Edward Nirenberg

The real lesson of this paper is not "one natural infection grants magical century-long protection." It is "immune memory can persist for decades and be continually reshaped by related exposures, leaving very old survivors with highly refined responses against the original strain."

Fig. 1.25 The course of a typical antibody response. the first encounter with an antigen produces a primary response. Antigen A introduced at time zero encounters little specific antibody in the serum. After a lag phase (light blue), antibody against antigen A (dark blue) appears; its concentration rises to a plateau and then gradually declines, typical of a primary response. When the serum is tested for antibody against another antigen, B (yellow), there is little preset. When the animal is later challenged with a mixture of antigens A and B, a very rapid and intense antibody secondary response to A occurs, illustrating immunological memory. this is the main reason for giving booster injections after an initial vaccination. note that the response to B resembles the primary response to A, as this is the first encounter with antigen B. Key point: antibody levels rise much faster and to a much higher level with the secondary response than with the primary response.

Generating immune responses from scratch takes time. When you can rely on memory cells, however, you can get things done much, much more quickly, even if they wouldn't do as good a job in terms of precise targeting.

rupress.org/jem/article/...

Naturally, this begs the question of why our immune systems keep relying on old exposures to guide immune responses against newer ones instead of starting from scratch so that data like that for the antibodies from 1918 flu survivors can't be much neater. The answer again goes back to speed.

Individuals cannot rely on COVID-19 herd immunity: Durable immunity to viral disease is limited to viruses with obligate viremic spread

And flu isn't special here. This is the norm for most respiratory infections. Some of them take longer than others to generate symptoms (especially if they have a phase where they have to get into the bloodstream, as measles does). Slower pathogens can be suppressed by a recall response.

For flu: unless you have very high levels of antibodies that match the strain of flu you encounter before the encounter, the chances are quite high that you will be infected and you will develop mild illness. The progression to severe illness takes longer, and a recall response might save you there.

Protection and immunity are not synonyms. Immunity does not always equate to protection (depending on the outcome e.g., mild illness, death, etc.), and with something like flu, it's especially hard because flu moves much more quickly than the immune system can. What does that mean practically?

Then we have no idea what the durability of this immunity would be. There's also a version of this that suggests that this is proof that natural immunity is also so powerful as to be super broad. The problem? The vast majority of antibodies against 1918 pandemic flu won't even recognize H3 flu.

It is difficult to be absolutely certain that the monoclonal antibodies isolated here were first stimulated by exposure during the 1918 pandemic. However, the clinical history of the subjects and the high functional specificity of the monoclonal antibodies for the 1918 strain strongly suggest that recent exposures do not account for this immunity. Probably, boosting by antigenically related viruses in the early decades of the twentieth century may have contributed to the ability of these subjects to sustain these B cells. The variable genes of five independent human neutralizing antibodies had a very high frequency of somatic mutations, associated with strong binding constants and high potency.

So, what does this tell us about how long immunity lasts to the pandemic strain of flu? In reality, not much! The existence of these memory B cells and their derived antibodies is almost certainly the result of repetitive encounters with influenza. What if those encounters didn't happen, though?

Sequence analysis of the antibody genes from the clones demonstrated that the five monoclonal antibodies were distinct and very highly mutated. Genetic features of the antibodies are shown in Table 1. It was of interest that the 1F1, 2B12 and 2D1 clones shared use of the VL1-44*01 gene segment, suggesting a particular fitness for binding of the 1918 virus HA by theCDR1/2 light-chain loops encoded by this VL gene segment. The three clones, however, were clearly independent as they differed in the location of somatic mutations, JL segment (1F1) and in heavy-chain pairing. The numbers of somatic mutations in the variable regions were exceptionally large, almost twice the median number of 18 mutations found in class-switched memory cells in randomly selected human B cells9 . These data probably suggest recurrent optimization of binding affinity through multiple rounds of somatic hypermutation and selection in vivo.

This is almost certainly what's happening here with these nonagenarians and centenarians. Why? Because those antibodies that recognized the pandemic flu strain have roughly double the amount of mutations that mature antibodies have—meaning they have undergone more cycles of affinity maturation.

For example, an antibody induced from an exposure to the pandemic H1N1 flu strain can end up recognizing a bunch more H1 proteins from different influenza viruses. That means that encounters with flu viruses throughout the lifespan can recall memory cells that targeted a different strain of flu.

This can go on for multiple cycles as long as you have B cells. You can see some genetic evidence of this based on the mutation patterns to the antibodies (more on that in a sec). Affinity maturation can also result in the broadening of an antibody to recognize more versions of the same antigen.

Meaning that the B cells with these mutations will die by neglect. However, a few B cells will mutate to get better binding to the antigen. These B cells will be able to get help from T cells, which comes with survival signals, and they can become antibody-secreting cells or memory B cells.

When a B cell is found, a process called affinity maturation is initiated. Basically, the B cells begin to randomly mutate their receptors (literally, their DNA changes) and get a change in the ability of the receptor to bind to the antigen. Most of these mutations will worsen binding strength...

Summary of affinity maturation. Details regarding the location of particular parts of this process within the lymph node (i.e., dark zone vs light zone vs mantle zone) are not important to the concept. Initially, B cells move to a specific region of the lymph node and then get signals to leave that site to investigate a potential target of an immune response (known as an antigen). Some B cells will express a protein on their surface (the B cell receptor) that recognizes an antigen. Each B cell receptor is unique to a particular B cell and its clones. An antibody is the secreted form of the B cell receptor. Most of the B cells will not bind the antigen, and so they don't participate in the antibody response (yellow cells). However some B cells will (orange in this diagram) and they can pick up antigen and process it. The B cells that can recognize the antigen then move to a different part of the lymph node where they rapidly mutate their genome to change the B cell receptor. The specific changes to the B cell receptor are random. This can cause loss of the ability to bind to the antigen (and that is the most common outcome). However, a tiny portion of the B cells will end up with a B cell receptor that binds more strongly. These will outcompete the other B cells for the ability to pick up antigen and can present that antigen to T cells. The T cells, in turn, give the B cells signals to promote their survival and differentiation into memory B cells or antibody-secreting cells.

To understand this, I have to explain a bit about how antibody responses work. When the immune system is trying to generate antibody responses, it takes the target of the immune response (called an antigen) and looks for a B cell that recognizes that antigen with its receptor.

Here is where an understanding of the immune system becomes secondary to selling a narrative for some. First: this study doesn't show that these antibodies and the memory B cells are the same ones as those that responded to the original 1918 pandemic strain, and there is evidence against it.

Supplementary Table 1. Serologic testing of volunteers of varying ages (Reciprocal titers are shown, for the indicated test) Donor birthdate category Subject # HAI, 1918 VLPs Neut, 1918 virus Neut, Sw/30 virus 1 640 640 320 2 80 80 80 3 160 320 80 4 1280 320 640 5 640 1280 640 6 640 640 640 7 80 20 80 9 160 160 80 10 320 320 320 11 160 640 320 12 160 320 320 13 80 40 80 14 160 640 160 16 160 320 160 17 320 1280 320 18 320 1280 320 19 640 2560 640 20 < 20 40 20 21 320 640 320 22 320 320 320 23 320 320 320 25 320 640 320 26 20 40 20 27 80 320 80 29 320 160 80 30 320 320 80 31 320 320 80 32 160 80 20 34 320 80 40 35 >1280 640 80 1915 or earlier 36 >1280 2560 640

38 >1280 640 320 37 20 10 <20 39 320 80 40 40 20 10 <20 41 20 <10 <20 42 <20 20 <20 43 <20 <10 <20 46 20 20 40 55 20 20 20 62 80 40 80 64 40 320 <20 1926-35 8 <20 <10 <20 15 <20 20 20 51 ~20 20 <20 53 <20 10 <20 54 <20 <10 <20 59 <20 <10 <20 60 80 40 20 61 40 40 <20 63 640 2560 640 1936-45 65 <20 20 <20 44 <20 <10 <20 45 20 <10 <20 47 <20 <10 <20 48 <20 <10 <20 49 <20 20 <20 50 80 20 <20 52 <20 20 <20 56 160 160 40 57 <20 <20 <10. 1946-55 58 640 40 640

Did they have antibodies and B cells against 1918 pandemic flu? Turns out, they did indeed have antibodies all those decades later. In fact, they had very high levels of antibodies that recognized the 1918 strain compared with younger individuals.

There is a bit of a problem here already with respect to some of the claims being made: most people do not live to 91-102 years old. It is naive to assume that the immune system of these participants generalizes to that of people aging more typically. But let's put that aside for the moment.

This study, published in 2008, took blood samples from 32 participants 91-102 years old, aged between 2 and 12 during the 1918 flu pandemic, and then examined antibodies and B cell receptors from memory B cells for their ability to neutralize the 1918 strain of pandemic influenza.

nature Vol 455| 25 September 2008| doi:10.1038/nature07231 LETTERS Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors Xiaocong Yu1 *, Tshidi Tsibane2 *, Patricia A. McGraw1 , Frances S. House1 , Christopher J. Keefer1 , Mark D. Hicar1 , Terrence M. Tumpey3 , Claudia Pappas2,3, Lucy A. Perrone3 , Osvaldo Martinez2 , James Stevens3,4, Ian A. Wilson4 , Patricia V. Aguilar2 , Eric L. Altschuler5 , Christopher F. Basler2 & James E. Crowe Jr

I'd like to spend a minute discussing this paper because it is frequently abused to make erroneous claims about the nature of the human immune system and our capacity to resist respiratory viruses:

rdcu.be/e7un8

A thread 🧵

I spent today so exhausted and I couldn’t figure out why.

Daylight Savings Time.

Rand Paul Doesn’t Understand How Immunity Works Folks like Rand Paul and Mel Gibson are trying to rewrite the history of COVID, making you think that vaccines were the problem. Don't believe their pandemic revisionism.

Folks like Rand Paul and Mel Gibson are trying to rewrite the history of COVID, making you think that vaccines were the problem. Don't believe their pandemic revisionism. stopantivaxpropaganda.substack.com/p/rand-paul-...

It's crazy to me how the papers that get published today could easily have been 3 or 4 papers even a decade or two ago. The amount of information they are saturated with is intense.

Gonna have another convo with the great @kavehmd.bsky.social on all things Iran tomorrow. What are you curious about? What would you like to hear more about from two diaspora Iranians?

#neurosky I'm sorry if this is a dumb question, but when some say that Huntington's patients are susceptible to placebo effects... how? I could understand the subjective perception of symptoms, but what about things like chorea and neurofilament light chain in CSF? Are those not valid readouts?

I do think that that point gets abused in popular media to suggest there is more of a conflict between the two than there is. A study lacking scientific rigor is definitionally not ethical.

Again!

For sure! Sham surgery in and of itself is a valid and important control in studies of surgery efficacy, but the Declaration of Helsinki doesn't say "do everything possible to protect participants (unless methodologically inconvenient)."

Sham surgery in and of itself is not a methodological problem. The issue is the level of risk that we would be exposing patients to in pursuit of confirmation of a therapeutic effect when there are reliable alternative study designs that could estimate an effect or lack thereof.

That seems like an appropriate level of caution for clinical research. You should ask for something safer. Like, instead of fasting blood draws, maybe put them under general anesthesia for 10-12 hours after they've eaten and draw blood from them then.

Honestly, I expected them to be worse, but largely because I underestimated the capacity of career scientists at the agencies.