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SARS-CoV-2 mass vaccination: Urgent questions on vaccine safety that demand answers from international health agencies, regulatory authorities, governments and vaccine developers

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Abstract

Since the start of the COVID-19 outbreak, the race for testing new platforms designed to confer immunity against SARS-CoV-2, has been rampant and unprecedented, leading to conditional emergency authorization of various vaccines. Despite progress on early multidrug therapy for COVID-19 patients, the current mandate is to immunize the world population as quickly as possible. The lack of thorough testing in animals prior to clinical trials, and authorization based on safety data generated during trials that lasted less than 3.5 months, raise questions regarding vaccine safety. The recently identified role of SARS-CoV-2 Spike glycoprotein for inducing endothelial damage characteristic of COVID-19, even in absence of infection, is extremely relevant given that most of the authorized vaccines induce endogenous production of Spike. Given the high rate of occurrence of adverse effects that have been reported to date, as well as the potential for vaccine-driven disease enhancement, Th2-immunopathology, autoimmunity, and immune evasion, there is a need for a better understanding of the benefits and risks of mass vaccination, particularly in groups excluded from clinical trials. Despite calls for caution, the risks of SARS-CoV-2 vaccination have been minimized or ignored by health organizations and government authorities. As for any investigational biomedical program, data safety monitoring boards (DSMB) and event adjudication committees (EAC), should be enacting risk mitigation. If DSMBs and EACs do not do so, we will call for a pause in mass vaccination. If DSMBs and EACs do not exist, then vaccination should be halted immediately, in particular for demographic groups at highest risk of vaccine-associated death or serious adverse effects, during such time as it takes to assemble these boards and commence critical and independent assessments. We urge for pluralistic dialogue in the context of health policies, emphasizing critical questions that require urgent answers, particularly if we wish to avoid a global erosion of public confidence in science and public health.
SARS-CoV-2 mass vaccination: Urgent questions on vaccine safety
that demand answers from international health agencies, regulatory
authorities, governments and vaccine developers
Roxana Bruno1, Peter A Mccullough2, Teresa Forcades I Vila3, Alexandra Henrion-Caude4,
Teresa Garc´ıa-Gasca5, Galina P Zaitzeva6, Sally Priester7, Mar´ıa J Mart´ınez Albarrac´ın8,
Alejandro Sousa-Escandon9, Fernando L´opez Mirones10, Bartomeu Payeras Cifre11 ,
Almudena Zaragoza Velilla10, Leopoldo M Borini1, Mario Mas1, Ramiro Salazar1, Edgardo
Schinder1, Eduardo A Yahbes1, Marcela Witt1, Mariana Salmeron1, Patricia Fern´andez1,
Miriam M Marchesini1, Alberto J Kajihara1, Marisol V De La Riva1, Patricia J Chimeno1,
Paola A Grellet1, Matelda Lisdero1, Pamela Mas1, Abelardo J Gatica Baudo12, Elisabeth
Retamoza12, Oscar Botta13 , Chinda C Brandolino13, Javier Sciuto14, Mario Cabrera
Avivar14, Mauricio Castillo15, Patricio Villarroel15, Emilia P Poblete Rojas15, B´arbara
Aguayo15, Dan I Mac´ıas Flores15, Jose V Rossell16, Julio C Sarmiento17, Victor
Andrade-Sotomayor17, Wilfredo R Stokes Baltazar18, Virna Cede˜no Escobar19, Ulises
Arr´ua20, Atilio Farina del R´ıo21, Tatiana Campos Esquivel22, Patricia Callisperis23, Mar´ıa
Eugenia Barrientos24, Christian Fiala25, and Karina Acevedo-Whitehouse26
1Epidemi´ologos Argentinos Metadisciplinarios
2Baylor University Medical Center
3Monestir de Sant Benet de Montserrat
4Simplissima International Research Institute, Mauritius.
5School of Natural Sciences, Autonomous University of Quer´etaro
6Retired Professor of Medical Immunology. Universidad de Guadalajara. Mexico
7edicos por la Verdad Puerto Rico
8Retired Professor of Clinical Diagnostic Processes. University of Murcia. Spain
9Hospital Comarcal de Monforte, University of Santiago de Compostela, Spain
10Bi´ologos por la Verdad, Espa˜na
11Retired Biologist. University of Barcelona. Specialized in Microbiology. Spain
12Center for Integrative Medicine MICAEL (Medicina Integrativa Centro Antropos´ofico
Educando en Libertad). Argentina
13edicos por la Verdad Argentina
14edicos por la Verdad Uruguay
15edicos por la Libertad Chile
16Physician, orthopedic specialist. Chile
17edicos por la Verdad Per´u
18edicos por la Verdad Guatemala
19Centro de Biotecnolog´ıas ´
Omicas (CEBIOMICS) - Concepto Azul, Ecuador
20edicos por la Verdad Brasil
21edicos por la Verdad Paraguay
1
22edicos por la Verdad Costa Rica
23edicos por la Verdad Bolivia
24edicos por la Verdad El Salvador
25Gynmed Ambulatorium, Vienna. Austria
26Affiliation not available
May 20, 2021
Abstract
Since the start of the COVID-19 outbreak, the race for testing new platforms designed to confer immunity against SARS-CoV-2,
has been rampant and unprecedented, leading to conditional emergency authorization of various vaccines. Despite progress on
early multidrug therapy for COVID-19 patients, the current mandate is to immunize the world population as quickly as possible.
The lack of thorough testing in animals prior to clinical trials, and authorization based on safety data generated during trials
that lasted less than 3.5 months, raise questions regarding vaccine safety. The recently identified role of SARS-CoV-2 Spike
glycoprotein for inducing endothelial damage characteristic of COVID-19, even in absence of infection, is extremely relevant
given that most of the authorized vaccines induce endogenous production of Spike. Given the high rate of occurrence of adverse
effects that have been reported to date, as well as the potential for vaccine-driven disease enhancement, Th2-immunopathology,
autoimmunity, and immune evasion, there is a need for a better understanding of the benefits and risks of mass vaccination,
particularly in groups excluded from clinical trials. Despite calls for caution, the risks of SARS-CoV-2 vaccination have been
minimized or ignored by health organizations and government authorities. As for any investigational biomedical program, data
safety monitoring boards (DSMB) and event adjudication committees (EAC), should be enacting risk mitigation. If DSMBs
and EACs do not do so, we will call for a pause in mass vaccination. If DSMBs and EACs do not exist, then vaccination should
be halted immediately, in particular for demographic groups at highest risk of vaccine-associated death or serious adverse
effects, during such time as it takes to assemble these boards and commence critical and independent assessments. We urge for
pluralistic dialogue in the context of health policies, emphasizing critical questions that require urgent answers, particularly if
we wish to avoid a global erosion of public confidence in science and public health.
SARS-CoV-2 mass vaccination: Urgent questions on vaccine safety that demand answers from
international health agencies, regulatory authorities, governments and vaccine developers
Roxana Bruno1, Peter A. McCullough2, Teresa Forcades i Vila3, Alexandra Henrion-Caude4, Teresa Garc´ıa-
Gasca5, Galina P. Zaitzeva6, Sally Priester7, Mar´ıa J. Mart´ınez Albarrac´ın8, Alejandro Sousa-Escandon9, Fer-
nando L´opez Mirones10 , Bartomeu Payeras Cifre11, Almudena Zaragoza Velilla10 , Leopoldo M. Borini1, Mario
Mas1, Ramiro Salazar1, Edgardo Schinder1, Eduardo A. Yahbes1, Marcela Witt1, Mariana Salmeron1, Patri-
cia Fern´andez1, Miriam M. Marchesini1, Alberto J. Kajihara1, Marisol V. de la Riva1, Patricia J. Chimeno1,
Paola A. Grellet1, Matelda Lisdero1, Pamela Mas1, Abelardo J. Gatica Baudo12, Elisabeth Retamoza12 ,
Oscar Botta13, Chinda C. Brandolino13 , Javier Sciuto14, Mario Cabrera Avivar14, Mauricio Castillo15, Pa-
tricio Villarroel15, Emilia P. Poblete Rojas15, B´arbara Aguayo15, Dan I. Mac´ıas Flores15 , Jose V. Rossell16,
Julio C. Sarmiento17, Victor Andrade-Sotomayor17, Wilfredo R. Stokes Baltazar18, Virna Cede˜no Escobar19,
Ulises Arr´ua20, Atilio Farina del R´ıo21, Tatiana Campos Esquivel22, Patricia Callisperis23, Mar´ıa Eugenia
Barrientos24, Christian Fiala25 , Karina Acevedo-Whitehouse5,*.
1Epidemi´ologos Argentinos Metadisciplinarios. Argentina.
2Baylor University Medical Center. Dallas, Texas. USA.
3Monestir de Sant Benet de Montserrat, Montserrat. Spain
2
4Simplissima International Research Institute. Mauritius.
5School of Natural Sciences. Autonomous University of Quer´etaro. Mexico.
6Retired Professor of Medical Immunology. Universidad de Guadalajara. Mexico.
7edicos por la Verdad Puerto Rico. Ashford Medical Center, San Juan. Puerto Rico.
8Retired Professor of Clinical Diagnostic Processes. University of Murcia. Spain.
9Hospital Comarcal de Monforte, University of Santiago de Compostela, Spain.
10 Bi´ologos por la Verdad. Spain.
11 Retired Biologist. University of Barcelona. Specialized in Microbiology. Spain.
12 Center for Integrative Medicine MICAEL (Medicina Integrativa Centro Antropos´ofico Educando en Li-
bertad). Argentina.
13 edicos por la Verdad. Argentina. ´
14 edicos por la Verdad. Uruguay.
15 edicos por la Libertad. Chile.
16 Physician, orthopedic specialist. Chile.
17 edicos por la Verdad. Per´u.
18 edicos por la Verdad. Guatemala.
19 Centro de Biotecnolog´ıas ´
Omicas (CEBIOMICS) - Concepto Azul, Ecuador.
20 edicos por la Verdad. Brasil.
21 edicos por la Verdad. Paraguay.
22 edicos por la Verdad. Costa Rica.
23 edicos por la Verdad. Bolivia.
24 edicos por la Verdad. El Salvador.
25 Gynmed Ambulatorium, Vienna. Austria.
*Corresponding author
Abstract
Since the start of the COVID-19 outbreak, the race for testing new platforms designed to confer immunity
against SARS-CoV-2, has been rampant and unprecedented, leading to conditional emergency authorization
of various vaccines. Despite progress on early multidrug therapy for COVID-19 patients, the current mandate
is to immunize the world population as quickly as possible. The lack of thorough testing in animals prior to
clinical trials, and authorization based on safety data generated during trials that lasted less than 3.5 months,
raise questions regarding vaccine safety. The recently identified role of SARS-CoV-2 Spike glycoprotein for
inducing endothelial damage characteristic of COVID-19, even in absence of infection, is extremely relevant
given that most of the authorized vaccines induce endogenous production of Spike. Given the high rate
of occurrence of adverse effects that have been reported to date, as well as the potential for vaccine-driven
disease enhancement, Th2-immunopathology, autoimmunity, and immune evasion, there is a need for a better
understanding of the benefits and risks of mass vaccination, particularly in groups excluded from clinical
trials. Despite calls for caution, the risks of SARS-CoV-2 vaccination have been minimized or ignored by
health organizations and government authorities. As for any investigational biomedical program, data safety
3
monitoring boards (DSMB) and event adjudication committees (EAC), should be enacting risk mitigation.
If DSMBs and EACs do not do so, we will call for a pause in mass vaccination. If DSMBs and EACs do not
exist, then vaccination should be halted immediately, in particular for demographic groups at highest risk
of vaccine-associated death or serious adverse effects, during such time as it takes to assemble these boards
and commence critical and independent assessments. We urge for pluralistic dialogue in the context of health
policies, emphasizing critical questions that require urgent answers, particularly if we wish to avoid a global
erosion of public confidence in science and public health.
Introduction
Since COVID-19 was declared a pandemic in March 2020, over 150 million cases and 3 million cases of deaths
from or with SARS-CoV-2 have been reported worldwide. Despite progress on early ambulatory, multidrug-
therapy for high-risk patients, resulting in 85% reductions in COVID-19 hospitalization and death [1], the
current paradigm for control is mass-vaccination. While we recognize the effort involved in development,
production and emergency authorization of SARS-CoV-2 vaccines, we are concerned that risks have been
minimized or ignored by health organizations and government authorities, despite calls for caution [2-8].
Vaccines for other coronaviruses have never been approved for humans, and data generated in the develop-
ment of coronavirus vaccines designed to elicit neutralizing antibodies show that they may worsen COVID-19
disease via antibody-dependent enhancement (ADE) and Th2 immunopathology, regardless of the vaccine
platform and delivery method [9-11]. Vaccine-driven disease enhancement in animals vaccinated against
SARS-CoV and MERS-CoV is known to occur following viral challenge, and has been attributed to immune
complexes and Fc-mediated viral capture by macrophages, which augment T-cell activation and inflammation
[11-13].
In March 2020, vaccine immunologists and coronavirus experts assessed SARS-CoV-2 vaccine risks based on
SARS-CoV-vaccine trials in animal models. The expert group concluded that ADE and immunopathology
were a real concern, but stated that their risk was insufficient to delay clinical trials, although continued
monitoring would be necessary [14]. While there is no clear evidence of the occurrence of ADE and vaccine-
related immunopathology in volunteers immunized with SARS-CoV-2 vaccines [15], safety trials to date have
not specifically addressed these serious adverse effects (SAE). Given that the follow-up of volunteers did not
exceed 2-3.5 months after the second dose [16-19], it is unlikely such SAE would have been observed. Despite
errors in reporting, it cannot be ignored that even accounting for the number of vaccines administered,
according to the US Vaccine Adverse Effect Reporting System (VAERS), the number of deaths per million
vaccine doses administered has increased more than 10-fold. We believe there is an urgent need for open
scientific dialogue on vaccine safety in the context of large-scale immunization. In this paper, we describe
some of the risks of mass vaccination in the context of phase 3 trial exclusion criteria and discuss the SAE
reported in national and regional adverse effect registration systems. We highlight unanswered questions and
draw attention to the need for a more cautious approach to mass vaccination.
SARS-CoV-2 phase 3 trial exclusion criteria
With few exceptions, SARS-CoV-2 vaccine trials excluded the elderly [16-19], making it impossible to identify
the occurrence of post-vaccination eosinophilia and enhanced inflammation in elderly people. Studies of
SARS-CoV vaccines showed that immunized elderly mice were at particularly high risk of life-threatening
4
Th2 immunopathology [9,20]. Despite this evidence and the extremely limited data on safety and efficacy of
SARS-CoV-2 vaccines in the elderly, mass-vaccination campaigns have focused on this age group from the
start. Most trials also excluded pregnant and lactating volunteers, as well as those with chronic and serious
conditions such as tuberculosis, hepatitis C, autoimmunity, coagulopathies, cancer, and immune suppression
[16-29], although these recipients are now being offered the vaccine under the premise of safety.
Another criterion for exclusion from nearly all trials was prior exposure to SARS-CoV-2. This is unfortunate
as it denied the opportunity of obtaining extremely relevant information concerning post-vaccination ADE
in people that already have anti-SARS-Cov-2 antibodies. To the best of our knowledge, ADE is not being
monitored systematically for any age or medical condition group currently being administered the vaccine.
Moreover, despite a substantial proportion of the population already having antibodies [21], tests to determine
SARS-CoV-2-antibody status prior to administration of the vaccine are not conducted routinely.
Will serious adverse effects from the SARS-CoV-2 vaccines go unnoticed?
COVID-19 encompasses a wide clinical spectrum, ranging from very mild to severe pulmonary pathology
and fatal multi-organ disease with inflammatory, cardiovascular, and blood coagulation dysregulation [22-24].
In this sense, cases of vaccine-related ADE or immunopathology would be clinically-indistinguishable from
severe COVID-19 [25]. Furthermore, even in the absence of SARS-CoV-2 virus, Spike glycoprotein alone
causes endothelial damage and hypertension in vitro and in vivo in Syrian hamsters by down-regulating
angiotensin-converting enzyme 2 (ACE2) and impairing mitochondrial function [26]. Although these findings
need to be confirmed in humans, the implications of this finding are staggering, as all vaccines authorized
for emergency use are based on the delivery or induction of Spike glycoprotein synthesis. In the case of
mRNA vaccines and adenovirus-vectorized vaccines, not a single study has examined the duration of Spike
production in humans following vaccination. Under the cautionary principle, it is parsimonious to consider
vaccine-induced Spike synthesis could cause clinical signs of severe COVID-19, and erroneously be counted
as new cases of SARS-CoV-2 infections. If so, the true adverse effects of the current global vaccination
strategy may never be recognized unless studies specifically examine this question. There is already non-
causal evidence of temporary or sustained increases in COVID-19 deaths following vaccination in some
countries (Fig. 1) and in light of Spike’s pathogenicity, these deaths must be studied in depth to determine
whether they are related to vaccination.
Unanticipated adverse reactions to SARS-CoV-2 vaccines
Another critical issue to consider given the global scale of SARS-CoV-2 vaccination is autoimmunity. SARS-
CoV-2 has numerous immunogenic proteins, and all but one of its immunogenic epitopes have similarities to
human proteins [27]. These may act as a source of antigens, leading to autoimmunity [28]. While it is true that
the same effects could be observed during natural infection with SARS-CoV-2, vaccination is intended for
most of the world population, while it is estimated that only 10% of the world population has been infected
by SARS-CoV-2, according to Dr. Michael Ryan, head of emergencies at the World Health Organization.
We have been unable to find evidence that any of the currently authorized vaccines screened and excluded
homologous immunogenic epitopes to avoid potential autoimmunity due to pathogenic priming.
Some adverse reactions, including blood-clotting disorders, have already been reported in healthy and
young vaccinated people. These cases led to the suspension or cancellation of the use of adenoviral vec-
5
torized ChAdOx1-nCov-19 and Janssen vaccines in some countries. It has now been proposed that vacci-
nation with ChAdOx1-nCov-19 can result in immune thrombotic thrombocytopenia (VITT) mediated by
platelet-activating antibodies against Platelet factor-4, which clinically mimics autoimmune heparin-induced
thrombocytopenia [29]. Unfortunately, the risk was overlooked when authorizing these vaccines, although
adenovirus-induced thrombocytopenia has been known for more than a decade, and has been a consistent
event with adenoviral vectors [30]. The risk of VITT would presumably be higher in those already at risk of
blood clots, including women who use oral contraceptives [31], making it imperative for clinicians to advise
their patients accordingly.
At the population level, there could also be vaccine-related impacts. SARS-CoV-2 is a fast-evolving RNA virus
that has so far produced more than 40,000 variants [32,33] some of which affect the antigenic domain of Spike
glycoprotein [34,35]. Given the high mutation rates, vaccine-induced synthesis of high levels of anti-SARS-
CoV-2-Spike antibodies could theoretically lead to suboptimal responses against subsequent infections by
other variants in vaccinated individuals [36], a phenomenon known as “original antigenic sin” [37] or antigenic
priming [38]. It is unknown to what extent mutations that affect SARS-CoV-2 antigenicity will become fixed
during viral evolution [39], but vaccines could plausibly act as selective forces driving variants with higher
infectivity or transmissibility. Considering the high similarity between known SARS-CoV-2 variants, this
scenario is unlikely [32,34] but if future variants were to differ more in key epitopes, the global vaccination
strategy might have helped shape an even more dangerous virus. This risk has recently been brought to the
attention of the WHO as an open letter [40].
Discussion
The risks outlined here are a major obstacle to continuing global SARS-CoV-2 vaccination. Evidence on the
safety of all SARS-CoV-2 vaccines is needed before exposing more people to the risk of these experiments,
since releasing a candidate vaccine without time to fully understand the resulting impact on health could
lead to an exacerbation of the current global crisis [41]. Risk-stratification of vaccine recipients is essential.
According to the UK government, people below 60 years of age have an extremely low risk of dying from
COVID-19[1]. However, according to Eudravigillance, most of the serious adverse effects following SARS-
CoV-2 vaccination occur in people aged 18-64. Of particular concern is the planned vaccination schedule for
children aged 6 years and older in the United States and the UK. Dr. Anthony Fauci recently anticipated that
teenagers across the country will be vaccinated in the autumn and younger children in early 2022, and the UK
is awaiting trial results to commence vaccination of 11 million children under 18. There is a lack of scientific
justification for subjecting healthy children to experimental vaccines, given that the Centers for Disease
Control and Prevention estimates that they have a 99.997% survival rate if infected with SARS-CoV-2. Not
only is COVID-19 irrelevant as a threat to this age group, but there is no reliable evidence to support vaccine
efficacy or effectiveness in this population or to rule out harmful side effects of these experimental vaccines.
In this sense, when physicians advise patients on the elective administration of COVID-19 vaccination, there
is a great need to better understand the benefits and risk of administration, particularly in understudied
groups.
In conclusion, in the context of the rushed emergency-use-authorization of SARS-CoV-2 vaccines, and the
current gaps in our understanding of their safety, the following questions must be raised:
* Is it known whether cross-reactive antibodies from previous coronavirus infections or vaccine-induced
antibodies may influence the risk of unintended pathogenesis following vaccination with COVID-19?
6
* Has the specific risk of ADE, immunopathology, autoimmunity, and serious adverse reactions been
clearly disclosed to vaccine recipients to meet the medical ethics standard of patient understanding for
informed consent? If not, what are the reasons, and how could it be implemented?
* What is the rationale for administering the vaccine to every individual when the risk of dying from
COVID-19 is not equal across age groups and clinical conditions and when the phase 3 trials excluded the
elderly, children and frequent specific conditions?
* What are the legal rights of patients if they are harmed by a SARS-CoV-2 vaccine? Who will cover
the costs of medical treatment? If claims were to be settled with public money, has the public been made
aware that the vaccine manufacturers have been granted immunity, and their responsibility to compensate
those harmed by the vaccine has been transferred to the tax-payers?
If vaccination programs worldwide do not institute independent data safety monitoring boards (DSMB),
event adjudication committees (EAC), and enact risk mitigation, we will call for a pause in the mass vacci-
nation program. If DSMBs and EACs do not exist currently, as would be imperative for any investigational
biomedical program, then vaccination should be immediately halted for those demographic groups at highest
risk of vaccine-associated death or serious adverse effects, during the time it takes to assemble these boards
and committees and commence their assessments.
In the context of these concerns, we propose opening an urgent pluralistic, critical, and scientifically-based
dialogue on SARS-CoV-2 vaccination among scientists, medical doctors, international health agencies, reg-
ulatory authorities, governments, and vaccine developers. This is the only way to bridge the current gap
between scientific evidence and public health policy regarding the SARS-CoV-2 vaccines. We are convinced
that humanity deserves a deeper understanding of the risks than what is currently touted as the official
position. An open scientific dialogue is urgent and indispensable to avoid erosion of public confidence in
science and public health and to ensure that the WHO and national health authorities protect the interests of
humanity during the current pandemic. Returning public health policy to evidence-based medicine, relying
on a careful evaluation of the relevant scientific research, is urgent. It is imperative to follow the science.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relation-
ships that could be construed as a potential conflict of interest.
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Figure 1: Number of new COVID-19 deaths in relation to number of people that have received at least one
vaccine dose for selected countries. Graph shows data from the start of vaccination to May 3rd, 2021. A)
India (9.25% of population vaccinated), B) Thailand (1.58% of population vaccinated), C) Colombia (6.79%
of population vaccinated), D) Mongolia (31.65% of population vaccinated), E) Israel (62.47% of population
vaccinated), F) Entire world (7.81% of population vaccinated). Graphs were built using data from Our
World in Data (accessed 4 May 2021) https://github.com/owid/covid-19-data/tree/master/public/
data/vaccinations.
[1] (https://www.gov.uk/government/publications/covid-19-reported-sars- cov-2-deaths-in-
england/covid-19-confirmed-deaths- in-england-report
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The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death.
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Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods Download a PDF of the Research Summary. In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)
Article
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Background Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19, in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. Methods In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18–55 years, 56–69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 10¹⁰ virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18–55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56–69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5–6·5 × 10¹⁰ virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18–55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. Findings Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18–55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56–69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18–55 years group, 22 (73%) of 30 in the 56–69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18–55 years group, 23 (77%) in the 56–69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18–55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898–33 550], n=39; 56–69 years, 16 170 AU/mL [10 233–40 353], n=26; and ≥70 years 17 561 AU/mL [9705–37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18–55 years, 193 [IQR 113–238], n=39; 56–69 years, 144 [119–347], n=20; and ≥70 years, 161 [73–323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18–55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841–2428], n=24; 56–69 years: 797 SFCs [383–1817], n=29; and ≥70 years: 977 SFCs [458–1914], n=48). Interpretation ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. Funding UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.
Preprint
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Currently, more than 33 million peoples have been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and more than a million people died from coronavirus disease 2019 (COVID-19), a disease caused by the virus. There have been multiple reports of autoimmune and inflammatory diseases following SARS-CoV-2 infections. There are several suggested mechanisms involved in the development of autoimmune diseases, including cross-reactivity (molecular mimicry). A typical workflow for discovering cross-reactive epitopes (mimotopes) starts with a sequence similarity search between protein sequences of human and a pathogen. However, sequence similarity information alone is not enough to predict cross-reactivity between proteins since proteins can share highly similar conformational epitopes whose amino acid residues are situated far apart in the linear protein sequences. Therefore, we used a hidden Markov model-based tool to identify distant viral homologs of human proteins. Also, we utilized experimentally determined and modeled protein structures of SARS-CoV-2 and human proteins to find homologous protein structures between them. Next, we predicted binding affinity (IC50) of potentially cross-reactive T-cell epitopes to 34 MHC allelic variants that have been associated with autoimmune diseases using multiple prediction algorithms. Overall, from 8,138 SARS-CoV-2 genomes, we identified 3,238 potentially cross-reactive B-cell epitopes covering six human proteins and 1,224 potentially cross-reactive T-cell epitopes covering 285 human proteins. To visualize the predicted cross-reactive T-cell and B-cell epitopes, we developed a web-based application “Molecular Mimicry Map (3M) of SARS-CoV-2” (available at https://ahs2202.github.io/3M/ ). The web application enables researchers to explore potential cross-reactive SARS-CoV-2 epitopes alongside custom peptide vaccines, allowing researchers to identify potentially suboptimal peptide vaccine candidates or less ideal part of a whole virus vaccine to design a safer vaccine for people with genetic and environmental predispositions to autoimmune diseases. Together, the computational resources and the interactive web application provide a foundation for the investigation of molecular mimicry in the pathogenesis of autoimmune disease following COVID-19.
Article
Background Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder. Methods We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)–heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4–heparin immunoassay. Results Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4–heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor–blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4–heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation. Conclusions Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.)
Article
Objective: To estimate the infection fatality rate of coronavirus disease 2019 (COVID-19) from seroprevalence data. Methods: I searched PubMed and preprint servers for COVID-19 seroprevalence studies with a sample size ≥ 500 as of 9 September 2020. I also retrieved additional results of national studies from preliminary press releases and reports. I assessed the studies for design features and seroprevalence estimates. I estimated the infection fatality rate for each study by dividing the cumulative number of COVID-19 deaths by the number of people estimated to be infected in each region. I corrected for the number of immunoglobin (Ig) types tested (IgG, IgM, IgA). Findings: I included 61 studies (74 estimates) and eight preliminary national estimates. Seroprevalence estimates ranged from 0.02% to 53.40%. Infection fatality rates ranged from 0.00% to 1.63%, corrected values from 0.00% to 1.54%. Across 51 locations, the median COVID-19 infection fatality rate was 0.27% (corrected 0.23%): the rate was 0.09% in locations with COVID-19 population mortality rates less than the global average (< 118 deaths/million), 0.20% in locations with 118-500 COVID-19 deaths/million people and 0.57% in locations with > 500 COVID-19 deaths/million people. In people younger than 70 years, infection fatality rates ranged from 0.00% to 0.31% with crude and corrected medians of 0.05%. Conclusion: The infection fatality rate of COVID-19 can vary substantially across different locations and this may reflect differences in population age structure and case-mix of infected and deceased patients and other factors. The inferred infection fatality rates tended to be much lower than estimates made earlier in the pandemic.