RNA vaccines the saviour…but the first iteration may not be good enough for prime time

It seems the makers of the COVID vaccine have turned their hand to stopping MS and on the back of the success with covid what will stop them and their partners. Tron. However like the film the current view is probably fanasty… but maybe it is a way of making protein that could be used for an MS vaccine. It does not appear to boost the immune response..so a new way to make Glatirimer acetate a non-pathogenic protein that blocks MS. Is it good enough?

Krienke et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis Science

https://pubmed.ncbi.nlm.nih.gov/33414215/

Antigen specific therapy is a holy grail and is achievable in EAE and it can completely stop naive animals from developing any disease and if it doesn;t the approach is simply not good enough and needs alot more work. The problem is how do you make the proteins for the tolerance. Myelin oliogodendrocyte glycoprotein is easy peezy as is myelin basic protein but get to proteolipid protein and it is brick dust. We started to use stem cells and oligodendrocytes to do this but they did not produce enough protein. I did think about it, DNA vaccination, We didn’t have the technology, but RNA vaccination/transfer may be a way.

It is said a messenger RNA vaccine strategy that delivers MS autoantigens into lymphoid dendritic cells. This approach expands a distinct type of antigen-specific effector regulatory T cell that suppresses autoreactivity against targeted autoantigens and promotes bystander suppression of autoreactive T cells against other myelin-specific autoantigens (Suppressor cells are back). In mouse models of MS, the vaccine delayed the onset and reduced the severity of established disease without showing overt symptoms of general immune suppression.

(a) If it does not erradicate disease it is just not good enough delay and reduce is not going to cut the mustard, half of MS is still MS.

(b) It works by bystander suppression so you inhibit the immune response to one antigen and it suppresses the immune response to another local immune response…Great so you don’t need to know the antigen (They did not show this properly)…Give it to us and we can put it to the test…However, beware if this local immune response is to JC virus and it is suppressed by bystander suppression, do we want bystander suppression? Animals are clean humans are not.

(c) Rememeber history tells us that vaccines are not that effective if you have already been infected. They are better to prevent disease.

So lets have a look

Normally RNA will make protein and this will be made to be immunogenic and make T and antibody responses. Here they claim by changing the RNA that can directit to cells to make suppresor T cells and no antibody. Remember peptides are not the best for making antibdoy responses

Abstract

The ability to control autoreactive T cells without inducing systemic immune suppression is the major goal for treatment of autoimmune diseases. The key challenge is the safe and efficient delivery of pharmaceutically well-defined antigens in a noninflammatory context. Here, we show that systemic delivery of nanoparticle-formulated 1 messenger RNA (m1Ψ mRNA) coding for disease-related autoantigens results in antigen presentation on splenic CD11c⁺ antigen-presenting cells in the absence of costimulatory signals. (Historically should give anergy and not bystander suppression). In several mouse models of multiple sclerosis, the disease is suppressed by treatment with such m1Ψ mRNA. The treatment effect is associated with a reduction of effector T cells and the development of regulatory T cell (T_reg cell) populations. (Yawn now what was I saying about dogmatic mechanisms of action and remeber two days ago it was suggested that transfer of these didnt work ) Notably, these T_reg cells execute strong bystander immunosuppression and thus improve disease induced by cognate and noncognate autoantigens.

They argue that RNA makes protein that causes pathogenic T cell responses but by modifying the RNA it can be made to be non-proinflammatory, they encapsulate it in a small particle and of they go tolerising. The cells induced made IL-10, IL-5, IL-13 . Next they give it before disease onset and it wipes disease out…Loooking good Billy-Ray

Then they look at the ability of one antigen to stop disease by a different antigen

Not quite as good Lewis, Remember we have shown you have to irradicate relapse in this type of scenario it is possible and this is what you need to get a vaccine. However, it indicates that MOG inhibits PLP disease.

Now this asks more questions than it answers (what happened on day 28 when the results show that disease was on the way up), it suggests you have to know the antigens. They should have given all of MOG protein and then seen if it works or perhaps given an antigen that is not pathogenic. That way you dont need to know the antigen. In this experimente SJL mice will respond to PLP 139-151 a water soluble epitope (if they produced PLP protein would it work) but they respond to MOG 92-106). C57BL/6 mice will respond to MOG35-55 and not PLP 139-151 in this experiment they use SJL x C57BL/6 cross mice so they can respond to both antigens but in reality in this combination PLP159-151 is dominant.. Could MOG35-55 do it in a straight SJL as in this strain MOG35-55 is not pathogenic (Disease causing) if not you need to know the pathogenic antigens ,which you dont in MS….So a problem with the approach.

Next question why the need for repeated injections.? If you have induced tolerance you have induced tolerance, you should not need to have to give it every other day. Here you could be simply sending the disease forming cells into the skin, spleen rather than the brains by making protein outside the brain , so we can give them a 5/10 and say do more experiments to see how good and applicable it really is.

There is no evidence that these T cells cause the problems but if it works by bystander suppression then you only need one antigen.

Historicallly vaccines dont work well in people that have had the disease already. MS is a complex disease and we know from animals that different strains respond to different antigens so do you have to know what they are. It would be simpler to try a diseasewhere you know the answer….DNA peptide vaccination has been tried before.

Where is Bayhill Therapeutics…..Haven’t heard of it…Maybe there’s an answer.

MS is the wrong condition to test the approach it is too complex, stop autoimmunity to a therapeutic antibody that is life saving may be a simpler startor chose a disease where the antigen is known and theare no treatment options/