21 May 2014

Unique Russian HIV vaccine

Egor VoroninIn connection with Skvortsova's loud statement that HIV vaccine samples will be ready for testing in Russia by the end of this year, I asked people there in Russia what kind of vaccine will be tested.

They themselves are completely perplexed – as far as they know, no one has allocated any money for HIV vaccines, samples have not been produced, clinical sites have not been organized, so there is not much to test and there is nowhere. Maybe, of course, somewhere at the top a decision was made to give money, but it has not yet reached ordinary people.

And why not tell us about the really interesting work at the Novosibirsk Vector Center – the Combivichvak vaccine? You can argue about how good it is, whether you can expect the right immune response from it, and even more so protection from the virus, but its uniqueness in design is undeniable. I do not know of any group in the States or Europe that would try to create something even remotely similar.

At the last annual AIDS Vaccine conference, they presented a report on the results of the trial of this vaccine in the first stage of clinical trials. The report is in the public domain, you can watch it in its entirety. I stole the following picture from it, which illustrates the idea of a vaccine:

As can be immediately seen from the picture, the vaccine consists of nanoparticles (40-100 nm in size, i.e. corresponds approximately to the size of an average virus) with a rather complex composition. Let's take it apart.

In the center of the particle is DNA encoding a synthetic protein assembled from conserved sections of viral proteins recognized by the cellular immune response.

The shell consists of dextran polysaccharide, to which spermidine and synthetic peptides are attached, collected from conservative sites of viral proteins recognized by the humoral immune response (antibodies). Spermidine binds to DNA and it is thanks to it that these nanoparticles are automatically assembled.

This approach is interesting in two things.

Firstly, the simultaneous delivery of DNA and proteins. DNA expresses proteins inside the cell and their constituent peptides will fall on MHC-I, which is important for stimulating cellular immunity. At the same time, proteins incorporated directly into the nanoparticle should be exposed to MHC-II and stimulate the production of antibodies.

(MHC, major histocompatibility complex – the main histocompatibility complex, a large region of the genome or a large family of genes found in vertebrates and playing an important role in the immune system and the development of immunity – VM).

Secondly, the structure and size of nanoparticles should give this vaccine an immunostimulating role – DNA can nonspecifically stimulate innate immunity (through TLR9 activation), and the location of multiple copies of proteins on the surface of the nanoparticle mimics how proteins are usually located on the surface of the virus, and should stimulate B cells more effectively than a standard recombinant protein, used in many other vaccines.

(TLR, Toll-like receptors, Toll-like receptors, from it. toll is a remarkable class of cellular receptors with a single transmembrane fragment that recognize the conservative structures of microorganisms and activate the cellular immune response. Play a key role in innate immunity – VM).

Unfortunately, in the first stage clinical trial, the immune response to this vaccine turned out to be quite weak, peaked 2-4 weeks after vaccination and then quickly disappeared. In modern Western vaccines, the results are usually much more impressive. But here we should not forget the context. As I wrote earlier, dozens, if not hundreds, of tests of this type have been done in the West. Plus a huge number of tests on macaques. All this allows optimization of approaches and selection of the most optimal ones. In Russian conditions, testing on macaques, as far as I know, is practically impossible, and no vaccine has been done for this vaccine, and three tests of the first stage (including this) have been done.

It would be wise now (or even earlier) to do a lot of different immunological analyses in mice and macaques in order to understand which immune cells are activated by this vaccine. It would also be possible to create several variants of different proteins to identify those that would be more effective. And it would be possible to try to improve immunogenicity by adding additional stimulators of innate immunity (or building it not on a relatively inert dextran, but on a more immunogenic polysaccharide). But all this in the Russian conditions of financing – things are quite unrealistic, if not fantastic. It's a pity, this approach seems very interesting and promising to me.

In an interview with the Dozhd TV channel, Vadim Pokrovsky (head of the federal AIDS Center) said that he did not know what Skvortsova was talking about (well, isn't the situation crazy?), but assumed that it was about the second stage of clinical trials of Kombivichvak. If true, it's great, of course, that Russia invests in such research, but it would really be much more useful (in my opinion) not to promote a mildly immunogenic vaccine in the second stage of expensive clinical trials, but to invest in its study and optimization, followed by retesting at the first stage.

Portal "Eternal youth" http://vechnayamolodost.ru21.005.2014

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