A tandem-repeat dimeric RBD protein-based covid-19 vaccine zf2001 protects mice and nonhuman primates

An, Yaling; Li, Shihua; Jin, Xin; Han, Jian; Xu, Kun; Xu, Senyu; Han, Yuxuan; Liu, Chuanyu; Zheng, Tianyi; Liu, Mei; Yang, Mi Young; Song, Tian-Zhang; Huang, Baoying; Zhao, Li; Wang, Wen; Ruhan, A; Cheng, Yi; Wu, Changwei; Huang, Enqi; Yang, Shuo; Wong, Gary; Bi, Yuhai; Ke, Changwen; Tan, Wenjie; Yan, Jinghua; Zheng, Yong‐Tang; Dai, Lianpan; Gao, George F.

doi:10.1080/22221751.2022.2056524

Cited by 68 publications

(62 citation statements)

References 41 publications

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“…Taken together, these results suggest less viral replication in vaccinated mice, which discards antibody-dependent enhancement (ADE) of the infection upon vaccination. Indeed, RBD is known to pose a low potential for risk of ADE because antibodies against this domain block receptor binding (An et al, 2021). Likewise, the histopathological evaluation of tissues from vaccinated mice showed no lesions in the brain and mild lesions in the lungs and nasal turbinate upon SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

Preclinical evaluation of a COVID-19 vaccine candidate based on a recombinant RBD fusion heterodimer of SARS-CoV-2

Barreiro¹,

Prenafeta²,

Bech-Sàbat³

et al. 2021

Preprint

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Since the genetic sequence of SARS-CoV-2 became available in January 2020, new vaccines have been developed at an unprecedented speed. The current vaccines have been directly associated with a decline in new infection rates, prevention of severe disease and an outstanding decrease in mortality rates. However, the pandemic is still far from being over. New Variants of Concern (VoCs) are continuously evolving. Thus, it is essential to develop accessible second-generation COVID-19 vaccines against known and future VoCs to mitigate the current pandemic. Here, we provide preclinical data showing the immunogenicity, efficacy, and safety results in mice of a receptor-binding domain (RBD)-based recombinant protein vaccine candidate (PHH-1V) which consists of a novel RBD fusion heterodimer containing the B.1.1.7 (alpha) and B.1.351 (beta) variants of SARS-CoV-2, formulated with an oil-based adjuvant equivalent to MF59C.1. BALB/c and K18-hACE2 mice were immunized with different doses of recombinant RBD fusion heterodimer, following a two-dose prime-and-boost schedule. Upon 20 μg RBD fusion heterodimer/dose immunization, BALB/c mice produced RBD-binding antibodies with neutralising activity against the alpha, beta, gamma, and delta variants. Furthermore, vaccination elicited robust activation of CD4+ and CD8+ T cells with early expression of Th1 cytokines upon in vitro restimulation, along with a good tolerability profile. Importantly, vaccination with 10 μg or 20 μg RBD fusion heterodimer/dose conferred 100% efficacy preventing mortality and bodyweight loss upon SARS-CoV-2 challenge in K18-hACE2 mice. These findings demonstrate the feasibility of this novel recombinant vaccine strategy, allowing the inclusion of up to 2 different RBD proteins in the same vaccine. Most importantly, this new platform is easy to adapt to future VoCs and has a good stability profile, thus ensuring its global distribution.

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Section: Discussionmentioning

confidence: 99%

Preclinical evaluation of a COVID-19 vaccine candidate based on a recombinant RBD fusion heterodimer of SARS-CoV-2

Barreiro¹,

Prenafeta²,

Bech-Sàbat³

et al. 2021

Preprint

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“…Preclinical studies of ZF2001 have shown the immunogenicity and protective efficacy of the vaccine in rodents and macaques. 20 The phase 1 and 2 clinical trials showed that the ZF2001 vaccine is safe, with an acceptable side-effect profile, and immunogenic in humans, and a three-dose regimen was selected for use in a phase 3 trial. 21 In serum samples, the majority of vaccine-elicited neutralizing activities against the B.1.351 (beta) variant of concern 22 and pseudovirus expressing a panel of spikes from variants of concern and variants of interest, including B.1.1.7 (alpha), beta, delta, B.1.617.1 (kappa), and omicron, 23 , 24 were shown to be preserved.…”

mentioning

confidence: 99%

Efficacy and Safety of the RBD-Dimer–Based Covid-19 Vaccine ZF2001 in Adults

Dai

Gao

Tao³

et al. 2022

N Engl J Med

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181

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Background The ZF2001 vaccine, which contains a dimeric form of the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 and aluminum hydroxide as an adjuvant, was shown to be safe, with an acceptable side-effect profile, and immunogenic in adults in phase 1 and 2 clinical trials. Methods We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to investigate the efficacy and confirm the safety of ZF2001. The trial was performed at 31 clinical centers across Uzbekistan, Indonesia, Pakistan, and Ecuador; an additional center in China was included in the safety analysis only. Adult participants (≥18 years of age) were randomly assigned in a 1:1 ratio to receive a total of three 25-μg doses (30 days apart) of ZF2001 or placebo. The primary end point was the occurrence of symptomatic coronavirus disease 2019 (Covid-19), as confirmed on polymerase-chain-reaction assay, at least 7 days after receipt of the third dose. A key secondary efficacy end point was the occurrence of severe-to-critical Covid-19 (including Covid-19–related death) at least 7 days after receipt of the third dose. Results Between December 12, 2020, and December 15, 2021, a total of 28,873 participants received at least one dose of ZF2001 or placebo and were included in the safety analysis; 25,193 participants who had completed the three-dose regimen, for whom there were approximately 6 months of follow-up data, were included in the updated primary efficacy analysis that was conducted at the second data cutoff date of December 15, 2021. In the updated analysis, primary end-point cases were reported in 158 of 12,625 participants in the ZF2001 group and in 580 of 12,568 participants in the placebo group, for a vaccine efficacy of 75.7% (95% confidence interval [CI], 71.0 to 79.8). Severe-to-critical Covid-19 occurred in 6 participants in the ZF2001 group and in 43 in the placebo group, for a vaccine efficacy of 87.6% (95% CI, 70.6 to 95.7); Covid-19–related death occurred in 2 and 12 participants, respectively, for a vaccine efficacy of 86.5% (95% CI, 38.9 to 98.5). The incidence of adverse events and serious adverse events was balanced in the two groups, and there were no vaccine-related deaths. Most adverse reactions (98.5%) were of grade 1 or 2. Conclusions In a large cohort of adults, the ZF2001 vaccine was shown to be safe and effective against symptomatic and severe-to-critical Covid-19 for at least 6 months after full vaccination. (Funded by the National Science and Technology Major Project and others; ClinicalTrials.gov number, NCT04646590 .)

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“…In addition, they demonstrated that the two-dose immunization protocol was also able to induce neutralizing antibodies at 7 days after the second immunization (day 21). Our data demonstrated similar results, showing that the second immunization via the ID route with S Ptn associated to Alum, Poly(I:C), and Alum plus Poly(I:C) is already sufficient to induce neutralizing antibodies and that a third immunization is capable of inducing even more mainly for the combination with Alum plus Poly(I:C).Although Alum is acknowledged for its ability to induce a Th2 response(49), many studies regarding SARS-CoV-2 vaccine development have reported a Th1 response directed by Alum(50)(51)(52), which was associated to the TLR9 adjuvant CpG + Alum coupled activity in some cases(53)(54)(55). Poly(I:C) is a TLR3 agonist and formulations of mixed adjuvant containing Alum + Poly(I:C) have been shown to elicit a T cell immune response.…”

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confidence: 99%

Immunogenicity of SARS-CoV-2 trimetric spike protein associated to Poly(I:C) plus Alum

Santos

Firmino-Cruz

Fonseca-Martins

et al. 2021

Preprint

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The SARS-CoV-2 pandemic has had a social and economic impact worldwide, and vaccination is an efficient strategy for diminishing those damages. New adjuvant formulations are required for the high vaccine demands, especially adjuvant formulations that induce a Th1 phenotype. Herein we assess a vaccination strategy using a combination of Alum and polyinosinic:polycytidylic acid (Poly(I:C)) adjuvants plus the SARS-CoV-2 spike protein in a prefusion trimeric conformation by an intradermal (ID) route. We found high levels of IgG anti-spike antibodies in the serum by enzyme linked immunosorbent assay (ELISA) and high neutralizing titers against SARS-CoV-2 in vitro by neutralization assay, after one or two boosts. By evaluating the production of IgG subtypes, as expected, we found that formulations containing Poly(I:C) induced IgG2a whereas Alum did not. The combination of these two adjuvants induced high levels of both IgG1 and IgG2a. In addition, cellular immune responses of CD4+ and CD8+ T cells producing interferon-gamma were equivalent, demonstrating that the Alum + Poly(I:C) combination supported a Th1 profile. Based on the high neutralizing titers, we evaluated B cells in the germinal centers, which are specific for receptor-binding domain (RBD) and spike, and observed that more positive B cells were induced upon the Alum + Poly(I:C) combination. Moreover, these B cells produced antibodies against both RBD and non-RBD sites. We also studied the impact of this vaccination preparation (S Ptn with Alum + Poly(I:C)) in the lungs of mice challenged with inactivated SARS-CoV-2 virus. We found a production of IgG, but not IgA, and a reduction in neutrophil recruitment in the bronchoalveolar lavage fluid (BALF) of mice, suggesting that our immunization scheme reduced lung inflammation. Altogether, our data suggest that Alum and Poly(I:C) together is a possible adjuvant combination for vaccines against SARS-CoV-2 by the intradermal route.

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A tandem-repeat dimeric RBD protein-based covid-19 vaccine zf2001 protects mice and nonhuman primates

Cited by 68 publications

References 41 publications

Preclinical evaluation of a COVID-19 vaccine candidate based on a recombinant RBD fusion heterodimer of SARS-CoV-2

Preclinical evaluation of a COVID-19 vaccine candidate based on a recombinant RBD fusion heterodimer of SARS-CoV-2

Efficacy and Safety of the RBD-Dimer–Based Covid-19 Vaccine ZF2001 in Adults

Immunogenicity of SARS-CoV-2 trimetric spike protein associated to Poly(I:C) plus Alum

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