Immunogenicity and safety of SpikoGen®, an adjuvanted recombinant SARS-CoV-2 spike protein vaccine as a homologous and heterologous booster vaccination: A randomized placebo-controlled trial

Payam Tabarsi, Nassim Anjidani, Ramin Shahpari, Khashayar Roshanzamir, Newsha Fallah, Greiciely Andre, Nikolai Petrovsky, Saghar Barati, Payam Tabarsi, Nassim Anjidani, Ramin Shahpari, Khashayar Roshanzamir, Newsha Fallah, Greiciely Andre, Nikolai Petrovsky, Saghar Barati

Abstract

SpikoGen® is a subunit recombinant spike protein vaccine combined with Advax-CpG55.2™ adjuvant. This COVID-19 vaccine was shown to be safe, immunogenic and efficacious in previous clinical trials. This study aimed to assess the safety and immunogenicity of SpikoGen® vaccine as a homologous and heterologous booster vaccination. This double-blind and randomized placebo-controlled (5:1) trial was performed on 300 already vaccinated participants. SpikoGen® or saline placebo was administered as a booster dose to participants who had received a full two-dose COVID-19 vaccination course. Immunogenicity assessments were done 14 days after the booster dose with the primary immunogenicity outcome seroconversion rate of neutralizing antibodies. Safety outcomes included the incidence of solicited adverse events up to 7 days after the booster dose. SpikoGen® vaccine induced a robust humoral response both as a homologous and heterologous booster, when compared to the placebo. At Day 14, seroconversion of neutralizing antibodies was 76% (95% confidence interval [CI]: 69%-82%) in the SpikoGen® group versus 3% (95% CI: 0%-13%) in the placebo group. The most common local and systemic reported adverse events were injection site pain and fatigue. No serious adverse events were reported. The SpikoGen®-booster induced cross-neutralization of other SARS-CoV-2 variants. Irrespective of the primary vaccine course received, SpikoGen® vaccine showed promising effects as both a homologous and heterologous booster dose. This vaccine also had a good safety profile with no vaccine-associated serious adverse events. On the basis of these results, SpikoGen® vaccine has been approved as a booster dose.

Keywords: COVID-19; SARS-CoV-2; SpikoGen; booster; cross-neutralization.

Conflict of interest statement

NA, RSH, NF and SB are members of the Orchid Pharmed medical department which is in collaboration with CinnaGen company with respect to conducting clinical trials. KhR is in CinnaGen Medical Biotechnology Research Center. GA and NP are members of the Vaxine Pty Ltd. The remaining authors have no other relevant affiliations.

© 2022 John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
CONSORT flowchart showing schema of screening, randomization and analysis of participants
FIGURE 2
FIGURE 2
Shown are geometric mean concentration (GMC) in the per‐protocol set for sVNTw responses (panel a), S1w IgG responses (panel b) and RBDw IgG responses (panel c) at Days 0 and 14 (14 days after the booster dose). Antibody values below the LLOQ were replaced by 0.5 × LLOQ. The 95% CI was calculated based on the t‐distribution of the log‐transformed values for GMC and GM levels, then back‐transformed to the original scale for presentation. CI, confidence interval; RBDw, receptor‐binding domain (W subscript refers to the Wuhan‐Hu‐1 strain); S1w, S1w part of the spike protein (W subscript refers to the Wuhan‐Hu‐1 strain); sVNTw, surrogate virus‐neutralizing test (W subscript refers to the Wuhan‐Hu‐1 strain).
FIGURE 3
FIGURE 3
Lentivirus pseudotyping neutralization test for Delta and Omicron BA.1 in a random subset of 14 baseline sera from each primary vaccine group (a). Results from the same individuals, 2 weeks after the SpikoGen® booster dose (b). Column height shows GMT
FIGURE 4
FIGURE 4
Lentivirus pseudotype viral neutralization test (pVNT) for each major variants of concern was performed on 42 trial subjects (14 per primary vaccine group). Baseline sera were tested for neutralization titres against Delta and Omicron. Individual titres and group GMT (top bar) for Day 14 post‐booster sera against each of the variants of concern are shown for the selected subjects (a). The fold‐change in pVNT for each variant was calculated by reference to the Alpha ancestral strain (b). The pVNT results against each variant for each individual subject are shown as a heatmap where the intensity of the shading reflects the level of the pVNT titre as shown by the colour scale on the right (c). Pairwise correlations were performed of pVNT results against each variant of concern for Day 14 post‐booster sera of 44 subjects and depicted as a heatmap with the correlations shown in each cell and colour scale depicting the extent of correlation shown on the right (all correlations shown were significant at p < 0.05 (d)
FIGURE 5
FIGURE 5
Solicited local and systemic adverse events. Shown is the percentage of participants in each group (SpikoGen®, placebo) with solicited local (upper figure) and systemic (lower figure) adverse events according to the toxicity grading scale during the 7 days after the booster. There were no grade 4 (life‐threatening) events
FIGURE 6
FIGURE 6
The trend of S1w and RBDw antibodies in primary vaccination and booster dose of SpikoGen®. RBDw, receptor‐binding domain (W subscript refers to the Wuhan‐Hu‐1 strain); S1w, S1w part of the spike protein (W subscript refers to the Wuhan‐Hu‐1 strain).

References

    1. Guo W, Duan K, Zhang Y, Yuan Z, Zhang YB, Wang Z, et al. Safety and immunogenicity of an inactivated SARS‐CoV‐2 vaccine in healthy adults aged 18 years or older: a randomized, double‐blind, placebo‐controlled, phase 1/2 trial. EClinicalMedicine. 2021;38:101010.
    1. Falsey AR, Frenck RW Jr, Walsh EE, Kitchin N, Absalon J, Gurtman A, et al. SARS‐CoV‐2 neutralization with BNT162b2 vaccine dose 3. N Engl J Med. 2021;385(17):1627–9.
    1. Hillus D, Schwarz T, Tober‐Lau P, Vanshylla K, Hastor H, Thibeault C, et al. Safety, reactogenicity, and immunogenicity of homologous and heterologous prime‐boost immunisation with ChAdOx1 nCoV‐19 and BNT162b2: a prospective cohort study. Lancet Respir Med. 2021;9(11):1255–65.
    1. Ai J, Zhang H, Zhang Q, Zhang Y, Lin K, Fu Z, et al. Recombinant protein subunit vaccine booster following two‐dose inactivated vaccines dramatically enhanced anti‐RBD responses and neutralizing titers against SARS‐CoV‐2 and variants of concern. Cell Res. 2022;32(1):103–6.
    1. Schmidt F, Muecksch F, Weisblum Y, Da Silva J, Bednarski E, Cho A, et al. Plasma neutralization of the SARS‐CoV‐2 omicron variant. N Engl J Med. 2022;386(6):599–601.
    1. Li L, Honda‐Okubo Y, Huang Y, Jang H, Carlock MA, Baldwin J, et al. Immunisation of ferrets and mice with recombinant SARS‐CoV‐2 spike protein formulated with Advax‐SM adjuvant protects against COVID‐19 infection. Vaccine. 2021;39(40):5940–3.
    1. Tabarsi P, Anjidani N, Shahpari R, Mardani M, Sabzvari A, Yazdani B, et al. Safety and immunogenicity of SpikoGen®, an Advax‐CpG55.2‐adjuvanted SARS‐CoV‐2 spike protein vaccine: a phase 2 randomized placebo‐controlled trial in both seropositive and seronegative populations. Clin Microbiol Infect. 2022, in press.
    1. Popmihajlov Z, Pang L, Brown E, Joshi A, Su SC, Kaplan SS, et al. A post hoc analysis utilizing the FDA toxicity grading scale to assess injection site adverse events following immunization with the live attenuated Zoster Vaccine (ZVL). Hum Vaccin Immunother. 2018;14(12):2916–20.
    1. Ibarrondo FJ, Hofmann C, Fulcher JA, Goodman‐Meza D, Mu W, Hausner MA, et al. Primary, recall, and decay kinetics of SARS‐CoV‐2 vaccine antibody responses. ACS Nano. 2021, Online ahead of print.
    1. Favresse J, Bayart JL, Mullier F, Elsen M, Eucher C, Van Eeckhoudt S, et al. Antibody titres decline 3‐month post‐vaccination with BNT162b2. Emerg Microbes Infect. 2021;10(1):1495–8.
    1. Khoury DS, Cromer D, Reynaldi A, Schlub TE, Wheatley AK, Juno JA, et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS‐CoV‐2 infection. Nat Med. 2021;27(7):1205–11.
    1. Evans JP, Zeng C, Carlin C, Lozanski G, Saif LJ, Oltz EM, et al. Neutralizing antibody responses elicited by SARS‐CoV‐2 mRNA vaccination wane over time and are boosted by breakthrough infection. Sci Transl Med. 2022;14(637):eabn8057.
    1. Liu C, Mendonça L, Yang Y, Gao Y, Shen C, Liu J, et al. The architecture of inactivated SARS‐CoV‐2 with postfusion spikes revealed by cryo‐EM and cryo‐ET. Structure. 2020;28(11):1218–24.
    1. Li J, Hou L, Guo X, Jin P, Wu S, Zhu J, et al. Heterologous prime‐boost immunization with CoronaVac and Convidecia. medRxiv. 2021;2021.09.03.21263062.
    1. Flaxman A, Marchevsky NG, Jenkin D, Aboagye J, Aley PK, Angus B, 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(10304):981–90.
    1. Feng S, Phillips DJ, White T, Sayal H, Aley PK, Bibi S, et al. Correlates of protection against symptomatic and asymptomatic SARS‐CoV‐2 infection. Nat Med. 2021;27(11):2032–40.
    1. Goldblatt D, Fiore‐Gartland A, Johnson M, Hunt A, Bengt C, Zavadska D, et al. Towards a population‐based threshold of protection for COVID‐19 vaccines. Vaccine. 2022;40(2):306–15.
    1. Zhou D, Dejnirattisai W, Supasa P, Liu C, Mentzer AJ, Ginn HM, et al. Evidence of escape of SARS‐CoV‐2 variant B.1.351 from natural and vaccine‐induced sera. Cell. 2021;184(9):2348–61.
    1. Shi X, Jarvis DL. Protein N‐glycosylation in the baculovirus‐insect cell system. Curr Drug Targets. 2007;8(10):1116–25.
    1. Urbanowicz RA, Wang R, Schiel JE, Keck ZY, Kerzic MC, Lau P, et al. Antigenicity and immunogenicity of differentially glycosylated hepatitis C virus E2 envelope proteins expressed in mammalian and insect cells. J Virol. 2019;93(7): 12–15.
    1. Petrovsky N, Larena M, Siddharthan V, Prow NA, Hall RA, Lobigs M, et al. An inactivated cell culture Japanese encephalitis vaccine (JE‐ADVAX) formulated with delta inulin adjuvant provides robust heterologous protection against West Nile encephalitis via cross‐protective memory B cells and neutralizing antibody. J Virol. 2013;87(18):10324–33.
    1. Komiya T, Honda‐Okubo Y, Baldwin J, Petrovsky N. An Advax‐adjuvanted inactivated cell‐culture derived Japanese encephalitis vaccine induces broadly neutralising anti‐flavivirus antibodies, robust cellular immunity and provides single dose protection. Vaccines. 2021;9(11): 4–5.

Source: PubMed

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