Could vaccine adjuvants lead to new Lupus therapies?

Therapeutic vaccines are hot right now thanks to Dendreon’s recent approval for Provenge and the H1N1 scare of 2009 that resulted in the government pumping hundreds of millions of dollars into venture backed vaccine companies.  Many of the therapeutic vaccines now in development are subunit vaccines that require co-administration with an adjuvant to pump up the seroconversion.  As a result, Toll-like receptors (TLRs) have become one of the hottest areas of adjuvant development for venture and strategic investors alike. 

While I have seen a number of interesting TLR stimulant opportunities over the last year, I have only seen one TLR antagonist idea – and it happened to be a pretty darn cool one.

Lupus is a disease that occurs when a person’s immune system turns on its owner, resulting in significant inflammation and subsequent tissue damage to healthy cells.  One of the key mediators of Lupus-associated inflammation is interferon-alpha (INF-α), a cell signaling molecule that recruits immune cells to destroy pathogens, or in the case of Lupus, the person’s healthy cells.  The binding of pathogens to TLR, specifically TLR-7 and TLR-9, has been shown to increase the expression of INF-α, making researchers wonder if by antagonizing TLR activation could they decreased INF-α expression and subsequent destructive inflammation?

Dynavax Technologies Corp. and the Baylor Institute for Immunology Research published a study in Nature where they administered a TLR-7 / TLR-9 antagonist in two separate lupus prone mouse strains and then monitored INF-α expression levels.  What the researchers found was fairly astonishing, namely that by antagonizing TLR-7/9 they were able to decrease INF-α expression.  As the INF-α levels dropped, the mice became more sensitive to glucocorticoid therapy, the standard steroid therapy used to treat inflammation. 

This is positive news for Lupus patients because over time most stop responding to low dose steroid therapies, which in turn forces doctors to increase dose strength.  While increasing the steroid dose decreases inflammation, it is also associated with a litany of dangerous side effects.  By antagonizing TLR-7/9, there is a glucocorticoid dose sparing effect that could protect Lupus patients from many of the unwanted side effects associated with prolonged exposure to high dose steroids.

Toll-like receptors are ideal adjuvant targets because they promote the activation of cell-specific immunostimulation, but it would now seem the same principle holds true in reverse.  TLRs might also be a new class of drug targets for a number of inflammatory disorders including rheumatoid arthritis, Lupus, and Crohn’s disease, that could benefit from selective inhibition of molecules that mediate inflammation.  

Vaccine-Autism Link Not Only Wrong, But an ‘Elaborate Fraud’

Vaccinating children is important, but has come under increasing scrutiny over the last decade.  So much so, that many parents have stopped vaccinating their children.  The result of this trend has been devastating as new cases of previously eradicated diseases in the US such as measles have been popping up.   Most pharma companies stopped working on measles decades ago, leaving the US unable to launch a counteroffensive if the disease popped its ugly head in greater numbers. 

Many parents have come to believe that autism was caused by vaccines.  This could not be farther from the truth, as local vaccine expert Paul Offit of the Children’s Hospital of Philadelphia, has been saying for over a decade.  Some people were so convinced of the autism-vaccine link that they sent death threats to Dr. Offit’s house.  In the end, Dr. Offit was right.  

The seminal study linking autism to children’s vaccines was found to be fraudulent (here’s a thorough accounting by BMJ).  I like this summary from NY Magazine:

“One of the most famous flawed studies ever conducted, Dr. Andrew Wakefield’s now-retracted 1998 paper that linked vaccines to autism has been found to be not a scientific error, but a deliberate lie. BMJ, a British medical journal, has just published its investigation of the matter and concluded that Dr. Wakefield purposely falsified his data. They report that he was contracted by lawyers determined to sue the vaccine manufacturers, regardless of scientific truth.

British authorities revoked Wakefield’s medical license back in May 2010, but the effects of his study persist on both sides of the Atlantic: Vaccination rates have hit record lows here in America, and measles rates have skyrocketed accordingly. It remains to be seen whether these new revelations about the Wakefield study will have any effect, or if they’ll be drowned out by the Jenny McCarthys of the world and their continuing campaign against childhood vaccination.”