Uninformed Consent: Do Subjects Need Warning that a COVID-19 Vaccine Can Worsen Disease?

Uninformed Consent Do Subjects Need Warning that a COVID-19 Vaccine Can Worsen Disease

On October 28, the International Journal of Clinical Practice published, “Informed consent disclosure to vaccine trial subjects of risk of COVID‐19 vaccines worsening clinical disease.” The authors of this perspective piece are NYU Grossman School of Medicine molecular pharmacologist Timothy Cardozo and Tulane University primate disease expert Ronald Veazey. Noting that “patient comprehension” is a key element of meeting ethical standard for informed consent, the authors sought to see if the extent literature leads to a requirement that clinicians, “disclose the specific risk that COVID‐19 vaccines could worsen disease upon exposure to challenge or circulating virus.” To conduct the review, published literature was examined for preclinical or clinical evidence that a COVID-19 vaccine might worsen the disease when subjects get exposed to the virus in the community or in a clinical challenge. The clinical trial protocols for vaccines were analyzed to see if such, “risks were properly disclosed.”

Risk of Antibody-Dependent Enhancement 

Veazey and Cardozo’s findings include the fact that vaccines for COVID-19 which elicit neutralizing antibodies might sensitize folks, “to more severe disease than if they were not vaccinated.” While no vaccines are approved for SARS, MERS, or RSV, data from vaccine trials for those diseases raise, “a serious mechanistic concern.” Namely, that vaccines developed with traditional methods such as using unmodified or minimally modified viral spikes to promote neutralizing antibodies could worsen COVID-19 due to antibody-dependent enhancement (ADE). Such risk exists with protein, viral vector, DNA, or RNA based vaccines. This risk is obscured in trial protocols and consent forms to the degree that, “adequate patient comprehension of this risk is unlikely to occur, obviating truly informed consent by subjects in these trials.” It is argued in conclusion that 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.” 

Nature Weighs In

Back on September 9, Nature Microbiology took a look at the ADE issue in the COVID-19 context. They also note that study data from the SARS-CoV experience suggests that SARS-CoV-2 antibodies, “could exacerbate COVID-19 through antibody-dependent enhancement.” In the past, studies revealed a danger of ADE in dengue and syncytial virus vaccines, leading to failed trials. The Nature article focuses on three points: key ADE mechanisms, strategies to mitigate such dangers for a COVID-19 vaccine, and a look at recent data to help determine how risky a COVID-19 vaccine might be. A major goal of a vaccine is to generate antibodies that can prevent SARS-CoV-2 from entering human cells, by “blocking either ACE2–RBD binding interactions or S-mediated membrane fusion.” The authors note that ADE can make multiple viral infections worse, including the measles. With respiratory infections like COVID-19, ADE is part of a broader category of “enhanced respiratory disease” (ERD) that also includes cytokine cascades and cell-mediated immunopathology. ERD-related clinical presentations are associated with medical interventions such as vaccines, but similar symptoms can be caused by natural infections. Ergo, ERD is detected in trials, “by comparing the distribution of disease severities between the intervention and placebo study arms.”

Broadly speaking ADE, can be “categorized into two different types based on the molecular mechanisms involved,” and the first is ADE via enhanced infections. Here, higher rates of infection for target cells happen in an antibody-dependent fashion and are mediated by Fc-FcR interactions. The most well-documented example is with Dengue virus. Second is ADE via immune activation. Here, enhanced disease is caused by overactive Fc-mediated effector functions, “and immune complex formation is an antibody-dependent manner.” Antibodies tied to enhanced viral disease are often non-neutralizing. Worries about ADE were raised in the SARS context, when “seroconversion and neutralizing antibody responses were found to correlate with clinical severity and mortality.” Similar findings in COVID-19 patients have been reported, with increased antibodies being tied to more severe disease. A simple hypothesis would be that severe COVID-19 cases cause greater antibody titres. But a recent study showed that upper respiratory tract viral shedding was, “indistinguishable between patients with asymptomatic and symptomatic COVID-19.” The symptomatic folks had higher antibody titres and also cleared the virus quicker, contradicting the “simple hypothesis” above.

Are COVID-19 Vaccines Going to Be Safe?

Safety worries about COVID-19 vaccines began when mouse studies showed ERD, or enhanced immunopathology with SARS-CoV following a viral challenge. Observers found that the pathology was related to Th2-cell-biased response and was mainly against the nucleocapsid protein. The pathology was not seen, “in challenged mice following the passive transfer of nucleocapsid-specific immune serum, confirming that the enhanced disease could not be replicated using the serum volumes transferred.” The evidence regarding vaccine-induced ADE in SARS-CoV animal models is “conflicting” and does raise safety concerns. Notably, vaccines that promote neutralizing antibodies, “against the S protein reliably protect animals from SARS-CoV challenge without evidence of enhancement of infection or disease.” 

So, the data suggest, “that human immunization strategies for SARS-CoV-2 that elicit high neutralizing antibody titres have a high chance of success with minimal risk of ADE.” As an example, “subunit” vaccines which elicit S-specific neutralizing antibodies should involve a lower ADE risk. Such “modern immunogen design” should preclude or reduce the immunopathology that  can be associated with non-neutralizing antibodies. Since ADE has been seen with SARS, MERS, and other viral infections, there is a real risk of ADE with a COVID-19 vaccine or antibody-based interventions. But clinical data has not “fully established” a place for ADE in COVID-19 pathology. Moving ahead, it will be key to look at animal and human datasets “for signs of ADE” and also to balance ADE-related risks against treatment efficacy “if clinical ADE is observed.” The authors conclude that, “Ongoing animal and human clinical studies will provide important insights into the mechanisms of ADE in COVID-19. Such evidence is sorely needed to ensure product safety in the large-scale medical interventions that are likely required to reduce the global burden of COVID-19.”

Responses

  1. Great article on a very important topic! ADE has been seen in other coronaviruses. It is a major concern with both natural immunity and vaccination derived immunity. From past cases of natural immunity there have been a growing number of cases of reinfection. Roughly 50% of those cases have been more severe in the second infection. This would support the theory that ADE is being seen in Covid-19 with natural immunity. Vaccination derived immunity is much more specific where it elicits antibodies for very discrete components of the SARS-CoV-2 virus i.e. the Spike protein or the receptor binding domain of the Spike protein. This approach should result is a much lower risk of ADE. Also, to date there is nothing in the early vaccine trial data that shows a signal of ADE. This is very good news. However, this needs to be monitored further as the numbers of vaccinated individuals increases who contract the virus. In addition, the vaccine designs vary greatly with some being much broader in the scope of the immunogenicity they illicit. This means that each vaccine should be monitored individually for signs of ADE.