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Volume: 19 Issue: 8 August 2021

FULL TEXT

REVIEW
Anti-Coronavirus Disease 2019 Vaccines: Need for Informed Consent

Abstract

Vaccines are among some of the most efficacious medical and public health methods ever employed to contain a pandemic, in addition to providing protective and preventive measures. Evaluation of vaccine-associated adverse events through experimentation and empirical evidence is an integral part of thoroughly assessing the safety of vaccines before authorization
of their widespread use. History has highlighted
the importance of continuous search for possible vaccine-related adverse effects and vaccine-induced immunogenicity long after licensure, suggesting that a primary concern with new vaccines is not only efficacy but also safety, particularly over the long term. Many of the various anti-COVID-19 vaccines have used different types of technology, with some being introduced for the first time or rushed shortly into testing, bypassing animal experimentations. They have been adopted for use through emergency use authorizations, leading to a less than optimal collection of broad data on safety, immunogenicity, effectiveness, and time span of protection, as well as short follow-up of few months, despite many infectious disease experts arguing that it takes 10 years to develop a vaccine. Given the valid concerns on well-recognized short-term and long-term safety issues, such as antibody-dependent enhance­ment and other processes like molecular mimicry and potential genomic transformation, the experimental nature of the vaccination process, the limited short-term follow-up in the main trials, and the dismissal by law of pharma companies and health care providers from any medico-legal responsibilities, the application of an informed consent should become not only a necessity but also mandatory by law in accordance with all declarations on human rights. Such information should be provided to every potential recipient in the form of an official written digital consent prior to the registration for or the receipt of the vaccine.


Key words : Adverse effects, mRNA vaccine, SARS-CoV-2

Introduction

In December 2019, in Wuhan, China, the COVID-19 outbreak started, caused by SARS-CoV-2. Shortly thereafter, on January 20, 2020, an official an­nouncement came from the World Health Organization, to what was a worldwide pandemic and the cause of an increasing number of fatalities.1,2 This announcement led to an urgent need for a plan to contain the pandemic, including a series of protective and preventive measures, with a vaccine targeted as a potential solution. Vaccines are among some of the most efficacious medical and public health methods ever employed. According to certain estimates, they may prevent around 6 million deaths every year worldwide.3

The evaluation of vaccine-associated adverse events through experimentation and empirical evi­dence is an integral part of the thorough assessment of the safety of vaccines before authorization of their widespread use. The first dengue vaccine, which was licensed to be used in children >9 years of age, decreased the rate of severe dengue disease in that particular age group. Over a 5-year period, both disease severity and hospitalization had decreased. Interestingly, although maximum protection was observed mainly in individuals who had been already exposed to the virus before immunization, vaccine-induced immunization exacerbated disease in seronegative individuals.4,5 As reported by Knipe and colleagues, protection was weakest in relation to the dengue serotype (DEN-2), implying that weak immune responses to specific serotypes (such as DEN-2) or in seronegative individuals may have led to antibody-dependent enhancement of the disease.6

In the spring of 1976, an influenza outbreak started in Fort Dix, New Jersey, which brought about considerable concern that a potentially pandemic influenza virus related to the 1918 pandemic H1N1 virus (which caused millions of deaths) was emerging. This resulted in an emergency vaccine plan that was approved by the US government.7 On October 1, 1976, testing was started in nearly 7000 individuals of an influenza vaccine against H1N1 deemed to be safe, with broad immunization. However, there was indication that the vaccine did not possess an antigenic form of the viral neuraminidase protein, leading to it being less effective. Nevertheless, the vaccine plan was carried through. About 25% of the United States population was immunized before approximately 450 cases of the paralytic Guillain-Barré syndrome disease emerged, a statistically significant increase above the normal population incidence. This influenza immunization program was terminated several months later in December 1976 with severe consequences, including diminished public confidence in vaccines and the public health care system. Later studies showed negligible Guillain-Barré syndrome related to other types of influenza virus vaccines,8 which asserted that this precise vaccine preparation was presumably involved. Both the possible absence of neuraminidase activity and the elicitation of autoimmune antibodies have been suggested as plausible causes for these adverse effects. In 2009, a 13-fold increased risk of narcolepsy was demonstrated, with irreversible neurological damage occurring in hundreds of Scandinavian and English young people aged 4 to 19 years old after they received an influenza A (HIN1) adjuvant containing squalene vaccine.9

History has highlighted the importance of a continuous search for possible vaccine-related adverse effects and vaccine-induced immunogenicity long after licensure, suggesting that a primary concern with the introduction of new vaccines is not only efficacy but also safety, particularly over the long term. Such monitoring, through various official systems and platforms, can validate safety and enhance our understanding for the underlying mechanisms of generated immunity and consequently the improvement in the development of current and future safe vaccines.6 Accordingly, modern regula­tions mandate the close pre- and post-licensure monitoring for rare side effects, which could lead to a pause in the use of a studied vaccine if serious adverse events are detected, as was the case last year for the AstraZeneca vaccine. In that case, the phase 1/2 trial was briefly paused after neurological symptoms had developed after vaccination, which were later linked to multiple sclerosis. The phase 3 trial was also paused after a vaccine recipient developed symptoms consistent with transverse myelitis.10 Indeed, such mid- and long-term safety precautions should be applied to all current anti-COVID-19 vaccine trials.

Current Anti-COVID-19 Vaccines
Several vaccine candidates have already entered phase 3 clinical trials in humans.10,11 These vaccines employ different types of technology.

mRNA vaccines
The mRNA vaccines, which are the most innovative, use genetic material mRNA and include the Pfizer-BioNTech- BNT162b2 (USA-Germany) and the Moderna-mRNA 1273 (USA), where the mRNA Vax is encapsulated in lipid nanoparticles and delivered to a person through a regimen of 2 injections given 3 and 4 weeks apart. As a result of the rapid spread of COVID-19, mRNA-based vaccines have come to the forefront as a possible preventive method, given their high efficacy in inducing neutralizing protective antibodies and being easy to manufacture.12 Modern processes for vaccine development dictate clinical trials and regulatory approval and usually at least 12 to 18 months is needed to develop this type of vaccine13,14; however, many infectious disease experts have argued that 18 months is an incredibly aggressive schedule, since, on average, it takes 10 years to fully develop a vaccine. Engineered mRNA production expedites large-scale manufacturing of necessary vaccine doses to treat mass populations.15,16 All of these aforementioned elements make the mRNA vaccine a suitable candidate for a speedy response to the COVID-19 pandemic, as suggested by Wang and colleagues.14

In March 2020, reports about unusual reactions for multiple mRNA vaccines spurred interest on safety and immunogenicity, including on the outcomes of the phase 1 trial on the Moderna mRNA-1273 vaccine.17,18 According to a recently published Pfizer-BioNTech study,19 up to 83% of recipients developed some kind of mild to moderate local event, which was shown more so in younger (78%-83%) than in elderly participants (66%-71%). Systemic adverse manifestations were also more predominant in younger (47%-59%) versus older participants (34%-51%). Vaccine recipients were 2 times more likely to develop a severe disease than nonvaccinated controls (12.5% in the vaccinated group vs 5.5% in the placebo group). Vaccine-associated immunogenicity is a well-recognized phenomenon related to either antigenic cross-reactivity or the adjuvants. Previous experience with veterinary coronavirus vaccines has raised safety concerns about the potential for vaccine-associated enhanced respiratory disease related to either increased susceptibility to antibody-dependent enhancement of replication or induction of antibodies with poor neutralizing activity.20-22 Thus, it is crucial to clearly recognize potential serious adverse events that are associated with this type of mRNA vaccine, which include local and systemic inflammatory responses, provoked immunogenic manifestations, and probable formation over the mid- and long-term of autoreactive antibodies and antibody-dependent enhancement of immunity.23

Adenoviruses vaccines
These vaccines use adenoviruses as vectors to deliver the spike protein and include the AstraZeneca-ChAdOx1 nCoV-19 from the University of Oxford (UK-USA), the Johnson & Johnson-Ad26.COV2.S (Jansen-USA), the Sputnik V-recombinant adenovirus type 26 (rAd26) and type 5 (rAd5) vector-based (Russia), which both carry the gene for the SARS-CoV-2 spike glycoprotein (rAd26-S and rAd5-S), and the CanSino Biologics-nonreplicating adenovirus type-5 (Ad5)-vectored (China) vaccines. After roll out of the AstraZeneca vaccine, cases of vascular thrombosis were reported in the United Kingdom and Europe. These events occurred predominantly in young female recipients, including an increased risk of death occurring (in nearly half of the cases) as a result of cavernous sinus venous thrombosis associated with low platelet count. Other blood clots associated with thrombocytopenia were also reported following the AstraZeneca vaccine, including arterial throm­boses and splanchnic vein thrombosis. Most of these thrombotic adverse events were associated with an immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against platelet factor 4, which clinically mimics autoimmune heparin-induced thrombocytopenia.24-28 Other similar cases of serious thrombosis were reported after the use of the Johnson & Johnson anti-COVID-19 vaccine, and its roll out was paused in the United States pending review of the data, as well as cancelled in many European countries, with the final annulation of the contract between the European Union and AstraZeneca starting June 2021. Little follow-up information is available on the Russian and Chinese vaccines.

Inactivated virus vaccines
These inactivated viruses (traditional vaccines) were created mainly by several Chinese Pharma companies such as Sinovac Biotech or Sinopharm and rolled out in different countries. Data on these vaccines are limited.

Risk of Antibody-Dependent Enhancement
Antibody-dependent enhancement is the phenomenon by which subneutralizing antibodies promote infection and viral replication by enhancing the entry of the virus into host cells. Experiments have shown that antibody-dependent enhancement was responsible for increasing the infectivity of SARS coronavirus in specific types of cells in laboratory cultures.29 As recently reported, a vaccine-induced augmentation of disease processes was witnessed with SARS and the feline coronavirus, which are close relatives of SARS-CoV-2, the virus that causes COVID-19. The underlying immune mechanism of this disease is related to the presence of antibodies. In addition to humoral components, such as direct antibody-dependent enhancement and immune complex formation, the mechanism also involves multiple cellular responses, such as Th2 T-cell skewing.22,30-33 As a result of antibody-dependent enhancement, inflammatory processes and tissue damage in the organs of animal models resembled the ones shown in organs of individuals infected with SARS who passed away from the disease. This was evident in recent studies that highlighted the correlation between immunoglobulin G-mediated lung injuries in animals with neutralizing antibody responses induced by vaccines. Another interesting resemblance was with regard to the chronology of disease progression, with the worst outcomes happening in later stages simultaneously with the buildup of the immune response. Surprisingly, the neutralizing antibodies that initially successfully combatted the virus in patients subsequently caused damaging, inflammatory responses in the organs. Moreover, similar inflam­matory responses and tissue damage were described with immune complex formation following respiratory syncytial virus vaccines, where vaccinated patients developed a more severe disease as a result of damaging inflammatory responses caused by those immune complexes. Similarly, the clinical manifes­tation of COVID-19 patients is accompanied by the formation of anti-SARS-CoV-2 antibodies,34-36 with disease severity correlating positively with antibody titers.37 In contrast, patients who are on the lower spectrum of anti-SARS-CoV-2 antibodies tend to have speedier recoveries.34,38

The induction of neutralizing antibodies is considered to be the hallmark of immunity following any of the current SARS-CoV-2 vaccines. However, the 2 landmark studies from Pfizer-BioNTech and Moderna19,39 were unable to assess durability of the immune responses, the protective effects of these antibodies, or any immunological risk (immune enhancement) associated with antibody induced by vaccination when the vaccine recipients were reexposed to the virus, a limitation in the Moderna trial that was raised by the study investigators themselves and by others.40 According to Dan and colleagues, circulating antibody titers are not predictive of T-cell memory and simple serological tests for SARS-CoV-2 antibodies do not reflect the richness and durability of immune memory to SARS-CoV-2.41 Previous controlled SARS studies in primates and clinical observations in SARS and COVID-19 seemed to indicate that vaccine-elicited antibody-dependent enhancement of disease is likely to occur with COVID-19 vaccines and, therefore, should deserve some degree of cautiousness. Consequently, vaccines comprising the SARS-CoV-2 viral spike and provoking the formation of any type of anti-SARS-CoV-2 antibody could place recipients at a possible risk for severe COVID-19 disease once their immune system is re-exposed to the virus.34

Concerns for Molecular Mimicry and Autoimmunity
Despite the considerable knowledge accumulated over the past year, concerns continue to be raised about the risk of immunogenicity of the vaccine. Ambiguities persist about the disease, such as the reason for steady clinical progression despite SARS-CoV-2 clearance and the causes of extended multiorgan damage in some patients, which may last for months after hospital discharge. These mysteries could be partly explained by autoimmunity,42 a mechanism through which the immune system mistakenly turns against the self and attacks specific proteins either circulating or expressed on specific cells belonging to different organs, mainly those most affected by the virus (such as vessels, lung, heart, intestine, kidney, and brain). Pathogens may trigger autoimmunity if a part of these epitopes resemble ones of similar structure expressed on human cells, as demonstrated in many postinfectious diseases that trigger many of the well-known autoimmune diseases. This process is likely in the context of genetic predisposition, such as in those with the HLA-DQB1 gene,42 which is strongly suspected to be the cause of the narcolepsy that occurred in hundreds of children after their vaccination against the novel influenza A (H1N1) virus (“swine flu”), a vaccine that was later discontinued. This process is known as molecular mimicry. Kanduc and Shoenfeld recently reported frequent similarities between numerous short sequences from the SARS-CoV-2 spike protein, which the virus uses to enter the cell, and human proteins.43 The present mRNA vaccines are designed to stimulate a human cell to become a pathogen-manufacturing site in which the cell produces the spike protein, which ultimately triggers the immune system to produce neutralizing antibodies against the spike protein and which may cross-react with one of the self-antigens and trigger an autoimmune disease,44 as recently reported with the AstraZeneca and Johnson & Johnson vaccines (discussed above). Vaccine-associated autoimmunity is a well-known phenomenon attributed to either the cross-reactivity between antigens or the effect of adjuvant.45 To our knowledge, the reactogenicity of COVID-19 mRNA vaccines in individuals with autoimmune diseases and a preexistent impairment in the immune response has not been investigated.

In addition to molecular mimicry, mRNA vaccines may give rise to a cascade of immunological events, eventually leading to the aberrant activation of the innate and acquired immune system.44 Up-regulation of these immunological pathways is widely consi­dered to be the basis of several immune-mediated diseases, especially in genetically predisposed individuals who have an impaired clearance of nucleic acids.46 Another concern, in case of a switch in the immune system and in people with genetic predisposition, is the risk of the continuous production of the spike protein and corresponding antibodies, which could lead to a state of chronic inflammation.44

Risk of Genomic Transformation
Concern remains regarding genetically based vaccines using either mRNA or DNA and the associated risks in transforming our genome and therefore the expression of our genes. Theoretically, with mRNA, this risk is minimal if not impossible according to the dogma of molecular biology. However, this risk become real in the presence of the “reverse transcriptase” enzyme that is present in retroviruses such as HIV and may be present in other viruses. Indeed, nonretroviral RNA virus sequences have been detected in the genomes of many vertebrate species.47,48 DNA copies of viral mRNAs may be integrated into the germline via ancient, long interspersed nuclear element retrotransposons. This may put patients with HIV and others at a considerable risk of genomic transformation if they receive the vaccine. The potential risk for genetic modification of the host (risk of DNA being reverse-transcribed from the vaccine mRNA and being incorporated into the host genome) cannot be completely excluded as trials have specifically excluded genetic analyses.50,51 Recently, SARS-CoV-2 RNA was reverse-transcribed and integrated into the genome of the infected cell and expressed as chimeric transcripts fusing viral with cellular sequences. Transcription of the integrated DNA copies could be responsible for positive polymerase chain reaction tests long after the initial infection has cleared.51

Anti-Coronavirus Disease 2019 Vaccines in Solid-Organ Transplant
None of the recently rolled out vaccines has been tested in solid-organ transplant recipients. There were no transplant recipients in the phase 3 trials for Pfizer19 or Moderna39 or in any of the remaining vaccine trials.52 The short-term and long-term safety results for any of the vaccines are still under investigation in solid-organ transplant recipients. Ou and colleagues53 recently reported their preliminary experience in 741 transplant recipients with a median age of 60 years (range, 44-69 years), who underwent BNT162b2 (54%) or mRNA-1273 (46%) vaccination. Participants were recruited prospectively through social media. Data were only collected within a short period, that is, within 7 days after doses 1 and 2. No anaphylaxis, neurologic diagnoses, or SARS-CoV-2 diagnoses were reported. Infections were minimal. One patient reported acute rejection after the second dose. Based on such a short follow-up period and on information obtained from social media, they concluded that, in solid-organ transplant recipients undergoing mRNA vaccination, reactogenicity was similar to that reported in the original trials, with no information available on the correlate of immunity and the potential above-mentioned immunogenic long-term adverse events or consequent true risks for acute or chronic rejection and graft loss.

Similarly, safety, immunogenicity, and clinical efficacy data on COVID-19 vaccination for potential recipients and recipients of pediatric solid-organ transplant are currently lacking, as reported in a recent review by L’Huillier and colleagues.54 In fact, data on all children, who were excluded from all vaccine trials, whether healthy or immunocom­promised, are lacking.55 Children receive many immunizations in early life. Data on the immunologic impact of COVID-19 vaccines, including de novo antibody formation posttransplant or implication of cross-match results pretransplant, as well as safety of COVID-19 vaccine concurrent with other vaccines, raise genuine concerns. This has been recently highlighted through the risk of vaccine-induced donor-specific antibodies following vaccination with seasonal trivalent inactivated influenza vaccines, which was clearly associated with acute allograft rejection.56,57

Emerging variants of SARS-CoV-2 continue to be recognized, such as the so-called UK variant, also known as B.1.1.7 (N501Y), as well as greater concerns for the South African variant, also known as B.1.351 (N501Y.V2), and the Brazilian variant, also known as P.1 or B.1.1.26; the latter variant has a mutation pattern similar to B.1.351 and likely shares its properties.54 Additional variants are expected to continue to emerge, evolve, and spread. Of major concern is the ongoing potential for the development of escape mutations against immunity derived from prior infections with older strains or from vaccines, as recently reported in India where 3 of 4 stable kidney transplant recipients (time from transplant 1.5-16 years) died after receiving the AstraZeneca vaccine (2 patients with symptoms occurring at 13 and 23 days after a single dose and 1 patient with symptoms occurring 20 days after receiving the second dose, at 4 weeks apart from the first one).58 In the Pfizer-BioNTech trial,19 immunocompetent participants who received the vaccine were 2 times more likely to develop severe disease compared with those who received placebo. As expected, this risk may be amplified in immunodeficient patients. In addition, immunocompromised hosts, such as solid-organ transplant recipients, may serve as source for development of SARS-CoV-2 variants.59 These variants may likely affect the relative contribution of T-cell responses to conserved peptide epitopes among SARS-CoV-2. Whether these conserved responses could mitigate the loss of antibody responsiveness remains unknown.60

In the absence of any well-defined correlate of humoral or cellular protective immunity, the asses­sment of immunogenicity of COVID-19 vaccines is an important challenge in immunodeficient populations, such as solid-organ transplant recipients irrespective of their age.39-41,61 Among solid-organ transplant recipients with confirmed infection, only 51% of patients had detectable anti-nucleocapsid antibodies.62 Quantitative antibody titers directed against different components of SARS-CoV-2, such as spike protein S, nucleocapsid protein, and the receptor binding domain, are frequently below the median titer in solid-organ transplant patients versus that shown in immunocompetent patients. Moreover, only half of patients in different organ transplant settings have shown detectable antibody levels after both doses of the vaccine and relatively infrequent detectable levels after the first dose. Transplant-related variables, including age, renal function level, and nature of immunosuppression, were important predictors.62-65

Circulating antibody titers were recently shown to not be predictive of T-cell memory, therefore suggesting that simple serological tests for SARS-CoV-2 antibodies do not reflect the richness and durability of immune memory to SARS-CoV-2.41 In contrast, Turner and colleagues recently reported that SARS-CoV-2 infection in humans robustly established the 2 arms of humoral immune memory: long-lived bone marrow plasma cells and memory B cells. These findings provided an immunogenicity benchmark for SARS-CoV-2 vaccines that may help evaluate the durability of primary humoral immune responses.61 Unfortunately, no study has looked at frequency of postvaccine cellular responses, and there is a definite lack of exploration of memory B-cell or T-cell responses in immunocompromised patients. Likewise, the rate of breakthrough and the severity of breakthrough infections have not been fully studied to assess clinical efficacy and safety of the vaccine in the transplant population.58,63-65

Given the many areas of uncertainty regarding short- and long-term efficacy and safety profiles across all ages for both immunocompetent and immunodeficient individuals,58, 66-68 as well as the potential associations with allograft rejection and the questionable benefit from COVID-19 vaccination in individuals who have had SARS-CoV-2 infections,39,69 COVID-19 vaccines in solid-organ transplant recipients will need to be carefully evaluated. Counting on voluntary reporting of adverse events through a 30-year-old electronic platform in the United States like VAERS (vaccine adverse events reporting system) to monitor long-term adverse events and to assess vaccine safety, as currently practiced, is of questionable accuracy and would certainly underestimate the real data. Adverse events from drugs and vaccines are common, but underreported. Although 25% of ambulatory patients experience an adverse drug event, less than 0.3% of all adverse drug events and only 1% to 13% of serious events are reported to the US Food and Drug Administration.70 Transplant-specific vaccine trials are rapidly needed before any nonevidence-based medicine recommendations are made that are solely based on expert opinion and adverse event underreporting. Given the impaired immunity in transplant recipients and the possibility of vaccine-mediated immunomodulation, as dis­cussed above, and the consequent risk of acute and chronic allograft rejection, caution is needed in extrapolating findings and conclusions from short-term non-transplant trials to solid-organ transplant recipients.

Many questions remain unanswered about the design and conduct of the COVID-19 vaccine trials. These include why children, immunocompromised patients, and pregnant women have been excluded from most trials; whether long-term safety is being adequately evaluated; whether an accurate correlate of protective immunity is being well defined; and whether the deficiencies in our understanding of the clinical implications of pre-existing T-cell responses to SARS-CoV-2 are being adequately addressed. Sixty years after influenza vaccination became routinely recommended for people aged 65 years or older in the United States, it is still unclear whether this vaccination lowers mortality. Randomized trials with this outcome have never been done.

Importance of Informed Consent
Many of the various anti-COVID-19 vaccines were rushed shortly into testing, bypassing animal experimentations, and have been adopted for use before complete regulatory acceptance. This is happening through emergency use authorization, which helps accelerate vaccine deployment due to the emergency nature of the pandemic. However, this has led to a less than optimal collection of usually broad data concerning safety, immunogenicity, effectiveness, and time span of protection, as well as very short-term follow-up of only a few months.19,39 Along with the vital need for COVID-19 vaccines, there must be parallel respect of recognized clinical safety testing protocols during vaccine development and roll out, both before and after deployment. Only this will allow for public trust in vaccine safety.6

An important point to emphasize is the very intricate details that come into play when analyzing and comparing data from the current ongoing studies. These studies can vary on different parameters of design, such as primary endpoints (what is considered a COVID-19 case, study populations in term of genetic and environmental settings, background risks, statistical methods for efficacy analysis, and duration of exposure).71 In all vaccine trials, different subpopulation groups, including children, pregnant women, and immunocompromised patients, have been excluded. In addition, no information has been provided about participants’ application of protective measures, which may affect outcomes, mainly in the setting of national and international recommendations. These protective measures may change from state to state in the United States (Moderna study) and among different countries, with different cultures and different protective measures/policies and application of these measures (Pfizer-BioNTech study), which could affect outcomes by either underestimation or overestimation of COVID-19 cases as a result of variable application of personal protective measures.72

The efficacy of a given vaccine is usually reported as a relative risk reduction (RRR) using relative risk (the ratio of disease rates with and without a vaccine). However, the RRR should be viewed along with consideration of other risks of getting COVID-19, which may differ between populations and over time. To consider risk in whole populations, an absolute risk reduction (ARR) would be a more representative parameter to assess. However, ARRs tend to be ignored because they give a much less impressive effect size than RRRs (1.3% vs 67% for the AstraZeneca-Oxford, 1.2% vs 94% for the Moderna-NIH, 1.2% vs 67% for the Johnson & Johnson, 0.93% vs 90% for the Gamaleya, and 0.84% vs 95% for the Pfizer-BioNTech vaccines). Absolute risk reduction is also used to determine the number needed to vaccinate (NNV). This calculation shows how many people need to be vaccinated to prevent 1 case of COVID-19. Again, as with other parameters, the NNV varies from one population to another depending on many variables. The recent Israeli massive vaccination campaign using the Pfizer-BioNTech product represented the only reported indication of vaccine effectiveness.73 The reported RRR was 94%, similar to the RRR of the phase 3 interim trial (95%) but with an ARR of 0.46%, which translates into an NNV of 217 (when the ARR was 0.84% and the NNV was 119 in the phase 3 trial). This means that, in a real-life setting, 1.8 times more individuals may need to be vaccinated to prevent 1 more case of COVID-19 than predicted in the corresponding clinical trial.71

An unanswered question is whether a vaccine will have the same efficacy across different populations, in distinct regions, with the presence of different viral variants and with the application of variable protective, preventive, and therapeutic measures. Another critical point to mention is that the studies were not designed to look at degrees of prevention of hospitalization, severe disease, or death or on prevention of infection and transmission potential. This should all play an important role on whether we should widely apply a vaccine as planned with the current COVID-19 vaccines.40,71

Cardozo and colleagues addressed the nature of informed consent practices for vaccines, which normally comprise disclosure of minimal hazards such as injection site reactions, risks from past vaccines, such as Guillain-Barre syndrome for swine flu (which most probably influenced the concern in Astra Zeneca’s recent vaccine transverse myelitis and thrombotic incidents),24-28 Bell’s palsy,19,39 and generic proclamations about the possibility of particular allergic anaphylactic and systemic reactions. Specific risks derived from biological mechanisms and deaths are rarely included since there is typically vagueness and difficulties in their applicability.34

Given the valid concerns regarding the well-recognized short- and long-term safety issues, the experimental nature of the vaccination process, the limited short-term follow-up in the main trials, and the dismissal by law of pharma companies and health care providers from any medico-legal responsibilities,72 the application of informed consent should become not only a necessity but also mandatory by law in accordance with all international laws and declarations on human rights, as done for other medical procedures.74,75

Conclusions

With the presence of compelling evidence that antibody-dependent enhancement of immunity and other processes like molecular mimicry, potential genomic transformation, and death as non-theoretical risks for COVID-19 vaccines and the vague nature of informed consents, the disclosure of particular risks of aggravated COVID-19 disease from vaccination calls for a precise informed consent form and proof of patient understanding to meet medical ethics standards. Although the COVID-19 global health emergency has led to accelerated vaccine trials, such acceleration does not negate the need for further consideration to informed consent measures specific to COVID-19 vaccines and in particular in the subgroups of the population who were excluded from the initial interim trials, such as children, pregnant women, and solid-organ transplant patients. Our sacred role as physicians and our duty are to enlighten and empower people the best we can by offering them to the best of our knowledge all available information regarding all forms of preventive and curative therapeutic approaches72 in an unbiased way, allowing individuals to make the most appropriate decision regarding the vaccine.

Given the ongoing discord within the scientific community regarding this issue, mainly in relation to the short-term and long-term efficacy and safety of the different types of anti-SARS-CoV-2 vaccines, their experimental nature, and the availability of other alternative therapeutic approaches,72,75 such information should be universal and should be provided to every potential vaccine recipient in the form of an official digital written informed consent before registration for or receipt of the vaccine.


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Volume : 19
Issue : 8
Pages : 753 - 762
DOI : 10.6002/ect.2021.0235


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From the 1International American University College of Medicine, Vieux Fort, Saint Lucia; and the 2Rafik Hariri University Hospital, Beirut, Lebanon
Acknowledgements: A. Barbari is the President of the Middle East Society of Organ Transplantation, Professor of Medicine at the Lebanese Faculty of Medical Sciences, Director of the Renal Transplant Unit, Rafik Hariri University Hospital, and Nephrology Senior Consultant, Clemenceau Medical Center, Bir Hassan, Beirut, Lebanon. The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest. Both authors contributed equally to this work.
Corresponding author: Antoine Barbari, Rafik Hariri University Hospital, Beirut, Lebanon
Phone: +961 01 832 040
E-mail: barbariantoine@gmail.com