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COVID-19 Vaccines and Thrombosis—Roadblock Or Dead-End Street?

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COVID-19 Vaccines and Thrombosis—Roadblock Or Dead-End Street? biomolecules Opinion COVID-19 Vaccines and Thrombosis—Roadblock or Dead-End Street? Kenneth Lundstrom 1,*, Debmalya Barh 2,3,* , Bruce D. Uhal 4 , Kazuo Takayama 5 , Alaa A. A. Aljabali 6 , Tarek Mohamed Abd El-Aziz 7,8 , Amos Lal 9 , Elrashdy M. Redwan 10 , Parise Adadi 11 , Gaurav Chauhan 12 , Samendra P. Sherchan 13, Gajendra Kumar Azad 14 , Nima Rezaei 15,16 , Ángel Serrano-Aroca 17 , Nicolas G. Bazan 18, Sk Sarif Hassan 19 , Pritam Kumar Panda 20 , Pabitra Pal Choudhury 21, Damiano Pizzol 22 , Ramesh Kandimalla 23,24 , Wagner Baetas-da-Cruz 25, Yogendra Kumar Mishra 26 , Giorgio Palu 27, Adam M. Brufsky 28 , Murtaza M. Tambuwala 29,* and Vladimir N. Uversky 30,* 1 PanTherapeutics, CH 1095 Lutry, Switzerland 2 Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Purba Medinipur 721172, India 3 Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil 4 Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; [email protected] 5 Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8397, Japan; [email protected] 6 Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, P.O. Box 566, Irbid 21163, Jordan; [email protected] 7 Zoology Department, Faculty of Science, Minia University, El-Minia 61519, Egypt; [email protected] 8 Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA 9 Citation: Lundstrom, K.; Barh, D.; Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Uhal, B.D.; Takayama, K.; Aljabali, Rochester, MN 55902, USA; [email protected] 10 Biological Science Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; A.A.A.; Abd El-Aziz, T.M.; Lal, A.; [email protected] Redwan, E.M.; Adadi, P.; Chauhan, 11 Department of Food Science, University of Otago, Dunedin 9054, New Zealand; [email protected] G.; et al. COVID-19 Vaccines and 12 School of Engineering and Sciences, Tecnológico de Monterrey, Av. Eugenio Garza Sada 2501 Sur, Thrombosis—Roadblock or Monterrey 64849, Mexico; [email protected] Dead-End Street? Biomolecules 2021, 13 Department of Environmental Health Sciences, Tulane University, New Orleans, LA 70112, USA; 11, 1020. https://doi.org/10.3390/ [email protected] biom11071020 14 Department of Zoology, Patna University, Patna 800005, India; [email protected] 15 Research Center for Immunodeficiency, Children’s Medical Center, Tehran University of Medical Sciences, Academic Editor: Moriya Tsuji Tehran 1416753955, Iran; [email protected] 16 Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), 17177 Stockholm, Sweden Received: 21 June 2021 17 Biomaterials and Bioengineering Lab, Centro de Investigación Traslacional San Alberto Magno, Accepted: 10 July 2021 Universidad Católica de Valencia San Vicente Mártir, c/Guillem de Castro 94, 46001 Valencia, Spain; Published: 13 July 2021 [email protected] 18 Neuroscience Center of Excellence, School of Medicine, LSU Health New Orleans, Publisher’s Note: MDPI stays neutral New Orleans, LA 70112, USA; [email protected] 19 with regard to jurisdictional claims in Department of Mathematics, Pingla Thana Mahavidyalaya, Maligram 721140, India; [email protected] 20 published maps and institutional affil- Condensed Matter Theory Group, Materials Theory Division, Department of Physics and Astronomy, Uppsala University, Box 516, 75120 Uppsala, Sweden; [email protected] iations. 21 Applied Statistics Unit, Indian Statistical Institute, Kolkata 700108, India; [email protected] 22 Italian Agency for Development Cooperation—Khartoum, Sudan Street 33, Al Amarat 11111, Sudan; [email protected] 23 Applied Biology, CSIR-Indian Institute of Technology, Uppal Road, Tarnaka, Hyderabad 500007, India; Copyright: © 2021 by the authors. [email protected] 24 Department of Biochemistry, Kakatiya Medical College, Warangal 506007, India Licensee MDPI, Basel, Switzerland. 25 Translational Laboratory in Molecular Physiology, Centre for Experimental Surgery, College of Medicine, This article is an open access article Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, Brazil; [email protected] distributed under the terms and 26 Mads Clausen Institute, University of Southern Denmark, NanoSYD, Alsion 2, 6400 Sønderborg, Denmark; conditions of the Creative Commons [email protected] Attribution (CC BY) license (https:// 27 Department of Molecular Medicine, University of Padova, 35122 Padova, PD, Italy; [email protected] creativecommons.org/licenses/by/ 28 UPMC Hillman Cancer Center, Division of Hematology/Oncology, Department of Medicine, University of 4.0/). Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; [email protected] Biomolecules 2021, 11, 1020. https://doi.org/10.3390/biom11071020 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, 1020 2 of 11 29 School of Pharmacy and Pharmaceutical Science, Ulster University, Coleraine BT52 1SA, UK 30 Department of Molecular Medicine and USF Health Byrd Alzheimer’s Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA * Correspondence: [email protected] (K.L.); [email protected] (D.B.); [email protected] (M.M.T.); [email protected] (V.N.U.) Abstract: Two adenovirus-based vaccines, ChAdOx1 nCoV-19 and Ad26.COV2.S, and two mRNA- based vaccines, BNT162b2 and mRNA.1273, have been approved by the European Medicines Agency (EMA), and are invaluable in preventing and reducing the incidence of coronavirus disease-2019 (COVID-19). Recent reports have pointed to thrombosis with associated thrombocytopenia as an adverse effect occurring at a low frequency in some individuals after vaccination. The causes of such events may be related to SARS-CoV-2 spike protein interactions with different C-type lectin receptors, heparan sulfate proteoglycans (HSPGs) and the CD147 receptor, or to different soluble splice variants of the spike protein, adenovirus vector interactions with the CD46 receptor or platelet factor 4 antibodies. Similar findings have been reported for several viral diseases after vaccine administration. In addition, immunological mechanisms elicited by viral vectors related to cellular delivery could play a relevant role in individuals with certain genetic backgrounds. Although rare, the potential COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) requires immediate validation, especially in risk groups, such as the elderly, chronic smokers, and individuals with pre-existing incidences of thrombocytopenia; and if necessary, a reformulation of existing vaccines. Keywords: COVID-19; vaccines; SARS-CoV-2; thrombosis; chronic smokers 1. Introduction The unprecedented development of several vaccines against coronavirus disease-2019 (COVID-19) promised that after 18 months of illnesses, deaths, confinements, and lock- downs, there was finally light at the end of the tunnel. Currently, four vaccines have been approved by the European Medicines Agency (EMA) that demonstrate protection against severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) variants, albeit with vari- able efficacy [1–4]. Notably, the lipid nanoparticle (LNP)-formulated mRNA COVID-19 vaccines BNT162b2 (Pfizer/BioNTech) [1] and mRNA-1273 (Moderna) [2] as well as the ade- novirus (Ad)-based vaccines ChAdOx1 nCoV-19 (University of Oxford/AstraZeneca) [3] and Ad26.COV2.S (Johnson & Johnson/Janssen) [4]. Then, potentially more transmissible, and pathogenic variants, such as the B.1.1.7 UK variant [5] and the South African B.1.351 variant [6], were detected and shown to spread rapidly in different parts of the world. Preliminary data indicated that the B.1.1.7 variant provided an increased infection but not viral burden [7]. However, a recent study showed that individuals who tested positive for the B.1.1.7 variant had a 10-fold higher viral load than non-B.1.1.7 subjects [8]. A significant immediate concern was also whether current vaccines could provide protection against these new variants and other variants expected to emerge in the future. In the context of the BNT162b2 vaccine, the B.1.1.7 and B.1.351 variants showed antibody resistance [9]. Moreover, the ChAdOx1 nCoV-19 vaccine failed to provide protection against the B.1.351 variant in a clinical trial in South Africa [10]. These findings fostered the need for develop- ing second-generation vaccines, capable of adjustment to the viral evolutionary variability and showing efficacy against newly emerged SARS-CoV-2 variants. As if that had not been bad enough, rare cases of thrombotic thrombocytopenia were then reported after vaccinations with the simian adenovirus AdChOx1 nCoV-19 vaccine [11,12]. In one study, 11 patients developed one or several thrombotic events 5–16 days after vaccination [12]. Nine patients had cerebral venous thrombosis, three had splanchnic-vein thrombosis, three had pulmonary embolism and four had other types of thromboses. Six patients died and five had disseminated intravascular coagulation. Cases of thrombosis associated with severe thrombocytopenia have also been reported after vaccinations with the Ad26.COV2.S Biomolecules 2021, 11, 1020 3 of 11 vaccine [13]. Very
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