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1.
Viruses ; 15(5)2023 04 29.
Article in English | MEDLINE | ID: covidwho-20232812

ABSTRACT

The rapid mutation and spread of SARS-CoV-2 variants recently, especially through the emerging variants Omicron BA5, BF7, XBB and BQ1, necessitate the development of universal vaccines to provide broad spectrum protection against variants. For the SARS-CoV-2 universal recombinant protein vaccines, an effective approach is necessary to design broad-spectrum antigens and combine them with novel adjuvants that can induce high immunogenicity. In this study, we designed a novel targeted retinoic acid-inducible gene-I (RIG-I) receptor 5'triphosphate double strain RNA (5'PPP dsRNA)-based vaccine adjuvant (named AT149) and combined it with the SARS-CoV-2 Delta and Omicron chimeric RBD-dimer recombinant protein (D-O RBD) to immunize mice. The results showed that AT149 activated the P65 NF-κB signaling pathway, which subsequently activated the interferon signal pathway by targeting the RIG-I receptor. The D-O RBD + AT149 and D-O RBD + aluminum hydroxide adjuvant (Al) + AT149 groups showed elevated levels of neutralizing antibodies against the authentic Delta variant, and Omicron subvariants, BA1, BA5, and BF7, pseudovirus BQ1.1, and XBB compared with D-O RBD + Al and D-O RBD + Al + CpG7909/Poly (I:C) groups at 14 d after the second immunization, respectively. In addition, D-O RBD + AT149 and D-O RBD + Al + AT149 groups presented higher levels of the T-cell-secreted IFN-γ immune response. Overall, we designed a novel targeted RIG-I receptor 5'PPP dsRNA-based vaccine adjuvant to significantly improve the immunogenicity and broad spectrum of the SARS-CoV-2 recombinant protein vaccine.


Subject(s)
COVID-19 Vaccines , COVID-19 , Animals , Mice , Adjuvants, Vaccine , SARS-CoV-2/genetics , COVID-19/prevention & control , Adjuvants, Immunologic , ABO Blood-Group System , Antibodies, Neutralizing , Recombinant Proteins/genetics , Antibodies, Viral , Spike Glycoprotein, Coronavirus
2.
Front Immunol ; 14: 1107639, 2023.
Article in English | MEDLINE | ID: covidwho-2261428

ABSTRACT

Neutralizing antibody (NtAb) levels are key indicators in the development and evaluation of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines. Establishing a unified and reliable WHO International Standard (IS) for NtAb is crucial for the calibration and harmonization of NtAb detection assays. National and other WHO secondary standards are key links in the transfer of IS to working standards but are often overlooked. The Chinese National Standard (NS) and WHO IS were developed by China and WHO in September and December 2020, respectively, the application of which prompted and coordinated sero-detection of vaccine and therapy globally. Currently, a second-generation Chinese NS is urgently required owing to the depletion of stocks and need for calibration to the WHO IS. The Chinese National Institutes for Food and Drug Control (NIFDC) developed two candidate NSs (samples 33 and 66-99) traced to the IS according to the WHO manual for the establishment of national secondary standards through a collaborative study of nine experienced labs. Either NS candidate can reduce the systematic error among different laboratories and the difference between the live virus neutralization (Neut) and pseudovirus neutralization (PsN) methods, ensuring the accuracy and comparability of NtAb test results among multiple labs and methods, especially for samples 66-99. At present, samples 66-99 have been approved as the second-generation NS, which is the first NS calibrated tracing to the IS with 580 (460-740) International Units (IU)/mL and 580 (520-640) IU/mL by Neut and PsN, respectively. The use of standards improves the reliability and comparability of NtAb detection, ensuring the continuity of the use of the IS unitage, which effectively promotes the development and application of SARS-CoV-2 vaccines in China.


Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , Calibration , Reproducibility of Results , SARS-CoV-2 , Antibodies, Viral , Antibodies, Neutralizing , China , World Health Organization
3.
MedComm ; 3(4), 2022.
Article in English | EuropePMC | ID: covidwho-2147815

ABSTRACT

Integrating different types of vaccines into a singular immunization regimen is an effective and accessible approach to strengthen and broaden the immunogenicity of existing coronavirus disease 2019 (COVID‐19) vaccine candidates. To optimize the immunization strategy of the novel mRNA‐based vaccine and recombinant protein subunit vaccine that attracted much attention in COVID‐19 vaccine development, we evaluated the immunogenicity of different combined regimens with the mRNA vaccine (RNA‐RBD) and protein subunit vaccine (PS‐RBD) in mice. Compared with homologous immunization of RNA‐RBD or PS‐RBD, heterologous prime‐boost strategies for mRNA and protein subunit vaccines failed to simultaneously enhance neutralizing antibody (NAb) and Th1 cellular response in this study, showing modestly higher serum neutralizing activity and antibody‐dependent cell‐mediated cytotoxicity for “PS‐RBD prime, RNA‐RBD boost” and robust Th1 type cellular response for “RNA‐RBD prime, PS‐RBD boost”. Interestingly, immunizing the mice with the mixed formulation of the two aforementioned vaccines in various proportions further significantly enhanced the NAb responses against ancestral, Delta, and Omicron strains and manifested increased Th1‐type responses, suggesting that a mixed formulation of mRNA and protein vaccines might be a more prospective vaccination strategy. This study provides basic research data on the combined vaccination strategies of mRNA and protein‐based COVID‐19 vaccines. The immunogenicity of vaccines can be enhanced by the optimization of immunization strategies. In this paper, we investigated the immunogenicity of different combined regimens with the mRNA vaccine RNA‐RBD and protein subunit vaccine PS‐RBD. The result showed that compared with homologous immunization, heterologous prime‐boost strategies for mRNA and protein subunit vaccines failed to simultaneously enhance NAb and Th1 cellular response, but immunizing the mice with the mixed formulation of the two aforementioned vaccines in various proportions further significantly enhanced the NAb responses and Th1 cellular response.

4.
Viruses ; 14(11)2022 Nov 04.
Article in English | MEDLINE | ID: covidwho-2143699

ABSTRACT

Small molecular nucleic acid drugs produce antiviral effects by activating pattern recognition receptors (PRRs). In this study, a small molecular nucleotide containing 5'triphosphoric acid (5'PPP) and possessing a double-stranded structure was designed and named nCoV-L. nCoV-L was found to specifically activate RIG-I, induce interferon responses, and inhibit duplication of four RNA viruses (Human enterovirus 71, Human poliovirus 1, Human coxsackievirus B5 and Influenza A virus) in cells. In vivo, nCoV-L quickly induced interferon responses and protected BALB/c suckling mice from a lethal dose of the enterovirus 71. Additionally, prophylactic administration of nCoV-L was found to reduce mouse death and relieve morbidity symptoms in a K18-hACE2 mouse lethal model of SARS-CoV-2. In summary, these findings indicate that nCoV-L activates RIG-I and quickly induces effective antiviral signals. Thus, it has potential as a broad-spectrum antiviral drug.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Mice , Animals , DEAD-box RNA Helicases/genetics , RNA, Viral/genetics , Cell Line , DEAD Box Protein 58 , Mice, Inbred BALB C , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Interferons
5.
Front Immunol ; 13: 949248, 2022.
Article in English | MEDLINE | ID: covidwho-2022731

ABSTRACT

To cope with the decline in COVID-19 vaccine-induced immunity caused by emerging SARS-CoV-2 variants, a heterologous immunization regimen using chimpanzee adenovirus vectored vaccine expressing SARS-CoV-2 spike (ChAd-S) and an inactivated vaccine (IV) was tested in mice and non-human primates (NHPs). Heterologous regimen successfully enhanced or at least maintained antibody and T cell responses and effectively protected against SARS-CoV-2 variants in mice and NHPs. An additional heterologous booster in mice further improved and prolonged the spike-specific antibody response and conferred effective neutralizing activity against the Omicron variant. Interestingly, priming with ChAd-S and boosting with IV reduced the lung injury risk caused by T cell over activation in NHPs compared to homologous ChAd-S regimen, meanwhile maintained the flexibility of antibody regulation system to react to virus invasion by upregulating or preserving antibody levels. This study demonstrated the satisfactory compatibility of ChAd-S and IV in prime-boost vaccination in animal models.


Subject(s)
Adenoviruses, Simian , COVID-19 , Viral Vaccines , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunization , Macaca , Mice , SARS-CoV-2 , Vaccination , Vaccines, Inactivated
6.
Viruses ; 14(9)2022 08 24.
Article in English | MEDLINE | ID: covidwho-1997806

ABSTRACT

The research and development (R&D) of novel adjuvants is an effective measure for improving the immunogenicity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recombinant protein vaccine. Toward this end, we designed a novel single-stranded RNA-based adjuvant, L2, from the SARS-CoV-2 prototype genome. L2 could initiate retinoic acid-inducible gene-I signaling pathways to effectively activate the innate immunity. ZF2001, an aluminum hydroxide (Al) adjuvanted SARS-CoV-2 recombinant receptor binding domain (RBD) subunit vaccine with emergency use authorization in China, was used for comparison. L2, with adjuvant compatibility with RBD, elevated the antibody response to a level more than that achieved with Al, CpG 7909, or poly(I:C) as adjuvants in mice. L2 plus Al with composite adjuvant compatibility with RBD markedly improved the immunogenicity of ZF2001; in particular, neutralizing antibody titers increased by about 44-fold for Omicron, and the combination also induced higher levels of antibodies than CpG 7909/poly(I:C) plus Al in mice. Moreover, L2 and L2 plus Al effectively improved the Th1 immune response, rather than the Th2 immune response. Taken together, L2, used as an adjuvant, enhanced the immune response of the SARS-CoV-2 recombinant RBD protein vaccine in mice. These findings should provide a basis for the R&D of novel RNA-based adjuvants.


Subject(s)
COVID-19 , Viral Vaccines , Adjuvants, Immunologic , Aluminum Hydroxide , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Mice , Mice, Inbred BALB C , RNA , Recombinant Proteins/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Tretinoin , Vaccines, Subunit/genetics , Vaccines, Synthetic/genetics
7.
Emerg Microbes Infect ; 11(1): 1145-1153, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1764465

ABSTRACT

Analysis of large-scale gene expression post vaccination can provide an overview of immune responses. We used transcriptional approaches to comprehensively analyze the innate immune response signatures elicited by protein subunit (PS) vaccine ZF2001 and an mRNA vaccine named RRV. A fine-grained time-dependent dissection of large-scale gene expression post immunization revealed that ZF001 induced MHC class II-related genes, including cd74 and H2-Aa, more expeditiously than the RRV. Notably, the RRV induced MHC class I-related genes such as Tap1/2, B2m, and H2-D1/K1. At day 21 post immunization, the titres of binding and neutralization antibody (NAb) induced by both vaccines were comparable, which were accordant with the expression level of genes essential to BCR/TCR signalling transduction and B/T cells activation at day 7. However, compared to ZF2001, the early responses of RRV were more robust, including the activation of pattern recognition receptors (PRRs), expression of genes involved in RNA degradation, and transcription inhibition, which are directly related to anti-viral signals. This pattern also coincided with the induction of cytokines by the RRV. Generally, the transcriptomic patterns of two very different vaccines mapped here provide a framework for establishing correlates between the induction of genes and protection, which can be tailored for evoking specific and potent immune responses against SARS-CoV-2.


Subject(s)
COVID-19 Vaccines , COVID-19 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Humans , Immunity, Innate , Protein Subunits/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus , Transcriptome , Vaccination , Vaccines, Subunit , Vaccines, Synthetic , mRNA Vaccines
8.
Vaccine ; 40(14): 2233-2239, 2022 03 25.
Article in English | MEDLINE | ID: covidwho-1757910

ABSTRACT

A reference standard is needed for quality control of protein subunit SARS-CoV-2 vaccines to meet urgent domestic needs. The Chinese National Institutes for Food and Drug Control (NIFDC) launched a project to establish the first reference material for the protein subunit SARS-CoV-2 vaccine to be used for calibration of antigen testing. The potency and stability of the national candidate standard (CS) were determined by collaborative calibration, and accelerated and freeze-thaw degradation studies. Moreover, a suitability study of the CS was performed. Eight laboratories in mainland China were asked to detect antigen content of CS using a common validated enzyme-linked immunosorbent assay (ELISA) kit established by NIFDC and in-house kits in the collaborative study. Six laboratories returned valid results, which established that the antigen content of the CS was 876,938 YU/mL, with good agreement across laboratories. In the suitability study, the CS exhibited excellent parallelism and a linear relationship with four samples produced by different expression systems and target proteins. In addition, good stability in the accelerated and freeze-thaw degradation study was observed. In conclusion, the CS was approved by the Biological Product Reference Standards Sub-Committee of the National Drug Reference Standards Committee as the first Chinese national standard for determining antigen content of protein subunit SARS-CoV-2 vaccines, with an assigned antigen content of 877,000 U/mL (Lot. 300050-202101). This standard will contribute to a standardized assessment of protein subunit SARS-CoV-2 vaccine in China and may provide experience for developing reference materials for antigen content detection of SARS-CoV-2 vaccine in other countries.


Subject(s)
COVID-19 Vaccines , COVID-19 , COVID-19/prevention & control , Humans , Protein Subunits , Reference Standards , SARS-CoV-2
9.
Emerg Microbes Infect ; 10(1): 1598-1608, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1316786

ABSTRACT

Since the outbreak of COVID-19, a variety of vaccine platforms have been developed. Amongst these, inactivated vaccines have been authorized for emergency use or conditional marketing in many countries. To further enhance the protective immune responses in populations that have completed vaccination regimen, we investigated the immunogenic characteristics of different vaccine platforms and tried homologous or heterologous boost strategy post two doses of inactivated vaccines in a mouse model. Our results showed that the humoral and cellular immune responses induced by different vaccines when administered individually differ significantly. In particular, inactivated vaccines showed relatively lower level of neutralizing antibody and T cell responses, but a higher IgG2a/IgG1 ratio compared with other vaccines. Boosting with either recombinant subunit, adenovirus vectored or mRNA vaccine after two-doses of inactivated vaccine further improved both neutralizing antibody and Spike-specific Th1-type T cell responses compared to boosting with a third dose of inactivated vaccine. Our results provide new ideas for prophylactic inoculation strategy of SARS-CoV-2 vaccines.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Immunization, Secondary , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Vaccines, Inactivated/immunology , Animals , Antibodies, Viral/immunology , COVID-19 Vaccines/administration & dosage , Cytokines , Disease Models, Animal , Female , Humans , Immunoglobulin G/immunology , Mice , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Vaccines, Inactivated/administration & dosage
10.
Signal Transduct Target Ther ; 6(1): 271, 2021 07 15.
Article in English | MEDLINE | ID: covidwho-1315588

ABSTRACT

COVID-19 vaccines from multiple manufacturers are needed to cope with the problem of insufficient supply. We did two single-center, randomised, double-blind, placebo-controlled phase 1 and phase 2 trials to assess the safety, tolerability and immunogenicity of a recombinant COVID-19 vaccine (Sf9 cells) in healthy population aged 18 years or older in China. Eligible participants were enrolled, the ratio of candidate vaccine and placebo within each dose group was 3:1 (phase 1) or 5:1 (phase 2). From August 28, 2020, 168 participants were sequentially enrolled and randomly assigned to receive the low dose vaccine, high dose vaccine or placebo with the schedule of 0, 28 days or 0, 14, 28 days in phase 1 trial. From November 18, 2020, 960 participants were randomly assigned to receive the low dose vaccine, high dose vaccine or placebo with the schedule of 0, 21 days or 0, 14, 28 days in phase 2 trial. The most common solicited injection site adverse reaction within 7 days in both trials was pain. The most common solicited systematic adverse reactions within 7 days were fatigue, cough, sore throat, fever and headache. ELISA antibodies and neutralising antibodies increased at 14 days, and peaked at 28 days (phase 1) or 30 days (phase 2) after the last dose vaccination. The GMTs of neutralising antibody against live SARS-CoV-2 at 28 days or 30 days after the last dose vaccination were highest in the adult high dose group (0, 14, 28 days), with 102.9 (95% CI 61.9-171.2) and 102.6 (95% CI 75.2-140.1) in phase 1 and phase 2 trials, respectively. Specific T-cell response peaked at 14 days after the last dose vaccination in phase 1 trial. This vaccine is safe, and induced significant immune responses after three doses of vaccination.


Subject(s)
COVID-19 Vaccines , COVID-19 , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Adolescent , Adult , COVID-19/blood , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Female , Humans , Male , Middle Aged
11.
Signal Transduct Target Ther ; 6(1): 199, 2021 05 18.
Article in English | MEDLINE | ID: covidwho-1233705

ABSTRACT

The outbreak of COVID-19 has posed a huge threat to global health and economy. Countermeasures have revolutionized norms for working, socializing, learning, and travel. Importantly, vaccines have been considered as most effective tools to combat with COVID-19. As of the beginning of 2021, >200 COVID-19 vaccine candidates, covering nearly all existing technologies and platforms, are being research and development (R&D) by multiple manufacturers worldwide. This has posed a huge obstacle to the quality control and evaluation of those candidate vaccines, especially in China, where five vaccine platforms are deployed in parallel. To accelerate the R&D progress of COVID-19 vaccines, the guidances on R&D of COVID-19 vaccine have been issued by National Regulatory Authorities or organizations worldwide. The Center for Drug Evaluation and national quality control laboratory in China have played a leading role in launching the research on quality control and evaluation in collaboration with relevant laboratories involved in the vaccine R&D, which greatly supported the progression of vaccines R&D, and accelerated the approval for emergency use and conditional marketing of currently vaccine candidates. In this paper, the progress and experience gained in quality control and evaluation of COVID-19 vaccines developed in China are summarized, which might provide references for the R&D of current and next generation of COVID-19 vaccines worldwide.


Subject(s)
COVID-19 Vaccines , COVID-19 , SARS-CoV-2/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Global Health , Humans , Quality Control
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