This guy is a heavyweight in the community btw and has been sourced so so many times. I got a lot of my info early on directly from his twitter feed and following his public posts, linked to a bunch on the CA board as well. Gonna highlight some of the best quotes and give them subtitles for specific questions people might have:
On mRNA vaccines and how they workThese vaccines looked incredible, but a lot of what was in the news and on Twitter was about fear of RNA vaccines. They were being called genetic vaccines, and I didn't see that being corrected anywhere or better communication about them.
At that point, I'd worked about 200 days straight since March. I was taking Thanksgiving Day off and I thought, Why don't I write something for Twitter on RNA vaccine safety, and what an RNA vaccine actually is and how it works? The safety data from the clinical trials were phenomenal. So that's what I did. It was seen about a million times in the first 24 hours and 3 million times in 72 hours. That's when I referred to RNA as being like a Post-it Note. It's just a temporary message that the cell writes instructions on. There are around 5000 Post-it Notes inside every single cell, and once they're read, they are shredded and thrown away. It's not a permanent change to the cell.
On how COVID replicates unlike most other virusesIn general, your innate immunity is important to dampen down the levels of viral replication and keep it from spreading further by activating those antiviral pathways in neighboring cells and tissues. But also, almost all of the adaptive immune response — your antibody and T-cell response — is completely dependent on that first innate immune signal. The adaptive immune response does not start until those innate immune alarm bells go off. You can think of it as a burglar alarm or a fire alarm. Until that alarm goes off, your B-cell and T-cell fire trucks are just sitting parked there because they don't do anything until they hear that alarm. That timing is a big deal, because the virus is replicating on an exponential scale and the adaptive immune response also replicates on an exponential scale. So any of those time lags matter.
On mRNA's effectiveness against DeltaThe most detailed analysis of RNA vaccine protection from Delta is from Public Health England, which calculated 88% efficacy still against Delta for symptomatic cases, essentially no change in protective efficacy against hospitalization that is still in that 95% range.
On the study from Israel vs. England, and its possible medical benefitsThere's definitely a flip side, which is the data coming out of Israel and more concern from the Israeli government about how much protection there is. We'll have to see how it plays out, but that definitely, as far as I can tell, gets pretty deep into the epidemiology of what's the proper way to calculate efficacy and how well you match the cases.
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Moreover, in England, they took this pretty bold strategy of giving the two doses 12 weeks apart instead of 3 weeks apart, whereas in Israel, they followed the clinical trial schedule with the 3-week interval. As a result, more people in Israel are further out from their last dose than in England. It will be interesting to see more head-to-head comparisons of that over time and how it affects protective efficacy.
On a potential shortcoming of the mRNA vax, and why boosters are neededWith our HIV vaccine, we asked whether we would get a different immune response if the immune system sees the antigen over a different period of time. Working with Darrell Irvine, our MIT collaborator, we compared a single bolus injection with a conventional syringe with providing the same amount of antigen and adjuvant over a 14-day window instead. The results were dramatically different. All of the monkeys made neutralizing antibodies in one case (14-day administration) and none of them in the other case. That sort of delivery of antigen over a 14-day period is more like what would happen during an infection. It matches what your immune system has essentially evolved to do. One thing we learned by doing that was that when you deliver the same amount of protein, the same amount of antigen, over a longer window of time your immune system gets a lot better at retaining that antigen, and as a result, it gets better at sustaining a protective immune response, even though in actuality it's the same amount of material.
Those results have been repeated in multiple experimental systems, so there's a lot of interest in trying to figure out whether that can be mimicked in other contexts. The thought at the moment is that the RNA vaccines aren't doing that. The reports of the RNA vaccines have been that the RNA probably results in expression of protein for just a couple of days. If that's true, and if that could be changed to protein being expressed over a longer period of a week or two, we might be able to produce a big improvement in the quality of the immune response just by changing the kinetics.
On the importance of antibodies, B cells, T cells - and when they are important:For any virus that's susceptible to neutralizing antibodies, your perfect vaccine is a vaccine that elicits high levels of neutralizing antibodies forever. If you can do that and you can get essentially sterilizing immunity, you have such high neutralizing antibodies, you stop the virus at the front door, and that's the end of it.
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So that then raises the question: If the virus gets past those neutralizing antibodies, that frontline defense, do you have additional lines of defense and/or do you have redundancies and backup systems in place?
For an acute infection like SARS-CoV-2, that's where the T cells come into play. Once you are infected, the T cells become more important than the antibodies because now you have a lot of virus inside cells, generally inaccessible to the antibodies. Combined with that, it's generally very hard for acute viruses to evolve and escape T cells because there are so many different epitopes available for the T cells to recognize. And my T cells will recognize different epitopes than your T cells. So if the virus could escape some of my T-cell epitopes, they wouldn't be escaping yours, and thus there's not that much evolutionary advantage. So it makes sense for there to be a high level of attention on the antibodies, along with a recognition that they're not the only source of protection, particularly when you shift from talking about protection from infection vs protection from hospitalization-level disease.
more about mRNA's limitations and the *actual* long-term questions we have about them / why boosters are necessaryOne of the things we haven't known about RNA vaccines is how long they generate memory for the virus. That's a big consideration when you're talking about the need for boosters. We studied the low-dose Moderna vaccine at 25 µg and, quite impressively, we found essentially no change in T-cell memory between 1 month post-vaccination and 6 months post-vaccination. So it looks like the RNA vaccines actually generate impressively stable T-cell memory, which is a positive sign.
If these backup systems, so to speak, the military reserves, are so good, why would you need boosters? I'd say that comes down to two things. First, there's no proof that T cells are providing that protection. It's much harder to show scientific proof for T cells than antibodies because you can purify them and passively transfer them into another person or a monkey and have direct experimental proof. It is 30 times more resource-intensive to study a T-cell response than an antibody response. It's harder to get samples, and biologically it's tougher to prove. So you have to hedge somewhat because there isn't enough proof on that side.
Second, it comes down to the definition of protection. One level of protection is hospitalization or death. Another level of protection is obviously infection and/or symptomatic infection. It's less likely that T cells are contributing protection against symptomatic disease and certainly against infection because they take some time to kick in. They have to wait until you're infected. Then they have to detect the infection. Then they have to get to the site of the infection and expand and whatnot. Normally, that's going to take time, which is fine for prevention of hospitalization, but this is a virus that's fast at replicating in your upper respiratory tract and transmitting in just a handful of days. So if the goal is to prevent symptomatic disease and transmission, you want to bias things more toward that antibody component.
Should you get vaccinated if you've already had COVID?Last question first. Is prior COVID plus one dose of mRNA vaccine better than, well, anything else? Yes. I summarized that literature in a one-page piece in Science a few weeks ago, which I called "Hybrid Immunity." Eric, you and some others have called it super-human immunity, which is bulletproof, and is fair enough. The immune responses in those individuals — the T-cell and antibody responses — are dramatically higher than what you get from either infection or immunization.
There is a lot of hope for natural immunity, but it should be tempered re: variants; especially relative to vaccinesDo people with prior COVID need vaccination? I think it's a topic about which reasonable people can disagree because the epidemiologic data so far have been out to 8 or 9 months post-infection. Those people are still something like 93%-100% protected, depending on the study. Those are relatively large studies, so that's pretty good evidence.
Against variants, however, that protection drops, and how much that protection drops really has not been quantified well. The best paper on the topic is the Science paper on the Manaus, Brazil, outbreak, which suggested something like a 30% drop in protective efficacy against the P-1 variant compared with the original virus in terms of reinfection.
That's obviously a big drop if it's occurring in other contexts and with other variants, whereas the vaccine seems to be more consistent than that. In our Science paper, where we measured the immune responses, the immune memory in people who had had COVID, it was quite encouraging 8 months out.
Why trusting natural immunity can be problematic but is not personally riskyThe status of the discourse before our paper was centered on the possibility that people don't have any memory at all and maybe don't have any protective immunity. Maybe coronaviruses are just strange in this way. We didn't think that would be the case immunologically, but obviously you want data. That was the largest ever study of immune memory to a virus over 6 months, with each of these different immunologic compartments. We showed that people do have antibodies over that period — a number of groups have shown that. We showed they have memory B cells over that period. If anything, they have more at 6 months than at 1 month. We also showed that memory T cells were retained rather well over that time period, such that we projected that people who have had COVID are likely to have a reasonable amount of protective immunity for years into the future; it wouldn't necessarily prevent infection or even symptomatic disease but it would prevent serious outcomes.
A caveat that we put on that is that there were 100-fold differences between individuals in those components of immunologic memory, and we don't know which ones are most important over time. So if you show me 100 people who had COVID, some of those people will have very low immune memory but I don't know which ones. A serum antibody test can't tell me. Public health officials always want to lean on the safety side, in which case the recommendation is certainly that all those people should be vaccinated. If they want to roll the dice and not get vaccinated, most of them probably are protected.
Someone has the audacity to share a different opinion as you and now you want segregation. Unfortunately for you that is not reality and we're living in 2021. Not 1951.