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. 2014 May 27;45(1):59.
doi: 10.1186/1297-9716-45-59.

The effect of the TLR9 ligand CpG-oligodeoxynucleotide on the protective immune response to alcelaphine herpesvirus-1-mediated malignant catarrhal fever in cattle

Nevi Parameswaran, George C Russell, Kathryn Bartley, Dawn M Grant, David Deane, Helen Todd, Mark P Dagleish, David M Haig  1
Affiliations

The effect of the TLR9 ligand CpG-oligodeoxynucleotide on the protective immune response to alcelaphine herpesvirus-1-mediated malignant catarrhal fever in cattle

Nevi Parameswaran et al. Vet Res. .

Abstract

We wished to determine the effect of of CpG ODN adjuvant on the magnitude and duration of protective immunity against alcelaphine herpesvirus-1 (AlHV-1) malignant catarrhal fever (MCF), a fatal lymphoproliferative disease of cattle. Immunity was associated with a mucosal barrier of virus-neutralising antibody. The results showed that CpG ODN included either with emulsigen adjuvant and attenuated AlHV-1 (atAlHV-1) or alone with atAlHV-1 did not affect the overall protection from clinical disease or duration of immunity achieved using emulsigen and atAlHV-1. This is in contrast to other similar studies in cattle with BoHV-1 or cattle and pigs with various other immunogens. In addition to this, several other novel observations were made, not reported previously. Firstly, we were able to statistically verify that vaccine protection against MCF was associated with virus-neutralising antibodies (nAbs) in nasal secretions but was not associated with antibodies in blood plasma, nor with total virus-specific antibody (tAb) titres in either nasal secretions or blood plasma. Furthermore, CpG ODN alone as adjuvant did not support the generation of virus-neutralising antibodies. Secondly, there was a significant boost in tAb in animals with MCF comparing titres before and after challenge. This was not seen with protected animals. Finally, there was a strong IFN-γ response in animals with emulsigen and atAlHV-1 immunisation, as measured by IFN-γ secreting PBMC in culture (and a lack of IL-4) that was not affected by the inclusion of CpG ODN. This suggests that nAbs at the oro-nasal-pharyngeal region are important in protection against AlHV-1 MCF.

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Figures

Figure 1
Figure 1
Survival plot for each of the four groups of cattle. Kaplan Maier survival plot. Group 1: 9 cattle immunised and boosted with atAlHV-1 (virus) along with Emulsigen (Em) adjuvant. Group 2: 9 cattle immunised and boosted as in group 1 but including CpG ODN (CpG) as well as Emulsigen; Group 3: 5 cattle immunised and boosted with atAlHV-1 (virus) and CpG ODN. Group 4: 5 cattle injected with adjuvant only. P = 0.02 for group 1 compared to group 4. P = 0.04 for group 2 compared to group 4. Groups 3 and 4 were not significantly different (p = 0.24).
Figure 2
Figure 2
Virus-specific antibody responses. (A, B) Virus-specific antibody titres in each of the 4 groups of cattle detected by ELISA. Group mean titres and standard deviation of the mean (SD, bars) are shown for each time point. Arrows show timing of primary (1°) and boost (2°) immunisations and virus challenge on week 27 (chall). (A) Blood plasma antibody; (B) antibody in nasal secretions (NS). (C, D) Virus neutralising antibody titres in each of the 4 groups of cattle. These were performed on samples prior to immunisation, at week 7 (3 weeks after booster immunisation) and on week 26, 1 week prior to virus challenge. Group mean titres and SD are shown for each time point; (C) Neutralising antibody titres in nasal secretions; (D) Neutralising antibody titres in blood plasma; (E, F) Comparison of total virus-specific antibody titres and virus-neutralising antibody titres in group 1 and 2 at week 26, just prior to virus challenge, in cattle that subsequently developed MCF or were protected (PROT); (E) Comparison in nasal secretions; (F) Comparison in blood plasma. P values for any significant comparisons are shown in the figures. (G, H) Comparison of total virus-specific antibody titres on week 26, just prior to virus challenge (pre-chall) and after challenge (taking the highest titre of the various time points after challenge) in animals that developed clinical MCF compared to those that were protected (PROT). (G) Nasal secretion antibody comparison. (H) Blood plasma antibody comparison. P values for any significant comparisons are shown in the figures.
Figure 3
Figure 3
IFN-γ secreting PBMC frequencies. (A, B) IFN-γ-secreting cells expressed as spot-forming cells (SFC) per 106 PBMC. Blood samples from weeks 0, 2, 7 (3 weeks after booster immunisation), 10, 18 and 26 (1 week prior to virus challenge- Pre-chall) were taken, as well as week 28 and the terminal blood sample prior to euthanasia (Term sample) in both the MCF and protected animals. A) Analysis of all animals in each group shown as group means and standard deviation of the mean (SD). (B) IFN-γ-secreting cell frequencies in individual animals (displayed as a scatter plot) comparing animals that developed MCF or were protected (PROT). Significant responses were recorded for the pre-challenge and after challenge terminal samples only. Note there were 3 terminal blood PBMC samples with 0 SFC in the MCF group and these do not show on the log scale used.
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