NIAID-DVI: Dengue subunit vaccine -- Beth-Ann Coller

Blog Series: NIAID-DVI

Development update - recombinant subunit dengue vaccine

Beth-Ann Coller

Merck & Co., Inc.

So Merck decide to nix the use of the whole genome and opted for focusing in on the Envelope gene; 80% of it.

The current status per the meeting abstract:

• Preclinical studies of this recombinant subunit vaccine have been conducted in non-human primates in order to evaluate immunogenicity and efficacy of tetravalent formulations
• They are doing testing with and without adjuvant
• The formulations have been evaluated in both dengue naive and experienced animals.
• The work has shown that recombinant proteins can induce balanced tetravelent responses without evidence of interference.
• They are in Phase 1 clinical trials with the vaccine in healthy flavivirus naive adults.

So I had one potentially naive question in this presentation which of course I kept to myself because it was a lively bunch and I feared for my life at times given I secretly harbor a copy of immunology for dummies book...

So presumably you have just the E gene...so the spectrum of antibodies (and I apologize for crapping all over proper immunological terminology--bear with me)...so the spectrum of antibodies produced by this vaccine will be limited yes? Limited to what can be produced for the E gene. Does this imply then that the rest of the genome doesn't matter in vaccine design?

I realize the E gene is the target...but is it really the golden nugget? Does all heaven and earth hinge only the E gene? Does the interstate light up with the magic of a thousand fairies when the E gene is 'turned on'? I find this hard to believe given genetically speaking I've been told we should all beg off the E gene and focus on full genome studies. I don't deny the power and importance of the E gene...heck we have massive troves of information on this piece of nucleic acid going back decades...decades. It has been INVALUABLE for surveillance...but how 'invaluable' is it...truly in total vaccine design? I really don't know...I'm asking. I know you can't ignore it...or rather shouldn't; but should all other genes be shunned in favor of 'the one' E gene?

BUT "a virus cannot live by it's envelope gene alone"....

Even if a focused candidate (ie. E gene subunit vaccine) works I can't help but think dengue is going to bust out NS1 on us and do something bat-shit crazy. Why? Because that's what dengue virus has been doing to us from the start:

• Wu SF et al., 2003. Evaluation of protective efficacy and immune mechanisms of using a non-structural protein NS1 in DNA vaccine against dengue 2 virus in mice. Vaccine. 21: 3191

• Mathew A et al., 1996.Dominant recognition by human CD8+ cytotoxic T lymphocytes of dengue virus nonstructural proteins NS3 and NS1.2a. JCI 98: 1684

• Bray et al., 1989. Mice immunized with recombinant vaccinia virus expressing dengue 4 virus structural proteins with or without nonstructural protein NS1 are protected against fatal dengue virus encephalitis. JVI 63: 2853 (this was an interesting study! where they show both protection with and without structural gene interplay...so perhaps it goes both ways? Of course this was a 'way above my head' study involving expression of dengue proteins in vaccinia virus...score one for Cowpox)

• Srivastava et al., 1995.Mice immunized with a dengue type 2 virus E and NS1 fusion protein made in Escherichia coli are protected against lethal dengue virus infection. Vaccine 13:1251 

Ok enough with the old stuff...how about some newer stuff...

• Zheng et al., 2011. Evaluation of a DNA vaccine candidate expressing prM-E-NS1 antigens of dengue virus serotype 1 with or without granulocyte-macrophage colony-stimulating factor (GM-CSF) in immunogenicity and protection. Vaccine 29: 763

• Lu et al., 2013. Preliminary evaluation of DNA vaccine candidates encoding dengue-2 prM/E and NS1: Their immunity and protective efficacy in mice. Molecular Immunol 54: 109

• Huang et al., 2013 Evaluation of protective efficacy using a nonstructural protein NS1 in DNA vaccine–loaded microspheres against dengue 2 virus. Int J of Nanomedicine 8: 3161 (International journal of nanomedicine...that's a new one for me--I feel like I'm in a Space Odyssey 2013)

• Tricou V,et al., 2011. Kinetics of Viremia and NS1 Antigenemia Are Shaped by Immune Status and Virus Serotype in Adults with Dengue. PLoS Negl Trop Dis 5: e1309.

Last one I promise:

• Henriques HR,  et al. 2013. Targeting the Non-structural Protein 1 from Dengue Virus to a Dendritic Cell Population Confers Protective Immunity to Lethal Virus Challenge. PLoS Negl Trop Dis 7(7): e2330

So perhaps the E gene alone is enough...perhaps we cannot ignore the structural genes after all...

Also perhaps a question that fits in the 'dolt' category but HEY this is a teaching blog so I'm going to ask it...immunologically speaking, do certain expression patterns, E gene epitope 'availabilty' either structurally or in some other form depend on any other gene/protein product or something else in 'sequence space'? Just throwing it out there...for instance influenza can use glycosylation patterns/numbers to 'make up for' defaults in another segments that have lost function (Mishin VP, et al. Effect of hemagglutinin glycosylation on influenza virus susceptibility to neuraminidase inhibitors.JVI 79: 12416.)...just a thought.

My intention is not the 'hate all over' the subunit vaccine premise...hell, I think we all realize now there is a vast amount we don't actually know about dengue just in terms of BASIC understanding...so we shall see. And subunit vaccines don't come with all the baggage of other 'genomic affects' or the probability of being 'alive' and therefore potentially harmful which is a risk all live-attenuated vaccines run.

All in all, I enjoyed Beth-Ann's update! Broadening my horizons on all the different types of vaccines that can be considered for viruses. For more information and most importantly, the paper describing the progress the subunit vaccine...

• Coller BA et al., 2011. The development of recombinant subunit envelope-based vaccines to protect against dengue virus induced disease. Vaccine 29: 7267

• Clements et al., 2010. Development of a recombinant tetravalent dengue virus vaccine: immunogenicity and efficacy studies in mice and monkeys. Vaccine 28: 2705

There are several other subunit vaccines in development including one using NS1 which is mentioned in Murphy and Whitehead's article in Annu Rev Immunol...which coincidentally or not so coincidentally NS1 uses glycosylation for modulation of secretion, cell-surface expression, hexamer stability, and interaction with human complement...hmmm, glycosylation thou wiley flu friend...or should I say fiend? 

For an additional summary of current dengue vaccines out there...which includes numerous subunit vaccines see Wan et al., 2013 article in the Journal of Biomedical Science given I just found/skimmed the article, I plan on giving it a good read.

Unfortunately no colorful schematics or youtube videos to keep you awake in this entry but plenty of links for sure...you cannot say you don't have some information overload to get started with if indeed you'd like to brush up on your subunit vaccine developments.