What are the risks associated with imidazoquinoline adjuvant (used in one Covid-19 vaccine) related to development of autoimmune diseases?

Question

Covaxin is an inactivated virus-based COVID-19 vaccine developed by Bharat Biotech. Recently, the Brazilian health regulator Anvisa raised few concerns regarding Covaxin, one of which was- use of a novel imidazoquinoline adjuvant that may increase the chance of developing an autoimmune disease.

Use of an innovative substance in the vaccine formula, imidazoquinoline or IMDG, not yet used commercially in any approved vaccine in the world. According to GGMED, this additional drug may be related to the development of autoimmune disease;

How risky is the use of IMDG in a vaccine like Covaxin?

Edit 1: On GGMED website, I found links to following papers that have findings that connect TLR 7/8 agonists with induction and acceleration of lupus-like autoimmune disease.

1. https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/toll-like-receptor-7
2. https://www.frontiersin.org/articles/10.3389/fimmu.2019.03054/full

Edit 2: Since many people, including me, cannot read Brazilian (Portuguese), I am putting the translation done by google here. The translation is not very good, but perhaps the general idea can be grasped. The actual source of these comments is a pdf in Portuguese that can be found on their official website at this link.

Of particular concern is the superficiality in which the assessment and the vaccine safety results from the phase 3 study, considering that the vaccine has a new adjuvant, imidazoquinoline, or IMDG, not yet used commercially in any approved vaccine in the world. This adjuvant is a 7/8 Toll-like receptor (TLR) agonist and has a potential relationship with development of autoimmune disease. (...) There is no description of adverse events deaths and deaths or analysis and conclusion of causality of adverse events deaths and deaths from the vaccine. It is still quite worrying that the definition is evaluation of adverse events of special interest, as described in the study phase 3, does not include the assessment of neurological, hematological and immunological events, and induction of autoimmune diseases that are especially important due to the presence of the IMDG adjuvant. The definition and assessment of adverse events of interest are at odds with expectations, with the assessment carried out by others. Covid vaccine developers already approved, and at odds with the consensus scientific research to define the safety profile of Covid vaccines.

Answer 1

I will try to summarize what I have gathered till now from reading on my own and insights from other people.

In the study 1 that I have cited, they have found that on mice, a dose of 100 micrograms of TLR7, 3 times a week, for 8 weeks not only leads to development of lupus-like disease, but is also lethal. But human beings are larger than mice. If we assume a rough scaling factor for toxicity as (body weight)^0.67, and assume that human beings are 3000 times heavier than mice, we find a scaling factor of 3000^0.67 which is approximately 200. That is, a similar test done on human beings, but with a dose of 20 milligram instead, will give similar results.

So, we observe the following 2 points.

1. A single dose of Covaxin contains 15 microgram of TLR 7/8 agonist. That is, one dose of Covaxin gives about 1 part in 1400 of the dose that was given to the mice.

2. Also, it should be noted that human beings are exposed to a total of 2 doses of Covaxin, 4-6 weeks apart, in contrast with the 24 doses that the mice received in 8 weeks.

I do not know what to conclude from these two points. But these points gives us some frame of reference to judge the situation.

Now, it should be noted that the people who developed Covaxin did do a maximum tolerated dose study (study 2) on mice. They found that the mice tolerated a single dose of 20 microgram of TLR7/8 agonist, and

demonstrated lack of erythema, edema or any other macroscopic lesions at the site of injection. (...) Histopathology examination of the injection site showed active inflammation, as demonstrated by mononuclear cell infiltration, which is likely a physiological local inflammatory reaction caused by aluminium salt in the vaccine adjuvant preparation. In any of the studies conducted, there were no mortality or no changes observed in clinical signs, body weight gain, body temperature, or feed consumption in the treated animals. (...) All animals were necropsied and examined macroscopically.

Now, a single dose of 20 microgram is equivalent to about a 4 milligram dose in human beings, if you account for the scaling factor of 200. That is, they exposed the mice to about 300 times of what a human being would be exposed in a single dose of Covaxin (15 microgram), and found no red flags.

One potential issue could be that unlike in the study 1, the study 2 perhaps did not actively look for the link between TLR7 agonism and development of lupus-like disease. For example, the study 1 found that TLR7 Stimulation Accelerates Glomerulonephritis in NZM2410 Mice and also leads to Splenomegaly (enlargement of spleen). Perhaps the study 2 did not look for nephritis. As for Splenomegaly, they may have examined the spleen and did not found any enlargement in the spleen, which is a good sign. They did not actively mention this observation.

My point is, in study 2, they have not mentioned issues like autoimmunity or lupus like disease anywhere in the paper. I think they should made a reference to why this is something not to be worried about.