Immunogenicity of GamLPV, an intranasal live vaccine for pertussis prevention, in adult volunteers: a blind, randomised, placebo-controlled trial to optimise the method and schedule of administration

INTRODUCTION. Currently used inactivated vaccines with acellular/whole-cell pertussis components do not provide sterilising or sufficiently long-lasting immunity, nor do these vaccines prevent the spread of the pathogen or infection. A live pertussis vaccine for intranasal administration, GamLPV, has passed the necessary preclinical studies and a clinical trial that established the optimal dose for single-dose vaccination.

AIM. This study aimed to optimise the method and schedule of administration of the GamLPV intranasal live vaccine for pertussis prevention on the basis of the immunogenicity results obtained in a clinical trial involving healthy volunteers aged 18 to 40 years.

MATERIALS AND METHODS. This blind, randomised, placebo-controlled clinical trial enrolled 50 healthy adults, who were then randomised into two groups according to the method of GamLPV administration (drops or spray). The study evaluated the efficacy of two administration schedules, including single-dose vaccination and double-dose vaccination with an interval of 60 days. The study analysed nasopharyngeal and oropharyngeal aspirates, serum samples, and peripheral blood mononuclear cells from volunteers. The levels of IgM, IgA, and IgG antibodies specific to Bordetella pertussis and the levels of secretory IgA antibodies were measured in serum samples and nasal aspirates, respectively, by enzyme-linked immunosorbent assay. Agglutinating antibody titres were determined by agglutination tests. The quantitative determination of B. pertussis DNA in aspirates used real-time polymerase chain reaction. Cell-mediated immune responses were assessed by the production of IFN-γ and IL-17 cytokines in peripheral blood mononuclear cells.

RESULTS. GamLPV administration to volunteers induced B. pertussis-specific IgG and IgA antibodies observed in serum samples, secretory IgA antibodies identified in aspirates, and increased titres of total antibodies to B. pertussis measured by agglutination tests, regardless of the vaccination schedule and the method of administration. Repeated GamLPV administration had a pronounced booster effect, as evidenced by elevated titres of antibodies of all classes from day 14. Moreover, repeated vaccination reduced the time for clearance of B. pertussis bacteria compared with that after the first vaccination (from 28 to 14 days). There were no significant differences in the time courses and values of the measured parameters for nasal vaccine delivery by spray and drops.

CONCLUSIONS. Intranasal vaccination with GamLPV induces pronounced humoral and cellular immune responses and nasal mucosal immunity against pertussis infection in adults. The recommended method for GamLPV administration is nasal drops. The accelerated clearance of bacteria observed after the second vaccination is indicative of sterilising immunity provided by the first vaccination, which can ultimately reduce pertussis transmission in the population.

1. Macina D, Evans KE. Bordetella pertussis in school-age children, adolescents and adults: a systematic review of epidemiology and mortality in Europe. Infect Dis Ther. 2021;10(4):2071–118. https://doi.org/10.1007/s40121-021-00520-9

2. Macina D, Evans KE. Bordetella pertussis in school-age children, adolescents, and adults: a systematic review of epidemiology, burden, and mortality in Africa. Infect Dis Ther. 2021;10(3): 1097–113. https://doi.org/10.1007/s40121-021-00442-6

3. Kardos P, Correia de Sousa J, Heininger U, Konstantopoulos A, MacIntyre CR, Middleton D, et al. Understanding the impact of adult pertussis and current approaches to vaccination: A narrative review and expert panel recommendations. Hum Vaccin Immunother. 2024;20(1):2324547. https://doi.org/10.1080/21645515.2024.2324547

4. Kandeil W, Atanasov P, Avramioti D, Fu J, Demarteau N, Li X. The burden of pertussis in older adults: What is the role of vaccination? A systematic literature review. Expert Rev Vaccines. 2019;18(5):439–55. https://doi.org/10.1080/14760584.2019.1588727

5. Warfel JM, Zimmerman LI, Merkel TJ. Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model. Proc Natl Acad Sci USA. 2014;111(2):787–92. https://doi.org/10.1073/pnas.1314688110

6. Warfel JM, Zimmerman LI, Merkel TJ. Comparison of three whole-cell pertussis vaccines in the baboon model of pertussis. Clin Vaccine Immunol. 2015;23(1):47–54. https://doi.org/10.1128/CVI.00449-15

7. Semin EG, Sinyashina LN, Medkova AYu, Karataev GI. Construction of recombinant attenuated Bordetella pertussis bacteria of ptxP3 genotype. Journal of Microbiology, Epidemiology and Immunobiology. 2018;(4):33–41 (In Russ.). https://doi.org/10.36233/0372-9311-2018-4-33-41

8. Medkova AYu, Lidzhieva AA, Semin EG, Sinyashina LN, Sioundioukova RA, Dyakov IN, et al. A clinical study of the safety and tolerability of live nasal vaccines for the prevention of pertussis. Drug Development & Registration. 2021:10(1):114–9 (In Russ.). https://doi.org/10.33380/2305-2066-2021-10-1-114-119

9. Medkova AYu, Lidzhiyeva AA, Semin EG, Sinyashina LN, Syundyukova RA, Snegireva NA, et al. Immunogenicity of the drug "Live intranasal vaccine for the prevention of pertussis" (GamLPV) with a single use in healthy volunteers. Journal of Microbiology, Epidemiology and Immunobiology 2021;98(6):706–20 (In Russ.). https://doi.org/10.36233/0372-9311-194

10. Karataev GI, Medkova AYu, Semin EG, Sinyashina LN, Sioundioukova RA, Kulikov SV et al. Development of a method and a scheme for the use of a live recombinant vaccine “GamLPV”. Safety and tolerability of double intranasal vaccination of healthy adult volunteers. Drug Development & Registration. 2022;11(3):202–8 (In Russ.). https://doi.org/10.33380/2305-2066-2022-11-3-202-208

11. Li R, Lim A, Ow ST, Phoon MC, Locht C, Chow VT, et al. Development of live attenuated Bordetella pertussis strains expressing the universal influenza vaccine candidate M2e. Vaccine. 2011;29(33):5502–11. https://doi.org/10.1016/j.vaccine.2011.05.052

12. Jahnmatz M, Richert L, Al-Tawil N, Storsaeter J, Colin C, Bauduin C, et al. Safety and immunogenicity of the live attenuated intranasal pertussis vaccine BPZE1: A phase 1b, double-blind, randomised, placebo-controlled dose-escalation study. Lancet Infect Dis. 2020;20(11):1290–301. https://doi.org/10.1016/S1473-3099(20)30274-7 Erratum in: Lancet Infect Dis. 2020;20(9):e215. https://doi.org/10.1016/S1473-3099(20)30628-9

13. Keech C, Miller VE, Rizzardi B, Hoyle C, Pryor MJ, Ferrand J, et al. Immunogenicity and safety of BPZE1, an intranasal live attenuated pertussis vaccine, versus tetanus–diphtheria– acellular pertussis vaccine: a randomised, double-blind, phase 2b trial. Lancet. 2023;401(10379):843–55. https://doi.org/10.1016/S0140-6736(22)02644-7

14. Medkova AYu, Sinyashina LN, Amichba AA, Semin EG, Shevtsova ZV, Matua AZ, et al. Preclinical studies of safety, immunogenicity and protective activity of attenuated Bordetella pertussis bacteria on the Macaca mulatta model. Journal of Microbiology, Epidemiology and Immunobiology. 2020;97(4):312–23 (In Russ.). https://doi.org/10.36233/0372-9311-2020-97-4-3

15. Djidaryan AA, Matua AZ, Medkova AYu, Semin EG, Sinyashina LN, Dyakov IN et al. Safety and immunogenicity of live intranasal pertussis vaccine GamLVP in the experimental infant hamadryas baboon model. Journal of microbiology, epidemiology and immunobiology. 2022;99(2):203–14 (In Russ.). https://doi.org/10.36233/0372-9311-190

16. Nesterova YuV, Medkova AYu, Babachenko IV, Semin EG, Kalisnikova EL, Sinyashina LN et al. Clinical-diagnostic value of Bordetella pertussis genetic markers in contact persons in familial foci. Journal Infectology. 2019;11(1):17–24 (In Russ.). https://doi.org/10.22625/2072-6732-2019-11-1-17-24

17. Lin A, Apostolovic D, Jahnmatz M, Liang F, Ols S, Tecleab T, et al. Live attenuated pertussis vaccine BPZE1 induces a broad antibody response in humans. J Clin Invest. 2020;130(5):2332–46. https://doi.org/10.1172/JCI135020

18. Locht C, Papin JF, Lecher S, Debrie AS, Thalen M, Solovay K, et al. Live attenuated Bordetella pertussis vaccine BPZE1 protects baboons against bordetella pertussis disease and infection. J Infect Dis. 2017;216(1):117–24. https://doi.org/10.1093/infdis/jix254

19. Karataev GI, Sinyashina LN, Semin EG, Medkova AYu, Lidzhieva AA, Kulikov SV, et al. Methods for assessing the protective activity and immunogenicity of pertussis vaccines in humans, the use of live pertussis recombinant vaccine GamLPV. Patent of the Russian Federation No. 2799018; 2023 (In Russ.). EDN: VEYJPZ