High titers of mucosal and systemic anti-PrP antibodies abrogate oral prion infection in mucosal-vaccinated mice

Abstract

Significant outbreaks of prion disease linked to oral exposure of the prion agent have occurred in animal and human populations. These disorders are associated with a conformational change of a normal protein, PrP C , to a toxic and infectious form, PrP Sc . None of the prionoses currently have an effective treatment. Some forms of prion disease are thought to be spread by oral ingestion of PrP Sc , such as chronic wasting disease and variant Creutzfeldt-Jakob disease. Attempts to obtain an active immunization in wild-type animals have been hampered by auto-tolerance to PrP and potential toxicity. Previously, we demonstrated that it is possible to overcome tolerance and obtain a specific anti-PrP antibody response by oral inoculation of the PrP protein expressed in an attenuated Salmonella vector. This past study showed that 30% of vaccinated animals were free of disease more than 350 days post-challenge. In the current study we have both optimized the vaccination protocol and divided the vaccinated mice into low and high immune responder groups prior to oral challenge with PrP Sc scrapie strain 139A. These methodological refinements lead to a significantly improved therapeutic response. 100% of mice with a high mucosal anti-PrP titer IgA and a high systemic IgG titer, prior to challenge, remained without symptoms of PrP infection at 400 days (long-rank test p<0.0001 versus sham controls). The brains from these surviving clinically asymptomatic mice were free of PrP Sc infection by Western blot and histological examination. These promising findings suggest that effective mucosal vaccination is a feasible and useful method for overcoming tolerance to PrP and preventing prion infection via an oral route ¶Corresponding Author:

Adoptive Transfer of T Lymphocytes Sensitized against the Prion Protein Attenuates Prion Invasion in Scrapie-Infected Mice

“…Still, on the basis of studies of amyloidosis and Alzheimer disease (21)(22)(23) and of reports showing that Abs prevent PrP conversion in vitro (24 -26), several teams have attempted to generate active or passive immunity against PrP in scrapie-infected mice. Passive Ab transfer (27,28), transgenic constitutive secretion of anti-PrP IgM Abs (29), or active immunization with whole PrP (30,31), PrP peptides (32,33), PrP fragments (34), or DNA constructs encoding Prnp sequences (35)(36)(37) have resulted in reduced invasion of secondary lymphoid organs, delayed onset, prolonged survival, and, in a few instances, definitive remission. None of these approaches is, however, totally satisfactory.…”

Mouse vaccination with dendritic cells loaded with prion protein peptides overcomes tolerance and delays scrapie

“…Active immunization with PrP 98-127 or PrP 158-187 in the presence of CpG induced T cells and Ab production but prolonged mouse survival by only 20 days (Sacquin et al, 2008). More encouraging results have been obtained by Goni et al (2008) following oral immunization with Salmonella typhimurium encoding one or two copies of mouse Prnp in their genome. The attack rate was reduced down to zero in mice immunized six times prior to challenge and selected for high IgA production.…”

New inhibitors of prion replication that target the amyloid precursor

“…Clinical trials have been conducted, with the use of quinacrine and pentosan polysulfate (PPS), but none of them appeared to be efficient or convenient (Stewart et al, 2008). Moreover, both active and passive immunotherapies have been developed (Trevitt & Collinge, 2006) and some have recently yielded promising results (Goni et al, 2008;Song et al, 2008;Wuertzer et al, 2008), which justifies the importance of continuing the search for new therapeutics.…”