Öz
Giriş: Anti-Şiddetli akut solunum sendromu-Koronavirüs-2 aşı adayı FINLAY-FR-02’nin tekrarlanan doz toksisitesi ve lokal tolerans çalışmasının bir parçası olarak, bağışıklık sistemine ait organlar üzerindeki etkilerinin daha ayrıntılı yorumunu elde etmek amacıyla morfometrik bir histopatolojik çalışma gerçekleştirilmiştir.
Gereç ve Yöntem: Sprague Dawley sıçanları 3 doz aşı adayı (37,5 µg reseptör bağlama domaini) ile aşılananlar, plasebo ile aşılananlar ve kontroller şeklinde üç gruba ayrıldı. Aşılama programının tamamlanmasından sonraki 3., 7. ve 21. günlerde grup başına beş hayvandan dalak, derin kasık lenf düğümü ve popliteal lenf düğümü örnekleri alındı. Histolojik çalışmalar için parafin doku kesitleri rutin yöntemlerle elde edildi, hematoksilen-eozin ile boyandı.
Bulgular: Dalakta Malpighian cisimciklerinin yoğunluğu, derin inguinal ve popliteal lenf düğümlerinde ise subkapsüler ve parakortikal sekonder lenfoid foliküllerin yoğunluğu, apoptoz, plazmosit, makrofaj ve mast hücrelerinin varlığı aşılanmış hayvanlarda artmıştır.
Sonuç: Dalak ve lenf düğümlerindeki histopatolojik ve morfometrik gözlemler, aşı adayı FINLAY-FR-02’ye karşı yoğun bir immün yanıtın geliştiğini doğruladı. Bu çalışmada geliştirilen morfometrik yöntemler, yeni aşı adaylarının değerlendirilmesi ile ilgili gelecekteki çalışmalarda uygulanabilir.
Anahtar Kelimeler: COVID-19, FINLAY-FR-02, morfometri, immünotoksikoloji, aşılar
Kaynakça
WHO Coronavirus Disease (COVID-19) Dashboard. Last Accessed Date: 19 April 2023. Available from: https://covid19.who.int/
Ali F, Anjum V, Chauhan G, Ali A, Ahamad J. Recent Evidence-based Treatments for COVID-19: A Review. Anti-Infective Agents. 2023;21:24-38.
Liang HY, Wu Y, Yau V, Yin HX, Lowe S, Bentley R, Ahmed MA, Zhao W, Sun C. SARS-CoV-2 Variants, Current Vaccines and Therapeutic Implications for COVID-19. Vaccines (Basel). 2022;10:1538.
Kılınç Toker A, Çerçioğlu Özdemir D, Eren E, Turunç Özdemir A, Kanat A, Çelik İ, Toker İ. Anti-Nucleocapsid Antibody Response After Two Doses of CoronaVac® Among Healthcare Workers. Mediterr J Infect Microb Antimicrob. 2022;11:24.
Valdes-Balbin Y, Santana-Mederos D, Quintero L, Fernández S, Rodriguez L, Sanchez Ramirez B, Perez-Nicado R, Acosta C, Méndez Y, Ricardo MG, Hernandez T, Bergado G, Pi F, Valdes A, Carmenate T, Ramirez U, Oliva R, Soubal JP, Garrido R, Cardoso F, Landys M, Gonzalez H, Farinas M, Enriquez J, Noa E, Suarez A, Fang C, Espinosa LA, Ramos Y, González LJ, Climent Y, Rojas G, Relova-Hernández E, Cabrera Infante Y, Losada SL, Boggiano T, Ojito E, León K, Chiodo F, Paquet F, Chen GW, Rivera DG, Garcia-Rivera D, Verez Bencomo V. SARS-CoV-2 RBD-Tetanus Toxoid Conjugate Vaccine Induces a Strong Neutralizing Immunity in Preclinical Studies. ACS Chem Biol. 2021;16:1223-33.
Ochoa-Azze R, Chang-Monteagudo A, Climent-Ruiz Y, Macías-Abraham C, Valenzuela-Silva C, de Los Ángeles García-García M, Jerez-Barceló Y, Triana-Marrero Y, Ruiz-Villegas L, Dairon Rodríguez-Prieto L, Guerra-Chaviano PP, Sánchez-Ramírez B, Hernández-García T, Orosa-Vázquez I, Díaz-Hernández M, Chiodo F, Calcagno A, Ghisetti V, Rodríguez-Acosta M, Noa-Romero E, Enríquez-Puertas J, Ortega-León D, Valdivia-Álvarez I, Delahanty-Fernández A, Palenzuela-Díaz A, Rodríguez-Noda L, González-Mugica R, Valdés-Balbín Y, García-Rivera D, Verez-Bencomo V. Safety and immunogenicity of the FINLAY-FR-1A vaccine in COVID-19 convalescent participants: an open-label phase 2a and double-blind, randomised, placebo-controlled, phase 2b, seamless, clinical trial. Lancet Respir Med. 2022;10:785-95.
Puga-Gómez R, Ricardo-Delgado Y, Rojas-Iriarte C, Céspedes-Henriquez L, Piedra-Bello M, Vega-Mendoza D, Pérez NP, Paredes-Moreno B, Rodríguez-González M, Valenzuela-Silva C, Sánchez-Ramírez B, Rodríguez-Noda L, Pérez-Nicado R, González-Mugica R, Hernández-García T, Fundora-Barrios T, Echevarría MD, Enriquez-Puertas JM, Infante-Hernández Y, Palenzuela-Díaz A, Gato-Orozco E, Chappi-Estévez Y, Francisco-Pérez JC, Suarez-Martinez M, Castillo-Quintana IC, Fernandez-Castillo S, Climent-Ruiz Y, Santana-Mederos D, García-Vega Y, Toledo-Romani ME, Doroud D, Biglari A, Valdés-Balbín Y, García-Rivera D, Vérez-Bencomo V; SOBERANA Research Group. Open-label phase I/II clinical trial of SARS-CoV-2 receptor binding domain-tetanus toxoid conjugate vaccine (FINLAY-FR-2) in combination with receptor binding domain-protein vaccine (FINLAY-FR-1A) in children. Int J Infect Dis. 2023;126:164-73.
Oliva-Hernández R, Fariñas-Medina M, Hernández-Salazar T, Oyarzabal-Vera A, Infante-Bourzac JF, Rodríguez-Salgueiro S, Rodríguez-Noda LM, Arranguren-Masorra Y, Climent-Ruíz Y, Fernández-Castillo S, G-Rivera D, Santana-Mederos D, Sánchez-Ramírez B, García-Rivera D, Valdés-Barbín Y, Vérez-Bencomo V. Repeat-dose and local tolerance toxicity of SARS-CoV-2 FINLAY-FR-02 vaccine candidate in Sprague Dawley rats. Toxicology. 2022;471:15361.
Abdullaevich SA. Changes in The Morphometric State of the Lymphoid Tissue of The Spleen Under The Condition of Polypragmasia. Eurasian Medical Research Periodical. 2022;15:30-4.
Budnik TS, Guralska SV. Cyto-And Histoarchitectonics of the Chicken Spleen in the Post-Vaccination Period. Ukrainian J Vet Agricult Sci. 2022;5:13-7.
Ravshanovich MS, Mardonovich AO. Morphological features of the spleen, benefits and harms of bio supplements when using them. Res J Trauma and Disability Studies. 2023;2:17-9.
Verdier F. Non-clinical vaccine safety assessment. Toxicology. 2002;174:37-43.
Diehl KH, Hull R, Morton D, Pfister R, Rabemampianina Y, Smith D, Vidal JM, van de Vorstenbosch C; European Federation of Pharmaceutical Industries Association and European Centre for the Validation of Alternative Methods. A good practice guide to the administration of substances and removal of blood, including routes and volumes. J Appl Toxicol. 2001;21:15-23.
Committee for the update of the guide for the care and use of laboratory animals. Guide for the care and use of laboratory animals. 8th ed. Washington: The National Academies Press, 2011.
Olfert ED, Cross BM, McWilliam AA. Guide to the Care and Use of Experimental Animals. Vol. 1 2nd ed. Canadian Council on Animal Care, 1993.
American Veterinary Medical Association. AVMA Guides for Euthanasia of Animals. American Veterinary Medical Association, Schaumburg, 2013. Available from: https://www.avma.org/resources-tools/avma-policies/avma-guidelines-euthanasia-animals
Morton DB. Humane endpoints in animal experimentation for biomedical research: Ethical, legal and practical aspects. In: Hendriksen CFM, Morton DB (eds). Humane Endpoints in Animal Experimentation for Biomedical Research. London: Royal Society of Medicine Press, 1999. p. 5-12.
Kittel B, Ruehl-Fehlert C, Morawietz G, Klapwijk J, Elwell MR, Lenz B, O’Sullivan MG, Roth DR, Wadsworth PF; RITA Group; NACAD Group. Revised guides for organ sampling and trimming in rats and mice--Part 2. A joint publication of the RITA and NACAD groups. Exp Toxicol Pathol. 2004;55:413-31.
Steinbach TJ, Patrick DJ, Cosenza ME. Toxicologic Pathology for Non-Pathologists. Springer Science+Business Media, LLC, part of Springer Nature, 2020.
National Institutes of Health USA. Image J. 1.39U. Available from: https://imagej.nih.gov/ij/
Quinlan BD, Mou H, Zhang L, Guo Y, He W, Ojha A, Parcells MS, Luo G, Li W, Zhong G, Choe H, Farzan M. The SARS-CoV-2 receptor-binding domain elicits a potent neutralizing response without antibody-dependent enhancement. bioRxiv. 2020.
Wang H, Zhang Y, Huang B, Deng W, Quan Y, Wang W, Xu W, Zhao Y, Li N, Zhang J, Liang H, Bao L, Xu Y, Ding L, Zhou W, Gao H, Liu J, Niu P, Zhao L, Zhen W, Fu H, Yu S, Zhang Z, Xu G, Li C, Lou Z, Xu M, Qin C, Wu G, Gao GF, Tan W, Yang X. Development of an Inactivated Vaccine Candidate, BBIBP-CorV, with Potent Protection against SARS-CoV-2. Cell. 2020;182:713-21.
Kandeil A, Mostafa A, Hegazy RR, El-Shesheny R, El Taweel A, Gomaa MR, Shehata M, Elbaset MA, Kayed AE, Mahmoud SH, Moatasim Y, Kutkat O, Yassen NN, Shabana ME, GabAllah M, Kamel MN, Abo Shama NM, El Sayes M, Ahmed AN, Elalfy ZS, Mohamed BM, Abd El-Fattah SN, El Hariri HM, Abdel Kader M, Azmy O, Kayali G, Ali MA. Immunogenicity and Safety of an Inactivated SARS-CoV-2 Vaccine: Preclinical Studies. Vaccines (Basel). 2021;9:214.
Zhao Y, He Z, Wang Z, He Y, Zhao X, Liang H, Guo Y, Wang Y, Zhang X, Zhu H, Dong Y, Liu Y, Li W, Ding L, Zhu X, Lan H, Zhang Y, Wang H, Yang X. Repeat-Dose Toxicity of Candidate Omicron COVID-19 Vaccine in Sprague-Dawley Rats. COVID. 2023;3:51-64.
Wojciech P, Ross MH. Histología: Texto y Atlas. Correlación con biología celular y molecular. 7 th ed. Wolters Kluwer, 2015.
Kotarev VI, Mikhailov E, Khokhlova N, Chaplygina YA, Samuilenko AY, Falkova YO, Misharin II. Histomorphometric indicators of chicken-broilers spleen of the cobb-500 cross within the species-specific interferon. BIO Web of Conferences. 2020;17:00100.
Greaves P. Histopathology of preclinical toxicity studies: interpretation and relevance in drug safety evaluation. Academic Press, 2011.
Ochoa RF, Baró IM, Menéndez J, Triana T, Mirabal M, Armesto M, Rodríguez V, Valmaseda T, Fernández Y, Aranguren Y, Creadh L, Domínguez R, Bayolo JV, Alvarez M, de los Angeles Peña M, de la Caridad Rodríguez M, Solís RL, Domínguez F. Reactogenicidad e inmunogenicidad de una nueva vacuna de toxoide tetánico y diftérico con concentración reducida en adolescentes cubanos. Vaccimonitor. 2006;15:13-7.
Abbas AK, Lichtman AH, Pillai S. Inmunología celular y molecular. 6ta ed. EE.UU. Elsevier Saunder 2011. Available from: https://www.berri.es/pdf/INMUNOLOG%C3%8DA%20CELULAR%20Y%20 MOLECULAR/9788413822068
Peperzak V, Vikstrom IB, Tarlinton DM. Through a glass less darkly: apoptosis and the germinal center response to antigen. Immunol Rev. 2012;247:93-106.
Abraham SN, St John AL. Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol. 2010;10:440-52.
Moran I, Grootveld AK, Nguyen A, Phan TG. Subcapsular Sinus Macrophages: The Seat of Innate and Adaptive Memory in Murine Lymph Nodes. Trends Immunol. 2019;40:35-48.
