key: cord-0760865-gw9hkw00 authors: Cardozo, Timothy; Veazey, Ronald title: Informed consent disclosure to vaccine trial subjects of risk of COVID‐19 vaccines worsening clinical disease date: 2020-10-28 journal: Int J Clin Pract DOI: 10.1111/ijcp.13795 sha: 6d240b44eeb11ac084b9a264ddad7ecf94b38516 doc_id: 760865 cord_uid: gw9hkw00 AIMS OF THE STUDY: Patient comprehension is a critical part of meeting medical ethics standards of informed consent in study designs. The aim of the study was to determine if sufficient literature exists to require clinicians to disclose the specific risk that COVID‐19 vaccines could worsen disease upon exposure to challenge or circulating virus. METHODS USED TO CONDUCT THE STUDY: Published literature was reviewed to identify preclinical and clinical evidence that COVID‐19 vaccines could worsen disease upon exposure to challenge or circulating virus. Clinical trial protocols for COVID‐19 vaccines were reviewed to determine if risks were properly disclosed. RESULTS OF THE STUDY: COVID‐19 vaccines designed to elicit neutralizing antibodies may sensitize vaccine recipients to more severe disease than if they were not vaccinated. Vaccines for SARS, MERS and RSV have never been approved, and the data generated in the development and testing of these vaccines suggest a serious mechanistic concern: that vaccines designed empirically using the traditional approach (consisting of the unmodified or minimally modified coronavirus viral spike to elicit neutralizing antibodies), be they composed of protein, viral vector, DNA or RNA and irrespective of delivery method, may worsen COVID‐19 disease via antibody‐dependent enhancement (ADE). This risk is sufficiently obscured in clinical trial protocols and consent forms for ongoing COVID‐19 vaccine trials that adequate patient comprehension of this risk is unlikely to occur, obviating truly informed consent by subjects in these trials. CONCLUSIONS DRAWN FROM THE STUDY AND CLINICAL IMPLICATIONS: The specific and significant COVID‐19 risk of ADE should have been and should be prominently and independently disclosed to research subjects currently in vaccine trials, as well as those being recruited for the trials and future patients after vaccine approval, in order to meet the medical ethics standard of patient comprehension for informed consent. This article is protected by copyright. All rights reserved well as those being recruited for the trials and future patients after vaccine approval, in order to meet the medical ethics standard of patient comprehension for informed consent. There is extensive knowledge of the risk of ADE in prior viral epidemics of SARS, MERS, dengue, measles and RSV. There is extensive knowledge about the molecular similarities between SARS, MERS and SARS-CoV-2, the causative agent of COVID-19, and extensive knowledge about the pattern of COVID-19 disease in individuals and populations. The composition and design of SARS, MERS and COVID-19 vaccines are known. Based on the clinical trial protocols, physicians are unlikely to be prominently and clearly disclosing the risk of ADE to COVID-19 vaccine recipients in clinical trials, which portends the standard of care after vaccine approval. Whether ADE will and has been occurring in COVID-19 remains unproven. This review reveals that the probability that ADE is occurring or will occur in COVID-19 and vaccine recipients is high enough to be significant, requiring disclosure as a specific, and probably the paramount, risk in informed consents for COVID-19 vaccines. This article is protected by copyright. All rights reserved Vaccine-elicited enhancement of disease was previously observed in human subjects with vaccines for respiratory syncytial virus (RSV), dengue virus and measles 1 . Vaccine-elicited enhancement of disease was also observed with the SARS and MERS viruses and with feline coronavirus, which are closely related to SARS-CoV-2, the causative pathogen of COVID-19 disease. The immune mechanisms of this enhancement have invariably involved antibodies, from direct antibody-dependent enhancement, to immune complex formation by antibodies, albeit accompanied by various coordinated cellular responses, such as Th2 Tcell skewing [2] [3] [4] [5] [6] [7] . Notably, both neutralizing and non-neutralizing antibodies have been implicated. A recent study revealed IgG-mediated acute lung injury in vivo in macaques infected with SARS that correlated with a vaccine-elicited, neutralizing antibody response 8 . The elicitation of antibodies, specifically neutralizing antibodies, is the goal of nearly every current SARS-CoV-2 vaccine candidate. The prior evidence that vaccine-elicited, antibodydependent enhancement (ADE) of disease is likely to occur to some degree with COVID-19 This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved after vaccination, which is when ADE/immunopathology is designed to occur. Thus, the absence of ADE evidence in COVID-19 vaccine data so far does not absolve investigators from disclosing the risk of enhanced disease to vaccine trial participants, and it remains a realistic, non-theoretical risk to the subjects. Informed consent procedures for vaccine trials commonly include disclosure of very minor risks such as injection site reactions, rare risks from past, unrelated vaccines/viruses, such presented by this report and widely available to any skilled practitioner in the field establishes that patient comprehension of the specific risk that receiving the vaccine could convert a subject from someone who experiences mild disease to someone who experiences severe disease, lasting morbidity or even death is unlikely to be achieved by the informed consent procedures planned for these clinical trials. Medical ethics standards required that, given the extent of evidence in the medical literature reviewed above, the risk of ADE should be clearly and emphatically distinguished in the informed consent from risks observed rarely as well as the more obvious risk of lack of efficacy, which is unrelated to the specific risk of ADE. Based on the published literature, it should have been obvious to any skilled medical practitioner in 2019 that there is a significant risk to vaccine research subjects that they may experience severe disease once vaccinated, while they might only have experienced a mild, self-limited disease if not vaccinated. The consent should also clearly distinguish the specific risk of worsened COVID-19 disease from generic statements about risk of death and generic risk of lack of efficacy of the vaccine. Given the strong evidence that ADE is a non-theoretical and compelling risk for COVID-19 vaccines and the "laundry list" nature of informed consents, disclosure of the specific risk of This article is protected by copyright. All rights reserved worsened COVID-19 disease from vaccination calls for a specific, separate, informed consent form and demonstration of patient comprehension in order to meet medical ethics standards. The informed consent process for ongoing COVID-19 vaccine trials does not appear to meet this standard. While the COVID-19 global health emergency justifies accelerated vaccine trials of candidates with known liabilities, such an acceleration is not inconsistent with additional attention paid to heightened informed consent procedures specific to COVID-19 vaccine risks. TC and RV conceived this commentary. TC wrote the manuscript. RV edited and approved the manuscript. Vaccineinduced enhancement of viral infections Biology of Infection and Disease Pathogenesis to Guide RSV Vaccine Development Potential for developing a SARS-CoV receptorbinding domain (RBD) recombinant protein as a heterologous human vaccine against coronavirus infectious disease (COVID)-19 SARS vaccine development. Emerging infectious diseases Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus Immunodominant SARS Coronavirus Epitopes in Humans Elicited both Enhancing and Neutralizing Effects on Infection in Nonhuman Primates Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection Antibody profiles in mild and severe cases of COVID-19 Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology Convergent Antibody Responses to SARS-CoV-2 Infection in Convalescent Individuals Accepted Article This article is protected by copyright. All rights reserved 12 Recent Advances in the Vaccine Development Against Middle East Respiratory Syndrome-Coronavirus Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates. The New England journal of medicine Phase 1/2 study of COVID-19 RNA vaccine BNT162b1 in adults SARS-CoV-2 viral spike G614 mutation exhibits higher case fatality rate. International journal of clinical practice Evidence that D614G Increases Infectivity of the COVID-19 Virus The SARS-CoV-2 Spike Variant D614G Favors an Open Conformational State The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity What should be disclosed to research participants? Three Major COVID Vaccine Developers Release Detailed Trial Protocols Supported by NIH award R21AI157604 (to TC). All data referenced in this report has been published in peer-reviewed literature or is available on the World Wide Web/Internet at the URL's indicated in the References section.Therefore, all data referenced in this report is publicly available in widely available data repositories. This article is protected by copyright. All rights reserved