BREAKING! COVID-19 Vaccine Exclusive: Possible Dangers Of Using Adeno-Associated Virus (AAV) Vectors For COVID-19 Vaccines
COVID-19 Vaccine Exclusive
: Adeno-associated viral vectors to deliver gene therapies and vaccines are a growing platform that is being used by more and more pharmaceutical companies in drug and vaccine development. But unknown to many there are possible repercussions taking such AAV vectors based meds or vaccines.
Two gene therapies using adeno-associated virus (AAV) vectors to deliver gene therapy, Luxturna for rare forms of blindness and Zolgensma for spinal muscular atrophy have since been approved by the US Food and Drug Administration (FDA), and several pharmaceutical companies are now pursuing regulatory approval of AAV-carried gene therapies for hemophilia B.
However about a decade ago seven patients with hemophilia B ie a disease caused by a mutation on the F9
gene that prevents patients from forming crucial clotting proteins volunteered to be the first humans to receive a gene therapy delivered using an adeno-associated virus as a vector. This particular treatment didn’t move past the Phase 1/2 trial because although it was deemed safe, the patients did not sustain expression of the gene.
Researchers recently followed up with four of those original patients. In a study published in the journal: Molecular Therapy
in September, the study team report that the patients are still free of any worrisome toxicities related to the treatment. https://www.sciencedirect.com/science/article/pii/S1525001620302914
But the study findings also revealed some bad news.
The researchers found that after all these years, the patients still had elevated levels of AAV-neutralizing antibodies. That means that if an AAV based gene therapy, drug or vaccine is approved to treat their illness or any other illness they might have in the future, they likely won’t be able to benefit from it as the antibodies would attack the vector before it could insert the corrective gene or deliver the relevant pharmaceutical ingredients or inactivated real or synthetic RNA parts of a pathogen for protective immune response.
The same possible reactions can occur with people given AAV vector based COVID-19 vaccines. Something that no pharmaceutical or biotech company, vaccine researchers or even health authorities are talking about.
The usage of an AAV gene therapy or any other AAV vector based protocol ie to deliver vaccines or drugs is essentially a vaccine against AAV itself, says Dr Lindsey George, a hematologist at the Children’s Hospital of Philadelphia who led the research.
Dr George’s study was not the first study to identify antibodies as a problem for those receiving AAV gene therapies or vaccines, but it is the first to show that elevated titers can last this long.
Dr George, “This role of AAV neutralizing antibodies is huge,” as it stands to undermine the effectiveness of gene therapies or vaccines.
As a result of AAVs being viruses, the human immune system creates antibodies upon exposure that recognize and neutralize them in subsequent encounters.
In some cases patients have neutralizing antibodies in their blood before ever having received a gene therapy or a vaccine because they’re exposed to AAVs in the environment.
Along with high levels of antibodies to the specific AAV vector that they have received ie AAV2, the patients the study team team evaluated also had neutralizing antibodies to several other commonly used AAV vectors, namely, AAV5 and AAV8.
The study findings suggest that not only will they not be able to receive a second dose of vector of the same type of AAV, but potentially even other types.
To date nobody has found a suitable solution yet that is likely to be accepted by patients. The body has evolved over millions of years, this immune system that helps fight off infections. So to overcome that, even temporarily, is not an easy task.
Certain immunosuppressant drugs won’t work if the body has already developed specific antibodies to a particular pathogen, such as AAV.
Adenoviral vectors are the new COVID-19 vaccine front-runners. CanSino Biologics, Johnson & Johnson, and the University of Oxford are all using genetically engineered common cold viruses to make COVID-19 vaccines. The technology is more than 30 years in the making, but it’s yet to yield an effective vaccine for humans
As with all vaccines, the idea is to trick our body into thinking it’s been infected. Those self-made spike proteins would train our bodies to detect and terminate any real SARS-CoV-2 infections before the virus wreaks havoc. The technique has been in development for more than 3 decades, but thanks to COVID-19, it is about to be put to the test like never before.
The fact that AAV neutralizing antibodies developing and hindering long term issues is just the first part of the problem and dangers.
There is also another potential problem. Just as human bodies develop immune responses to most real viral infections, and as the bodies also develop immunity to adenoviral vectors, that makes booster shots of adenoviral vector vaccines problematic. Upon a second injection, our bodies will unleash an antibody attack on the vaccine itself. And since adenoviral vectors are based on natural viruses that some of us might already have been exposed to, the vaccines might not work for everyone.
Adenovirus vaccines might be grabbing the limelight amid the coronavirus pandemic, but they have a checkered past.
When researchers began creating adenoviral vectors in the 1980s, most worked with a particular kind of adenovirus called Ad5, which ubiquitously infects humans and causes the common cold. Researchers stripped Ad5 of the genes it needed to replicate and inserted those genes into genetically engineered cell lines. That ensured that the modified viruses could be grown only in these special cells in the lab. It also opened up space in the Ad5 genome for scientists to stitch in new genes of their choosing.
Numerous scientists hoped to use Ad5 to deliver a human gene that could correct rare genetic mutations ie an approach called gene therapy. Those efforts came to a grinding halt in 1999 when a teenage boy with a rare genetic liver disease died after receiving an injection of an Ad5-based gene therapy, which had been designed in James Wilson’s lab at the University of Pennsylvania.
It was found that the large dose of 38 trillion viruses the patient was given sparked massive body-wide inflammation and sent his immune system into overdrive. After that, scientists mostly stopped using adenoviral vectors for gene therapy, in which the dose needs to be high to reach many cells of the body.
However vaccine developers viewed adenovirus-induced inflammation as an asset.
Professor Dr Luk Vandenberghe, a viral vector expert at Harvard Medical School told Thailand Medical News, “There is an expression out there that a failed gene therapy makes a good vaccine One attractive feature is that adenoviruses’ inflammatory effects mean developers don’t have to use adjuvants, molecules added to conventional vaccines to direct the immune system’s attention to the viral protein. The adenoviruses themselves drive the inflammation, which is kept under control by giving the vaccines at low doses.(however it should be noted that this low range inflammation over a period of time can also give rise to other chronic medical conditions)
Many vaccine developers turned to adenoviral vectors in the early 2000s to tackle diseases, such as AIDS, malaria, and tuberculosis, caused by pathogens that hide out in cells. The largest, and most infamous, effort was led by Merck & Co., which had developed an Ad5-based vaccine for HIV.
Shockingly the two large clinical trials were halted early in 2007 when it became clear that the vaccine was not working and, alarmingly, may have even increased the risk of HIV infections in a subset of people with preexisting immunity to Ad5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721012/
That incidence halted AAV usage for the next 5 years.
The U.S. National Institutes of Health, which partly funded the trials, called a meeting to decide whether to proceed with trials of Ad5-based vaccines. In 2009, it decided to push forward with a modified version of a planned HIV vaccine trial so long as the participants didn’t have preexisting immunity to Ad5. Results from the 2,500-person study showed that the vaccine was, did not work.
The research curbed enthusiasm for Ad5, but didn’t eliminate it altogether. CanSino, a Chinese company founded by former Sanofi vaccine developers, developed an Ad5-based vaccine for Ebola during the 2014 outbreak, and a Phase II study showed that the vaccine induced an antibody response only 4 weeks after injection.
China in 2017 approved the vaccine, but only for emergency use and national stockpiling. That made it the first, and still only, adenoviral vector vaccine approved for humans with the big caveat that the Phase II study did not prove the vaccine prevented Ebola infections. Furthermore, the antibody levels dropped sharply within 6 months of vaccination. Most participants had preexisting immunity to Ad5, which some scientists believe may have curtailed the vaccine’s ability to induce a longer-lasting immune response.
The Chinese firm’s Ebola experience enabled it to move quickly on a COVID-19 vaccine using Ad5. On March 16, CanSino became the first company to begin a clinical trial of a COVID-19 vaccine.
Many scientists have cast doubt about CanSino’s chances of success, but industry veterans say that preexisting immunity to Ad5 can be overcome with a higher dose of the vaccine which will require more stringent monitoring of side effects.
Numerous smaller firms are also developing COVID-19 vaccines based on AAV vectors. One of them is ImmunityBio, which uses Ad5 vectors with additional gene deletions.
Other companies, including Altimmune, Stabilitech BioPharma, and Vaxart, believe they can circumvent preexisting immunity to Ad5 in the bloodstream by administering their vaccines as nasal sprays or pills rather than injections. The experimental formulations could also be easier to manufacture, store, distribute, and use.(all not proven to date!)
Many of the clinical trial results for the various COVID-19 vaccines either never mentioned or even conducted booster or second shots and in some cases the reactions that took place considered as ‘normal’ and were never reported. There was never any mention about the AAV neutralizing antibodies issues or whether about the true efficacy or potency of these vaccines although some are still in testing stages.
The public are asked to exercise due diligence before accepting any AAV vector based vaccines and to ask for a written signed document that promises no future issues when taking booster shots or future AAV vector based drug, gene or vaccine therapies.
It must be noted that there are proven and safer platforms which other COVID-19 vaccines being developed are based upon and they might prove to be a better alternative.
For more COVID-19 Vaccine Exclusive articles coming soon, kindly keep on logging to Thailand Medical News.