NIAID-DVI: TV003 live attenuated tetravalent dengue vaccine -- Stephen Whitehead

Blog Series: NIAID-DVI

Safety and immunogenicity of the NIH live attentuated tetravalent dengue vaccine candidate TV003

Stephen Whitehead
National Institutes of Allergy and Infectious Diseases, NIH

January 13, 2013, the NIH releases a news statement: NIH-developed candidate dengue vaccine shows promise in early-stage trial where they discuss the new vaccine for dengue that has done well in an early stage clinical trial, the study having been published in the Journal of Infectious disease 17 January 2013. Unfortunately the article is behind a paywall...curses!!! So I will do my best to convey what I can through other numerous links and information garnered from pillaged internet slides about the vaccine and of course what I learned in the meeting.

Falling back on John T. Roehrig's presentation because it's such a nice clear presentation...here is the make up TV003.

So their vaccine is a dengue 1, 3 and 4 with a dengue 2/4 hybrid where the backbone is dengue 4 with prM and E swapped for dengue 2. All vaccines have changes within the 3' UTR region; dengue 3 with a 30/31 change while the others at just the 30. For those unfamiliar what a delta 30 mutation, it's basically a deletion at the end of the dengue genome and for those, like myself who enjoy looking at sequence data...here's the mutation on the dengue 1:

source: Durbin et al., 2006. (Yay for open access!)

The mutation, or rather, deletion was originally discovered when they were working on attenuating Dengue 4 (Durbin et al., 2001 and Durbin et al., 2005) and it was found to be effective at attenuation creating a vaccine that appeared "safe, immunogenic and highly infectious"; so they decided to attenuate all their viruses with it.

In formulating their vaccine NIH made an effort to look at several and I mean several possibilities:

source: http://www.denguevaccines.org/sites/default/files/files/Day%201_2_1_Butantan_APrecioso.pdf

They looked at 100's of constructs and you can see by the slide above that as they went through testing the list got narrowed down quite a bit. 

Early studies did indicate that the neutralizing antibody response to serotype 2 was lower than observed for the other serotypes (50% seroconversion). What is it about Dengue 2? The Sanofi failed on dengue 2 as well...hmmmmm

In response NIH tried a few things like administrating a second dose of vaccine 6 mos after primary dose of a 10 fold higher potency DENV-2 vaccine component. There able to observe a significant improvement when serology was analyzed 2 or more month post-vaccination. 

Rapid Fire, Phase 1 (Durbin et al., 2013):

• Single subcutaneous dose (10^3 pfu each serotype) 
• They first tested in Flavivirus-naïve adult subjects 
• No serious adverse events 
• Remarkably few reported symptoms 
• 55% of subjects had asymptomatic, faint rash 
• Very low vaccine viremia 
• Up to 36% of vaccinees had peak antibody titers after day 56
• After just ONE dose: 
• 74% of subjects had tetravalent antibody response 
• 95% of subjects had at least a trivalent response 
• After SECOND dose: 
• No detectable vaccine replication. No vaccine rash 
• 91% of subjects had tetravalent antibody response 

Source: Roehrig's presentation; results from expanded study (can also be seen in NIH Presentation at Instituto Butantan)

Originally their serology didn't go out very far...when they took it out to 90 days post vaccination they found the frequency of seroconversion to each serotype was >76%, even to dengue 2.

• Tetravalent response in 74% of vaccinees
• Trivalent response in 92% of vaccinees

The adverse affect they found which became characteristic for the vaccine was the presence of rash and it was indicative of 'take' of the vaccine virus. It was on the trunk and arms and was mild to asymptomatic.

source: Butantan presentation

Prior to heading to endemic areas, they are trying out their vaccine in flavivirus experienced individuals from Baltimore, MD and Burlington, VT:

• 56 subjects were enrolled that had a history of flaviviral infection.
• 6 mos after receiving first dose of vaccine they were challenged with a second dose.
• Serum collected at 0, 28, 56, 90, 150, and 180 days post immunization
• 60% of all vaccinees had at least one virus recovered from blood after the first immunization.
• No detectable virus was found after second dose
• After 1st immunization:
• tetravalent neutralizing antibody response was detected in 85% of vaccinees
• trivalent or better response in 100% of vaccinees.
• The study as of writing this is still blinded to my knowledge so we still don't know what else is going on or the 'final' results.

Future plans will be with partners working on some Phase II trials.

source: Roehrig's Presentation

As Dr. Whitehead stated in the NIH news report:

“What is promising about TV003 is that it elicited solid antibody responses after just one dose,” explained Stephen Whitehead, Ph.D., of NIAID’s Laboratory of Infectious Diseases, who led the development of the vaccine candidates. “Other vaccines in development require two or three injections at higher doses to achieve similar results.”

The other attractive thing about TV003 is that it is inexpensive at about $1/dose which makes it attractive for use in developing countries.

We shall cross our fingers with you NIH...

For more information about the clinical trials in progress and that have been completed: 

Phase 1: Evaluation of the Safety and Immune Response of Five Admixtures of a Tetravalent Dengue Virus Vaccine has been completed.

Phase 2: Phase II Trial to Evaluate Safety and Immunogenicity of a Dengue 1,2,3,4 (Attenuated) Vaccine is not yet open for recruitment

Relevant publications that go along with both trials are at the bottom of the clinical trials listings.

Well it seems fitting we started with Sanofi...so the next post will end our vaccine updates with an evaluation from Jean Lang and Bruno Guy both from Sanofi Pasteur as to the update of what's going on with the Sanofi vaccine and looking back on the trial hypothesizing why the vaccine failed for dengue 2 and so forth...