Safety and immunogenicity of inactive vaccines as booster doses for COVID-19 in Türkiye: A randomized trial

Ahmet Omma, Ayse Batirel, Mehtap Aydin, Fatma Yilmaz Karadag, Abdulsamet Erden, Orhan Kucuksahin, Berkan Armagan, Serdar Can Güven, Ozlem Karakas, Selim Gokdemir, Lutfiye Nilsun Altunal, Aslihan Ayse Buber, Emin Gemcioglu, Oguzhan Zengin, Osman Inan, Enes Seyda Sahiner, Gulay Korukluoglu, Zafer Sezer, Aykut Ozdarendeli, Ates Kara, Ihsan Ates, Ahmet Omma, Ayse Batirel, Mehtap Aydin, Fatma Yilmaz Karadag, Abdulsamet Erden, Orhan Kucuksahin, Berkan Armagan, Serdar Can Güven, Ozlem Karakas, Selim Gokdemir, Lutfiye Nilsun Altunal, Aslihan Ayse Buber, Emin Gemcioglu, Oguzhan Zengin, Osman Inan, Enes Seyda Sahiner, Gulay Korukluoglu, Zafer Sezer, Aykut Ozdarendeli, Ates Kara, Ihsan Ates

Abstract

Protective neutralizing antibody titers reduce in time after COVID-19 vaccinations, as in individuals who have had COVID-19. This study aimed to evaluate the safety and immunogenicity of CoronaVac and TURKOVAC vaccines used as a booster dose after CoronaVac primary vaccination. This double-blind, randomized, controlled, phase II, multicenter study included healthy male and female adults (18-60 years) who were vaccinated with two doses of CoronaVac vaccine and did not exceed the duration of at least 90 days and a maximum of 270 days from the second dose of vaccination. Among 236 eligible volunteers, 222 were recruited for randomization between July 12, 2021 and September 10, 2021; 108 and 114 were randomized to the TURKOVAC and CoronaVac arms, respectively. The primary endpoint was adverse events (AEs) (ClinicalTrials.gov; Identifier: NCT04979949). On day 28, at the neutralizing antibody threshold of 1/6, the positivity rate reached 100% from 46.2% to 98.2% from 52.6% in the TURKOVAC and CoronaVac arms, respectively, against the Wuhan variant and the positivity rate reached 80.6% from 8.7% in the TURKOVAC arm vs. 71.9% from 14.0% in the CoronaVac arm against the Delta variant. IgG spike antibody positivity rate increased from 57.3% to 98.1% and from 57.9% to 97.4% in the TURKOVAC and CoronaVac arms, respectively. The TURKOVAC and CoronaVac arms were comparable regarding the frequency of overall AEs. Both vaccines administered as booster yielded higher antibody titers with acceptable safety profiles.

Keywords: Booster vaccine; COVID-19; CoronaVac; TURKOVAC; inactive.

Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Study flowchart.
Figure 2.
Figure 2.
Neutralizing antibody positivity against the (a) Wuhan and (b) Delta variants, and (c) immunoglobulin G-Spike (IgG-S) positivity before and after booster doses in the two study arms.

References

    1. Jara A, Undurraga EA, González C, Paredes F, Fontecilla T, Jara G, Pizarro A, Acevedo J, Leo K, Leon F, et al. Effectiveness of an inactivated SARS-CoV-2 vaccine in Chile. N Engl J Med. 2021;385(10):1–10. doi:10.1056/NEJMoa2107715.
    1. Tanriover MD, Doğanay HL, Akova M, Güner HR, Azap A, Akhan S, Köse Ş, Erdinç FŞ, Akalın EH, Tabak ÖF, et al. Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey. Lancet. 2021;398(10296):213–22. doi:10.1016/S0140-6736(21)01429-X.
    1. Zhang Y, Zeng G, Pan H, Li C, Hu Y, Chu K, Han W, Chen Z, Tang R, Yin W, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2021;21(2):181–92. doi:10.1016/S1473-3099(20)30843-4.
    1. Sharma O, Sultan AA, Ding H, Triggle CR.. A review of the progress and challenges of developing a vaccine for COVID-19. Front Immunol. 2020;11:585354. doi:10.3389/fimmu.2020.585354.
    1. Genetic Engineering & Biotechnology News . Sinovac biotech – CoronaVac; 2020. May 18. [accessed 2021 Nov 29]. .
    1. Pavel STI, Yetiskin H, Uygut MA, Aslan AF, Aydın G, İ̇nan Ö, Kaplan B, Ozdarendeli A. Development of an inactivated vaccine against SARS CoV-2. Vaccines (Basel). 2021;9(11):1266. doi:10.3390/vaccines9111266.
    1. Pavel STI, Yetiskin H, Aydin G, Holyavkin C, Uygut MA, Dursun ZB, Celik İ, Cevik C, Ozdarendeli A. Isolation and characterization of severe acute respiratory syndrome coronavirus 2 in Turkey. PLoS One. 2020;15(9):e0238614. doi:10.1371/journal.pone.0238614.
    1. Al Kaabi N, Zhang Y, Xia S, Yang Y, Al Qahtani MM, Abdulrazzaq N, Al Nusair M, Hassany M, Jawad JS, Abdalla J, et al. Effect of 2 inactivated SARS-CoV-2 vaccines on symptomatic COVID-19 infection in adults: a randomized clinical trial. JAMA. 2021;326(1):35–45. doi:10.1001/jama.2021.8565.
    1. Anand SP, Prévost J, Nayrac M, Beaudoin-Bussières G, Benlarbi M, Gasser R, Brassard N, Laumaea A, Gong SY, Bourassa C, et al. Longitudinal analysis of humoral immunity against SARS-CoV-2 spike in convalescent individuals up to 8 months post-symptom onset. Cell Rep Med. 2021;2(6):100290. doi:10.1016/j.xcrm.2021.100290.
    1. Widge AT, Rouphael NG, Jackson LA, Anderson EJ, Roberts PC, Makhene M, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ, et al. Durability of responses after SARS-CoV-2 mRNA-1273 vaccination. N Engl J Med. 2021;384(1):80–82. doi:10.1056/NEJMc2032195.
    1. Zinkernagel RM. On natural and artificial vaccinations. Annu Rev Immunol. 2003;21(1):515–46. doi:10.1146/annurev.immunol.21.120601.141045.
    1. Pollard AJ, Bijker EM. A guide to vaccinology: from basic principles to new developments. Nat Rev Immunol. 2021;21(2):83–100. doi:10.1038/s41577-020-00479-7.
    1. Wang X, Guo X, Xin Q, Pan Y, Hu Y, Li J, Chu Y, Feng Y, Wang Q. Neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 in coronavirus disease 2019 inpatients and convalescent patients. Clin Infect Dis. 2020;71(10):2688–94. doi:10.1093/cid/ciaa721.
    1. Pavel STI, Yetiskin H, Aydin G, Holyavkin C, Uygut MA, Dursun ZB, Celik İ, Cevik C, Ozdarendeli A, Li K. Isolation and characterization of severe acute respiratory syndrome coronavirus 2 in Turkiye. PLoS One. 2020;15(9):e0238614. doi:10.1371/journal.pone.0238614.
    1. Perera RA, Mok CK, Tsang OT, Lv H, Ko RL, Wu NC, Yuan M, Leung WS, Chan JM, Chik TS, et al. Serological assays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), March 2020. Euro Surveill. 2020;25(16):2000421. doi:10.2807/1560-7917.ES.2020.25.16.2000421.
    1. Reed LJ, Muench H. A simple method of estimating fifty percent end points. Am J Hyg. 1938;27:493–97. doi:10.1093/oxfordjournals.aje.a118408.
    1. World Health Organization . Laboratory Procedures, Serological detection of avian influenza A(H7N9) infections by microneutralization assay; 2013. May 23. [accessed 2022 July 29]. .
    1. Lee YW, Lim SY, Lee JH, Lim JS, Kim M, Kwon S, Joo J, Kwak SH, Kim EO, Jung J, et al. Adverse reactions of the second dose of the BNT162b2 mRNA COVID-19 vaccine in healthcare workers in Korea. J Korean Med Sci. 2021;36(21):e153. doi:10.3346/jkms.2021.36.e153.
    1. Swain SL, McKinstry KK, Strutt TM. Expanding roles for CD4+ T cells in immunity to viruses. Nat Rev Immunol. 2012;12(2):136–48. doi:10.1038/nri3152.
    1. Choi A, Koch M, Wu K, Chu L, Ma L, Hill A, Nunna N, Huang W, Oestreicher J, Colpitts T, et al. Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis. Nat Med. 2021;27(11):2025–31. doi:10.1038/s41591-021-01527-y.
    1. Brnjarchevska Blazhevska T, Babačić H, Sibinovska O, Dobrevski B, Kirijas M, Milanovski G, Arsov T, Petlichkovski A. A single dose of BNT162b2 vaccine elicits strong humoral response in SARS-CoV-2 seropositive individuals. Allergy. 2022;77(1):296–98. doi:10.1111/all.15047.
    1. Levin EG, Lustig Y, Cohen C, Fluss R, Indenbaum V, Amit S, Doolman R, Asraf K, Mendelson E, Ziv A, et al. Waning immune humoral response to BNT162b2 Covid-19 vaccine over 6 months. N Engl J Med. 2021;385(24):e84. doi:10.1056/NEJMoa2114583.
    1. Kara A. Genel İmmünizasyon Prensipleri. Cocuk Enfeksiyon Dergisi 2(Supp 1) . 2008;3–14. [Article in Turkish].
    1. Yue L, Xie T, Yang T, Zhou J, Chen H, Zhu H, Li H, Xiang H, Wang J, Yang H, et al. A third booster dose may be necessary to mitigate neutralizing antibody fading after inoculation with two doses of an inactivated SARS-CoV-2 vaccine. J Med Virol. 2022;94(1):35–38. doi:10.1002/jmv.27334.
    1. Khoury DS, Cromer D, Reynaldi A, Schlub TE, Wheatley AK, Juno JA, Subbarao K, Kent SJ, Triccas JA, Davenport MP. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med. 2021;27(7):1205–11. doi:10.1038/s41591-021-01377-8.
    1. Pfizer quarterly corporate performance — second quarter 2021; 2021. July 28 [accessed 2021 Nov 29]. .
    1. Lee HK, Knabl L, Knabl L, Kapferer S, Pateter B, Walter M, Furth PA, Hennighausen L. Robust immune response to the BNT162b mRNA vaccine in an elderly population vaccinated 15 months after recovery from COVID-19. medRxiv. 2021. Preprint 2021.09.08.21263284. doi:10.1101/2021.09.08.21263284.
    1. Keskin AU, Bolukcu S, Ciragil P, Topkaya AE. SARS-CoV-2 specific antibody responses after third CoronaVac or BNT162b2 vaccine following two-dose CoronaVac vaccine regimen. J Med Virol. 2022;94(1):39–41. doi:10.1002/jmv.27350.
    1. Bar-On YM, Goldberg Y, Mandel M, Bodenheimer O, Freedman L, Kalkstein N, Mizrahi B, Alroy-Preis S, Ash N, Milo R, et al. Protection of BNT162b2 vaccine booster against Covid-19 in Israel. N Engl J Med. 2021;385(15):1393–400. doi:10.1056/NEJMoa2114255.
    1. Lancet Infectious Diseases . COVID-19 vaccine equity and booster doses. Lancet Infect Dis. 2021;21(9):1193. doi:10.1016/S1473-3099(21)00486-2.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe