Clostridium septicum, Clostridium chauvoei, and Clostridium novyi. 40 ml of polyvalent clostridial vaccine mixed with 6 g lyophilised powder formulated culture filtrate PLD. The polyvalent is a local vaccine prepared by Veterinary Serum and Vaccine Research Institute (Abbasia, Cairo, Egypt). The 2 ml dose of the vaccine was inoculated subcutaneously in the middle third of the neck.

Group E (control): Unvaccinated animals.
All the vaccinated animals were revaccinated after 3 weeks of the first vaccination.
After 3 weeks of the last vaccination, all five groups were challenged with virulent biovar 1 sheep origin isolate with 2 ml suspension containing 4×106 colony forming unit (CFU), 1 ml vaccine was inoculated subcutaneously in the middle third of the each side of the neck. The non-specific cellular immune response represented by stimulated macrophages was measured at 2 weeks after the challenge while the specific excited lymphocytes response was assessed at 4 weeks.
Statistical analysis was done using model Generalised Linear Model (GLM) of Statistical Analysis System (SAS) and software version 6.12.

Study design: Randomised controlled trial
Outcome studied: Perform a comparative innate and acquired immune response assessment of four different vaccine formulas to evoke protection against induced CLA in sheep.
The specific immune response was evaluated through lymphocyte proliferation assay using ELISA BrdU kit, while the non-specific response was estimated by superoxide anion production and lysozyme activity assays.

Main findings: (relevant to PICO question):
The study indicated that the toxoid PLD vaccine alone (group A) was most efficient and provided innate and acquired immune response in animals against CLA. The vaccine evoked the highest stimulation index, which expressed specific lymphocyte proliferation response by a big margin compared to the other combined vaccines.
Limitations: It does not inform whether the control animals were vaccinated with placebo and does not report the method of randomisation. Outcome studied: The study was directed to develop oil adjuvant vaccine from killed local isolated C. pseudotuberculosis field strain and evaluation of its humoral and cellular immunity response in sheep of the prepared vaccine only and combined with BCG.

Eshra
They were evaluated as cellular and humoral immune responses, through evaluation by phagocytic activity and index, and differential count of leukocytes and ELISA, respectively.

Main findings: (relevant to PICO question):
Proved (in groups I and II) to induce cellular and humoral immunity and could be used for prevention and control of CLA in sheep.
Group I: Immune response mediated by phagocytic activity and phagocytic index between 0 and 44 days average of 62.25%; Group II: Immune response mediated by phagocytic activity and phagocytic index between 0 and 44 days average of 61%; Population: Male lambs (Awassi), ages ranged 5-7 months old. The animals were bred in the Veterinary Medicine University of Baghdad. All lambs were treated by ivermectin 200 μg per kg of body weight subcutaneous at the rate of 1 ml per 50 kg as anthelminthic treatment for internal and external parasites before starting the experiment. Lambs divided into three groups each group consisted of five lambs.

Sample size: 15 lambs (five per group)
Intervention details: The animals were separated into three groups. There is no information on how this allocation was made.
Group I: five lambs as negative control.
Group II: five lambs vaccinated (a commercial vaccine prepared by Colorado Serum Company (U.S.A.), detoxified and purified the whole culture of C. pseudotuberculosis contains thimerosal as preservative used in healthy sheep as a killed bacterin-toxoid vaccine. The vaccine injected subcutaneously in a dose of 2 ml in axillary space and repeated in four weeks in opposite axillary space).
Group III: five lambs as positive control.

Study design: Randomised controlled trial
Outcome studied: To know the efficacy of commercial vaccine (Case-Bac Vaccine) by immunisation trials against the CLA disease in sheep and study cellular and humoral immunity.
Humoral and cell mediated immune response was detected during the period of experiments, the temperature, pulse rate and Cellular immune responses of the vaccinated and control groups were evaluated by delayed type of hypersensitivity (DTH) skin test.

Main findings: (relevant to PICO question):
The vaccine appeared to offer an excellent protection against the development of CLA in sheep and the vaccine could play an important role in the control of the disease in infected sheep flocks.
Antibody titer two weeks after first vaccination dose (mean optical density values): Group II: with a vaccine prepared from C. pseudotuberculosis Cy 5 strain. The vaccine injected subcutaneously in a dose of 0.5 ml (two doses).
Group III: was used as a control and was subcutaneously injected with 2.0 ml phosphate buffer solution (PBS). were evaluated by DTH skin test.

Main findings: (relevant to PICO question):
When a local C. pseudotuberculosis (Pl 18) strain was used and formulated as per ml of the vaccine, 1.5x10 8 colony-forming unit (CFU) of C. pseudotuberculosis bacterin + toxoid + 1/2 FCA of the toxoid, obtained a high percentage of protection regarding the potential of this vaccine to control CLA in sheep, as seen in groups I and II.
Limitations: Method of randomisation not stated and not all animals present at the beginning of the study were allocated to the groups.

DTH.
Serum samples were collected prior to vaccination from all animals (mature stock and lambs) and 1, 3, 6, 9, and 12 months after vaccination.

Main findings: (relevant to PICO question):
When a local C. pseudotuberculosis (Pl 18) strain was used and formulated as per ml of the vaccine, 1.5x10 8 CFU of C. pseudotuberculosis bacterin + toxoid + 1/2 FCA of the toxoid, we obtained protection regarding the potential of this vaccine to control of CLA in sheep. In all industry flocks, antibody titres for both lambs and mature stock were significantly higher than those of controls immediately prior to, and 1 month after, the booster vaccination.
Limitations: It does not report the doses of each vaccine type and how randomisation was performed.

Sample size: 450 lambs
Intervention details: Three groups (150 lambs per group) In each group 50 lambs were artificially infected with C. pseudotuberculosis and 100 were uninfected, and were separated for 40 months. One lot of 50 infected lamb and 100 uninfected lambs were vaccinated against CLA.
Four weeks after the second vaccination, 50 lambs from each group were artificially infected with C. pseudotuberculosis and run separately for a further 4 weeks.
50 artificially infected lambs being run with 100 uninfected lambs.
Sorology was checked to verify soroconversion, by means of antibodies of C. pseudotuberculosis through ELISA.
Differences in CLA infection rates and seroconversion rates between groups of lambs were analysed using chi-square. Analysis of differences in numbers of lesions was done by Kruskal-Wallis one way analysis of variance.
In each group 50 lambs were vaccinated as indicated before artificial infection: In each group 100 lambs were run with 50 artificially infected lambs: Evaluated percentage of lambs with lesion CLA and number of lesions, besides the presence of antibodies to C. pseudotuberculosis exotoxin and cell wall.

Main findings: (relevant to PICO question):
Lambs vaccinated against CLA and naturally exposed to infection had 74% lower infection rate than unvaccinated sheep. Lambs vaccinated against CLA had a 97% lower infection rate (groups I and II).

Unvaccinated lambs had a 76% infection rate (groups III).
Vaccinated lambs infected with CLA have 96% fewer lung abscesses compared with unvaccinated infected lambs and therefore less likely to spread this disease to other lambs.

Limitations: Does not inform if vaccines have been administered intramuscularly
or subcutaneously and how randomisation was performed. The serums were analysed by microagglutination assay for the detection of antibodies to C. pseudotuberculosis. Animals were monitored for the development of abscesses by the technician at each serum collection visit and by routine observation by the farm managers.
The level of significance of the microagglutination was determined by the Student's t-test and was used the logrank test for difference in proportions of new cases in each group over time.

Study design: Randomised controlled trial
Outcome studied: The purpose of this field trial was to evaluate the efficacy of a killed whole cell vaccine in preventing CLA in sheep by induction of infection.

Main findings: (relevant to PICO question):
There was a significant difference in the proportion of vaccinated sheep that developed CLA compared to the control sheep at each time interval except less than 6 months post initial vaccination.
The vaccine appeared to produce a persistently elevated serum antibody titre to C. pseudotuberculosis as measured by the microagglutination assay. There was also a statistically significant degree of protection in sheep against the development of clinical CLA.
The vaccine could have a significant role in the control of CLA in infected sheep.
Limitations: It does not detail the populations or how the randomisation was performed and does not inform if vaccines have been administered intramuscularly or subcutaneously.

Group 4 -control; 33 lambs
Serology and necropsy were performed (to verify lesions caused by CLA).

Study design: Randomised controlled trial
Outcome studied: Compare the protective efficacy of monocomponent and combined clostridial-corynebacterial vaccines.
All three vaccines afforded an equal and high level of protection. 91% (91/100) of vaccinated sheep exhibiting no lesions of caseous lymphadenitis CLA, compared with 51.5% (17/33) affected sheep in the control group).
Average lesion counts were 1.2 per affected vaccinated sheep and 4.5 per affected control sheep.
Antitoxin responses to the clostridial toxoids incorporated in the combined vaccines were not affected by inclusion of the C. pseudotuberculosis toxoid or the sodium selenate.
The results indicate the overall efficacy of vaccines in controlling CLA infection.
Limitations: It does not detail the populations or how the randomisation was performed and does not report whether placebo was used in the control group
Sample size: 84 (16 animals were omitted from the study because they died).
Intervention details: Each group started with 20 lambs, but 16 animals were omitted from the study because they died.
Vaccine was prepared from C. pseudotuberculosis toxoid combined with aluminum hydroxide as adjuvant.
Each sheep received two doses of 2 ml of the appropriate vaccine administered subcutaneously in the neck. The interval between doses was 34 days.
The primary responses and peak secondary responses to the four vaccines did not differ widely, and the subsequent decline of antitoxin titres with time was identical for vaccine groups 3 and 4, with only minor exception in the fourth vaccine group. The protective potency of the vaccines was not improve by the inclusion of cells of C. pseudotuberculosis.