Blog Series: NIAID-DVI
Tetravalent dengue purified inactivated vaccine (DPIV): status of the GSK/FIOCRUZ/US Army dengue vaccine candidate
Alexander Schmidt
So some of these talks I processed more than others, there were quite a few after all, so some postings will be more detailed than others. That being said, this is one of those lesser 'noted' talks so essentially you'll be hearing a lot from the abstract and I'll do my best to augment what I can with further research links.
Lucky for me there are two great slide sets freely available about GSK's DPIV as well as their mission within the dengue vaccine 'initiative'. They state not to reproduce any of the content/slides at the bottom of all the slides without permission so I'll just be linking them.
Slide Presentation 1: Rationale for and Status of GSK/FIOCRUZ/WRAIR new
Slide Presentation 2: Tetravalent Dengue Purified Inactivated Vaccine (DPIV)
So by way of introduction (a.k.a.: Mel digging around the net) The partnership between GSK and the US Army began around in the early 2000's when they decided to jointly develop a LIVE-attenuated tetravalent dengue vaccine candidate. The main findings from that work were courtesy of the presentations above and the published paper (see below):
- TDEN LAV was shown to be well tolerated and to have an acceptable safety profile after administration to N ~500 healthy subjects
- TDEN LAV was shown to elicit tetravalent N antibodies in ~ 90% of unprimed subjects – Vaccine profile:
- Requires 2 doses over at least 6 months
- Protection of naïve subjects after a single dose is unlikely
- The duration of immunity is uncertain, but it is known that antibody responses decline over 1 yr after vaccination
- TDEN LAV was shown to boost N antibodies in primed subjects after 1 dose
- In naïve subjects, immunogenicity is conditioned by virus potency
- A 1-log reduction of one component reduces the homologous GMT >3-fold → establishing a minimum release titer providing effective immunization will be challenging.
Here are the strains used in the study:
Table 1
DENV vaccine potency: DENV strains, PDK passage, and assayed viral concentration of each monovalent DENV component in the blended tetravalent vaccine preparations retained from each day of vaccine dosing
| Origin | No. of PDK passages | Viral concentration (log10 FFU/mL) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| First dose | Second dose | |||||||||
| A (dil) | A (und) | B | C | A (dil) | A (und) | B | C | |||
| DENV-1 (45AZ5) | West Pacific | PDK 27 | 5.0 | 6.2 | 6.1 | 6.0 | 4.9 | 6.1 | 6.2 | 6.2 |
| DENV-2 (S16803) | Thailand | PDK 50 | 5.3 | 6.3 | 6.3 | 6.2 | 5.3 | 6.3 | 6.2 | 6.3 |
| DENV-3 (CH53489) | Thailand | PDK 20 | 4.1 | 4.9 | 4.8 | 4.8 | 3.9 | 5.2 | 5.0 | 4.7 |
| DENV-4 (341750) | Colombia | PDK 6 | 5.0 | 6.0 | 5.8 | 6.1 | 5.3 | 6.2 | 6.1 | 5.9 |
- Cohort A (dil 1:10 and und): dose 1 on February 29, 2004 and dose 2 on August 29, 2004.
- Cohort B: dose 1 on May 9, 2004 and dose 2 on November 14, 2004.
- Cohort C: dose 1 was split between July 18 and 25, 2004, dose 2 was split between January 9 and 14, 2005, and the titers were averaged. Dil 1:10 = 1.0 mL of the full-dose preparation was diluted in 9.0 mL diluent (1/10th dose). UnD = undiluted (full-dose).
from Watanaveeradej et al., 2011.
So why the switch?
According to Eduardo Ortega-Barria's presentation (linked above):
- "It is difficult to predict whether the live-attenuated virus approach will successfully address the global medical need associated with dengue":
- Limitations with dosing schedule (ill suited for travelers, outbreak control)
- Suitability is uncertain for extremes of age (<12 months, >50 years), the chronically ill and the immunosuppressed
- Risks of transmission and reversion are a potential issue that will be difficult to quantify
- Persistence of immunity is uncertain (N Ab wanes over time, though there is also natural boosting)
- Manufacture and release of the vaccine will be complex
So to that end...they decided to work on a purified inactivated vaccine which was discussed at this meeting (DPIV).
Here's a schematic of the 'set up' for the vaccines courtesy of John T. Roehrig's presentation during the SAGE/Immunization meeting this past April. Nothing too crazy, four serotypes, four strains...all inactivated.
From Alexander Schmidt's NIAID-DVI meeting abstract:
- GSK, Fiocruz and the US Army are collaborating to develop a prophylactic, adjuvanted, tetravalent dengue purified inactivated vaccine (DPIV) produced in vero cells.
- The vaccine contains one strain per serotype, adjuvanted with either Alum or GSK's proprietary adjuvant systems.
- DPIV is attractive because:
- It should permit rapid onset of durable protection (ie. within 6 weeks follwing 2 doses given 4 weeks apart)
- Similar inactivated flaviviruses have been successful in the past (Japanese encephalitis and tick-borne encephalitis viruses)
- Preliminary findings of Phase 1 (2 doses, 28 days apart)
- Robust neutralizing antibody response in rhesus macaques with detectable titers 10 months post second dose.
- Vaccinated monkeys tolerated all adjuvanted vaccine formulations with acceptable local and systemic reactogenicity.
- Post-challenge data confirm near complete protection as measured by virus isolation.
- There evidence of RNA-emia and anamnestic response may indicate low levels of viral replication or detection of neutralized virus.
- Suitable for co-administration with other vaccines
- No risk of transmission or reversion
- No viral interference between serotypes
- Two Phase I safety / immunogenicity studies are being conducted in
- 2012-2013 in collaboration with WRAIR
- Both studies evaluate Alum, AS01E and AS03B as adjuvant systems
- Phase I Study in the continental United States (non-endemic)
- 100 subjects received 2 doses of vaccine or placebo on Study Days 0 and 28
- First subject vaccinated September 2012, enrolment completed
- Phase I Study in Puerto Rico (endemic)
- 100 subjects to receive 2 doses of vaccine or placebo on Study Days 0 and 28
- Long-term follow-up for a total of 3 years for safety and immunogenicity
- First subject vaccinated November 2012, enrolment ongoing
I encourage you to check out the presentation links from GSK (linked above) as well as Dr. Roehrig's presentation.
The clinical trials listing can be found here.
So we're going to be bouncing a bit back and forth between live-attenuated options, inactivated options and subunit vaccine options...bear with me. I'm going in speaking order. Three more to go before we jump out of currently developing vaccine candidates and into characterizing immunological response to dengue infection.
Next Up: Beth-Ann Colter clues us into Merck & Co. efforts at developing a recombinant subunit dengue vaccine
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