Aims of the study Patient comprehension is a critical part of meeting standards of informed consent in study designs. The aim of the study was to determine if extant 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 extant preclinical and clinical evidence that COVID-19 vaccines could worsen disease upon exposure to challenge or circulating virus. Results of the study Based on the history of coronavirus vaccine development, 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) of either infection or disease. Conclusions drawn from the study and clinical implications The specific and significant COVID-19 risk of ADE should have been and should be clearly and emphatically 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.

Aim: The COVID pandemic is caused by infection with the SARS-CoV-2 virus. The major mutation detected to date in the SARS-CoV-2 viral envelope spike protein, which is responsible for virus attachment to the host and is also the main target for host antibodies, is a mutation of an aspartate (D) at position 614 found frequently in Chinese strains to a glycine (G). We sought to infer health impact of this mutation. Result: Increased case fatality rate correlated strongly with the proportion of viruses bearing G614 on a country by country basis. The amino acid at position 614 occurs at an internal protein interface of the viral spike, and the presence of G at this position was calculated to destabilize a specific conformation of the viral spike, within which the key host receptor binding site is more accessible. Conclusion: These results imply that G614 is a more pathogenic strain of SARS-CoV-2, which may influence vaccine design. The prevalence of this form of the virus should also be included in epidemiologic models predicting the COVID-19 health burden and fatality over time in specific regions. Physicians should be aware of this characteristic of the virus to anticipate the clinical course of infection. What is known about this topic? Nothing is known about the health significance of the D614G SARS-CoV-2 variant. What does this article add? A molecular clue to viral molecular pathogenesis of COVID-19 disease.