Biodistribution of genetic vaccines

[Andreas "Mega" Stuermer]

Hi guys, 

Disclaimer: Everyone who knows me knows that I am a big fan of vaccines. 

You might have heard that mRNA vaccines might be connected to myocarditis; and Adenovirus vector vaccine might be connected to rare blood clots.

I came across this very interesting scientific opinion piece in the BMJ. They argue that with genetic vaccines, the biodistribution should be better studied. 

"The pharmacovigilance data confirmed the [cerebral venous sinus thrombosis (CVST) ] incidences with all genetic vaccines (viral or non-viral vector), however, the regulatory authorities in their recent investigations reported that the CVST was unusually accompanied with thrombocytopenia in subjects injected with CoViD-19 viral vector vaccines (such as AstraZeneca and J&J/Janssen) than those injected with mRNA vaccines. We, therefore, looked at the preclinical studies of these vaccines to ascertain their biodistribution to body tissues (for instance brain) beyond the injection site for a possible explanation of the rare fatal clots formed in the brain."

"For COVID-19 mRNA Vaccine (Pfizer or Moderna), the biodistribution studies in animals were not conducted. The surrogate studies with luciferase and solid-lipid nanoparticles (Pfizer) confirm a biodistribution to the liver and other body tissues beyond the administration site [5]. For Moderna, the biodistribution of mRNA-1647 (encoding CMV genes) formulated in a similar lipid nanoparticulate delivery system confirms a biodistribution beyond the injection site, in particular, the distribution to the lymph nodes, spleen and the eye was noted [6]. However, the detailed tissue-specific distribution of mRNA vaccines encoding SARS-CoV-2 spike proteins (Pfizer or Moderna) is not fully known that can offer invaluable insights into the potential safety of these vaccines in peoples with pre-existing conditions or those on certain medications."

https://www.bmj.com/content/373/bmj.n958/rr-1

It does not sound too unreasonable that not all the LNPs/virus you inject into muscles remain there and gets taken up by muscle cells. Especially when you work with cationic liposomes, they will get taken up by any cell. And I have seen videos of people being injected with contrast liquid for radiologic imaging - that liquid gets distributed insanely fast through the blood. Assuming some mRNA gets delivered to heart cells... How much will stay in the injection site and ho much might leak? How long would they stay in the heart to fuse with those cells? Isn't there epithelial lining? Lots of questions. 

The article mentions that the current vaccines are still much better than the alternative (blood clots by COVID, which occur at a much higher rate). 

The recommendation is, to change the viral vectors or Lipid-Nanoparticles to be tissue specific. I have read of a company that incorporates proteins into uncharged LNPs and when the proteins bin to their ligand, tissue specific delivery is achieved. Here is the company (I don't have any ties to them or currently buy from them: Precision NanoSystems, Inc.). Viruses might be pseudotyped to go into specific cells only (fibroblasts, muscle cells?).

"However, if genetic vaccines were to be sustained beyond the CoViD19 pandemic, a tissue targeted approach may be the way forward to limit the antigen (the encoding gene) distribution to the intended tissues only to improve the vaccine safety profile for a global mass public rollout. In comparison, the conventional vaccine approaches (classic non-genetic formulations) have a long history of human use across much wider age groups (infants to elderly) and have an established safety profile despite the current challenges in antigen propagation and large-scale production in a timely manner using conventional methods."

[Andreas "Mega" Stuermer]

Basically, I was wondering to hear your opinions on this matter, as here are a lot of smart people from all sub-fields of biology and biotechnology

[Ravi Ramana]

Just noted this message & no replies for this important thread here is kinda weird! It does imply some implicit caution on expressing any opinions

about Vaccines (given the prevalent antivaxx sentiments & their possible blowups its understandable, but this is mental censoring!). 

Any followups, comments @Andreas? 

I think we are very much capable of developing more targeted delivery vehicles & mechanisms. mRNA/genetic vaccines give us tremendous power & 

abilities to counter new viruses and pathogens at a rapid pace. Their deliveries ought to be streamlined quite a lot - rather than broad brushing

we could/must do site/tissue/cell specific mechanisms. We will evolve into such a scenario quickly given so much of R&D and $$ out there on this area

with the huge success of Covid Vax.