Gabriella Gita Febriana, B.Sc., M.Res (i3L Supervisor)
Sultan Syarief Abdullah
19010216 / Biomedicine
PREFACE
This report is written to present the outcome of the internship program in Indonesia International Institute for Life Sciences organized at the campus. The objective of this internship is to familiarize the students with writing a literature review.
The increase in the rate of vaccinations due to the COVID-19 pandemic has proven to be a good way to combat the spread of COVID-19 as the vaccine yields many benefits such as immunity to SARS-CoV-2 virus, but this does not mean that the vaccine is without its side effects in small groups of individuals. This Internship literature review has the purpose of reviewing the available prior literature that studies the correlation between the vaccination against COVID-19, specifically the mRNA variant BNT162B2, with the autoimmune thyroid complication referring to Hypothyroidism, known as Hashimoto’s Thyroiditis.
First and foremost, I would like to thank Indonesia International Institute for Life Sciences I3L for providing an Internship project for me to work on, along with sincere gratitude, I would like to thank Miss Gabriella Gita Febriana for guiding me throughout this internship project. I would also like to thank Miss Elizabeth Sidharta as my Head of Department for giving me the opportunity to do a literature review Internship. Another mention is to thank the google search engine for helping me access the information that may be required during the internship and allowing me to advance with the literature review writing project.
I would like to also thank Allah SWT for giving me the blessings of a conducive environment with friends and families that gives me a supportive condition that helps me during the conducting of the internship literature review project along with the writing of this internship report.
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ACKNOWLEDGEMENT PAGE
The effects of SARS-CoV-2 mRNA vaccines towards the development of Hashimoto’s Thyroiditis disease.
Indonesia International Institute for Life Sciences I3L
AUTHOR:
Sultan Syarief Abdullah 19010216 BIOMEDICINE
ACKNOWLEDGED BY:
FIELD SUPERVISOR SUPERVISOR AT I3L
Dr.rer.medic.Gabriella Gita Febriana, S.Si.,M.Res. Dr.rer.medic. Gabriella Gita Febriana, S.Si., M.Res.
HEAD OF DEPARTMENT AT I3L
TABLE OF CONTENTS
PREFACE 2
ACKNOWLEDGEMENT PAGE 3
Indonesia International Institute for Life Sciences I3L 3
ACKNOWLEDGEMENT 3
LIST OF TABLES 5
LIST OF ABBREVIATIONS 6
CHAPTER 1: INTRODUCTION 8
1.1 Background 8
1.2 Introduction to Hypothyroidism 8
1.3 mRNA Vaccines 9
CHAPTER 2: PROJECT DESCRIPTION 10
2.1 Internship Project 10
2.2 Aim 10
CHAPTER 3: PROJECT OUTLINE 11
3.1 Activity outline 11
3.2 Research Methodology 11
CHAPTER 4: RESEARCH FINDINGS 13
4.1 Findings 13
4.2 Discussion 14
4.3 Previous Research Hypothesis 14
5.2 Possible Recommendations 15
CHAPTER 6: SELF-REFLECTION 16
APPENDIX 17
REFERENCES 21
4
LIST OF TABLES
AgeCategory Th1 levels post
vaccination Thyroid function levels post
vaccination Case source
25-30 Increased Increased (fast decline afterwards, shows HT).
Two cases of Graves’ Disease Following SARS-CoV-2 Vaccination: an
autoimmune/inflammatory syndrome induced by adjuvants
40-45 increased Increased (decline afterwards to
decreased from normal levels, a symptom of HT).
Thyroid Inconveniences With Vaccination Against SARS-CoV-2:
The Size of the Matter. A Systematic Review
25-30 increased Decreased (was diagnosed after the
symptoms manifested).
Silent thyroiditis following vaccination against COVID-19:
report of two cases
60-65 increased Decreased (was diagnosed after the
symptoms manifested).
Response to Letter to the Editor From Raven: Three Cases of Subacute Thyroiditis Following SARS-CoV-2 Vaccine
30-35 increased Decreased (was diagnosed after the
symptoms manifested).
Current Evidence in SARS-CoV-2 mRNA Vaccines and
Post-Vaccination Adverse Reports: Knowns and Unknowns
Figure 1refers to cases of Hashimoto’s Thyroiditis development in the variables of age categories. this table shows no bias towards a certain age category and they all have elevated Th1 levels
Article Title
Summary
Patients with autoimmune Thyroiditis present similar immunological responses to COVID-19 BNT162b2 mRNA Vaccine with healthy subjects, while vaccination may affect thyroid function: a clinical study.
Kinetics of Neutralizing antibodies (Nabs) after BNT162b2 (pPfizer) Vaccination is observed both in subjects with specific controls to match their age and gender, and with no history of thyroid dysfunction. And individuals who suffer from autoimmune thyroiditis.
Two substudies including the patients’ level of NABs are observed the day after the first dose is administered, and up to three months after the second dose has been received. The second field observes the level of thyroid hormones (T3, T4, TSH) and thyroid antibody levels (Anti-TG, anti-TPO).
- In patients with autoimmune thyroiditis, NABs level shows 62.5% before the second dose, but increases to 96.7% one month after, three months after shows a similar percentage of 94.5%
- In healthy patients, the NABs level shows 53.6%, after one month it has increased to 95.1% and after three months the levels show 89.2%.
- Levels of thyroid function do not show significant differences in T4 with a mean of 89.797 nmol/L before vaccination, 89.11 nmol/L after one month.
- T3 level mean was 2.064 mlU/ml before vaccination and 1.840 mlU/ml one month after the second dose.
From the highlighted data above, it can be seen that patients with autoimmune thyroiditis present a similar immunological response to the BNT162b2 mRNA vaccine for COVID-19 with healthy subjects without any history of thyroid diseases, it can also be seen that the vaccine does alter some levels of thyroid function in both parties.
Safety of Inactivated and mRNA COVID-19 Vaccination among patients treated for Hypothyroidis m: A population-Ba sed Cohort Study.
Patients that suffer from hypothyroidism are often treated with Levothyroxine (LT4), these are classified as unvaccinated individuals. They are then vaccinated with either inactivated (CoronaVac) and BNT162b2 (mRNA) vaccines for a comparative study.
Expected study outcomes were either dosage reduction or the escalation in the levels of LT4.
- Show 47.086 LT4 users (BNT162b2: n=12.310; CoronaVac: n=11.353; and unvaccinated: n=23.423).
- Both the vaccine does not show any levels of fluctuation in the levels of LT4 or the dosage reduction and some patients that are affected were considered coincidental with the current condition of the body (Coincidence Interval CI 0,892 - 1,058).
Both mRNA and Inactivated vaccines do not show any association of unstable thyroid status or create a higher risk of adverse outcomes that can occur in patients that are being treated for hypothyroidism in general.
SARS-CoV-2 vaccine may trigger thyroid autoimmunity:
real-life experience and review of the literature.
Susceptible individuals are suspected to develop destructive thyroiditis and trigger thyroid autoimmunity from the administration of mRNA-based vaccines.
Three patients that have developed / exacerbated autoimmune thyroid diseases shortly after receiving the mRNA-based vaccine were reported and relevant literature were summarized.
- Results show that the three patients who developed AITDs all have in common in which they have a family history of autoimmune disorders, but not limited to thyroid autoimmune illnesses.
- This risk is even larger and can be counted as recurrence if the patient has the specific autoimmune disease with their thyroid, up to 51 other cases have been reported in other literature.
- The case report of developing autoimmune thyroid illness occurs mainly in female patients without a personal history of AITDs.
The immune response against mRNA based SARS-CoV-2 vaccines can trigger an autoimmune reaction because of the elevated IL6 levels that can trigger changes in the thyroid hormone that causes the immune cells to attack thyroid, this causes the thyroid to inflame and prevents the thyroid to produce enough hormones.
In cases like this, monitoring of the thyroid function is recommended, especially in those who are subjects with a personal or family history of AITDs.
Thyroid as a target of adjuvant autoimmunity / inflammatory syndrome due to
mRNA-based SARS-CoV-2 vaccination:
from Graves’
disease to silent thyroiditis
The pandemic has forced the use of vaccines in order to combat the adverse effects of COVID-19, vaccines may cause adjuvants which are not exempt from adverse effects and may trigger an autoimmune / inflammatory syndrome.
Three cases have been reported and review of literature shows that the adjuvants induced inflammation upon the vaccination of mRNA based SARS-CoV-2 vaccines.
- The first case shows silent thyroiditis in the context of vaccination with Pfizer / BioNTech. ST is a part of Hashimoto’s Disease and shows that a significant percentage of patients with ST present elevated anti-TPO and antithyroglobulin antibodies.
- The second case shows De Quervain’s thyroiditis patient suffering from thyroid inflammation.
- The third case shows the reaction of the COVID vaccine to the patient with Graves’ Disease developing abnormal levels of thyroid profile upon receiving Moderna Vaccine.
Patients that are suffering from multiple types of thyroid diseases are shown to have different reactions when administered with mRNA vaccines, but the reason for adverse effects alone can just be coincidental to the individual as they can react to vaccines differently. To solidify the theory further studies must be needed to demonstrate the causal relationship between mRNA vaccines and how patients’ with thyroid illnesses react to them.
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LIST OF ABBREVIATIONS
GD Graves’ Disease
HT Hashimoto’s Thyroiditis
IL6 Interleukin-6
Th1 T helper cell 1
SAT Subacute Thyroiditis
TSH Thyroid Stimulating Hormone
ABSTRACT
The increase in the rate of vaccinations against SARS-CoV-2 has proven to be an excellent counter against the pandemic of COVID-19, but the increase of the rate in vaccinations have inevitably caused detrimental side effects to a small group of people who received the vaccination.
The focus of this literature review will be the autoimmune thyroid disorders which have affected a small number of people, primarily women after the vaccination of COVID-19, specifically the BNT162B2 mRNA variant.
Hashimoto’s thyroiditis refers to the autoimmune thyroid illness where the immune cells attack the thyroid cells, even without the administration of mRNA vaccines, the pathogenesis of Hashimoto’s Thyroiditis is yet to be known. Hashimoto’s Thyroiditis also belongs on one of the types of autoimmune thyroid complications, the other more common autoimmune thyroid complication refers to Graves’ Disease, Graves’ Disease is an autoimmune disorder that causes Hyperthyroidism which causes the thyroid to be hyperactive while Hashimoto’s Thyroiditis refers to hypothyroidism where the thyroid gland is underactive due to the inflammation caused by the attacking immune cells.
The definite cause of the development of Hashimoto’s Thyroiditis in patients who have received their vaccination is yet to be known, as there is also very little to no previous literature that supports this statement in the first place. Most autoimmune thyroid disorders developed from the administration of mRNA vaccines include Graves’ Disease, while some also develop Subacute thyroiditis counting non-autoimmune thyroid disorders. Because of the limited amount of literature available, most research papers have resorted to hypotheses that are based on the current understanding of the theory regarding the development of Hashimoto’s Thyroiditis, which may help future researchers in continuing the research and draw a more reliable conclusion.
Keyword: Hashimoto’s Thyroiditis, BNT162B2 vaccine, Dosage, IL6, Th1.
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CHAPTER 1: INTRODUCTION
1.1 Background
In the time where the world is currently facing a Pandemic against COVID-19, the use of vaccines has increased significantly. While it is true that the increased use of vaccines has helped most individuals in fighting against COVID-19, it is inevitable that there are some individuals that will experience adverse effects. There are many adverse effects upon vaccination, but the focus of this internship project is to review the available literature regarding the effects of mRNA vaccines such as Pfizer BioNtech & Moderna vaccines with the development of autoimmune thyroid complications.
The autoimmune thyroid complication within subject for this internship literature review project is Hashimoto’s Thyroiditis which is an autoimmune complication that causes the thyroid to be underactive (hypothyroidism).
1.2 Introduction to Hypothyroidism
Hypothyroidism is often used interchangeably with Hashimoto’s Thyroiditis, and is the least common thyroid complication reported in study cases before, with Graves’ Disease being the far more commonly reported cases of thyroid complications from vaccination from an autoimmune perspective, along with Subacute Thyroiditis which is often associated with the infection of the upper respiratory tract, and with COVID-19 known to cause a respiratory disorder. It is the reason why the occurrence of thyroiditis after the vaccination has Subacute Thyroiditis being the most common (Franquemont & Galvez, 2021). The primary cause of Hashimoto’s Thyroiditis is yet to be known, as most cases occur at random and show no bias between age categories for Hashimoto’s, but not Graves’ Disease.
Hypothyroidism can cause many complications such as difficulty in moving, unregulated body
temperature, and muscle cramps. The effects of hypothyroidism also goes to a psychological
standpoint where depression, mood changes, and an individual’s way of thinking may be altered. It is
also known to be primarily found in women compared to men, with a proportion of women having
Hashimoto’s Thyroiditis, may it be from the vaccination or as a hereditary condition, shows a
proportion of 1:10 (Ying Jie et al, 2022), this is due to their high Thyroid Stimulating Hormone levels
that may be altered after the vaccination of BNT162B2. With that being said, the solid relation
between the two is still not proven, and this study is a Literature review on which previous studies
are featured in order to see the correlation between the mRNA vaccine and how it causes and
manifests in Hashimoto’s Thyroiditis.
1.3 mRNA Vaccines
During the COVID-19 pandemic, many vaccines from different brands have been published and released to quickly counter SARS-CoV-2, these vaccines are often categorized into three types of vaccines. Sinovac is one of the most commonly used vaccines in the entire world during the delta wave of COVID-19, along with the most commonly used type of vaccine mRNA vaccines such as Pfizer-BioNtech and Moderna Vaccines (Alessio et al, 2022). Vaccines such as Sinovac belong to the category of virus-attenuated vaccines which refer to the type of vaccine that has the SARS-CoV-2 pathogen that is weakened and they cannot replicate or cause severe detrimental effects after the administration to the recipient (Yangzhuo et al, 2022). The other common type is the Adenovirus vector vaccine which is found in Astrazeneca vaccines, this vaccine works by using the harmless adenovirus to create spike proteins that is found in SARS-CoV-2 (Yangzhuo et al, 2022). The other type which is the focus of this research is the mRNA vaccine, mRNA vaccines as their name suggests does not use inactivated pathogens or a mediator virus like the previously mentioned types of vaccines. mRNA vaccines work by presenting the protein in question that triggers the immune response in the body, mRNA vaccines work like a blueprint or the instruction’s manual of the potentially infecting pathogen (Enyue et al, 2022).
In general, vaccines work with similar principles to each other, all of them present data of the pathogen so that the immune system can formulate a counter in a form of either phagocytic T cells or using antibodies created by B cells (Alessio et al, 2022). These vaccines just differ from each other on how they present the data to the immune system of the body. Because of how mRNA vaccines have much less ‘mass’ to work with (mRNA vaccines only contain the mRNA based blueprints to create the surface proteins found in SARS-CoV-2, previous studies have proven that the efficacy of mRNA vaccines are much higher compared to the previously mentioned types of vaccines (Yangzhuo et al, 2022).
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CHAPTER 2: PROJECT DESCRIPTION
2.1 Internship Project
This internship literature review project focuses on reviewing previous literature and case reports that have been written before, the gathered papers with the relevant literature are then compiled into one word document where it is summarized, and any relevant information are then written in bigger detail upon the writing of the literature review. The focus topic is that of how mRNA vaccines cause some reported cases of autoimmune thyroid complications such as Graves’ Disease or Hashimoto’s Thyroiditis, the focus of my internship project will be the Hashimoto’s Thyroiditis.
In this internship project, there were time allocations where the internee can work on the literature review and meet with the internship advisor once a week, work is done in an independent schedule where the internee works to find the relevant literature and writing, to meet the internship advisor by the end of the week via online meeting to discuss how to move on to the next step. The internship advisor overviews the gathered literature and drafts where they then give comments on how to improve or move on to the next step (what literature goes in, what theories are most relevant to the point of discussion, etc.) The final output of the internee should be a literature review paper that explains the findings of previous papers and case reports, the paper includes the supporting theories on why the hypothesis was true or false.
2.2 Aim
The aim of this internship literature review project is to go over and review the available
literature from previous studies and research. Hashimoto’s Thyroiditis is a disorder that is not
observable at a glance, and the symptoms does not present themselves easily, this internship
literature review has the aim to analyze the pathogenesis of HT development in patients with
another goal to gather enough information that may be helpful to those who needed the treatment
or prevent the formation of Hashimoto’s Thyroiditis.
CHAPTER 3: PROJECT OUTLINE
3.1 Activity outline
The internship project is done remotely by the internee, where they are allocated weeks in order to find and compile the literature in order for it to be reviewed by the supervisor. The internship is done under the wing of I3L, but it is not a wet laboratory project and the work done by the internee is done remotely.
The project is a literature review project where the internee works by spending most of the time on the internet looking for information that is related to the focus of the research project. The internship supervisor holds meetings with the internee / volunteers to monitor the progress and give feedback to the internee on how to step forward and improve the literature review, the meetings are usually held every week and two weeks at the most. The discovered information from the found literature are then selectively chosen or reviewed by the internship supervisor and they tell the internee on what to write next and how to move on forward with the literature review.
3.2 Research Methodology
To obtain the necessary and relevant information for the systematic literature review, the search engine Google is most often used as it provides a more reliable and concise information along with the link for the references as well, there are some articles from websites such as Nature.com that documented the cases of Hashimoto’s Thyroiditis occurrence following the vaccination against COVID-19 with the mRNA BNT162B2 variant, however, these articles are just case reports and does not elaborate on the theories of pathogenesis on why the disease can occur upon vaccination, nor does it explain the reason why the development of the disease shows no bias towards any age category as shown in Figure 1.
To obtain these theories, a scholarly article search engine is preferred due to the focus of the search engine in browsing and searching through the compilations of scholarly articles and data case reports that has been written before, not to mention Google Scholar’s ability to search by the year the article was published because due to the COVID-19 pandemic being a very recent event, the internship advisor advised to look for articles that are published in 2020 being the earliest year, this is so that the literature is still ‘relevant’ and allows for older references to be put on for supporting theories and the formulation of hypotheses.
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Most of the articles found for the literature review are from the Google Scholar search engine, as the scholarly articles and data case reports are most accessible from the Google Scholar search engine which allows access of the papers and articles in question through other websites and platforms such as Nature.com, Pubmed, Springer.com and others.
Upon finding the papers and articles that are suspected to have the relevant information for the
literature review, the papers are then summarized by reading the abstract along with the presented
data of cases, Figure 2 refers to the amount of papers found with the relevant literature that has
been summarized and can be used as a data reference and citation later on. With enough literature
that are considered relevant because they present the cases of the development of Hashimoto’s
Thyroiditis in patients who are administered with the mRNA BNT162B2 vaccine.
CHAPTER 4: RESEARCH FINDINGS
4.1 Findings
Cases of Hashimoto’s thyroiditis occurrence due to the BNT162B2 mRNA vaccine have not shown absolute correlation, some that developed the disease have previous comorbidities while some do not. Some cases of Hashimoto’s development post vaccination shows that the elevated levels of Th1 after the vaccination plays a role in the pathogenesis of HT (Qin et al, 2012). HT is caused by the immune cells attacking the thyroid, and some literature have described that the increase of Th1 levels has caused the increased production of Interleukin-6, which plays a role in creating antibodies that can attack the thyroid and cause the autoimmune thyroid complication (Qin et al, 2012).
There are multiple factors that contribute to the decline in thyroid function that leads to hypothyroidism disorders such as Hashimoto’s Thyroiditis. The one mentioned most commonly in previous research papers are through the elevation of IL6 levels, the receptacles of the thyroid cells can undergo molecular changes that makes its structure similar to those surface protein structure found in the BNT162B2 vaccine, causing the activated killer T cells from the overstimulation of Th1 to attack the thyroid cells and cause hypothyroidism as the thyroid gets swollen and lost its work efficiency (Lacey et al, 2022).
Administration of mRNA vaccine does not always cause elevations of Th1 levels, and some cases are more severe than others. The cause of this variability is not yet known, but some scientists have hypothesized that it is due to the fixed dosage of vaccines that are administered to many individuals (Xiong et al, 2022). Different individuals have been hypothesized to have different tolerances to the vaccine doses and some may overreact due to overstimulation (Park et al, 2021).
Age Category
Th1 levels post vaccination
Thyroid function levels post vaccination
Case source 25-30 Increased Increased (fast decline afterwards,
shows HT). Two cases of Graves’ Disease
Following SARS-CoV-2 Vaccination: an
autoimmune/inflammatory syndrome induced by adjuvants
40-45 increased Increased (decline afterwards to
decreased from normal levels, a symptom of HT).
Thyroid Inconveniences With Vaccination Against SARS-CoV-2:
The Size of the Matter. A Systematic Review
25-30 increased Decreased (was diagnosed after the
symptoms manifested). Silent thyroiditis following vaccination against COVID-19:
report of two cases
14
60-65 increased Decreased (was diagnosed after the symptoms manifested).
Response to Letter to the Editor From Raven: Three Cases of Subacute Thyroiditis Following SARS-CoV-2 Vaccine
30-35 increased Decreased (was diagnosed after the
symptoms manifested).
Current Evidence in SARS-CoV-2 mRNA Vaccines and
Post-Vaccination Adverse Reports: Knowns and Unknowns
Figure 1refers to cases of Hashimoto’s Thyroiditis development in the variables of age categories. this table shows no bias towards a certain age category and they all have elevated Th1 levels
4.2 Discussion
The reason why overstimulation is looked upon is because of the ‘randomness’ in occurrence of Hashimoto’s Thyroiditis in patients who were administered with mRNA vaccine BNT162B2 variant.
Previous research has tried to find a pattern in occurrence of the presented cases of patients developing Hashimoto’s Thyroiditis. There is no observable bias of the development of Hashimoto’s Thyroiditis. The bias should be observed between the observed patients’ age and body weight as a variable that is visible or easy to determine is preferred over variables that require further analysis such as overall health, thyroid function count, and other data that needs further laboratory testing just for an observational study. The study and data cases present no bias towards any of these categories and variables that can be observed hence the occurrence has been labeled as randomized, with the explanation of different tolerances in different individuals being a possible hypothesis, but not a solid connection between the two.
4.3 Previous Research Hypothesis
With that said, all of the research and case reports all have a disclaimer upon the conclusion,
with most of the papers said that the research is not yet complete and cannot be used as a solid
baseline in which it causes Hashimoto’s Thyroiditis, not to mention the random occurrence and how
it only affects certain individuals at random despite having the ‘criteria’ to develop Hashimoto’s
Thyroiditis. Due to the very limited amount of data and literature possible, scientists have
hypothesized that Hashimoto’s Thyroiditis development in patients who were administered with the
vaccine has a similar effect to an allergic reaction. Further research and investigation of the
development of Hashimoto’s Thyroiditis in mRNA recipients is needed with fewer variables and more
control towards the margin of errors and variables needs to be conducted in order to obtain a source
that is reliable enough to base other research on.
CHAPTER 5: CONCLUSIONS AND FUTURE RECOMMENDATIONS 5.1 Conclusive Summary
Using the available literature and data presented from the cases of Hashimoto’s Thyroiditis’
development in those who fulfill the ‘criteria’ or not, a reliable conclusion cannot be drawn from the available data and literature yet. Most research papers have hypothesized that the cause of this random occurrence is simply caused by the different tolerances of people to vaccines based on mRNA technology such as the BNT162B2 mRNA vaccine (Pfizer). The different tolerance levels explained the occurrence and development of Hashimoto’s Thyroiditis without looking at a specific age category, however, this is not a solid line of connection between the development of Hashimoto’s Thyroiditis and mRNA vaccines with the variant or type of BNT162B2.
5.2 Possible Recommendations
The way to counter this according to the supporting literature is to make vaccinations a more systematic approach where all the recipients of the vaccines take more time to be analyzed, seeing how they tolerate the vaccine and then tailor the dosage of the mRNA vaccine according to the individual. But while the idea seems easy to execute, the cost of effort is far too high to be executed in the near future, not to mention there are two other factors that hinder the development of this technique, the first is obviously the fact that most people have already gotten their vaccinations, the second being the occurrence of Hashimoto’s Thyroiditis or any other thyroid complications are quite small, in a business perspective it does not make sense to invest time and money in order to iron out a kink that only affects small groups that can be argued as negligible, especially compared to the numbers of people who did get the vaccination and most people enjoying the benefits of the vaccine. Because the effort and hurdle is high to develop a treatment that only affects a small group of people, not to mention that the theory of different vaccine tolerances is still just a hypothesis provided by previous scientists, the application of the selective tailored vaccination may not happen in the near future.
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CHAPTER 6: SELF-REFLECTION
Through this internship project, I have learned how to do a literature review of many previous research papers that may refer to and support the main topic of the literature review.
Through the guidance of the Internship Supervisor Miss Gabriella Gita Febriana I was able to select what gives the most relevant information which in turn can be put into the literature review. This internship project also taught me on how to formulate an effective discussion where all the variables and shortcomings are analyzed in which a hypothetical solution can be formulated. Through analyzing the variables and shortcomings of the data a hypothetical answer can also be formulated and create a basis of explanation for other researchers to either prove or disprove the hypothesis.
Seeing that this project focuses on a niche topic that affects very little to no groups of people, prior research and studies can be rather difficult to find. To remedy this the Internship advisor told me to analyze the papers and find any theories that may prove useful in writing the literature review.
Through this internship project I also learned on how a research with a very little to no background or prior research can prove a challenge to find, the lack of information has allowed me to be more
‘creative’ in formulating the discussion part of the reason there are little to no previous discussions
due to the research regarding this topic is not greenlit due to the very little number of people that
are actually affected by the mRNA vaccines and most cases only show the benefits of getting
vaccinated and the COVID-19 pandemic is slowly coming to an end. Hypotheses of previous research
have been formed on the amount of limited information that they have, forcing me to think more
logically on why it causes autoimmune thyroid disorders especially the hypothyroidism Hashimoto’s
Thyroiditis aspect. There are multiple hypotheses that explain the theories systematically and I now
know how to elaborate in detail whilst writing a discussion. In short, I have learned new skills in
elaboration and analysis whilst reading and writing a literature review.
APPENDIX
Article Title
Summary
Patients with autoimmune Thyroiditis present similar immunological responses to COVID-19 BNT162b2 mRNA Vaccine with healthy subjects, while vaccination may affect thyroid function: a clinical study.
Kinetics of Neutralizing antibodies (Nabs) after BNT162b2 (pPfizer) Vaccination is observed both in subjects with specific controls to match their age and gender, and with no history of thyroid dysfunction. And individuals who suffer from autoimmune thyroiditis.
Two substudies including the patients’ level of NABs are observed the day after the first dose is administered, and up to three months after the second dose has been received. The second field observes the level of thyroid hormones (T3, T4, TSH) and thyroid antibody levels (Anti-TG, anti-TPO).
- In patients with autoimmune thyroiditis, NABs level shows 62.5% before the second dose, but increases to 96.7% one month after, three months after shows a similar percentage of 94.5%
- In healthy patients, the NABs level shows 53.6%, after one month it has increased to 95.1% and after three months the levels show 89.2%.
- Levels of thyroid function do not show significant differences in T4 with a mean of 89.797 nmol/L before vaccination, 89.11 nmol/L after one month.
- T3 level mean was 2.064 mlU/ml before vaccination and 1.840 mlU/ml one month after the second dose.
From the highlighted data above, it can be seen that patients with autoimmune thyroiditis present a similar immunological response to the BNT162b2 mRNA vaccine for COVID-19 with healthy subjects without any history of thyroid diseases, it can also be seen that the vaccine does alter some levels of thyroid function in both parties.
Safety of Inactivated and mRNA COVID-19 Vaccination among patients treated for Hypothyroidis m: A population-Ba sed Cohort Study.
Patients that suffer from hypothyroidism are often treated with Levothyroxine (LT4), these are classified as unvaccinated individuals. They are then vaccinated with either inactivated (CoronaVac) and BNT162b2 (mRNA) vaccines for a comparative study.
Expected study outcomes were either dosage reduction or the escalation in the levels of LT4.
- Show 47.086 LT4 users (BNT162b2: n=12.310; CoronaVac: n=11.353; and unvaccinated: n=23.423).
- Both the vaccine does not show any levels of fluctuation in the levels of LT4 or the dosage reduction and some patients that are affected were considered coincidental with the current condition of the body (Coincidence Interval CI 0,892 - 1,058).
Both mRNA and Inactivated vaccines do not show any association of unstable thyroid status or create a higher risk of adverse outcomes that can occur in patients that are being treated for hypothyroidism in general.
SARS-CoV-2 vaccine may trigger thyroid autoimmunity:
real-life experience and review of the literature.
Susceptible individuals are suspected to develop destructive thyroiditis and trigger thyroid autoimmunity from the administration of mRNA-based vaccines.
Three patients that have developed / exacerbated autoimmune thyroid diseases shortly after receiving the mRNA-based vaccine were reported and relevant literature were summarized.
- Results show that the three patients who developed AITDs all have in common in which they have a family history of autoimmune disorders, but not limited to thyroid autoimmune illnesses.
- This risk is even larger and can be counted as recurrence if the patient has the specific autoimmune disease with their thyroid, up to 51 other cases have been reported in other literature.
- The case report of developing autoimmune thyroid illness occurs mainly in female patients without a personal history of AITDs.
The immune response against mRNA based SARS-CoV-2 vaccines can trigger an autoimmune reaction because of the elevated IL6 levels that can trigger changes in the thyroid hormone that causes the immune cells to attack thyroid, this causes the thyroid to inflame and prevents the thyroid to produce enough hormones.
In cases like this, monitoring of the thyroid function is recommended, especially in those who are subjects with a personal or family history of AITDs.
Thyroid as a target of adjuvant autoimmunity / inflammatory syndrome due to
mRNA-based SARS-CoV-2 vaccination:
from Graves’
disease to silent thyroiditis
The pandemic has forced the use of vaccines in order to combat the adverse effects of COVID-19, vaccines may cause adjuvants which are not exempt from adverse effects and may trigger an autoimmune / inflammatory syndrome.
Three cases have been reported and review of literature shows that the adjuvants induced inflammation upon the vaccination of mRNA based SARS-CoV-2 vaccines.
- The first case shows silent thyroiditis in the context of vaccination with Pfizer / BioNTech. ST is a part of Hashimoto’s Disease and shows that a significant percentage of patients with ST present elevated anti-TPO and antithyroglobulin antibodies.
- The second case shows De Quervain’s thyroiditis patient suffering from thyroid inflammation.
- The third case shows the reaction of the COVID vaccine to the patient with Graves’ Disease developing abnormal levels of thyroid profile upon receiving Moderna Vaccine.
Patients that are suffering from multiple types of thyroid diseases are shown to have different reactions when administered with mRNA vaccines, but the reason for adverse effects alone can just be coincidental to the individual as they can react to vaccines differently. To solidify the theory further studies must be needed to demonstrate the causal relationship between mRNA vaccines and how patients’ with thyroid illnesses react to them.
18
Impact of COVID-19 vaccines on Thyroid Function and Autoimmunity and effect of thyroid Autoimmunity on antibody response.
Effects of COVID-19 vaccination needs to be evaluated on the thyroid function and antibodies, in this study the influence of preexisting thyroid autoimmunity on neutralizing antibodies (NABs) responses are observed.
Adults without a history of both COVID-19 and thyroid disorders that received the vaccine are recruited, they are then observed for their levels of Thyrotropin (TSH), free thyroxine (fT4), free 3,5,3’ - triiodothyronine (fT3), antithyroid peroxidase (anti-TPO) and antithyroglobulin (anti-Tg). Antibodies were measured at baseline and 8 weeks post the second dose of vaccination, where the NAB against the SARS-CoV-2 receptor binding domain was measured.
- 215 individuals (60% of them received BNT162b2, 40% of them received CoronaVac).
- Mean age is 49.6, and 37.2% of participants are male.
- After the vaccination, the TSH levels did not change, but fT4 does slightly increase from 12.0 +- 1.1 to 12.2 +- 1.2 pmol/L.
- fT3levels have shown to slightly decrease to 4.1 +- 0.4 pmol / L.
- Only 3 participants show abnormal thyroid function post vaccination, and none are clinically averted.
- The evidence of the vaccine inducing the thyroid illness is not strong enough, it could be caused by allergies or history of prior thyroid illnesses.
COVID-19 vaccination was associated with a modest increase in antithyroid antibody titers, and the increase is shown to be greater in recipients that got the BNT162b2 vaccine. However, significant or life threatening thyroid illnesses are absent in all of the participants regardless of what vaccines they use.
Painless thyroiditis after mRNA vaccination for SARS-CoV-2
Thyroid dysfunction can be caused by either acute infection, or as an autoimmune response when certain circumstances have triggered it to occur, but there are some cases of thyroid illnesses following the vaccination against SARS-CoV-2.
There are three patients in total where they are reported, first is a 39-year old woman with Hashimoto’s Disease for 13 years, she presents palpitations and anxiety about 10 days after receiving the vaccination. All of the cases present similar results that is:
- The thyroid function test presented elevated fT4 of 4.08 ng/dL(normal range is 0.9-1.7).
- fT3 levels also increased to 7.30 pg/mL (normal range is 2.3-4.0).
- TSH levels severely dropped to 0.005 uIU/mL (normal is 0.61-4.23).
In some individuals, the similarities between their TPO and the SARS-CoV-2 spike proteins are structurally similar; the antibodies that were developed against SARS-CoV-2 cause this autoimmune response against the thyroid. Although evidence of vaccination causing thyroid illnesses was not strong enough, there are enough reported cases which in turn can trigger autoimmune thyroiditis.
Thyroiditis following vaccination against COVID-19, a report of two cases and review of the literature
The immune response following a viral infection has been considered probable to cause complications such as subacute thyroiditis or even autoimmune responses against the thyroid. Two cases of patients have shown that the vaccination does have an effect on their health, patient 1 has no history of thyroid illnesses, while patient 2 is known to have a history of thyroid autoimmune disease (her mother had Hashimoto’s Thyroiditis).
- Patient 1 was a 51 year old female that presented symptoms such as nausea, anterior neck pain and a fever up to 38,2 ‘C.
- The symptoms started 11 days prior to the checkup, and 4 days after receiving the first dose of BNT162B2 mRNA vaccine (Pfizer-BioNTech).
- Patient 2 was a 39 year old female without a personal history of thyroid illnesses, but her mother had hypothyroidism due to Hashimoto’s Thyroiditis.
- Patient 2 was administered with AstraZeneca ChAdOx1-S recombinant vaccine, and in the following weeks she does not exhibit any physical abnormalities.
As can be seen on the results, patient 1 with no9 history of thyroid illnesses has shown to develop subacute thyroiditis upon the vaccination of BNT162B2 mRNA vaccine, while patient 2 developed no visible abnormalities (although her thyroid function levels does still fluctuate like patient 1s) upon the administration of AstraZeneca vaccine. This proves that mRNA vaccines can alter the thyroid hormones at a more severe rate compared to recombinant vaccines, but the correlation between the two and thyroid illnesses are not yet solid and further studies must be done to investigate the pathogenesis of thyroid dysfunction following the vaccination against COVID-19.
Autoimmune and inflammatory thyroid diseases following vaccination with SARS-CoV-2 vaccines: from etiopathogene sis to clinical management.
The start of a pandemic has forced all individuals to be vaccinated, and cases of vaccine-induced thyroid illnesses have been reported and described in the literature.
Mainly in women, most cases are reported to be subacute thyroiditis, the count is then followed by autoimmune thyroiditis patients suffering from Graves’ disease and silent thyroiditis.
- Thyroid function tests were done, these tests include inflammatory markers, thyroid echography with color flow doppler, radio-activity uptake on thyroid scan, medical treatments and follow ups.
- The results from the previous tests are then compared to those who were suffering from SARS-CoV-2 vaccine induced thyroid diseases.
- Factors such as molecular mimicry (SARS-CoV-2 surface proteins may mimic thyroid cells), and autoimmune / inflammatory syndrome induced by adjuvants are also observed.
It is uncommon to develop adverse effects upon the vaccination against COVID-19, and the benefits greatly outweigh the demerits, but clinics should have awareness against the thyroid illnesses that may develop after the administration of the vaccine and offer medical help / assistance to those who are affected.
Part II
Response to Letter to the Editor From Raven: Three Cases of Subacute Thyroiditis Following SARS-CoV-2 Vaccine
Some cases of subacute thyroiditis and recurrence of Graves’ disease has been reported associated with vaccines against SARS-CoV-2, activation of Subacute Thyroiditis was associated with inactivated viral vaccines such as CoronaVac and cases of the formation of Graves’ Disease are often associated with the nature of the Pfizer-BioNtech vaccine (BNT162B2) to alter the levels of thyroid functions through their hormones.
- Occurrence of Subacute Thyroiditis is NOT limited to inactivated vaccines, case 3 presents some occurrences of mRNA based vaccines to cause Subacute Thyroiditis.
- One case presents the formation of Hashimoto’s thyroiditis, in cases of autoimmune thyroiditis hypothyroidism can also occur, not just Graves’ disease.
- All formations (SAT, HT, GD) have their occurrence in common as the clinical manifestation always appears around a few days after the vaccination, despite the usage of different types of vaccines.
Silent thyroiditis following vaccination against COVID-19:
report of two cases
Prior research in the past year has proven that occurrences of thyroid illnesses can occur upon administering the vaccination against COVID-19, but concrete evidence of Autoimmune / Inflammatory thyroid syndromes that are caused by vaccine Adjuvants is not available or determined yet.
Following vaccination against SARS-CoV-2, cases of Thyrotoxicosis have been reported.
- A pair of husband and wife received their first dose of SARS-CoV-2, a few weeks later both developed clinical manifestations of thyroid hyperactivity.
- Both husband and wife are tested for their thyroid function, and the results show abnormal (elevated) levels of hormones.
- Diagnosis resulted in silent thyroiditis (Graves’ Disease, Hashimoto’s Disease) after the 4th week after the first dose despite being healthy before.
- The symptoms were not severe and continued to not take any form of treatment.
- The 6th week after the first dose, the husband and wife become wholly asymptomatic and their levels of thyroid function return to normal levels.
It can be seen that the induction of thyrotoxicosis may occur, but not always, upon the vaccination of SARS-CoV-2, the variable is usually the Adjuvant used and ho the host reacts to the Adjuvants, but further research is needed to confirm and verify the theory.
Two cases of Graves’
Disease Following SARS-CoV-2 Vaccination:
an
autoimmune/in flammatory syndrome induced by adjuvants
The autoimmune/inflammatory syndrome induced by adjuvants (ASIA) comprises four entities, including the post vaccination phenomenon, which appears after being exposed to adjuvants in vaccines that increase the immune response.
There is limited information about autoimmune endocrine diseases and ASIA after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination.
Depending on the individual, some that develop the autoimmune thyroid illness may either develop hyperthyroidism (Graves’ disease) or Hypothyroidism (Hashimoto’s Disease).
- Two female healthcare workers received SARS-CoV-2 Vaccine, both developing clinical manifestations of hyperthyroidism three days after the vaccination.
- In thyroid function tests, thyroid hormone levels and antithyroid antibodies are increased.
- The exposure to an adjuvant from the vaccine may cause the alteration in thyroid functions.
The way both female health workers get the same autoimmune disease three days after receiving the supposedly same vaccine, indicates the variable is in the Adjuvant reacting to certain individuals, but further research needs to be done in order to confirm and verify the theory.
SARS-CoV-2 Vaccine–induc ed Thyroiditis:
Safety of Revaccination s and Clinical Follow-up
The increased number of vaccinations has shown some individuals developing adverse side effects, specifically on their thyroid.
Vaccine induced Subacute Thyroiditis, and Graves’ Disease reports are growing, but in some cases, Hashimoto’s Thyroiditis may also develop.
- SAT and GD patients induced from vaccines are diagnosed, where the data of their thyroid function levels are directly compared with each other.
- Hashimoto’s patients were not found, further literature review is needed to correlate the development of Hashimoto’s Disease and vaccination.
- A total of 19 patients (15 SAT, 4 GD) that are administered with BNT162B2 shows a median time of clinical manifestation development of 7 days for SAT, and 11.5 days for GD.
Revaccinations appear to be safe in patients with SARS-CoV-2 vaccine–induced SAT cases, while more evidence is needed regarding SARS-CoV-2 vaccine–induced GD.
Study of Thyroid function among COVID-19 affected and non-affected people during pre and post vaccination
The global pandemic has led to the massive use of vaccines throughout many individuals, and there are some cases of the vaccine altering the hosts’ thyroid function post vaccination.
30 COVID-19 positive patients with no vaccination records and 30 COVID-19 negative patients with vaccination records are diagnosed so that their thyroid function levels are compared with each other.
- An ELISA assay was used to evaluate the function tests, results show levels of TT3, TT4, and TSH.
- In unvaccinated patients, TT3 levels show normal, lower than average TT4, and decreased TSH levels compared to the healthy group.
- In vaccinated patients, the thyroid functions all show normal readings.
As we can see, in unvaccinated individuals that are ill, the thyroid function is altered while in healthy vaccinated individuals, the readings show normal values. This presents the individuals that are NOT affected by thyroid illnesses post vaccination that is presented in previous cases.
The presented cases only show very little alteration in thyroid level functions, not enough to cause illnesses such as Graves’ or Hashimoto’s thyroiditis, further research is needed to confirm the correlation between the vaccine and alterations in thyroid function.
20
Current Evidence in SARS-CoV-2 mRNA Vaccines and Post-Vaccinati on Adverse Reports:
Knowns and Unknowns
The increase of usage for vaccines against the Coronavirus has presented some cases of adverse effects, primarily allergic reactions.
Skin occurrences, hepatic and kidney events, and endocrine functions are the primary ones to take note of.
Most of these cases are presented after the patient has received a dose of mRNA vaccine BNT162B2.
- A group of individuals show signs of Graves’ disease post mRNA vaccination.
- The BMT162B2 vaccine is known to have Th1 increasing properties, which is the precursor to Graves’ Disease.
- The increase in Th1 may also cause thyrotoxicosis which induces long term autoimmune hypothyroidism in the long run (Hashimoto’s Thyroiditis).
- The occurrence of Hypothyroidism is significantly less common than Hyperthyroidism, with most studies showing that occurrences of hypothyroidism is just an allergic reaction or a hereditary illness.
BNT162B2 vaccine has been shown to cause some thyroiditis cases, but the majority of the recipients are unaffected, the margin could be from the reaction of the host to the Adjuvants contained within the vaccine, but the correlation could be just another margin of error and further research is needed to be done to confirm the correlation.
Thyroid Inconvenience s With Vaccination Against SARS-CoV-2:
The Size of the Matter. A Systematic Review
After the beginning of COVID-19 vaccination campaigns, several reports of thyroid disease possibly related to the COVID-19 vaccination progressively appeared in the literature, raising the question of whether the thyroid disorder might be a SARS-CoV-2 vaccine complication.
Forty six articles with a total of 99 patients with the age margin of around 26 - 73 years were described, reporting the cases of thyroid illnesses following the vaccination of COVID-19.
50% of patients received the BNT162B2 vaccine from Pfizer-BioNtech, 14% from CoronaVc, 12% from Astrazeneca, and 11% moderna.
- 59 cases were diagnosed with subacute thyroiditis, 29 graves disease, 2 recurrence of Subacute thyroiditis and Graves’ disease, and 6 Painless thyroiditis (background of Hashimoto’s Thyroiditis).
- The timeline between the vaccination and occurence of thyroid complications has an average of 10 days, with the actual result being the range of 0.5 - 60 days.
Considering the limited follow-up time, a complete remission was reported in most of SAT and PT cases while a persistence was observed in GD. In conclusion, both size and quality of published data about thyroid inconveniences after COVID-19 vaccination are limited; thyroid disorders may occur within 2 months after COVID-19 vaccination; among all thyroid diseases after COVID-19 vaccination, GD and SAT seem to be more frequent.
list of summarized research papers and literatures for the Literature Review
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