PERSPECTIVES www.jasn.org

SARS-CoV-2 Vaccines in Kidney Transplant Recipients: Will They Be Safe and Effective and How Will We Know?

Madeleine R. Heldman and Ajit P. Limaye

Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington

JASN 32: ccc–ccc, 2021. doi: https://doi.org/10.1681/ASN.2021010023

Coronavirus disease 2019 (COVID-19) will far outweigh risks of vaccination. viral vector–based vaccines could be- has had a major effect on kidney and Accordingly, current guidance from come replication competent and cause other solid organ transplant recipients.1 multiple professional organizations disease, especially in immunocompro- In addition to public health measures, recommend vaccination for all eligible mised individuals. For example, in cells improved access to testing, and thera- organ transplant recipients.2,4,5 concurrently infected with two different peutic developments, vaccination has Each vaccine platform has distinct AdVes, homologous recombination of emerged as a key tool for controlling safety considerations for kidney transplant genetic elements could occur and result the ongoing pandemic. In December recipients. Live (replication-competent) in the emergence of new, pathogenic, 2020, multiple regulatory agencies vaccines are generally contraindicated in replication-competent AdV types.9 This worldwide authorized the use of two immunocompromised individuals be- has been observed in patients with ad- mRNAvaccines for severe acute respiratory cause of a risk of vaccine-acquired dis- vanced HIV disease during natural AdV syndrome coronavirus 2 (SARS-CoV- ease.6 The SARS-CoV-2 candidate vaccines infections, and is theoretically possible 2), and several other vaccine platforms that are furthest along in development with AdV vector–based vaccines in pa- are in advanced-stage clinical trials.2,3 do not contain replication-competent tients who are immunocompromised Individuals who have received a trans- SARS-CoV-2 virus, and therefore do with a concurrent wild-type AdV infec- planted kidney or other solid organ not carry risk of SARS-CoV-2 infection tion.9 Although infrequent, severe AdV have been identified as high-risk popu- (Table 1). infections, including allograft nephritis, lations and prioritized for vaccination However, viral vector–based vaccines can occur in kidney transplant recipients in public health guidelines, but unfortu- that incorporate viruses other than during natural infection.9 Notably, nately have been excluded from major SARS-CoV-2 are in advanced-phase vaccine-associated AdV disease has not SARS-CoV-2 vaccine clinical trials.1,2 studies, including adenovirus (AdV) been reported, albeit there is little ex- Thus, studies are urgently needed to vector–based vaccines that have been li- perience in immunocompromised characterize the safety, immunogenicity, censed in Europe. These vaccines consist populations. and ultimately, efficacy of SARS-CoV-2 of intact virions that are engineered to It should be emphasized that, de- vaccines for such patients. include the gene encoding the SARS- spite the theoretical concerns with Below, we provide an overview of CoV-2 spike protein, a technique that replication-deficient viral vector–based SARS-CoV-2 vaccines and highlight leverages the viral vector’s ability to effi- vaccines, immunosuppression is not key concepts that should be considered ciently infect cells and enhances spike considered a contraindication to their in evaluating their safety in solid organ gene delivery. Vaccines that use viral vec- use.11 Replication-competent viral- transplant recipients. Despite the theo- tors contain either replication-deficient vectored vaccines carry a greater risk of retical concerns described below, we em- or replication-competent viruses (Ta- vaccine-derived vector infection in phasize that available evidence from ble 1). The majority of viral-vectored studies demonstrates safety and effi- vaccines in the most advanced phases cacy in the general population. Because of development have been rendered Published online ahead of print. Publication date of the known substantial risks of replication-deficient through deletion available at www.jasn.org. COVID-19–associated morbidity and of genes essential for replication.8 By Correspondence: Dr.AjitP.Limaye,Professorof mortality in recipients of kidney and limiting vector replication, the potential Medicine, Division of Allergy and Infectious Dis- eases, University of Washington, 1959 NE Pacific other solid organs, and the long track for vaccine-associated AdV disease is Street, Seattle, WA 98195-6174. Email: limaye@uw. record of safety of other vaccinations in greatly diminished. edu such recipients, we anticipate the ben- There are, however, theoretical mech- Copyright © 2021 by the American Society of efits of selected SARS-CoV-2 vaccines anisms by which replication-deficient Nephrology

JASN 32: ccc–ccc, 2021 ISSN : 1046-6673/3205-ccc 1 2 PERSPECTIVES Table 1. Major SARS-CoV-2 platforms in developmenta Vaccine Name Safety and Efficacy in the General Specific Considerations for JASN Vaccine Platform Vehicle Phase of Development Adjuvant (Manufacturer) Population Kidney Transplant Recipients mRNA BNTb162b2 (Pfizer/ mRNA encapsulated in Authorized for Unadjuvanted, 95% efficacy in phase 3 trials.1 Does not contain live virus. No BioNTech) lipid nanoparticles emergency use in the but lipid Anaphylaxis has been evidence of vaccine- mRNA-1273 (Moderna) United States and other nanoparticles reported. Avoid in patients induced off-target immune www.jasn.org countries possess with a known allergy to a responses in large phase 3 natural vaccine component (e.g., clinical trials.2,3 adjuvant polyethylene glycol). Close activity7 monitoring after administration for patients with a history of anaphylaxis to any food or drug.3 Replication-defective AZD122 (Oxford/ Human-chimpanzee Phase 3 Unadjuvanted 70%–90% efficacy depending Removal of genes necessary viral vectors AstraZeneca) adenovirus (ChAdOx1) on dose in phase 3 trials.8 for replication reduces risk of Transverse myelitis vaccine-associated AdV reported.8 disease.9 Theoretical risk of JNJ78436735/ Human adenovirus Phase 3 Unadjuvanted Unknown emergence of new AdV type Ad26.COV2.S (Janssen) (Ad26) with replicative potential Convidecia (Ad5-nCov) Human adenovirus (Ad5) Approved for limited use Unadjuvanted Unknown through homologous in China recombination, although Sputnik V (Gamaleya) Human adenovirus (Ad5 Early use in Russia, Unadjuvanted Unknown this has never been and Ad26 in Belarus, and Argentina demonstrated to occur with consecutive doses) AdV-vectored vaccines.9 Protein subunit NVX-CoV2373 (Novavax) Recombinant spike Phase 3 Matrix-M1 Unknown Does not contain live virus. glycoprotein system plus Matrix-M1 contains the an additional, same QS21 saponin as the unnamed AS01B adjuvant system adjuvant contained in the recombinant varicella zoster vaccine.7 SARS-CoV-2 recombinant Recombinant spike Phase 2 AS03 adjuvant Unknown High incidence of anti-HLA protein formulation protein antibodies in KTR (GSK/Sanofi) vaccinated with AS03- adjuvanted influenza vaccines, but no association between AS03 exposure and 3,10 JASN rejection. EpiVacCorona (Vector Peptide epitope Early use in Russia Unknown Limited data available 32: Institute) ccc Whole-inactivated BBIBP-CoV (Sinopharm) Whole-inactivated SARS- Limited use in China and Unknown Unknown Does not contain live virus. –

ccc (killed) CoronaVac (SinoVac) CoV-2 viral particles other countries Limited data available in peer-reviewed literature. ,2021 GSK, GlaskoSmithKline; KTR, kidney transplant recipients. aDoes not include all candidate vaccines or platforms under investigation; limited to platforms in advanced stages of clinical development or authorized for use as of December 31, 2020. www.jasn.org PERSPECTIVES patients who are immunocompromised allograft rejection. Concern about adju- organ transplant recipients suggest they and should only be administered under vant safety in organ transplant recipients have relative humoral response rates that carefully controlled circumstances (spe- arose from observations of an unusually are approximately 50%–70%ofthose cifically, clinical trials). Other vaccine high incidence of anti-HLA antibodies seen in nontransplant populations.6,7 candidates that are in advanced stages in kidney transplant recipients who re- Patients with ESRD may have more a ro- of development, including mRNA, pro- ceived the 2009 influenza A(H1Na1) bust response to vaccines before rather tein subunit, or whole virus–inactivated pdm09 vaccine, which contained the than after kidney transplant,6 and when SARS-CoV-2 vaccines, do not contain squalene-based AS03 adjuvant system.6,7 possible, SARS-CoV-2 vaccines should intact virus and thus do not carry a risk However, only a fraction of these anti- be given before transplantation.2 In the of vaccine-associated infection.3 HLA antibodies were donor specific, and post-transplant setting, age .65 years, Induction of generalized systemic in- a subsequent investigation of .10,000 more recent transplantation, use of flammation by either the vaccine antigen solid organ transplant recipients found mycophenolate and mammalian target or an associated adjuvant, or by more no definitive association between the of rapamycin inhibitors, and lower specific cellular and humoral cross- AS03 adjuvant system and acute allograft graft function are associated with de- reactivity between vaccine epitopes rejection.6 The AS01B adjuvant used in creased serologic responses to influ- and allograft antigens, theoretically the recombinant varicella zoster virus enza vaccines.6,7 Despite the effects of could promote undesired allograft- vaccine contains a combination of lymphocyte-depleting immunosuppres- directed immune responses. AdV vectors monophosphoryl lipids and QS21, a sa- sion in the early period after transplant elicit potent innate immune responses ponin.13 This adjuvant induces a potent or treatment for rejection, the benefits of through complement activation and innate immune response and associated even modest SARS-CoV-2 protection induce a diverse cytokine repertoire.10 concerns for precipitating acute allograft might outweigh the risk of delaying im- Although this phenomenon is most rejection in kidney transplant recipients. munization during a pandemic.2 In gen- prominent at the site of AdV-vector in- Several recombinant spike protein eral, vaccines are not recommended oculation, systemic inflammation SARS-CoV-2 vaccines contain adju- immediately post-transplant due to a could promote vaccine-associated allo- vants, such as AS03 and the novel Matrix presumed decrease in immunogenicity graft rejection. Concern for autoimmu- M1 adjuvant, which contains the same after recent high-level immunosuppres- nity related to the SARS-CoV-2 vaccine QS21 saponin found in the recombinant sion. Expert opinion advises that delaying on the basis of a modified chimpanzee varicella zoster vaccine.3 Viral-vectored SARS-CoV-2 vaccination of vaccine- AdV vector (ChAdOx1) arose after two and mRNA vaccines do not generally naive transplant recipients until 3 months vaccine recipients developed transverse contain adjuvants, although lipid nano- after transplant or receipt of T cell or B cell myelitis, although the possibility of an particle delivery devices used in the ablative therapies may be appropriate; unrecognized preexisting demyelinating mRNA vaccines have natural adjuvant for patients who received a first dose condition has raised questions about activity.13 before transplant, administration of the significance of one of these events.8 Postmarketing surveillance will be es- theseconddoseshouldbedelayeduntil In vitro reactivity between spike protein sential to assess any potential association at least 4 weeks post-transplant.2 Higher antibodies and human collagen has between SARS-CoV-2 vaccine compo- doses, booster doses, adjuvants, and in- been demonstrated, but molecular nents and acute allograft rejection. In tradermal delivery have all been used mimicry has not been identified as a the interim, theoretical concerns associ- with variable success to improve immu- primary mechanism of kidney injury ated with any vaccine must be weighed nogenicity of commonly administered in COVID-19.12 Available data suggest against the benefits of preventing vaccines in solid organ transplant recip- acute allograft rejection is uncommon or mitigating the severity of a life- ients.6,7 If immunogenicity of standard during COVID-19, despite frequent re- threatening infection in a vulnerable regimens in kidney transplant recipients duction in immunosuppression as a population. We emphasize that a broad is suboptimal, these alternative ap- therapeutic strategy.1 In the absence range of vaccines have a substantial track proaches should be considered. of an observed association between record of safety in kidney and other solid The diversity of vaccine platforms natural SARS-CoV-2 infection and organ transplant recipients. Further- and phased vaccine allocation present acute allograft rejection in kidney more, no definitive association between unique challenges for assessing the transplant recipients, it is unlikely that any vaccine or adjuvant and allograft re- safety, immunogenicity, and efficacy of vaccine antigens would precipitate jection has been identified to date.2,6 SARS-CoV-2 vaccination in kidney clinically significant immune responses Immunosuppression in kidney trans- transplant recipients. Surveillance for to renal allografts. plant recipients is anticipated to reduce adverse events related to each specific In general, adjuvants used to enhance the immunogenicity of SARS-CoV-2 formulation through prospective multi- vaccine immunogenicity also elicit non- vaccines, and immunogenicity may center registries of vaccinated solid organ specificinflammatory responses, and vary by vaccine platform. Available data transplant recipients is one potential thus have the potential to induce acute across a broad range of vaccines in solid approach to assessing safety, especially

JASN 32: ccc–ccc, 2021 SARS-CoV-2 Vaccines after Transplant 3 PERSPECTIVES www.jasn.org given that large population-specific vaccination of caregivers and close REFERENCES studies of kidney transplant recipients contacts of kidney transplant recipients, may not be feasible. Prospective clini- recommended for influenza vaccination, 1. Kates OS, Haydel BM, Florman SS, Rana MM, cal trials should directly compare dif- would be an important strategy to reduce Chaudhry ZS, Ramesh MS, et al.; UW ferent SARS-CoV-2 vaccine platforms, the risk of infection.6 Assessment of vac- COVID-19 SOT Study Team: COVID-19 in fi solid organ transplant: A multi-center cohort assess the magnitude and durability of cine ef cacy against emerging SARS- study [published online ahead of print August humoral and cellular responses, and CoV-2 variants is necessary to establish 7, 2020]. Clin Infect Dis 10.1093/cid/ciaa1097 utilize the same functional laboratory optimal vaccine strategies for both im- 2. 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