Immunization delays the onset of prion disease in mice

Abstract

The outbreak of new variant Creutzfeldt-Jakob disease has raised the specter of a potentially large population being at risk to develop this prionosis. None of the prionoses currently have an effective treatment. Recently, vaccination has been shown to be effective in mouse models of another neurodegenerative condition, namely Alzheimer's disease. Here we report that vaccination with recombinant mouse prion protein delays the onset of prion disease in mice. Vaccination was performed both before peripheral prion exposure and after exposure. A delay in disease onset was seen in both groups, but was more prolonged in animals immunized before exposure. The increase in the incubation period closely correlated with the anti-prion protein antibody titer. This promising finding suggests that a similar approach may work in humans or other mammalian species at risk for prion disease.

Figure 1.

A: Prophylactic vaccination with recPrP delays disease onset in mice inoculated intraperitoneally both at the 10-fold (P = 0.002) and 1000-fold (P = 0.040) dilution of PrP^Sc with day 0 being the first day an animal scored positive for disease. Group 1 mice were controls receiving brain inoculum at a 10-fold dilution, while group 2 was inoculated at the same dilution but also received recPrP vaccination. Group 3 mice were controls inoculated with brain homogenate at a 1000-fold dilution, while group 4 received the same dilution of inoculum along with recPrP vaccination. The two control groups received adjuvant and vehicle injections. B and C: Levels of serum antibody against PrP^C (PrP^Sc treated with formic acid rendering it protease-sensitive) correlate with incubation time of the disease both at 10-fold (B; r² = 0.453, P < 0.005) and 1000-fold (C; r² = 0.744, P < 0.0001) dilution of brain inoculum. Each data point represents the mean ± SEM of duplicate plasma samples.

Figure 2.

A: Vaccination with recPrP initiated 24 hours after inoculation with PrP^Sc delays disease onset only at the lower dilution (P = 0.021). Group assignments were the same as depicted in Figure 1A ▶ . B: Levels of serum antibodies against PrP^C (PrP^Sc treated with formic acid rendering it protease-sensitive) correlate with incubation time of the disease at the 1000-fold dilution of brain inoculum (r² = 0.772, P < 0.0001). Each data point represents the mean ± SEM of duplicate plasma samples.

Figure 3.

Coronal representative sections stained with cresyl violet through the pyramidal layer of the hippocampus in a control (A) and in a prophylactically vaccinated (B) mouse, showing extensive spongiform change. Both mice were infected intraperitoneally with a 10-fold dilution of a 139A PrP^Sc brain homogenate. All mice were examined histologically and had similar spongiform change. Even though the vaccinated animals had a longer incubation period, the extent of pathology was not apparently different in the two groups. This is expected because all of the mice were sacrificed at an equivalent time point after developing disease (each mouse had been rated clinically ill for 3 consecutive weeks using an established protocol). Original magnifications, ×100. Scale bar, 100 μm.