key: cord-0920536-dmvalm9n authors: Knoll, Michael F.; Cooper, David K. C.; Bottino, Rita title: How the COVID‐19 pandemic may impact public support for clinical xenotransplantation in the United States? date: 2020-06-28 journal: Xenotransplantation DOI: 10.1111/xen.12623 sha: 9fc6efd51a50595c124827531b2f29454dc708da doc_id: 920536 cord_uid: dmvalm9n Many patients who would undergo organ transplantation cannot proceed due to the inability of human organ donation to satisfy medical needs. Xenotransplantation has the potential to offer unlimited availability of pig organs for transplantation, and pig‐to‐non‐human primate models have demonstrated outcomes that may soon justify clinical trials. However, one of the unique ethical challenges faced by xenotransplantation is that the risk of introducing potential zoonotic disease into the community must be weighed along with the benefit to the patient. While most experts believe that zoonosis is manageable, apprehension over disease transmission from animal donors to human recipients remains a frequent concern of many who are undecided or opposed to clinical xenotransplantation. The COVID‐19 pandemic represents a scenario (rapid worldwide spread of a highly contagious novel zoonotic disease with no natural defense in humans) that would seem to justify apprehension, especially in the United States, which has largely avoided previous pandemic outbreaks. However, there are many differences between zoonosis found in the wild or after xenotransplantation that favor the safety of the latter. Still, these differences, as well as the benefits of xenotransplantation, are not widely understood outside of the field. We must therefore ask what impact the COVID‐19 pandemic will have on attitudes toward xenotransplantation. clinical trials. However, one of the unique ethical challenges faced by xenotransplantation is that the risk of introducing potential zoonotic disease into the community must be weighed along with the benefit to the patient. While most experts believe that zoonosis is manageable, apprehension over disease transmission from animal donors to human recipients remains a frequent concern of many who are undecided or opposed to clinical xenotransplantation. The COVID-19 pandemic represents a scenario (rapid worldwide spread of a highly contagious novel zoonotic disease with no natural defense in humans) that would seem to justify apprehension, especially in the United States, which has largely avoided previous pandemic outbreaks. However, there are many differences between zoonosis found in the wild or after xenotransplantation that favor the safety of the latter. Still, these differences, as well as the benefits of xenotransplantation, are not widely understood outside of the field. We must therefore ask what impact the COVID-19 pandemic will have on attitudes toward xenotransplantation. COVID-19, pandemic, PERV, xenotransplantation, zoonosis 2 of 3 | COMMENTARY genetic engineering technology to improve pig donor compatibility with primate recipients, and (c) the introduction of novel immunosuppressive agents capable of overcoming the remaining immunological barriers. [7] [8] [9] [10] [11] Benchmarks of success in pig-to-non-human primate xenotransplantation may soon justify clinical trials. However, anxiety felt over COVID-19 may lead many to question the safety of xenotransplantation. The rapid spread of COVID-19 demonstrates the difficulty in controlling a novel pathogen occurring in nature. In China, and even in the United States, with advance warning, COVID-19 quickly spread beyond easy containment. During this time of heightened concern over the ability of zoonotic diseases to spread, it is important to recognize that the deliberate and controlled nature of xenotransplantation provides a level of safety not found in nature. 12 There will be several differences between clinical xenotransplantation and a natural outbreak of a virus into the community, and these are all in favor of xenotransplantation. 1. The designated pathogen-free organ-source pigs will be bred and housed under strict biosecure isolation conditions and will not be exposed to any animal vector that could transfer a pathologic microorganism to the pigs. The US Food and Drug Administration's (FDA) guidelines require that only the second generation of pigs in the facility can be used as sources of organs for clinical trials. 13 The founder pigs will be born by Cesarean section, immediately transferred into the biosecure facility, and raised under these isolation conditions, but it will only be their offspring (born and raised entirely within the facility) that will be able to provide organs for human recipients. 4. The specific organ-source pig will be tested before or at the time of organ transplantation to ensure no transfer of a potentially pathologic microorganism to the recipient. 5 . In the initial clinical trials, the number of patients who will be included will be very small, and the trial will be spread over a relatively long period of time. This will provide time to determine whether any infectious (or other) complication has developed before a subsequent patient receives a pig organ graft. 6 . The recipient of the pig graft will be monitored by the medical team at regular intervals, and this will include monitoring for novel infectious complications. 7. If relative self-isolation is maintained during the first few weeks after the transplant, any patient that might develop features of infection can be immediately isolated for investigation, and his/ her contacts can be readily traced. When this proposed protocol is compared with the circumstances that the community has been exposed to during the COVID-19 outbreak, and furthermore compared with the usual scenario when an organ from a deceased human donor is transplanted, the differences will be obvious. The risk of a pathologic microorganism, for example, cytomegalovirus and Epstein-Barr virus, being transferred with a deceased human organ is high, and even the transfer of an unusual or rare infectious agent, for example, rabies and West Nile virus, cannot be entirely excluded. 14 Typically, unexpected donor-derived infections are recognized only when identical infections occur among a cluster of recipients of organs from a specific deceased human donor. 15 This will not be the case with the first trials of xenotransplantation. Porcine endogenous retroviruses (PERVs) represent a special case of potential infection. They can infect human cells in specific laboratory conditions, 16, 17 but experts have pointed to several key factors that mitigate this threat. 18 PERV can be inactivated [24] [25] [26] or deleted 27,28 by genetic manipulation, if this is believed to be necessary (which is not the case at present). 14 (e) PERVs are susceptible to several pharmacologic agents available to us at present. 29, 30 It has been said that adversity provides opportunity. That the current pandemic provides adversity is apparent, and opportunities, though less visible, must be sought. A new respect for researchers seeking vaccines and other solutions to the COVID-19 crisis may also provide credibility for those in xenotransplantation research. As some physicians have advocated treatments for COVID-19 that are unwarranted by scientific evidence or have not undergone adequate testing, it is important that scientists advocating for xenotransplantation stick to a consensus and not risk the credibility of the field in this manner. The likely immediate aftermath of the pandemic may be a less favorable landscape for xenotransplantation unless supporters present a positive message. As part of its mission, the International Xenotransplantation Association is positioned to play a role in educating the public with consensus opinions backed by solid scientific evidence that mitigates concerns about safety and demonstrates a more balanced risk-to-reward ratio. We have the data and the message, all that remains is to move forward with careful deliberation in these uncertain times. The authors would like to acknowledge the brave individuals who have helped to minimize the disruptions brought about by the COVID-19 pandemic, the medical workers who are caring for patients under difficult conditions, and those who have battled or continue to battle the disease. David K. C. Cooper https://orcid.org/0000-0002-8899-9431 Recent advances in understanding xenotransplantation: implications for the clinic Meta-analysis of public perception toward xenotransplantation. Xenotransplantation. 2020:e12583 Building the road to a regional zoonoses strategy: a survey of zoonoses programmes in the Americas The proximal origin of SARS-CoV-2 Coronavirus COVID-19 global cases by the Center for Systems Science and Engineering Impact of 2009 pandemic H1N1 influenza A virus on veterinary students' perception of xenotransplantation Renal xenotransplantation: experimental progress and clinical prospects Xenotransplantation: back to the future? Xenotransplantation: current status in preclinical research Genetically modified pigs as donors of cells, tissues, and organs for xenotransplantation Introduction: the present status of xenotransplantation research Xenotransplantation: public health risks-patient vs society in an emerging field Source animal, product, preclinical, and clinical issues concerning the use of xenotransplantation products in humans; guidance for industry Infectious disease risks in xenotransplantation Donor-derived infection-the challenge for transplant safety Infection of human cells by an endogenous retrovirus of pigs Type C retrovirus released from porcine primary peripheral blood mononuclear cells infects human cells Porcine endogenous retrovirus (PERV) -molecular structure and replication strategy in the context of retroviral infection risk of human cells Cellular xenotransplantation of animal cells into people: benefits and risk Search for cross-species transmission of porcine endogenous retrovirus in patients with living pig tissue: the XEN III study group Microbiological safety of the first clinical pig islet xenotransplantation trial in New Zealand Why was PERV not transmitted during preclinical and clinical xenotransplantation trials and after inoculation of animals? Retrovirology How active are porcine endogenous retroviruses (PERVs)? Viruses Inhibition of porcine endogenous retroviruses (PERVs) in primary porcine cells by RNA interference using lentiviral vectors Knockdown of porcine endogenous retrovirus (PERV) expression by PERV-specific shRNA in transgenic pigs Production of transgenic pigs that express porcine endogenous retrovirus small interfering RNAs Genome-wide inactivation of porcine endogenous retroviruses (PERVs) Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9 Antiretroviral agents inhibit infection of human cells by porcine endogenous retroviruses Can antiretroviral drugs be used to treat porcine endogenous retrovirus (PERV) Infection after Xenotransplantation? Viruses