Preclinical and clinical development of preventive rotavirus vaccines: special considerations

INTRODUCTION. Vaccination is recognised as the only effective method for preventing rotavirus disease. Rotavirus remains a leading cause of death in young children, mainly, in developing countries. Currently, oral rotavirus vaccines for infant immunisation are available worldwide, and novel types of rotavirus vaccines are also under development, in particular, in the Russian Federation. However, there are no regulations or guidelines helping developers to design an optimal preclinical and clinical programme for rotavirus vaccines.

AIM. This study aimed to analyse and summarise global experience in planning and conducting preclinical and clinical studies of rotavirus vaccines in order to provide recommendations for national vaccine developers.

DISCUSSION. This study presents an analysis of the available data (and, specifically, the data obtained for the past five years) on all rotavirus vaccines used in the world that have been clinically proven to be effective in preventing severe rotavirus gastroenteritis and reducing the number of hospital admissions due to acute intestinal infections. The effectiveness of rotavirus vaccines varies in different regions of the world and may be lower in developing countries for various reasons. The safety profile of oral rotavirus vaccines is generally considered favourable. Nevertheless, there are still some concerns regarding intestinal intussusception in infants following vaccination. To address the abovementioned problems, researchers, including those in Russia, are developing novel types of rotavirus vaccines, predominantly focusing on inactivated (subunit or recombinant) preparations. For planning and conducting preclinical studies of a rotavirus vaccine, it is advisable to adopt general approaches that involve assessing the acute and chronic toxicity, immunogenicity, and safety pharmacology of the rotavirus vaccine and the virus-neutralising activity of vaccination-induced antibodies. Clinical trials of a rotavirus vaccine should assess its effectiveness in preventing rotavirus gastroenteritis of any severity, hospitalisation, and acute viral intestinal infections of any aetiology in the target age group of young children. Furthermore, it is important to confirm the safety of the rotavirus vaccine and demonstrate the absence of mutual interference with the immunogenicity of the rotavirus vaccine and other vaccines co-administered in the vaccination schedule.

CONCLUSIONS. Preclinical studies of rotavirus vaccines may use standard and generally accept­ed approaches. However, planning and conducting clinical trials requires specific considerations associated with both the nature of rotavirus infection and the national infant vaccination schedule.

1. Du Y, Chen C, Zhang X, Yan D, Jiang D, Liu X, et al. Global burden and trends of rotavirus infection-associated deaths from 1990 to 2019: an observational trend study. Virol J. 2022;19(1):166. https://doi.org/10.1186/s12985-022-01898-9

2. Tate JE, Burton AH, Boschi-Pinto C, Parashar UD. Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000–2013. Clin Infect Dis. 2016;62 Suppl 2:S96–S105. https://doi.org/10.1093/cid/civ1013

3. Korovkin AS, Ignatyev GM. Results and prospects of rotavirus immunisation in the Russian Federation. Biological Products. Prevention, Diagnosis, Treatment. 2023;23(4):499–512 (In Russ.). https://doi.org/10.30895/2221-996X-2023-23-4-499-512

4. McGeoch LJ, Finn A, Marlow RD. Impact of rotavirus vaccination on intussusception hospital admissions in England. Vaccine. 2020;38(35):5618–26. https://doi.org/10.1016/j.vaccine.2020.06.078

5. Latifi T, Kachooei A, Jalilvand S, Zafarian S, Roohvand F, Shoja Z. Correlates of immune protection against human rotaviruses: natural infection and vaccination. Arch Virol. 2024;169(3):72. https://doi.org/10.1007/s00705-024-05975-y

6. Luan LT, Trang NV, Phuong NM, Nguyen HT, Ngo HT, Nguyen H, et al. Development and characterization of candidate rotavirus vaccine strains derived from children with diarrhoea in Vietnam. Vaccine. 2009;27:F130–8. https://doi.org/10.1016/j.vaccine.2009.08.086

7. Zade JK, Kulkarni PS, Desai SA, Sabale RN, Naik SP, Dhere RM. Bovine rotavirus pentavalent vaccine development in India. Vaccine. 2014;32 Suppl 1:A124–8. https://doi.org/10.1016/j.vaccine.2014.03.003

8. Gorenkov DV, Komarovskaya EI, Soldatov AA, Avdeeva ZhI, Bondarev VP. Current regulatory requirements for non-clinical evaluation of prophylactic vaccines. Biological Products. Prevention, Diagnosis, Treatment. 2023;23(1):7–25 (In Russ.). https://doi.org/10.30895/2221-996X-2023-23-1-7-25

9. Skansberg A, Sauer M, Tan M, Santosham M, Jennings MC. Product review of the rotavirus vaccines ROTASIIL, ROTAVAC, and Rotavin-M1. Hum Vaccin Immunother. 2021;17(4):1223–34. https://doi.org/10.1080/21645515.2020.1804245

10. Burke RM, Tate JE, Kirkwood CD, Steele AD, Parashar UD. Current and new rotavirus vaccines. Curr Opin Infect Dis. 2019;32(5):435-444. https://doi.org/10.1097/QCO.0000000000000572

11. Li J, Zhang Y, Yang Y, Liang Z, Tian Y, Liu B, et al. Effectiveness of Lanzhou lamb rotavirus vaccine in preventing gastroenteritis among children younger than 5 years of age. Vaccine. 2019;37(27):3611–6. https://doi.org/10.1016/j.vaccine.2019.03.069

12. Rosillon D, Buyse H, Friedland LR, Ng SP, Velázquez FR, Breuer T. Risk of intussusception after rotavirus vaccination: meta-analysis of postlicensure studies. Pediatr Infect Dis J. 2015;34(7):763–8. https://doi.org/10.1097/inf.0000000000000715

13. Clark HF, Offit PA, Ellis RW, Eiden JJ, Krah D, Shaw AR, et al. The development of multivalent bovine rotavirus (strain WC3) reassortant vaccine for infants. J Infect Dis. 1996;174 Suppl 1:S73­80. https://doi.org/10.1093/infdis/174.supplement_1.s73

14. Ruiz-Palacios GM, Pérez-Schael I, Velázquez FR, Abate H, Breuer T, Clemens SC, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med. 2006;354(1):11–22. https://doi.org/10.1056/NEJMoa052434

15. Vesikari T, Matson DO, Dennehy P, Van Damme P, Santosham M, Rodriguez Z, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med. 2006;354(1):23–33. https://doi.org/10.1056/NEJMoa052664

16. Kulkarni PS, Desai S, Tewari T, Kawade A, Goyal N, Garg BS, et al. A randomized phase III clinical trial to assess the efficacy of a bovine-human reassortant pentavalent rotavirus vaccine in Indian infants. Vaccine. 2017;35(45):6228–37. https://doi.org/10.1016/j.vaccine.2017.09.014

17. Bhandari N, Rongsen-Chandola T, Bavdekar A, John J, Antony K, Taneja S, et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian children in the second year of life. Vaccine. 2014;32 Suppl 1:A110–6. https://doi.org/10.1016/j.vaccine.2014.04.079

18. Thiem VD, Anh DD, Ha VH, Hien ND, Huong NT, Nga NT, et al. Safety and immunogenicity of two formulations of rotavirus vaccine in Vietnamese infants. Vaccine. 2021;39(32):4463–70. https://doi.org/10.1016/j.vaccine.2021.06.056

19. Dang DA, Nguyen VT, Vu DT, Nguyen TH, Nguyen DM, Yuhuan W, et al. A dose-escalation safety and immunogenicity study of a new live attenuated human rotavirus vaccine (Rotavin-M1) in Vietnamese children. Vaccine. 2012;30 Suppl 1:A114–21. https://doi.org/10.1016/j.vaccine.2011.07.118

20. Xia S, Du J, Su J, Liu Y, Huang L, Yu Q, et al. Efficacy, immunogenicity and safety of a trivalent live human-lamb reassortant rotavirus vaccine (LLR3) in healthy Chinese infants: a randomized, double-blind, placebo-controlled trial. Vaccine. 2020;38(46):7393–400. https://doi.org/10.1016/j.vaccine.2020.04.038

21. Schnadower D, Tarr PI, Gorelick MH, O’Connell K, Roskind CG, Powell EC, et al. Validation of the modified Vesikari score in children with gastroenteritis in 5 US emergency departments. J Pediatr Gastroenterol Nutr. 2013;57(4):514–9. https://doi.org/10.1097/MPG.0b013e31829ae5a3

22. Ermolenko KD, Gonchar NV, Behtereva MK, Lobzin YuV. Comparison of Vezikari and Clark scale for determination of viral intestinal infections sevitity and predicting their outputs in children. Journal Infectology. 2018;10(4):64–71 (In Russ.). https://doi.org/10.22625/2072-6732-2018-10-4-64-71

23. Plotkin SA. Recent updates on correlates of vaccine-­induced protection. Front Immunol. 2023;13:1081107. https://doi.org/10.3389/fimmu.2022.1081107

24. Fix A, Kirkwood CD, Steele D, Flores J. Next-generation rotavirus vaccine developers meeting: summary of a meeting sponsored by PATH and the Bill & Melinda Gates Foundation (19–20 June 2019, Geneva). Vaccine. 2020;38(52):8247–54. https://doi.org/10.1016/j.vaccine.2020.11.034

25. Dukhovlinov IV, Bogomolova EG, Fedorova EA, Simbirtsev AS. Protective activity study of a candidate vaccine against rotavirus infection based on recombinant protein FliCVP6VP8. Medical Immunology (Russia). 2016;18(5):417–24 (In Russ.). https://doi.org/10.15789/1563-0625-2016-5-417-424

26. Yagovkin EA, Reshetov AA, Kolpakova EP, Kovrizhko MV, Vanzha VS, Trotsenko AA. Study of the possibility of using conjugation technologies in the development of a rotavirus inactivated vaccine. In: Topical issues of epidemiological surveillance of infectious and parasitic diseases in the South of Russia. Ermolyeva Readings. Rostov-on-Don: Rostov Research Institute of Microbiology and Parasitology; 2021. P. 154–8 (In Russ.). EDN: YNTIDR

27. Kolpakova EP, Kolpakov SA. Method of human culture rotavirus inactivation. Patent of the Russian Federation No. 2743300; 2021. EDN: VLTMHM

28. Cherepushkin SA, Tsibezov VV, Yuzhakov AG, Latyshev OE, Alekseev KP, Altayeva EG, et al. Synthesis and characterization of human rotavirus A (Reoviridae: Sedoreovirinae: Rotavirus: Rotavirus A) virus-like particles. Problems of Virology. 2021;66(1):55–64 (In Russ.). https://doi.org/10.36233/0507-4088-27

29. Groome MJ, Fairlie L, Morrison J, Fix A, Koen A, Masenya M, et al. Safety and immunogenicity of a parenteral trivalent P2-VP8 subunit rotavirus vaccine: a multisite, randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2020;20(7):851–63. https://doi.org/10.1016/S1473-3099(20)30001-3

30. Malm M, Diessner A, Tamminen K, Liebscher M, Vesikari T, Blazevic V. Rotavirus VP6 as an adjuvant for bivalent norovirus vaccine produced in Nicotiana benthamiana. Pharmaceutics. 2019;11(5):229. https://doi.org/10.3390/pharmaceutics11050229

31. Resch TK, Wang Y, Moon S, Jiang B. Serial passaging of the human rotavirus CDC-9 strain in cell culture leads to attenuation: characterization from in vitro and in vivo studies. J Virol. 2020;94(15):e00889-20. https://doi.org/10.1128/JVI.00889-20

32. Roier S, Mangala Prasad V, McNeal MM, Lee KK, Petsch B, Rauch S. mRNA-based VP8* nanoparticle vaccines against rotavirus are highly immunogenic in rodents. NPJ Vaccines. 2023;8(1):190. https://doi.org/10.1038/s41541-023-00790-z