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Immunogenicity and Efficacy

Adverse events from exposure to foreign antigens reflect a number of processes in the host. One of the most critical processes, which is rarely specifically called-out is immunogenicity. Efficacy is the effect that we want to see in a drug/pharmaceutical agent, and it is often confused that high immunogenicity reflects poor efficacy. They are actually distinct processes. Immunogenicity is often terms thought of in negative terms (negative immunogenicity) such as anaphylactic shock from eating peanuts and getting bee stings (two of the more common very immunogenic events). but beneficial immunogenicity (positive immunogenicity) is the basis of vaccination: developing an immune response- creating neutralizing antibodies to the virus that the vaccine is designed to create. Another not fully correct simplification, is that vaccines generate just antibodies (a B-cell elaboration), but not fully explored is that often a T-cell response (which is direct cell activity rather than a cell product [eg: an antibody) is likely also a positive occurrence.

The important consideration in immunogenicity is the likelihood of an immune reaction (there are many different kinds of immune reactions) to an agent. There is no agent where this concept is higher in the medical eye and public eye than with Covid-19 vaccines. Since these vaccines work on the basis of getting the immune system to recognize/react/neutralize the virus particles, their major adverse event is negative immunogenicity. That is stimulating the immune system, but comparing one potential vaccine to another, a quality that is undesirable: which vaccine is more likely than other vaccines to stimulate it in a higher percentage of individuals a negative reaction.The most feared, a cytokine storm that can result in death. It is often not clear if the reaction is too much of a good thing (overwhelming creation of neutralizing antibodies), or if it is frank creation of undesirable antibodies (that just trigger anaphylaxis or similar). Remember there is 1,000 moving parts in the immune system, so the likelihood for something to go wrong is obvious, but occurs generally relatively rarely with vaccines.

A simple way to look at it is the nut: peanuts have a relatively high incidence of allergic reactions, in contrast walnuts do not. The explanation: the difference, percentage wise, the number of humans who have the genetic disposition of their immune system to react to certain protein/other molecules in peanuts, than they do to walnuts... But there will be people very allergic to walnuts, just a much less common genetic variation.

I believe even the layperson has been acquainted in the news media with the concept of cytokine storm- that the virus or a vaccine can initiate tremendous host reaction, but in. such a fashion that certain destructive cytokines are dramatically released to cause not only harm but death. The other troubling aspect of viral vaccines is that they can cause horrific CNS developmental crises in children. Hence the school of thought of antivaccine. The reality in that delivering a substance with the design to stimulate an immune reaction, it is invariable that some individuals will experience a reaction that goes horribly wrong. Scientifically it is fascinating to me that the injuries often sustained are CNS in nature. My fascination stems from the fact that sympathetic dystrophies (neural) are closely associated with the presumed T-cell dysregulation of GDD - immune system and neural system closely tied. It seems from my reading that even the best of vaccines (such as measles) have a serious complication rate (as I describe above) of 1 in 1 million, even if a clean vaccine with near no impurities). The risk of serious injury of disease varies with each virus, but for most is atleast 1 in 1,,000. So we have to make the risk-benefit evaluation of this: 1 in 1 million chance of a devastating CNS complication from vaccine compared to 1 in 1,000 chance of deadly outcome from the disease. So from that perspective one can see why the scales tip very much in favor of vaccines..However the pure math of it is no consolation to the devastated child and toermented parents.. We can do better than that - clearly there is a distinct immunological variant that the individual possesses that is genetic in nature. If we know the individual has the genetic predisposition for a severe outcome to the vaccine, then they don't get the vaccine. This knowledge is within our grasp.

But I am not writing about vaccines I am writing about GDD and GBCAs. When the tool you have is a hammer then everything looks like a nail.... Everything looks to me relatable to GDD.

The great majority of the literature on adverse events with GBCAs has focused on whether the agent is linear or macrocyclic and whether ionic or nonionic. The general medical community knowledge of Gadolinium toxicity, which is founded on NSF and further supported by the Gadolinium Storage Condition phenomenon of high signal in the Dentate Nucleus and Globus Pallidus: GBCA that is macrocyclic: good (and really good if ionic), and bad if linear (and especially very bad if nonionic).

But maybe that is too simplistic. Maybe the more important toxicity we are overlooking is the toxicity unrelated to stability: the toxicity of immunogenicity. The occasional radiologist expert had in the past described that although Omniscan was the evil orphan of the GBCA world because of NSF, and then T1 brightening in the brain on MRI,, but, their contention was, that there was less acute hypersensitivity reactions (AHR), less immunogenicity in other words, with Omniscan to other GBCAs, and that this was more important No other radiologists, including me, believed them, and it did not help that they were paid by the manufacturers to say that. But what if they were right?

The uncertainty stems from the fact that very serious reactions, anaphylactoid reaction leading to death, occurs in an incidence of much lower than 1 in 100,000 (reported as 1 in 300,000), hence it is impossible for one dedicated University center to accumulate enough numbers to distinguish severe anaphylactoid events between agents. The problem with pooled data, is that some centers may be inaccurate, even to the point of knowing what agent was used, and the simple fact that sick people get MRIs and they may die from a 1,000 other different causes not related to GBCA. The same problem of rarity also hounds GDD, coupled with the fact that radiologists essentially never followup patients (including my former self), so they don't know if there are subacute toxicities- because they don't see the patients in followup.

So it may be the controversial experts were right about the incidence of severe AHRs. Not necessarily that overall Omniscan may be safer than some other agents, but the concept, that GBCA stability of chelate is important, but perhaps immunogenicity is an even more important adverse event, once you control for not giving patients with advanced renal failure a GBCA (controlling for NSF)..

I use as a baseline of description and comparison for GDD to AHR. That is because of time of onset, GDD occurs often very early post contrast, and all agents can result in GDD as is the case with AHR.

I am gaining experience with the concept of immunogenicity of GBCA agents, and also of treatability of GDD secondary to particular agents. One of the problems though is that since linear nonionic agents are now rarely in common use, the low incidence of GDD secondary to Omniscan, for example, may not reflect that it has lower immunogenicity, but rather comparatively lower market share, so fewer administrations of this agent, hence fewer incidences of GDD. Many individuals have thought that GDD arose because the GBCA was linear, or if macrocyclic because it was not transported or stored well, or expired (like a carton of milk), essentially somehow broke up even though it was macrocyclic. I don't think that has occurred, maybe at all in North America. GDD results not because the GBCA is a linear agent, nor that it is a spoiled agent. All GBCAs can cause GDD; and it is likely the ones with higher immunogenicity cause it more (the vaccine analogy). It is too early for me to feel comfortable reporting... but it is not a linear agent I am most concerned with GDD, in part as one would expect, linear agents chelate out in greater volume with DTPA, and hence I am less worried (but macrocyclic agents also chelate out and often well), it is a macrocyclic agent. In my opinion the issue is immunogenicity.


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