New Pfizer Document Release - Repeat-Dose Toxicity Study in Rats

And number of births in the UK in December drop 12%

The latest Pfizer document drop happened at the beginning of March (It has been pointed out to me that we are still waiting on April’s tranche). Included in this latest tranche is a Repeat-Dose Toxicity Study of Three LNP-Formulated RNA Platforms Encoding for Viral Proteins by Repeated Intramuscular Administration to Wistar Han Rats. The document was published on 1 July 2020 and approved on 18 September 2020.

Photo by Oxana Golubets on Unsplash

Various doses and formulations were tested including the final concoction used on humans - BNT162b2 (I have been told the formulation used in this study was V8, whilst the final commercial candidate was V9). I’ll therefore focus on the results for this formulation. The report is 2,237 pages long so I’ve massively summarised everything but it is interesting reading if anyone wants a longer read!

129 males and 126 females were used. In the main study there were 10 males and 10 females in seven groups including the control group. During the recovery period there were 5 males and 5 females in each group. Additionally there were 3 male and 3 female satellite animals in the seven groups. For BTN162b2, the rats were injected on days 1, 8 and 15.

I’ve summarised any findings of interest below:

Local tolerance

• The incidence and severity of the reactions were higher after the 2nd or 3rd injections compared with the 1st injection;

• A few animals had severe oedema (build up of fluid) 24 hours after the 3rd injection of 100 µg BNT162b2/animal. The majority of these observations of oedema were resolved or showed signs of resolution by 144 hours post dose;

• All groups experienced mostly moderate inflammation at the injection site but the most severe findings were consistently in animals administered with BNT162b2.

Haematology and coagulation

• Observations included decreases in the absolute and relative reticulocyte count, the number of platelets, and red cell mass, and increases in the numbers of leucocytes, neutrophils, monocytes, eosinophils, large unstained cells (LUC), basophils and/or the levels of fibrinogen. All changes fully reversed by the end of the recovery phase.

Clinical chemistry

• An elevated plasma activity of gamma-glutamyltransferase (gamma-GT) was noted for all groups in comparison to the control group. Elevated GGT levels may be an indicator of cardiovascular disease and/or hypertension. Some studies have shown that if you have increased GGT levels you have an elevated risk of dying from heart disease, but the reason for this association is not yet known.

Macroscopic post mortem findings

• Enlarged iliac lymph nodes were still noted for a few animals at the end of the 3-week recovery period including 1/5 males and 3/5 females.

Organ weights

• The macroscopic findings of enlarged spleens correlated with increased relative and absolute spleen weights.

Conclusion

The report says that the injection was tolerated without evidence of systemic toxicity and produced nonadverse inflammatory changes at the injection sites and the draining lymph nodes, increased haematopoiesis in the bone marrow and spleen, and clinical pathology changes consistent with an immune response or inflammation in the injection sites. The findings are reversible, consistent with those typically associated with the intramuscular administration of antigens/ and or LNPSs.

However, many findings were considered as isolated findings and therefore spontaneous changes that were not test item related. These findings included:

• Dilated uterus, in some cases filled with a clear liquid;

• Prostate and seminal vesicles (glands that produce the fluid in semen) that were reduced in size.

Other problems in the BNT162b2 group, observed in the post mortem findings, included jellied muscles and sciatic nerves adhering to the injection site.

After weighing the male rats’ organs on day 17, differences between the BNT162b2 group and the control group are shown below:

• Adrenal gland (left) - 24% heavier;

• Epididymis (left) - 33% heavier;

• Epididymis (right) - 34% heavier;

• Testis (left & right) - 12% heavier;

• Heart - 9% heavier;

• Cervical lymph nodes - 18% lighter;

• Mesenteric lymph nodes - 67% heavier;

• Spleen - 37% heavier

• Thymus - 21% lighter;

These changes had all reduced by day 38 but the mesenteric lymph node was still 48% heavier.

In female rats at 17 days, noticeable differences in organ weights compared with the control group included:

• Liver - 20% heavier;

• Lungs - 15% heavier;

• Spleen - 62% heavier;

Taking a closer look at some issues observed in the microscopic findings:

• 100% of the skeletal muscles in males were within normal limits. Only 66.7% fell within these normal limits in the vaccine group and only 50% when only looking at the main study;

• 100% of the sciatic nerve in both males and females fell within normal limits in the control group. In the vaccine group, this was 20% for males and 26.7% for females (0% in the main study for both);

• In the main female study, 90% of the control group animals rectums fell within normal limits but this dropped to 40% in the vaccine group;

• Whilst 80% of females’ lungs with bronchi fell within normal limits, only 20% did so in the vaccine group;

• 100% of recovery period males’ hearts were within normal limits whilst only 60% of the vaccine group were;

• Only 60% of males’ prostate glands fell within normal limits in the vaccine group with 100% in the control group;

• 80% of females in the control group had vaginas within normal limits but this dropped down to 40% in the vaccine group.

As you can see from the summary above, there were serious differences between the control group and the vaccine group that maybe should have been looked at further before injecting half the world. Just looking at a few rats and concluding the vaccine was safe maybe wasn’t the most truthful conclusion.

For example with only 60% of the male rats’ hearts falling within normal limits, this should have set off some warning bells. Is the reason so many people are dying from heart disease linked to the elevated plasma activity of gamma-glutamyltransferase (gamma-GT) observed in these trials? As mentioned above, studies have shown that when GGT increases there is an elevated risk of dying.

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In other news, the UK Health Security Agency have just released their latest vaccine surveillance report. As we have seen with other data in the past, this month the report has changed the format of the pregnancy data, indicating it is causing some problems and is on its way out. Previously a whole year of data was shown whilst now it is only the last four months.

However, even with these reduced stats we can now work out the declining birth rate in December 2022. Using the previous surveillance report, we can compare numbers to conclude that there was a 12% decline in year on year births in December. This follows a 13% drop in November. Let’s hope things improve in 2023.