NIAID-DVI --A Preamble: The Sanofi Dengue Vaccine Failure (Chimerivax)

Blog Series: NIAID-DVI

A preamble: The Sanofi dengue vaccine failure, ChimeriVax

So given I am not daily entrenched in the world of vaccine development, the most that I ever heard about dengue vaccines was that there were several out there in development and Sanofi's was the furthest along. Then I heard the Sanofi vaccine failed. It illicited good response to dengue 1, 3 and 4 and did a fantastic fail on dengue serotype 2.

I could end this blog there but my curiosity and incessant need to comb the internet and literature revealed just how 'fantastic' of a fail this was:

Reuters -- "Sanofi SA has started producing its experimental dengue vaccine, the most advanced against the tropical disease, in a move to keep its lead over competitors ahead of the product's likely launch in 2015."

Reuters -- "The world's most advanced vaccine against dengue fever, being developed by French drugmaker Sanofi SA, proved only 30 percent effective in a large clinical trial in Thailand - far less than hoped"

Sanofi has been working on this vaccine upwards of 20 years...the fan fare for it's testing was quite large. The press releases go on to state that although the vaccine didn't protect against one of the dengue types it demonstrated that a safe vaccine is possible for dengue virus.

• Vaccine efficacy was only 30.2% a far cry from the 70% desired
• The phase IIb study though is showing 60% against dengue 1 and 80-90% for dengue 3 and 4

The biotechs had a few things to say about the Sanofi failure as well:

"Analysts grow skeptical about Sanofi's $800M bet on dengue vaccine"...they go on to discuss the gamble that Sanofi took with their vaccine.

Although personally I wouldn't say it was a terrible gamble...they did show protection to multiple serotypes. Granted they missed one of the most prevalent serotype that plagues SE Asia but Dr. Halstead made a good point, quoted in the Reuters article, that perhaps a vaccine against three types is good enough. After all it's been shown that secondary infection with a different serotype is usually worse clinically than the initial infection; so if we can keep people from getting dengue again...that's progress. This sentiment was echoed by Duane J Gubler in the NY Times article about the vaccine failure. Dr. Tornieporth of Sanofi also mentioned the vaccine may have utility in regions where dengue serotype 2 is less prevalent in the same NY Times article.

With so much hullabalo about the failure it was nice to see on the ASTMH blog Dr. Farrar talking about managing expectations when it comes to dengue. 

"Farrar said whether it’s a soccer game or a vaccine trial, 'if you go into something overselling expectations for the results, it may be that you fall from a greater height.'"

He went on to talk about the trial was about safety more than anything and the fact that Sanofi was able to say it was a 'safe' vaccine...that's progress so the 'glass is more half full than empty'.

Alright...well as much as I love the drama and intrigue of press releases and media; lets do some primary lit diving:

Firstly, lets take a look at the Sanofi vaccine design courtesy of Clinical and Vaccine Immunology:

Link to original graphic: http://cvi.asm.org/content/16/12/1709/F3.large.jpg

So it is a Yellow Fever backbone where the coat proteins have been replaced with each of the dengue serotype's coat proteins (prM and E). This is an idea that will pop again during the meeting talks; a backbone with parts replaced specific to dengue serotypes.

If you would like to hear data and opinions from the horses mouths, read these articles for a starter: 

• The CDC's take on the vaccine failure: A Call to Action for Dengue Vaccine Failure

• The Lancet: Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial ...and the follow up article where the authors got to respond to letters about the vaccine trial: Efficacy of tetravalent dengue vaccine in Thai schoolchildren — Authors' reply and of course we cannot forget to include Dr. Scott Halstead's Lancet comment as well on the study: Dengue vaccine development: A 75% solution.

• Sanofi's release of their results and comments

• Here's a Vaccine article: From research to phase III: Preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine. Unfortunately it's behind a paywall...boo. And I typically don't like to post articles behind a paywall, but if you have access it's got some interesting considerations.

So where do we go from here?

Back in 2011 two great proponents of dengue vaccine development Dr. Timothy Endy and Dr. Stephen Thomas posted an article in Current Opinion in Infectious Diseases regarding "Critical issues in dengue vaccine development". It highlights the challenges of this disease which is constantly throwing us curve balls. Once again, this article is behind a paywall (doh!) but if you have access to the journal I encourage a reading of it. 

Just this month, Dr. Halstead followed up with an article in Vaccine which is freely available (huzzah!): Identifying protective dengue vaccines: Guide to mastering an empirical process where he details areas where the vaccine trial failed and how we might think about vaccine development in the future. The article is a bit technical for me as I'm not familiar with immunology as much but it does a good job of summarizing the Sanofi findings and offering up hypotheses as to the causes of failure. He calls for a tetravalent vaccine as a necessity, however, I feel Dr. Halstead (and later echoed by Dr. Gubler)'s point in the Reuter's press release that a tri-valent option is also useful, shouldn't be ignored.

And with that...lets dive into the Dengue Vaccine Initiative Meeting of 2013 and regale ourselves of tales concerning current developments and advancements in the world of dengue vaccines...