An immunoinformatic approach to universal therapeutic vaccine design against BK virus Varun Kesherwani a , Shikha Tarang b,⇑ a Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA b Creighton University School of Dentistry, Department of Oral Biology, Omaha, NE 68178, USA article info Article history: Received 24 December 2018 Received in revised form 10 April 2019 Accepted 30 April 2019 Available online xxxx Keywords: BK virus (BKV) BKV-associated nephropathy (BKVAN) Kidney-transplant recipients (KTRs) Reverse vaccinology Multi-epitope subunit vaccine for BKV (MVBKV) HLA (human leukocyte antigen) abstract In kidney transplant recipients (KTRs) long-term immunosuppression leads to BK virus (BKV) reactiva- tion, with an increased incidence of BKV-associated pathologies and allograft rejection. The current approaches to limit BKV infection include a reduction in immunosuppression and use of anti-BKV drugs, which are clinically sub-optimal and lead to undesirable therapeutic outcomes. Here, we adopted an immune-based approach to augment the endogenous BKV specific T-cells. Using reverse vaccinology based in silico analyses, we designed a peptide-based multi-epitope vaccine for BKV (MVBKV). A major advantage of our approach is that the selected epitopes show an affinity towards all the 12 superfamilies of HLA class I alleles and 27 reference alleles of HLA class II. This suggests MVBKV’s universal nature and its potential effectiveness in a wide-population base. To improve MVBKV’s immunogenic properties, a synthetic Toll-like Receptor (TLR) 4 peptide ligand (RS09) was added to the final vaccine construct. The sequences of the individual epitopes were molecularly linked to form a 3D-stable synthetic protein. Overall, our immunoinformatic-based approach led to the design of a new MVBKV vaccine, which remains to be validated experimentally. Ó 2019 Elsevier Ltd. All rights reserved. 1. Introduction BK virus (BKV) is a small, non-enveloped double-stranded DNA virus. Most people get BKV infection during childhood, which per- sists in adults as a latent infection without any major symptoms [1–4]. However, immunosuppression in kidney transplant recipi- ents (KTRs) leads to BKV reactivation and emergence of life- threatening conditions. An untreated BKV infection can lead to sev- ere complications such as BKV-associated nephropathy (BKVAN), BKV-associated hemorrhagic cystitis (BKVHC), and ureteric steno- sis [5–8]. While several factors contribute to an increased risk of BKV reactivation, it’s prevalence varies between 11 and 43% in kid- ney transplant patients [9]. The single most important risk factor contributing to an opportunist BKV reactivation is the overall degree of immunosuppression after renal transplant, which causes the development of BKVAN leading to allograft dysfunction and rejection [10–12]. Therefore, decreasing immunosuppression (thereby boosting the body’s immune system) to limit BKV infec- tion is the mainstay therapy in KTRs. While this approach shows effectiveness in reducing the viral load, it also leads to the develop- ment of a non-specific immune response increasing the likelihood of allograft rejection. Currently, there are no satisfactory anti-viral drugs against BK viremia. Anti-BKV drugs to treat BK viremia (used either alone or in combination with immunosuppressive drugs) show variable clinical effectiveness in viral clearance and high inci- dence of side-effects [13]. In addition, excessive use of anti- microbial drugs may lead to the emergence of new drug- resistant BKV species posing a threat to global health [13]. To cir- cumvent these limitations of traditional therapeutic approaches, we have developed a peptide-vaccine based immunotherapeutic approach. The multi-epitope vaccine for BKV (MVBKV) is expected to induce a BKV-specific cellular immune response, which offers advantages of low-toxicity and minimal effects on long-term allo- graft survival. Cell-mediated immunity plays an important role in controlling BK infection [14]. In healthy individuals, an effective immune response against BK viremia is dependent on the induction of a stable antiviral memory T-cell response by the activation of both CD4 + (helper) and CD8 + (cytotoxic) T-cell subtypes [15–17]. The most commonly detected BK specific T-cells epitopes are against the large T-antigen (LTA) and VP1 capsid protein [9,18–21]. CD4 + T-cells predominate immune response to BKV and can control its reactivation through the generation of IFN-c even in the absence of CD8 + T-cells [15–17,22,23]. However, in most KTRs this natural https://doi.org/10.1016/j.vaccine.2019.04.096 0264-410X/Ó 2019 Elsevier Ltd. All rights reserved. ⇑ Corresponding author at: Creighton University School of Dentistry, Dept. of Oral Biology, 780729 California Plaza, Omaha, NE, 68178-0729, USA. E-mail address: shikhatarang@creighton.edu (S. Tarang). Vaccine xxx (xxxx) xxx Contents lists available at ScienceDirect Vaccine journal homepage: www.elsevier.com/locate/vaccine Please cite this article as: V. Kesherwani and S. Tarang, An immunoinformatic approach to universal therapeutic vaccine design against BK virus, Vaccine, https://doi.org/10.1016/j.vaccine.2019.04.096