Safety and Immunogenicity of the Third Booster Dose with Inactivated, Viral Vector, and mRNA COVID-19 Vaccines in Fully Immunized Healthy Adults with Inactivated Vaccine

Sitthichai Kanokudom, Suvichada Assawakosri, Nungruthai Suntronwong, Chompoonut Auphimai, Pornjarim Nilyanimit, Preeyaporn Vichaiwattana, Thanunrat Thongmee, Ritthideach Yorsaeng, Donchida Srimuan, Thaksaporn Thatsanatorn, Sirapa Klinfueng, Natthinee Sudhinaraset, Nasamon Wanlapakorn, Sittisak Honsawek, Yong Poovorawan, Sitthichai Kanokudom, Suvichada Assawakosri, Nungruthai Suntronwong, Chompoonut Auphimai, Pornjarim Nilyanimit, Preeyaporn Vichaiwattana, Thanunrat Thongmee, Ritthideach Yorsaeng, Donchida Srimuan, Thaksaporn Thatsanatorn, Sirapa Klinfueng, Natthinee Sudhinaraset, Nasamon Wanlapakorn, Sittisak Honsawek, Yong Poovorawan

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has become a severe healthcare problem worldwide since the first outbreak in late December 2019. Currently, the COVID-19 vaccine has been used in many countries, but it is still unable to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, despite patients receiving full vaccination doses. Therefore, we aimed to appraise the booster effect of the different platforms of vaccines, including inactivated vaccine (BBIBP), viral vector vaccine (AZD122), and mRNA vaccine (BNT162b2), in healthy adults who received the full dose of inactivated vaccine (CoronaVac). The booster dose was safe with no serious adverse events. Moreover, the immunogenicity indicated that the booster dose with viral vector and mRNA vaccine achieved a significant proportion of Ig anti-receptor binding domain (RBD), IgG anti-RBD, and IgA anti-S1 booster response. In contrast, inactivated vaccine achieved a lower booster response than others. Consequently, the neutralization activity of vaccinated serum had a high inhibition of over 90% against SARS-CoV-2 wild-type and their variants (B.1.1.7-alpha, B.1.351-beta, and B.1.617.2-delta). In addition, IgG anti-nucleocapsid was observed only among the group that received the BBIBP booster. Our study found a significant increase in levels of IFN-ɣ secreting T-cell response after the additional viral vector or mRNA booster vaccination. This study showed that administration with either viral vector (AZD1222) or mRNA (BNT162b2) boosters in individuals with a history of two doses of inactivated vaccine (CoronaVac) obtained great immunogenicity with acceptable adverse events.

Keywords: booster; clinical trial; inactivated vaccine; mRNA vaccine; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); third dose; viral vector vaccine.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Reactogenicity of a booster dose of SARS-CoV-2 vaccines within 7 days of vaccination. A booster dose of the inactivated vaccine BBIBP (A), viral vector vaccine AZD1222 (B), and mRNA vaccine BNT162b2 (C). The percentages of participants who recorded local, systemic, and any adverse events are shown on the Y-axis. Fever was defined as mild: 38.0 °C to <38.5 °C; moderate: 38.5 °C to <39.0 °C; severe: ≥39.0 °C. For local and systemic symptoms, grading was classified as mild—easily tolerated with no limitation on regular activity; moderate—some limitation of daily activity; severe—unable to perform regular daily activity [19].
Figure 2
Figure 2
Antibody responses against SARS-CoV-2 assay. The circulating total immunoglobulin anti-RBD of SARS-CoV-2 (U/mL) (A). The circulating IgG-specific RBD of SARS-CoV-2 (BAU/mL) (B). IgG anti-N of SARS-CoV-2 index (S/C) (C). IgA anti-S1 of SARS-CoV-2 ratio (S/C) (D). The serum samples were obtained from participants who received two completed doses of the inactivated vaccine, CoronaVac; followed by the inactivated vaccine, BBIBP (green); the viral vector vaccine, AZD1222 (red); or the mRNA vaccine, BNT162b2 (blue), at 3–4 months after the first dose. Lines represent GMTs (95% CI); ns indicates no statistical difference; p < 0.0001 (****).
Figure 3
Figure 3
Neutralization activities against wild-type and SARS-CoV-2 variants measured by surrogate virus neutralization test (sVNT). The serum samples obtained from participants who received two completed doses of the inactivated vaccine, CoronaVac; followed by the inactivated vaccine, BBIBP (green); the viral vector vaccine, AZD1222 (red); or the mRNA vaccine, BNT162b2 (blue), at 3–4 months after the first dose were compared. The neutralizing activities against SARS-CoV-2 Wide-type (A), Alpha (B.1.1.7) (B), Beta (B.1.351) (C), and Delta (B.1.617.2) (D) were shown. Lines represent medians with interquartile ranges (IQR); ns indicates no significant difference; p-value < 0.001 (***), 0.0001 (****).
Figure 4
Figure 4
SARS-CoV-2-stimulating IFN-ɣ assay. The heparinized samples were obtained from participants who received two completed doses of the inactivated vaccine, CoronaVac; followed by the inactivated vaccine, BBIBP (green); the viral vector vaccine, AZD1222 (red); or the mRNA vaccine, BNT162b2 (blue), at 3–4 months after the first dose and incubated in a QFN blood collection tube for 21 h. The plasma fraction was evaluated by QFN IFN-ɣ ELISA. The IFN-ɣ produced by CD4-specific Ag1 (A). The IFN-ɣ produced by CD4- and CD8-specific Ag2 (B). Lines represent medians (IQR); ns indicates no significant difference; p < 0.05 (*), 0.0001 (****).

References

    1. Worldmeter. Lastest news. COVID-19 Coronavirus pandemic. [(accessed on 2 December 2021)]. Available online:
    1. Glatman-Freedman A., Bromberg M., Dichtiar R., Hershkovitz Y., Keinan-Boker L. The BNT162b2 vaccine effectiveness against new COVID-19 cases and complications of breakthrough cases: A nation-wide retrospective longitudinal multiple cohort analysis using individualised data. EBio Med. 2021;72:103574. doi: 10.1016/j.ebiom.2021.103574.
    1. Lopez Bernal J., Andrews N., Gower C., Gallagher E., Simmons R., Thelwall S., Stowe J., Tessier E., Groves N., Dabrera G., et al. Effectiveness of Covid-19 vaccines against the B.1.617.2 (Delta) Variant. N. Engl. J. Med. 2021;385:585–594. doi: 10.1056/NEJMoa2108891.
    1. Tartof S.Y., Slezak J.M., Fischer H., Hong V., Ackerson B.K., Ranasinghe O.N., Frankland T.B., Ogun O.A., Zamparo J.M., Gray S., et al. Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: A retrospective cohort study. Lancet. 2021;398:1407–1416. doi: 10.1016/S0140-6736(21)02183-8.
    1. Thailand Medicines Regulation Division [(accessed on 2 December 2021)]. Available online: .
    1. Ongkittikul S., Rompho P. SARS-CoV-2 IgG antibody response after immunization of healthcare workers with inactivated COVID-19 vaccine (CoronaVac) at Phyathai 3 Hospital. Bangk. Med. J. 2021;17:100. doi: 10.31524/bkkmedj.2021.21.002.
    1. Vacharathit V., Aiewsakun P., Manopwisedjaroen S., Srisaowakarn C., Laopanupong T., Ludowyke N., Phuphuakrat A., Setthaudom C., Ekronarongchai S., Srichatrapimuk S., et al. CoronaVac induces lower neutralising activity against variants of concern than natural infection. Lancet Infect. Dis. 2021;21:1352–1354. doi: 10.1016/S1473-3099(21)00568-5.
    1. Angkasekwinai N., Sewatanon J., Niyomnaitham S., Phumiamorn S., Sukapirom K., Sapsutthipas S., Sirijatuphat R., Wittawatmongkol O., Senawong S., Mahasirimongkol S., et al. Safety and immunogenicity of CoronaVac and ChAdOx1 against the SARS-CoV-2 circulating variants of concern (Alpha, Delta, Beta) in Thai healthcare workers. MedRxiv. 2021 doi: 10.1101/2021.10.03.21264451.
    1. Del Rio C., Malani P.N., Omer S.B. Confronting the Delta variant of SARS-CoV-2, Summer 2021. JAMA. 2021;326:1001–1002. doi: 10.1001/jama.2021.14811.
    1. Vaughan A. Delta to dominate world. New Sci. 2021;250:9. doi: 10.1016/S0262-4079(21)01121-0.
    1. Levine-Tiefenbrun M., Yelin I., Alapi H., Katz R., Herzel E., Kuint J., Chodick G., Gazit S., Patalon T., Kishony R. Viral loads of Delta-variant SARS-CoV-2 breakthrough infections after vaccination and booster with BNT162b2. Nat. Med. 2021;27:2108–2110. doi: 10.1038/s41591-021-01575-4.
    1. Mizrahi B., Lotan R., Kalkstein N., Peretz A., Perez G., Ben-Tov A., Chodick G., Gazit S., Patalon T. Correlation of SARS-CoV-2-breakthrough infections to time-from-vaccine. Nat. Commun. 2021;12:6379. doi: 10.1038/s41467-021-26672-3.
    1. Yorsaeng R., Suntronwong N., Phowatthanasathian H., Assawakosri S., Kanokudom S., Thongmee T., Vichaiwattana P., Auphimai C., Wongsrisang L., Srimuan D., et al. Immunogenicity of a third dose viral-vectored COVID-19 vaccine after receiving two-dose inactivated vaccines in healthy adults. Vaccine. 2021 doi: 10.1016/j.vaccine.2021.11.083. in press.
    1. Zhang J., He Q., An C., Mao Q., Gao F., Bian L., Wu X., Wang Q., Liu P., Song L., et al. Boosting with heterologous vaccines effectively improves protective immune responses of the inactivated SARS-CoV-2 vaccine. Emerg. Microbes. Infect. 2021;10:1598–1608. doi: 10.1080/22221751.2021.1957401.
    1. Wang H., Zhang Y., Huang B., Deng W., Quan Y., Wang W., Xu W., Zhao Y., Li N., Zhang J., et al. Development of an inactivated vaccine candidate, BBIBP-CorV, with potent protection against SARS-CoV-2. Cell. 2020;182:713–721.e9. doi: 10.1016/j.cell.2020.06.008.
    1. Falsey A.R., Sobieszczyk M.E., Hirsch I., Sproule S., Robb M.L., Corey L., Neuzil K.M., Hahn W., Hunt J., Mulligan M.J., et al. Phase 3 safety and efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine. N. Engl. J. Med. 2021;385:2348–2360. doi: 10.1056/NEJMoa2105290.
    1. Polack F.P., Thomas S.J., Kitchin N., Absalon J., Gurtman A., Lockhart S., Perez J.L., Perez Marc G., Moreira E.D., Zerbini C., et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N. Engl. J. Med. 2020;383:2603–2615. doi: 10.1056/NEJMoa2034577.
    1. Jaganathan S., Stieber F., Rao S.N., Nikolayevskyy V., Manissero D., Allen N., Boyle J., Howard J. Preliminary evaluation of QuantiFERON SARS-CoV-2 and QIAreach anti-SARS-CoV-2 total test in recently vaccinated individuals. Infect. Dis. Ther. 2021;10:2765–2776. doi: 10.1007/s40121-021-00521-8.
    1. Shaw R.H., Stuart A., Greenland M., Liu X., Nguyen Van-Tam J.S., Snape M.D. Heterologous prime-boost COVID-19 vaccination: Initial reactogenicity data. Lancet. 2021;397:2043–2046. doi: 10.1016/S0140-6736(21)01115-6.
    1. Juno J.A., Wheatley A.K. Boosting immunity to COVID-19 vaccines. Nat. Med. 2021;27:1874–1875. doi: 10.1038/s41591-021-01560-x.
    1. Mallapaty S. China’s COVID vaccines have been crucial—Now immunity is waning. Nature. 2021;598:398–399. doi: 10.1038/d41586-021-02796-w.
    1. Barda N., Dagan N., Cohen C., Hernan M.A., Lipsitch M., Kohane I.S., Reis B.Y., Balicer R.D. Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: An observational study. Lancet. 2021;398:2093–2100. doi: 10.1016/S0140-6736(21)02249-2.
    1. Flaxman A., Marchevsky N.G., Jenkin D., Aboagye J., Aley P.K., Angus B., Belij-Rammerstorfer S., Bibi S., Bittaye M., Cappuccini F., et al. Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: A substudy of two randomised controlled trials (COV001 and COV002) Lancet. 2021;398:981–990. doi: 10.1016/S0140-6736(21)01699-8.
    1. Pan H., Wu Q., Zeng G., Yang J., Jiang D., Deng X., Chu K., Zheng W., Zhu F., Yu H., et al. Immunogenicity and safety of a third dose, and immune persistence of CoronaVac vaccine in healthy adults aged 18–59 years: Interim results from a double-blind, randomized, placebo-controlled phase 2 clinical trial. MedRxiv. 2021 doi: 10.1101/2021.07.23.21261026.
    1. Ulhaq Z.S., Soraya G.V., Indriana K., Devitasari R., Pradiptha I.P.Y., Zulfikar D.B., Uxiana V., Zulkarnain , Rachma L.N., Arisanti D. The level of Ig anti-RBD SARS-CoV-2 after two doses of CoronaVac vaccine. J. Med. Virol. 2021 doi: 10.1002/jmv.27390.
    1. Benjamanukul S., Traiyan S., Yorsaeng R., Vichaiwattana P., Sudhinaraset N., Wanlapakorn N., Poovorawan Y. Safety and immunogenicity of inactivated COVID-19 vaccine in health care workers. J. Med. Virol. 2021 doi: 10.1002/jmv.27458.
    1. Intapiboon P., Seepathomnarong P., Ongarj J., Surasombatpattana S., Uppanisakorn S., Mahasirimongkol S., Sawaengdee W., Phumiamorn S., Sapsutthipas S., Sangsupawanich P., et al. Immunogenicity and Safety of an Intradermal BNT162b2 mRNA vaccine booster after two doses of inactivated SARS-CoV-2 vaccine in healthy population. Vaccines. 2021;9:1375. doi: 10.3390/vaccines9121375.
    1. Wanlapakorn N., Suntronwong N., Phowatthanasathian H., Yorsaeng R., Vichaiwattana P., Thongmee T., Auphimai C., Srimuan D., Thatsanatorn T., Assawakosri S., et al. Safety and immunogenicity of heterologous and homologous inactivated and adenoviral-vectored COVID-19 vaccines in healthy adults. MedRxiv. 2021 doi: 10.1101/2021.11.04.21265908.
    1. Liu X., Shaw R.H., Stuart A.S.V., Greenland M., Aley P.K., Andrews N.J., Cameron J.C., Charlton S., Clutterbuck E.A., Collins A.M., et al. Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): A single-blind, randomised, non-inferiority trial. Lancet. 2021;398:856–869. doi: 10.1016/S0140-6736(21)01694-9.
    1. Barros-Martins J., Hammerschmidt S.I., Cossmann A., Odak I., Stankov M.V., Morillas Ramos G., Dopfer-Jablonka A., Heidemann A., Ritter C., Friedrichsen M., et al. Immune responses against SARS-CoV-2 variants after heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination. Nat. Med. 2021;27:1525–1529. doi: 10.1038/s41591-021-01449-9.
    1. Cervia C., Nilsson J., Zurbuchen Y., Valaperti A., Schreiner J., Wolfensberger A., Raeber M.E., Adamo S., Weigang S., Emmenegger M., et al. Systemic and mucosal antibody responses specific to SARS-CoV-2 during mild versus severe COVID-19. J. Allergy. Clin. Immunol. 2021;147:545–557.e9. doi: 10.1016/j.jaci.2020.10.040.
    1. Sterlin D., Mathian A., Miyara M., Mohr A., Anna F., Claer L., Quentric P., Fadlallah J., Devilliers H., Ghillani P., et al. IgA dominates the early neutralizing antibody response to SARS-CoV-2. Sci. Transl. Med. 2021;13:577. doi: 10.1126/scitranslmed.abd2223.
    1. Galipeau Y., Greig M., Liu G., Driedger M., Langlois M.-A. Humoral responses and serological assays in SARS-CoV-2 infections. Front. Immunol. 2020;11:610688. doi: 10.3389/fimmu.2020.610688.
    1. Wisnewski A.V., Campillo Luna J., Redlich C.A. Human IgG and IgA responses to COVID-19 mRNA vaccines. PLoS ONE. 2021;16:e0249499. doi: 10.1371/journal.pone.0249499.
    1. Hiscox J.A., Wurm T., Wilson L., Britton P., Cavanagh D., Brooks G. The coronavirus infectious bronchitis virus nucleoprotein localizes to the nucleolus. J. Virol. 2001;75:506–512. doi: 10.1128/JVI.75.1.506-512.2001.
    1. Kang S., Yang M., He S., Wang Y., Chen X., Chen Y.Q., Hong Z., Liu J., Jiang G., Chen Q., et al. A SARS-CoV-2 antibody curbs viral nucleocapsid protein-induced complement hyperactivation. Nat. Commun. 2021;12:2697. doi: 10.1038/s41467-021-23036-9.
    1. Albecka A. A functional assay for serum detection of antibodies against SARS-CoV-2 nucleoprotein. EMBO J. 2021;40:e108588. doi: 10.15252/embj.2021108588.
    1. Yue L., Zhou J., Zhou Y., Yang X., Xie T., Yang M., Zhao H., Zhao Y., Yang T., Li H., et al. Antibody response elicited by a third boost dose of inactivated SARS-CoV-2 vaccine can neutralize SARS-CoV-2 variants of concern. Emerg. Microbes Infect. 2021;10:2125–2127. doi: 10.1080/22221751.2021.1996210.
    1. Swanson P.A., Padilla M., Hoyland W., McGlinchey K., Fields P.A., Bibi S., Faust S.N., McDermott A.B., Lambe T., Pollard A.J., et al. T-cell mediated immunity after AZD1222 vaccination: A polyfunctional spike-specific Th1 response with a diverse TCR repertoire. MedRxiv. 2021 doi: 10.1101/2021.06.17.21259027.
    1. Sahin U., Muik A., Vogler I., Derhovanessian E., Kranz L.M., Vormehr M., Quandt J., Bidmon N., Ulges A., Baum A., et al. BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans. Nature. 2021;595:572–577. doi: 10.1038/s41586-021-03653-6.
    1. Callaway E. Heavily mutated Omicron variant puts scientists on alert. Nature. 2021;600:21. doi: 10.1038/d41586-021-03552-w.
    1. Garcia-Beltran W.F., Denis K.J.S., Hoelzemer A., Lam E.C., Nitido A.D., Sheehan M.L., Berrios C., Ofoman O., Chang C.C., Hauser B.M., et al. mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant. Cell. 2022 doi: 10.2139/ssrn.3985605.
    1. Ai J., Zhang H., Zhang Y., Lin K., Zhang Y., Wu J., Wan Y., Huang Y., Song J., Zhangfan F., et al. Omicron variant showed lower neutralizing sensitivity than other SARS-CoV-2 variants to immune sera elicited by vaccines after boost. Emerg. Microbes Infect. 2021 doi: 10.1080/22221751.2021.2022440.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅