Effects of post-challenge administration of ST-246 on dissemination of IHD-J-Luc vaccinia virus in normal and in immune deficient mice reconstituted with T cells.
Whole body bioimaging was used to study dissemination of vaccinia virus (VACV) in normal and in immune deficient (nu-/nu-) mice protected from lethality by post challenge administration of ST-246. Total fluxes were recorded in the liver, spleen, lungs, and nasal cavity in live mice following intranasal infection with a recombinant IHD J Luc VACV expressing luciferase. Areas Under the flux Curve (AUC) were calculated for individual mice to assess viral loads. Two to five days treatment of normal BALB c mice with ST-246 at 100 mg/kg starting 24 hr post challenge conferred 100% protection and reduced viral loads in 4 organs compared with control mice. Mice also survived after 5-day treatment with 30 mg kg of ST-246, yet viral loads and poxes were higher in these mice compared with 100 mg/kg group. Nude mice were not protected by ST-246 alone or by 10 million adoptively transferred T cells. In contrast, nude mice that received T cells and 7 day treatment with ST-246 survived infection and exhibited reduced viral loads compared with non-reconstituted and ST-246-treated mice after ST-246 was stopped. Similar protection of nude mice was achieved using adoptively transferred 1.0, 0.1, but not 0.01 million of purified T cells or CD4+ or CD8+ T cells in conjunction with ST-246 treatment. These data suggest that ST-246 protects immune competent mice from lethality and reduces viral dissemination in internal organs and poxvirus lesions. Furthermore, immune deficient animals with partial T cell reconstitution can control virus replication after a course of ST-246 and survive lethal vaccinia challenge."
A whole lot of paper coming out. See, they were sandbagging for 2 years. Guess it’s over! Three main points in this paper:
a) In looking at fluorescent markers, they could see exactly what tissues and organs were affected by model infections and treatment with ST-246. Very instructive on what is going on.
b) They discovered the precise differences in treatments between 30 and 100 mg/kg, even though both work.
c) They have a model of mice with no immune system. If you try ST-246 in that, it doesn’t work. If you add some of the immune system back, then ST-246 will work. Shows that ST-246 alone may not work in people very severely compromised immune systems. Woulda been nice if it had worked alone, but well...
I think this explains BARDA interest in CMX-001. It does not require an intact immune system. There's a much smaller need for this population, but they are at much greater risk of death from smallpox. And we've seen that even vaccinia can be very serious in immune-compromised hosts.