Tuk Tuk’s mom is a high school English teacher The teachers in Virginia have begun. Tuk Tuk doesn’t know how he feels about that.Gigi thinks she should go. She could help the students when they begin next week. Toasty is contemplating all this.
The mRNA-based coronavirus vaccines were most prevalent in many countries, but there were many, many people worldwide who were dosed with some sort of adenovirus-vector vaccine as well. At the time I mentioned a concern about this sort of platform, i.e., the development of an immune response to the viral vector itself (rather than, or alongside the desired immune response to the antigens that it's delivering). That worry goes beyond adenoviruses (any viral vector could have this problem) and it goes beyond vaccines, too. Here's an article from earlier in the summer at Nature about gene therapy using adeno-associated viruses (AAV) platforms, and it's very much on the minds of people in that field.
That's because gene therapy, as it moves from the Maybe Some Day stage and into the real world, is showing its real-world wrinkles and complications. The hope was that these could be one-and-done therapies: you fix the defective gene in the patients' tissues with a blast of the correct one, and they go off to live a far better life. But the first treatment doesn't always do enough, and even when it does, the effects can and do wane as the body's cells turn over. That was always expected to some degree (with allowances for different tissue types), but the problem is that once you've hit someone with a whacking dose of some particular AAV, their immune system is probably going to shoot it down if it shows up again. And unfortunately you will probably need another treatment, sooner (to get the initial effect up to useful levels) or later (to make up for its diminuation over time).
Everyone was willing to kick that can down the road back at the time, because the big project was getting gene therapy to work in the first place, and to provide relief to patients who had no other options. An even nastier issue has been the discovery that some populations tend to already have such an immune response in place from prior exposure to wild-type viruses: there are regions where 70% of the population will inactivate an AAV vector before it has a chance to do any good at all. The expansion to viral-vector vaccines is not helping this much, either, honestly. Companies working in this area are well aware of the problem and have been taking care to use unusual viruses as platforms (rare subtypes, forms found only in chimpanzees, etc.), but the problem remains that some of these are going to have to be taken off the list in the future for anyone who's had them.
As that Nature piece shows, there are now early gene therapy recipients who could very much do with another treatment, but they simply cannot get one due to this vector immunity problem. This didn't get solved over the years, so now these folks are in a very tough situation. Here's a review of some of the approaches that people are taking to deal with this. There are modifications to the viral vectors themselves to change the immune response, different routes of administration and different formulations, administration of immune-modifying agents on a second dosing, and more. As with anything involving immunology, it's a complicated landscape: we may well end up with different approaches with different vectors, tissues, diseases, and patient populations. A general solution would be great, but will be very difficult to realize - we'd better be prepared to take what we can get.
Addendum: the entire phenomenon of "This looked so perfect at first" is neatly summed up by Robert Frost:
Nature's first green is gold
Her hardest hue to hold
Her early leaf's a flower
But only holds an hour.
Then leaf subsides to leaf
So Eden sank to grief
So dawn goes down to day
Nothing gold can stay.
I don't think anyone ever did the reverse-zoom effect from particular to general any better - see "Design" for another vivid example.
There have been many, many attempts over the years to link Alzheimer's disease (and other forms of dementia) with some sort of infectious agent. It's not an implausible idea, but given the slow development of the disease and its clinical variability, it's a very difficult one to prove. It seems clear that inflammation is a player in AD and other such conditions, and you can't rule out that being set off (or exacerbated) by some pathogen, perhaps even one that was first encountered many years in the past. From this point of view, the characteristic proteins seen in Alzheimer's diagnosis (beta-amyloid and tau) might be better viewed as the brain's response to infection rather than the cause of disease in themselves (although you also can't rule out such a response causing problems of its own if it goes too far).
It's been believed for some time that being vaccinated against herpes zoster virus confers some resistance to developing dementia later in life. There are a number of lines of evidence, such as this study in Wales that uses the 1933 birth date that was a cutoff for receiving the Zostavax vaccine to show that there really does seem to be a significant effect. And just recently, the same sort of thing has been shown with the newer recombinant vaccine for shingles (Shingrix). I've had that vaccination myself, so I was glad to hear it! Not that I want shingles, either - I got chicken pox when I was 23, in grad school, and I hope to never encounter the virus doing anything to me again after that experience.
These sorts of studies control for both other comorbidities and for other vaccinations. There is, for example, no apparent dementia protection conferred by tetanus or influenza vaccination, just against herpes zoster. And the fact that both the older live-virus vaccines and the newer recombinant one show the same effects is strong evidence in itself that this virus (at least in some people) has some connection with some types of dementia in later life. It would seem obvious that any such connection is worth examining in detail.
This recent article by Jennifer Couzin-Frankel here at Science reports on an upswing in the whole dementia-pathogen story. There are clues with the herpes virus, with yeast, with bacteria, and more, and I'm very happy to hear about it. My gradually developing antipathy to the classic amyloid etiology story of Alzheimer's is well-documented on this blog over the years, exacerbated most recently by the FDA's approvals of anti-amyloid antibodies for which I find the evidence of harm much more compelling than the evidence of any benefit. (For now, the EMA agrees with me on that one, recently refusing a marketing authorization for lecanemab). I am nowhere near ready to embrace the infectious disease hypothesis as The Answer, but I think (given the evidence) that it is very deserving of investigation, and that the dominance of the amyloid hypothesis over the years has made it difficult for alternatives to get the hearing that they might deserve. Let's see!