RECHTSANWALT DDR RENATE HOLZEISEN

I When comparing the information EMA is providing about BNT162b2 to the general public to the one BioNTech is providing for “recipients”, one notes interesting omissions relating to fertility, pregnancy and lactation.

This is the information provided on the EMA webpage regarding threats to pregnancy and breast-feeding:

“Animal studies do not show any harmful effects in pregnancy, however data on the use of “Comirnaty” during pregnancy are very limited. Although there are no studies on breast-feeding, no risk for breast-feeding is expected.”

And this is the information provided on page 114 (section “Conclusions on the clinical safety”) of the EMA’s assessment report for Corminaty:

“Long term safety data, interaction with other vaccines, data on use in pregnancy and other subgroups (e.g. frail subjects, or subjects with pre-existing autoimmune diseases) are missing at this stage.”

It is not clear on what grounds EMA made the determination that “… no risk for breast feeding is expected.”

The assessment report further states (page 56):

“The CHMP noted that no data are available on BNT162b2 placental transfer or excretion in milk.”

This means that it is unknown whether BNT162b2 (Corminaty) is excreted in human milk. A risk to newborns/infants cannot be ruled out.

The EMA also noted that it is not known if placental transfer/passage of BNT162b2 occurs (see page 50 and page 51 of the report):
“In the DART study, the test substances used were BNT162b1, BNT162b2 and BNT162b3, which were given to female rats twice before the start of mating and twice during gestation at the human clinical dose (30 gg RNA/dosing day). […] No effects on the estrous cycle or fertility index were observed. There was an increase (~2x) of pre-implantation loss (9.77%, compared to control 4.09%) although this was within historical control data range (5.1%-11.5%). Among fetuses (from a total of n=21 dams/litters), there was a very low incidence of gastroschisis, mouth/jaw malformations, right sided aortic arch, and cervical vertebrae abnormalities, although these findings were within historical control data. Regarding skeletal findings, the exposed group had comparable to control group levels of presacral vertebral arches supernumerary lumbar ribs, supernumerary lumbar short ribs, caudal vertebrae number < 5). There were no signs of adverse effects on the postnatal pups (terminated at PND21). It is noted that there is currently no available data on the placental transfer of BNT162b2. This information is reflected in section 5.3 of the SmPC.”

The placenta is the interface between mother and fetus. Functions of the placenta include gas exchange, metabolic transfer, hormone secretion, and fetal protection. Nutrient and drug transfer across the placenta are by passive diffusion, facilitated diffusion, active transport, and pinocytosis. Placental drug transfer is dependent on the physical properties of the placental membrane and on the pharmacological properties of the drug.

A transplacental passage of drugs may have detrimental effects on the fetus, including teratogenicity (abnormalities of physiological development) or impairment of fetal growth and development

It is unknown whether BNT162b2 has an impact on fertility in human females. BNT162b2 is expected to induce the formation of humoral antibodies against spike proteins of SARS-CoV-2. Syncytin-1, which is derived from human endogenous retroviruses (HERV) and is responsible for the development of a placenta in mammals and humans, is therefore an essential prerequisite for a successful pregnancy. It is also found in homologous form in the spike proteins of SARS viruses. There is no indication whether antibodies against spike proteins of SARS viruses would also act like anti-Syncytin-1 antibodies. However, if this were to be the case this would then also prevent the formation of a placenta which would result in vaccinated women essentially becoming infertile. According to section 10.4.2 of trial protocol, a woman of childbearing potential (WOCBP) is eligible to participate if she is not pregnant or breastfeeding, and is using an acceptable contraceptive method as described in the trial protocol during the intervention period (for a minimum of 28 days after the last dose of study intervention). This means that it could take a relatively long time before a noticeable number of cases of postvaccination infertility could be observed.
Antibody Dependent Enhancement (ADE)
) For BNT162b2 to work, our immune system needs to be stimulated to produce a neutralizing antibody, as opposed to a non-neutralizing antibody. A neutralizing antibody is one that can recognize and bind to some region (epitope) of the virus, and that subsequently results in the virus either not entering or replicating in your cells. A non-neutralizing antibody is one that can bind to the virus, but for some reason, the antibody fails to neutralize the infectivity of the virus. In some viruses, if a person harbors a non-neutralizing antibody to the virus, a subsequent

infection by the virus can cause that person to elicit a more severe reaction to the virus due to the presence of the non-neutralizing antibody.

This is not true for all viruses, only particular ones. This is called Antibody Dependent Enhancement (ADE), and is a common problem with Dengue Virus, Ebola Virus, HIV, RSV, and the family of coronaviruses.

And in the same way that viral infections can involve ADE, so can the antibody responses raised by BNT162b2s. In fact, this problem of ADE is a major reason why previous vaccine trials for other coronaviruses failed. Major safety concerns were observed in animal models. If ADE occurs in an individual, their response to the virus can be worse than their response if they had never developed an antibody in the first place. Some of the earlier attempts at a SARS vaccine showed ADE effects in mouse and primate models.

ADE can cause a hyperinflammatory response, a cytokine storm, and a generally dysregulation of the immune system that allows the virus to cause more damage to our lungs, liver and other organs of our body. In addition, new cell types throughout our body are now susceptible to viral infection due to the additional viral entry pathway. There are many studies that demonstrate that ADE is a persistent problem with coronaviruses in general, and in particular, with SARS-related viruses. ADE has proven to be a serious challenge with, and this is the primary reason many of such vaccines have failed in early in-vitro or animal trials.
In the briefing document for the Vaccines and Related Biological Products Advisory Committee Meeting date December 10, 2020, the FDA noted on page 44: “Pfizer submitted a Pharmacovigilance Plan (PVP) to monitor safety concerns that could be associated with Pfizer-BioNTech COVID-19 Vaccine. The Sponsor identified vaccine-associated enhanced disease including vaccine-associated enhanced respiratory disease as an important potential risk.” [29]

EMA has also acknowledged that the risk of ADE needs to be investigated further: “Any important potential risks that may be specific to vaccination for COVID-19 (e.g. vaccine associated enhanced respiratory disease) should be taken into account. The Applicant has included VAED/VAERD as an important potential risk and will further investigate it in the ongoing pivotal study and a post-authorization safety study.”

The Vaccines and Related Biological Products Advisory Committee Briefing Document on the vaccine contains disturbing indications that might be a safety signal on pathogenic priming, especially in older adults. [29]

Before those are reviewed, there are fundamental issues with the classification of serious adverse events. The first issue is the categorization of “Serious vs. NonSerious” adverse events in the study and in the report. To a person experiencing neurologic adverse events including Bell’s Palsy, neuroinflammatory and thrombotic events, these events are not “non-serious” and can, over time, develop into life- threatening conditions that require continuous medical intervention and repeated billable office visits for care. The short-term study excludes any means of detecting whether the initial exposure may play a fundamental root cause role in setting up patients for life-long chronic illness. BNT162b2 adverse events themselves seen in the BioNTech clinical trial may be indicative of pathogenic priming, especially since more serious adverse events were seen with the second dose. The second issue is that the design and analysis set-up of the study are biased against finding adverse events. The report states:

“Among non-serious unsolicited adverse events, there was a numerical imbalance of four cases of Bell’s palsy in the vaccine group compared with no cases in the placebo
group, though the four cases in the vaccine group do not represent a frequency above that expected in the general population.”

The comparison to baseline rates is meaningless because other vaccines are in use in the population. Thus, any risk due to BNT162b2 adds to or multiplies existing risk present in the population from other vaccines.

Among the 18-55 year-old participants, there were 370 solicited serious adverse events (SSAEs) in the vaccinated group and 73 in the unvaccinated. Of the vaccinated, 18% experienced SSAEs; in the placebo group, only 3% did, implying that SSAEs can be expected at a rate five times greater in the vaccinated compared to the unvaccinated.

These included severe fatigue, headache, chills, vomiting, diarrhea, muscle and joint pain. Whether these conditions represent instances of pathogenic priming, identifying individuals who are now at higher risk of serious morbidity and mortality if they become infected with SARS-CoV-2 is unknown, but given past studies, seems likely.

In the over 55 group, which was a smaller group, there were 60 SSAEs in the vaccinated group and 24 in the unvaccinated. Of the vaccinated, 6.5% experienced SAEs, compared to 1.4% in the unvaccinated, implying a 4.46 times increased risk overall of SSAEs due to vaccination.

However, in the older group, the vaccinated group was 10 times more likely to have a SSAE upon receipt of the second BNT162b2 dose than the first dose compared to the 1:1 ratio in the unvaccinated. In the younger group, the vaccinated were only 3.61 times more likely to have second-dose SSAEs than the age-matched placebo group, which had about as many SSAEs in the first and second dose.

The patients in the study reviewed were healthy — and thus the spectrum of adverse events is not representative of those that might occur after BNT162b2 has come to market. In the previous studies in animals that are susceptible to SARS-CoV infection, the first dose was a vaccine, but the second was natural infection, leading to severe injury and often death. In the human trial for BNT162b2, both doses were from BNT162b2, so it is also not reassuring that these adverse events did not include the more serious and deadly conditions that afflicted animals. This human trial did not rule out pathogenic priming in any way.

The study should be extended to long-term follow up, including any further vaccination or exposure to SARS-CoV-2 viral proteins by infection.
Inadequate preclinical BNT162b2 testing in animals
The preclinical testing of BNT162b2 in animals was inadequate.
The EMA’S CPMP “Note for guidance on preclinical pharmacological and toxicological testing of vaccines” (CPMP/SWP/465) was withdrawn on July 21, 2016 because the EMA had decided to reference the “WHO guidelines on nonclinical evaluation of vaccines” (hereafter referred to as the “WHO guideline”).
BioNTech completed two BNT162b2-specific preclinical 17 day toxicology (repeat-dose toxicity and acute toxicity) studies (no. 38166 and no. 20GR142) in rats. Another toxicology (developmental and reproductive toxicity) study in rats (no. 20256434 DART) is ongoing (preliminary results were made available mid- December 2020). BioNTech also completed one BNT162b2-specific preclinical pharmacology (in vivo immunogenicity and SARS-CoV-2 challenge) study in rhesus macaques.

The last sentence in section 3.5 of the EMA BNT162b2-specific assessment report (“3.5. Uncertainties and limitations about unfavourable effects”) reads as follows:

“The scientific data available at this stage do not raise noticeable concerns regarding immunogenicity or immunotoxicity of the PEG, but current evidence is not definitive.” This lack of evidence alone should have made EMA mandate that BioNTech performs a full set of standard toxicity studies in animals. The standards for such studies are set out in ICH Topic S 8 (“Immunotoxicity Studies for Human Pharmaceuticals”):

“Data from STS should be evaluated for signs of immunotoxic potential. Signs that should be taken into consideration are the following:

) Hematological changes such as leukocytopenia/leukocytosis, granulocytopenia/

granulocytosis, or lymphopenia/ lymphocytosis;

) Alterations in immune system organ weights and/or histology (e.g. changes in

thymus, spleen, lymph nodes, and/or bone marrow);

) Changes in serum globulins that occur without a plausible explanation, such as

effects on the liver or kidney, can be an indication that there are changes in serum immunoglobulins;

) Increased incidence of infections;
) Increased occurrence of tumors can be viewed as a sign of immunosuppression

in the absence of other plausible causes such as genotoxicity, hormonal effects, or liver enzyme induction.

Changes in these parameters could reflect immunosuppression or enhanced activation of the immune system. Immunosuppression is usually reflected by reduced values of immune parameters, whereas immunoenhancement is usually reflected by increased values. However, these relationships are not absolute and can be inverted in some cases. Similar to the assessment of risk with toxicities in other organ systems, the assessment of immunotoxicity should include the following:

Statistical and biological significance of the changes,

Severity of the effects,

Dose/exposure relationship,Safety factor above the expected clinical dose,

Treatment duration,Number of species and endpoints affected,

Changes that may occur secondarily to other factors (e.g. stress, see the Appendix, section 1.4),Possible cellular targets and/or mechanism of action,

Doses which produce these changes in relation to doses which produce other toxicities and

Reversibility of effect(s).”

The animal studies in rats did not meet the standards set out in page 47 of the WHO guideline:

“A complete gross necropsy should be conducted and tissues collected and preserved, gross lesions should be examined and organ weights recorded […]. Histopathological examinations of tissues should be performed and special attention paid to the immune organs, i.e. lymph nodes (both local and distant from site of administration), thymus, spleen, bone marrow and Peyer’s patches or bronchus associated lymphoid tissue, as well as organs that may be expected to be affected as a result of the particular route of administration chosen. Histopathological examinations should always include pivotal organs (e.g. brain, kidneys, liver and reproductive organs) and the site of vaccine administration. The choice of tissues to be examined (ranging from a short list limited to immune and pivotal organs to a full list as provided in the Appendix) will depend on the vaccine in question, and the knowledge and experience obtained from previous nonclinical and clinical testing of the vaccine components. For example, full tissue examination will be required in the case of novel vaccines for which no prior nonclinical and clinical data are available.

Therefore, the list of tissues to be tested should be defined on a case-by-case basis, following consultation with the relevant regulatory authority.”

Surprisingly, the EMA assessment report (see pages 54 and 55) does not confirm that any histopathological examination of rat brains, kidneys and reproductive organs as well as a necessary full tissue examination required in case of novel BNT162b2s took place.

What is more, while the animal studies in rats apparently studied potential markers of pathogenic priming, it failed to measure one: interleukin-5 (IL-5), which had been found in prior coronavirus studies to be elevated in conjunction with pathogenic priming- induced disease enhancement.

Recalling that animal studies conducted on prior COVID vaccines found pathogenic priming leading to disease enhancement in older animals more than younger animals, older adults may be at highest risk of serious chronic illness due to autoimmunity resulting from BNT162b2-induced pathogenic priming.

Maternal or fetal toxicity in animals has not been properly assessed. Developmental toxicity tests assess the potential of a drug/vaccine to cause harm to the developing fetus. They are conducted in female animals, who are force-fed the substance during their pregnancy and then killed, along with their unborn babies.

For small molecules (most pharmaceutical drugs are small molecules, although some drugs can be proteins), the generally accepted standard for preclinical animal studies to assess developmental and reproductive toxicity (including but not limited t0 embryofetal development [EFD]) is perform the necessary tests in two species (one rodent and one non-rodent).

According to ICH S5 (R3) guideline on reproductive toxicology: Detection of Toxicity to Reproduction for Human Pharmaceuticals, it is usually sufficient to conduct developmental toxicity studies in a single animal species.

“The animal species selected for testing of vaccines (with or without adjuvants) should demonstrate an immune response to the vaccine. The type of developmental toxicity study conducted, and the choice of the animal model, should be justified based on the immune response observed and the ability to administer an appropriate dose. Typically, rabbits, rats, or mice are used in developmental toxicity studies for vaccines. Even though quantitative and qualitative differences can exist in the responses (e.g., in humoral and cellular endpoints) between species, it is usually sufficient to conduct developmental toxicity studies in a single species.”

The sometime practice of testing for developmental toxicity in two species arose in the 1960s in the wake of the Thalidomide tragedy. Toxicologists struggled to replicate the characteristic limb defects seen in human babies in several species – that in itself should have rung alarm bells about extrapolation from animal species to humans. They finally achieved replication in a single strain of rabbit (the New Zealand white). Regulatory toxicologists are well aware that animal models of developmental toxicity are poorly predictive of human effects.

Given that until now no mRNA vaccine has ever reached the same stage of development that BNT162b2 did, EMA should have required BioNTech to test for developmental toxicity in two species.

What is even more surprising is that the EMA did not deem genotoxicity nor carcinogenicity studies in animals to be necessary (see page 55 of the report):

“No genotoxicity nor carcinogenicity studies have been provided. The components of the vaccine formulation are lipids and RNA that are not expected to have genotoxic potential.”