Are DNA vaccines the future?

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Andreas Stuermer

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Jun 4, 2017, 10:35:29 PM6/4/17
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Hi everyone!

I came across DNA vaccination studies and this quite confuses me. There are no DNA vaccines approved as of yet (for humans).

A) If you inject DNA, isn't there a chance that this induces anti-dsDNA antibodies? Most studies say no, some say it may be possible (if you are a lupus prone mouse).

B) This might be explained by this - before immune cells are released into action, they have to mature in the thymus. There the body disposes of autoreactive cells. But there won't be much DNA floating outside so it may not clear all anti-dsDNA reactive antibodies?

C) Injecting complexed DNA is safer because it is being shielded from immune cells?

D) vaccines have adjuvants, one of them is synthetic CpG oligonucleotide. If one was afriad of getting lupus from injecting anti-dsDNA antibodies, one would have to avoid vaccines in general?

E) One study for malaria DNA vaccine tested for dsDNA antibodies and just one guy tested positive. But then they retested his old blood sample and he help being positive even before the vaccine. Also HIV DNA vaccine didn't show anti dsDNA antibodies.

Would love to hear your thoughts!

Andreas Stuermer

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Jun 5, 2017, 7:50:35 AM6/5/17
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EDIT:
E) they retested his blood and found out that he had been positive for anti-dsDNA antibodies before the vaccine

ukitel

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Jun 7, 2017, 9:45:26 AM6/7/17
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I don't think it's not so straightforward, with the inject dsDNA->anti-dsDNA antibodies idea
There is free DNA in the blood all the time, coming from your own dead cells, which is indeed now used for liquid biopsy and sequencing.
This must mean that developing the mere presence of free DNA does not lead automatically to anti-dsDNA antibodies.

It would probably depend (among many other things) on the concentration. And for a DNA vaccine I imagine that such concentration is quite low. Indeed, you would rely on the subsequent expression of protein at high levels from that DNA.

I would be more "worried" about the immune cells mounting a response against your own cells (transfected with the DNA) and developing an auto-immune disease in the process. The survival of plasmacells depends on the inflammatory environment and their stimulation with the antigen, this leads to some tolerance for cross-reactive and auto-antibodies during infections.
In the case of DNA vaccine the non-self antigen is being produced and presented (on MHC-I complexes) by self-cells, so I can imagine that there will be a certain degree of cross-fire.
Once the transfected cells are cleared out, the cross-reactive antibodies should also clear out, but there might be some exceptions to this.

Andreas Stuermer

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Jun 7, 2017, 1:27:18 PM6/7/17
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Is the "free DNA" really free? I thought I read it's enclosed into lipid particles/vesicles very soon, and if this is defect this might cause problems? 

There are lots of nucleases in the blood so any free DNA sould be degraded pretty soon  https://www.ncbi.nlm.nih.gov/pubmed/25746148 "The endogenous nuclease activity was 14.9-fold higher in serum compared to EDTA-plasma. The DNAse I treatment did not alter the ccffDNA yields in EDTA-plasma, but completely degraded it in serum."

Andreas Stuermer

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Jun 7, 2017, 1:28:55 PM6/7/17
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"In the case of DNA vaccine the non-self antigen is being produced and presented (on MHC-I complexes) by self-cells," Isn't that the case in every natural virus infection and attenuated vaccine?

ukitel

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Jun 12, 2017, 3:46:37 AM6/12/17
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Yes, actually you are right. So one reason less to worry about it.
Regarding the other point "is it really free DNA?", with DNA vaccines you need to vehiculate the DNA inside the cell in some way. Lipid particles are one option, but not the only one and I guess that different vaccines have been tested with different delivery systems. However, wouldn't it be a very short moment between the injection and the absorption?

I'm afraid there are too many factors and the only way to evaluate it all is through a clinical trial in humans.


On Wednesday, 7 June 2017 19:28:55 UTC+2, Andreas Stuermer wrote:

Mega [Andreas Stuermer]

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Jun 12, 2017, 6:55:21 AM6/12/17
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Well, a lot of time it seems to be eklectroporation or gene gun; and I bet with you that 10% of the plasmid won't make it into cells that way. Maybe even 50%. 

ukitel

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Jun 12, 2017, 9:26:58 AM6/12/17
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Sure, but what doesn't get into the cells, gets degraded quickly according to the other article you linked.

Gordana Ostojic

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Jun 12, 2017, 11:14:11 AM6/12/17
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