Comment by ralusek | Hacker News Reader

Comment by ralusek | Hacker News Reader

The viral vector vaccines are a very similar development as the mRNA vaccines, and I'm curious as to why they've received less attention as a technological wonder.

Brief summary:

Goal of vaccine is to get antigens in body in order to stimulate immune response to antigen, ideally at a lower risk than via infection from associated pathogen.

- "Traditional" vaccines inject a dead or weakened pathogen. Protein subunit vaccines inject just the antigen(s). Antigen directly put in body

Both mRNA and viral vector vaccines, however, are genetic vaccines. Rather than injecting your body with the antigen directly, they inject your body with code (mRNA and DNA, respectively), with the goal of having your own body produce the antigen(s).

- mRNA vaccines deliver a snippet of mMRNA via lipid nanoparticles to your cells' cytoplasm, where your ribosomes pick it up and produce and express the antigen themselves

- viral vector vaccines deliver a snippet of code via living virus (in the case of COVID vaccines, a living adenovirus delivering a DNA payload) to your cells' nucleus, where your cells reads the DNA, produces mRNA in your cytoplasm, after which it behaves the same as the mRNA vaccines

Basically, both the mRNA vaccines and viral vector vaccines are genetic in nature and rely on delivering code to your body rather than antigens. The analogy I've used before is that traditional vaccines are SSR, and the genetic platforms are SPA. I'm just curious as to why mRNA as a platform has been so much more hyped than the viral vectors; they're novel in fundamentally the same exact way.

The 4th paragraph in the Nobel Prize press release suggests that it's because mRNA based vaccines are easier to scale up and mass produce in response to a pandemic:

"Producing whole virus-, protein- and vector-based vaccines requires large-scale cell culture. This resource-intensive process limits the possibilities for rapid vaccine production in response to outbreaks and pandemics."

Likely due to the limitations and challenges with the viral vaccines. Perhaps the biggest limitation is that the virus used as the vector must be one to which you don't already have immunity. For instance the adenovirus used by the Chinese and Russian vaccines is pretty common in the west, with something nearly half of all Americans have some immunity to it.

Yes, the delivery system definitely has that drawback. However, the lipid nanoparticles as a delivery system have problems of their own, which I laid out in a sibling comment to your own.

But my question is more related to the pop-science perception of mRNA vs viral vector. mRNA were presented as new technology, but on media publication after media publication, the viral vectors were presented as the "old"/"traditional" way of doing things. 9/10 people have that understanding of the mRNA vs vv vaccines. The truth is that both are radical departures from existing technologies and they're both genetic platforms very similar in nature, and both completely novel being deployed at this scale.

On the popular press I can imagine three reasons.

One is that the mRNA vaccines were brand new, while VV was old enough that most people have already taken a few shots using it. The media has a very non-linear response to novelty.

Another one is that the most profit-seeking laboratories were working with it. And they are the ones with closest relation to the media.

Finally, it may be some reflection of the experts hype. People were very rationally hyped due to the lack of restrictions, easiness to ramp-up new vaccines, and the bare beauty of the idea. It's possible that journalists perceived that, even if they couldn't understand or explain the reasons.

Neither mRNA nor viral vector vaccines were new. mRNA had a vastly better safety and efficacy profile. AstraZeneca had the clots, the Russians had the issue with replication (and use Ad5), and the Chinese exclusively used a virus that nearly half of all Americans are immune to. And IIRC the mRNA vaccines were still more effective against the variants.

As another note, the mRNA platform has a few concerns that the viral vector vaccines do not.

In particular, the delivery of the mRNA payload is done via lipid nanoparticles that are not in any way targeted to a specific cell type.

The European Medicines Agency released a report on the distribution of the mRNA found in various organs:

https://www.ema.europa.eu/en/documents/assessment-report/spi...

> "Besides injection site [muscle] and lymph nodes [proximal and distal], increased mRNA concentrations (compared to plasma levels) were found in the spleen and eye. Both tissues were examined in the frame of the toxicological studies conducted with mRNA-1273 final vaccine formulation. Low levels of mRNA could be detected in all examined tissues except the kidney. This included heart, lung, testis and also brain tissues, indicating that the mRNA/LNP platform crossed the blood/brain barrier

A similar 2017 study was conducted using mRNA coded for luciferase as a tracking mechanism:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5475249/

And it, likewise, found the protein was produced in the muscles, lymph nodes, spleen, liver, heart, bone marrow, kidney, lung, stomach, rectum, intestines, testes, and brain.

One of the main draws of using the lipid nanoparticle as a delivery mechanism for other payloads in the past has specifically been that the lipid nanoparticle can readily cross the brain-blood barrier (BBB). And the EMA paper/quotation referenced above seems to verify that this is, in fact, the case.

A question that both platforms have to contend with is: "what, if any, risks are associated with having your cells producing and expressing a pathogenic antigen that your immune system is to identify and attack?" But one that the lipid nanoparticle delivery system has to contend with is the same question, but in the context that it has very little differentiation WRT where it is going to be deployed and expressed.

With the viral vector vaccines, the delivery mechanism is a living virus, and has much more predictable infection pathways. For one, our bodies have millions of years of evolution for dealing with viral infection, and particularly safeguarding the parts of our body least desirable for infection. Viruses have a very hard time crossing the blood brain barrier, whereas lipid nanoparticles do not.

There are, meanwhile, concerns associated with the viral vector vaccines which are not associated with the mRNA vaccines, but I've yet to see this sufficiently addressed as a major shortcoming of the mRNA platform. Targeted delivery is a very important topic in the world of gene therapies, and seems to have been completely neglected in the available platforms.

Isn’t the non-specificity a good thing for a disease like COVID that attacks the whole body?

No, the immune response would be systemic no matter where the antigen manifests. You don't want the antigen being produced everywhere.

I may be wrong here but aren’t the eyes separated from the body’s general immune system?

> As another note, the mRNA platform has a few concerns that the viral vector vaccines do not.

E.g. the target patient might already have a good immune response to the vector hull. I.e. the patient's immune systems would destroy the vaccine before it can do its work. One of the vector vaccines against covid did use two different vectors because of that. But repeated usage of the same vector might decrease its effectiveness.

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