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SARS-CoV-2 mass vaccination: Urgent questions on vaccine safety that 1
demand answers from international health agencies, regulatory 2
authorities, governments and vaccine developers 3
4
Roxana Bruno1, Peter A. McCullough2, Teresa Forcades i Vila3, Alexandra Henrion-Caude4, 5
Teresa García-Gasca5, Galina P. Zaitzeva6, Sally Priester7, María J. Martínez Albarracín8, 6
Alejandro Sousa-Escandon9, Fernando López Mirones10, Bartomeu Payeras Cifre11, Almudena 7
Zaragoza Velilla10, Leopoldo M. Borini1, Mario Mas1, Ramiro Salazar1, Edgardo Schinder1, 8
Eduardo A. Yahbes1, Marcela Witt1, Mariana Salmeron1, Patricia Fernández1, Miriam M. 9
Marchesini1, Alberto J. Kajihara1, Marisol V. de la Riva1, Patricia J. Chimeno1, Paola A. 10
Grellet1, Matelda Lisdero1, Pamela Mas1, Abelardo J. Gatica Baudo12, Elisabeth Retamoza12, 11
Oscar Botta13, Chinda C. Brandolino13, Javier Sciuto14, Mario Cabrera Avivar14, Mauricio 12
Castillo15, Patricio Villarroel15, Emilia P. Poblete Rojas15, Bárbara Aguayo15, Dan I. Macías 13
Flores15, Jose V. Rossell16, Julio C. Sarmiento17, Victor Andrade-Sotomayor17, Wilfredo R. 14
Stokes Baltazar18, Virna Cedeño Escobar19, Ulises Arrúa20, Atilio Farina del Río21, Tatiana 15
Campos Esquivel22, Patricia Callisperis23, María Eugenia Barrientos24, Christian Fiala25 , Karina 16
Acevedo-Whitehouse5,*. 17
18 1 Epidemiólogos Argentinos Metadisciplinarios. Argentina. 19 2 Baylor University Medical Center. Dallas, Texas. USA. 20 3 Monestir de Sant Benet de Montserrat, Montserrat. Spain 21 4 INSERM U781 Hôpital Necker-Enfants Malades, Université Paris Descartes-Sorbonne Cité, 22
Institut Imagine. France. 23 5 School of Natural Sciences. Autonomous University of Querétaro. Mexico. 24 6 Retired Professor of Medical Immunology. Universidad de Guadalajara. Mexico. 25 7 Médicos por la Verdad Puerto Rico. Ashford Medical Center, San Juan. Puerto Rico. 26 8 Retired Professor of Clinical Diagnostic Processes. University of Murcia. Spain. 27 9 Hospital Comarcal de Monforte, University of Santiago de Compostela, Spain. 28 10 Biólogos por la Verdad. Spain. 29 11 Retired Biologist. University of Barcelona. Specialized in Microbiology. Spain. 30 12 Center for Integrative Medicine MICAEL (Medicina Integrativa Centro Antroposófico 31
Educando en Libertad). Argentina. 32 13 Médicos por la Verdad. Argentina. ´ 33 14 Médicos por la Verdad. Uruguay. 34 15 Médicos por la Libertad. Chile. 35 16 Physician, orthopedic specialist. Chile. 36 17 Médicos por la Verdad. Perú. 37 18 Médicos por la Verdad. Guatemala. 38 19 Centro de Biotecnologías Ómicas (CEBIOMICS) - Concepto Azul, Ecuador.
39 20 Médicos por la Verdad. Brasil. 40 21 Médicos por la Verdad. Paraguay. 41 22 Médicos por la Verdad. Costa Rica. 42 23 Médicos por la Verdad. Bolivia. 43 24 Médicos por la Verdad. El Salvador. 44 25 Gynmed Ambulatorium, Vienna. Austria. 45 *Correspondence: Karina Acevedo-Whitehouse, karina.acevedo.whitehouse@uaq.mx 46
Abstract 47
Since the start of the COVID-19 outbreak, the race for testing new platforms designed to confer 48
immunity against SARS-CoV-2, has been rampant and unprecedented, leading to conditional 49
emergency authorization of various vaccines. Despite progress on early multidrug therapy for 50
COVID-19 patients, the current mandate is to immunize the world population as quickly as 51
possible. The lack of thorough testing in animals prior to clinical trials, and authorization based 52
on safety data generated during trials that lasted less than 3.5 months, raise questions regarding 53
vaccine safety. The recently identified role of SARS-CoV-2 Spike glycoprotein for inducing 54
endothelial damage characteristic of COVID-19, even in absence of infection, is extremely 55
relevant given that most of the authorized vaccines induce endogenous production of Spike. 56
Given the high rate of occurrence of adverse effects that have been reported to date, as well as 57
the potential for vaccine-driven disease enhancement, Th2-immunopathology, autoimmunity, 58
and immune evasion, there is a need for a better understanding of the benefits and risks of mass 59
vaccination, particularly in groups excluded from clinical trials. Despite calls for caution, the 60
risks of SARS-CoV-2 vaccination have been minimized or ignored by health organizations and 61
government authorities. As for any investigational biomedical program, data safety monitoring 62
boards (DSMB) and event adjudication committees (EAC), should be enacting risk mitigation. If 63
DSMBs and EACs do not do so, we will call for a pause in mass vaccination. If DSMBs and 64
EACs do not exist, then vaccination should be halted immediately, in particular for demographic 65
groups at highest risk of vaccine-associated death or serious adverse effects, during such time as 66
it takes to assemble these boards and commence critical and independent assessments. We urge 67
for pluralistic dialogue in the context of health policies, emphasizing critical questions that 68
require urgent answers, particularly if we wish to avoid a global erosion of public confidence in 69
science and public health. 70
71
Introduction 72
73
Since COVID-19 was declared a pandemic in March 2020, over 150 million cases and 3 million 74
cases of deaths from or with SARS-CoV-2 have been reported worldwide. Despite progress on 75
early ambulatory, multidrug-therapy for high-risk patients, resulting in 85% reductions in 76
COVID-19 hospitalization and death [1], the current paradigm for control is mass-vaccination. 77
While we recognize the effort involved in development, production and emergency authorization 78
of SARS-CoV-2 vaccines, we are concerned that risks have been minimized or ignored by health 79
organizations and government authorities, despite calls for caution [2-8]. 80
81
Vaccines for other coronaviruses have never been approved for humans, and data generated in 82
the development of coronavirus vaccines designed to elicit neutralizing antibodies show that they 83
may worsen COVID-19 disease via antibody-dependent enhancement (ADE) and Th2 84
immunopathology, regardless of the vaccine platform and delivery method [9-11]. Vaccine-85
driven disease enhancement in animals vaccinated against SARS-CoV and MERS-CoV is known 86
to occur following viral challenge, and has been attributed to immune complexes and Fc-87
mediated viral capture by macrophages, which augment T-cell activation and inflammation [11-88
13]. 89
90
In March 2020, vaccine immunologists and coronavirus experts assessed SARS-CoV-2 vaccine 91
risks based on SARS-CoV-vaccine trials in animal models. The expert group concluded that 92
ADE and immunopathology were a real concern, but stated that their risk was insufficient to 93
delay clinical trials, although continued monitoring would be necessary [14]. While there is no 94
clear evidence of the occurrence of ADE and vaccine-related immunopathology in volunteers 95
immunized with SARS-CoV-2 vaccines [15], safety trials to date have not specifically addressed 96
these serious adverse effects (SAE). Given that the follow-up of volunteers did not exceed 2-3.5 97
months after the second dose [16-19], it is unlikely such SAE would have been observed. 98
Despite errors in reporting, it cannot be ignored that even accounting for the number of vaccines 99
administered, according to the US Vaccine Adverse Effect Reporting System (VAERS), the 100
number of deaths per million vaccine doses administered has increased more than 10-fold. We 101
believe there is an urgent need for open scientific dialogue on vaccine safety in the context of 102
large-scale immunization. In this paper, we describe some of the risks of mass vaccination in the 103
context of phase 3 trial exclusion criteria and discuss the SAE reported in national and regional 104
adverse effect registration systems. We highlight unanswered questions and draw attention to the 105
need for a more cautious approach to mass vaccination. 106
107
SARS-CoV-2 phase 3 trial exclusion criteria 108
109
With few exceptions, SARS-CoV-2 vaccine trials excluded the elderly [16-19], making it 110
impossible to identify the occurrence of post-vaccination eosinophilia and enhanced 111
inflammation in elderly people. Studies of SARS-CoV vaccines showed that immunized elderly 112
mice were at particularly high risk of life-threatening Th2 immunopathology [9,20]. Despite this 113
evidence and the extremely limited data on safety and efficacy of SARS-CoV-2 vaccines in the 114
elderly, mass-vaccination campaigns have focused on this age group from the start. Most trials 115
also excluded pregnant and lactating volunteers, as well as those with chronic and serious 116
conditions such as tuberculosis, hepatitis C, autoimmunity, coagulopathies, cancer, and immune 117
suppression [16-29], although these recipients are now being offered the vaccine under the 118
premise of safety. 119
120
Another criterion for exclusion from nearly all trials was prior exposure to SARS-CoV-2. This is 121
unfortunate as it denied the opportunity of obtaining extremely relevant information concerning 122
post-vaccination ADE in people that already have anti-SARS-Cov-2 antibodies. To the best of 123
our knowledge, ADE is not being monitored systematically for any age or medical condition 124
group currently being administered the vaccine. Moreover, despite a substantial proportion of the 125
population already having antibodies [21], tests to determine SARS-CoV-2-antibody status prior 126
to administration of the vaccine are not conducted routinely. 127
128
Will serious adverse effects from the SARS-CoV-2 vaccines go unnoticed? 129
130
COVID-19 encompasses a wide clinical spectrum, ranging from very mild to severe pulmonary 131
pathology and fatal multi-organ disease with inflammatory, cardiovascular, and blood 132
coagulation dysregulation [22-24]. In this sense, cases of vaccine-related ADE or 133
immunopathology would be clinically-indistinguishable from severe COVID-19 [25]. 134
Furthermore, even in the absence of SARS-CoV-2 virus, Spike glycoprotein alone causes 135
endothelial damage and hypertension in vitro and in vivo in Syrian hamsters by down-regulating 136
angiotensin-converting enzyme 2 (ACE2) and impairing mitochondrial function [26]. Although 137
these findings need to be confirmed in humans, the implications of this finding are staggering, as 138
all vaccines authorized for emergency use are based on the delivery or induction of Spike 139
glycoprotein synthesis. In the case of mRNA vaccines and adenovirus-vectorized vaccines, not a 140
single study has examined the duration of Spike production in humans following vaccination. 141
Under the cautionary principle, it is parsimonious to consider vaccine-induced Spike synthesis 142
could cause clinical signs of severe COVID-19, and erroneously be counted as new cases of 143
SARS-CoV-2 infections. If so, the true adverse effects of the current global vaccination strategy 144
may never be recognized unless studies specifically examine this question. There is already non-145
causal evidence of temporary or sustained increases in COVID-19 deaths following vaccination 146
in some countries (Fig. 1) and in light of Spike’s pathogenicity, these deaths must be studied in 147
depth to determine whether they are related to vaccination. 148
149
Unanticipated adverse reactions to SARS-CoV-2 vaccines 150
151
Another critical issue to consider given the global scale of SARS-CoV-2 vaccination is 152
autoimmunity. SARS-CoV-2 has numerous immunogenic proteins, and all but one of its 153
immunogenic epitopes have similarities to human proteins [27]. These may act as a source of 154
antigens, leading to autoimmunity [28]. While it is true that the same effects could be observed 155
during natural infection with SARS-CoV-2, vaccination is intended for most of the world 156
population, while it is estimated that only 10% of the world population has been infected by 157
SARS-CoV-2, according to Dr. Michael Ryan, head of emergencies at the World Health 158
Organization. We have been unable to find evidence that any of the currently authorized 159
vaccines screened and excluded homologous immunogenic epitopes to avoid potential 160
autoimmunity due to pathogenic priming. 161
162
Some adverse reactions, including blood-clotting disorders, have already been reported in 163
healthy and young vaccinated people. These cases led to the suspension or cancellation of the use 164
of adenoviral vectorized ChAdOx1-nCov-19 and Janssen vaccines in some countries. It has now 165
been proposed that vaccination with ChAdOx1-nCov-19 can result in immune thrombotic 166
thrombocytopenia (VITT) mediated by platelet-activating antibodies against Platelet factor-4, 167
which clinically mimics autoimmune heparin-induced thrombocytopenia [29]. Unfortunately, the 168
risk was overlooked when authorizing these vaccines, although adenovirus-induced 169
thrombocytopenia has been known for more than a decade, and has been a consistent event with 170
adenoviral vectors [30]. The risk of VITT would presumably be higher in those already at risk of 171
blood clots, including women who use oral contraceptives [31], making it imperative for 172
clinicians to advise their patients accordingly. 173
174
At the population level, there could also be vaccine-related impacts. SARS-CoV-2 is a fast-175
evolving RNA virus that has so far produced more than 40,000 variants [32,33] some of which 176
affect the antigenic domain of Spike glycoprotein [34,35]. Given the high mutation rates, 177
vaccine-induced synthesis of high levels of anti-SARS-CoV-2-Spike antibodies could 178
theoretically lead to suboptimal responses against subsequent infections by other variants in 179
vaccinated individuals [36], a phenomenon known as "original antigenic sin" [37] or antigenic 180
priming [38]. It is unknown to what extent mutations that affect SARS-CoV-2 antigenicity will 181
become fixed during viral evolution [39], but vaccines could plausibly act as selective forces 182
driving variants with higher infectivity or transmissibility. Considering the high similarity 183
between known SARS-CoV-2 variants, this scenario is unlikely [32,34] but if future variants 184
were to differ more in key epitopes, the global vaccination strategy might have helped shape an 185
even more dangerous virus. This risk has recently been brought to the attention of the WHO as 186
an open letter [40]. 187
188
Discussion 189
190
The risks outlined here are a major obstacle to continuing global SARS-CoV-2 vaccination. 191
Evidence on the safety of all SARS-CoV-2 vaccines is needed before exposing more people to 192
the risk of these experiments, since releasing a candidate vaccine without time to fully 193
understand the resulting impact on health could lead to an exacerbation of the current global 194
crisis [41]. Risk-stratification of vaccine recipients is essential. According to the UK 195
government, people below 60 years of age have an extremely low risk of dying from COVID-196
191. However, according to Eudravigillance, most of the serious adverse effects following 197
SARS-CoV-2 vaccination occur in people aged 18-64. Of particular concern is the planned 198
vaccination schedule for children aged 6 years and older in the United States and the UK. Dr. 199
Anthony Fauci recently anticipated that teenagers across the country will be vaccinated in the 200
autumn and younger children in early 2022, and the UK is awaiting trial results to commence 201
vaccination of 11 million children under 18. There is a lack of scientific justification for 202
subjecting healthy children to experimental vaccines, given that the Centers for Disease Control 203
and Prevention estimates that they have a 99.997% survival rate if infected with SARS-CoV-2. 204
Not only is COVID-19 irrelevant as a threat to this age group, but there is no reliable evidence to 205
support vaccine efficacy or effectiveness in this population or to rule out harmful side effects of 206
these experimental vaccines. In this sense, when physicians advise patients on the elective 207
administration of COVID-19 vaccination, there is a great need to better understand the benefits 208
and risk of administration, particularly in understudied groups. 209
210
In conclusion, in the context of the rushed emergency-use-authorization of SARS-CoV-2 211
vaccines, and the current gaps in our understanding of their safety, the following questions must 212
be raised: 213
214
• Is it known whether cross-reactive antibodies from previous coronavirus infections or 215
vaccine-induced antibodies may influence the risk of unintended pathogenesis following 216
vaccination with COVID-19? 217
218
• Has the specific risk of ADE, immunopathology, autoimmunity, and serious adverse 219
reactions been clearly disclosed to vaccine recipients to meet the medical ethics standard of 220
patient understanding for informed consent? If not, what are the reasons, and how could it be 221
implemented? 222
223
• What is the rationale for administering the vaccine to every individual when the risk of dying 224
from COVID-19 is not equal across age groups and clinical conditions and when the phase 3 225
trials excluded the elderly, children and frequent specific conditions? 226
1 (https://www.gov.uk/government/publications/covid-19-reported-sars-cov-2-deaths-in-england/covid-19-
confirmed-deaths-in-england-report
227
• What are the legal rights of patients if they are harmed by a SARS-CoV-2 vaccine? Who will 228
cover the costs of medical treatment? If claims were to be settled with public money, has the 229
public been made aware that the vaccine manufacturers have been granted immunity, and 230
their responsibility to compensate those harmed by the vaccine has been transferred to the 231
tax-payers? 232
233
If vaccination programs worldwide do not institute independent data safety monitoring boards 234
(DSMB), event adjudication committees (EAC), and enact risk mitigation, we will call for a 235
pause in the mass vaccination program. If DSMBs and EACs do not exist currently, as would be 236
imperative for any investigational biomedical program, then vaccination should be immediately 237
halted for those demographic groups at highest risk of vaccine-associated death or serious 238
adverse effects, during the time it takes to assemble these boards and committees and commence 239
their assessments. 240
241
In the context of these concerns, we propose opening an urgent pluralistic, critical, and 242
scientifically-based dialogue on SARS-CoV-2 vaccination among scientists, medical doctors, 243
international health agencies, regulatory authorities, governments, and vaccine developers. This 244
is the only way to bridge the current gap between scientific evidence and public health policy 245
regarding the SARS-CoV-2 vaccines. We are convinced that humanity deserves a deeper 246
understanding of the risks than what is currently touted as the official position. An open 247
scientific dialogue is urgent and indispensable to avoid erosion of public confidence in science 248
and public health and to ensure that the WHO and national health authorities protect the interests 249
of humanity during the current pandemic. Returning public health policy to evidence-based 250
medicine, relying on a careful evaluation of the relevant scientific research, is urgent. It is 251
imperative to follow the science. 252
253
254
Conflict of Interest Statement 255
The authors declare that the research was conducted in the absence of any commercial or 256
financial relationships that could be construed as a potential conflict of interest. 257
258
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Figure 1. Number of new COVID-19 deaths in relation to number of people that have received at 382
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May 3rd, 2021. A) India (9.25% of population vaccinated), B) Thailand (1.58% of population 384
vaccinated), C) Colombia (6.79% of population vaccinated), D) Mongolia (31.65% of population 385
vaccinated), E) Israel (62.47% of population vaccinated), F) Entire world (7.81% of population 386
vaccinated). Graphs were built using data from Our World in Data (accessed 4 May 2021) 387
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