mRNA-based SARS-CoV-2 vaccine candidate CVnCoV induces high levels of virus-neutralising antibodies and mediates protection in rodents

AbstractmRNA technologies have recently proven clinical efficacy against coronavirus disease 2019 and are among the most promising technologies to address the current pandemic. Here, we show preclinical data for our clinical candidate CVnCoV, a lipid nanoparticle-encapsulated mRNA vaccine that encodes full-length, pre-fusion stabilised severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein. In contrast to previously published approaches, CVnCoV is exclusively composed of naturally occurring nucleotides. Immunisation with CVnCoV induced strong humoral responses with high titres of virus-neutralising antibodies and robust T-cell responses. CVnCoV vaccination protected hamsters from challenge with wild-type SARS-CoV-2, demonstrated by the absence of viral replication in the lungs. Hamsters vaccinated with a suboptimal dose of CVnCoV leading to breakthrough viral replication exhibited no evidence of vaccine-enhanced disease. Overall, data presented here provide evidence that CVnCoV represents a potent and safe vaccine candidate against SARS-CoV-2.

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Protective Immunity to Pseudomonas aeruginosa Induced with a Capsid-Modified Adenovirus Expressing P. aeruginosa OprF

Journal of Virology ◽

10.1128/jvi.01246-07 ◽

2007 ◽

Vol 81 (24) ◽

pp. 13801-13808 ◽

Cited By ~ 41

Author(s):

Stefan Worgall ◽

Anja Krause ◽

JianPing Qiu ◽

Ju Joh ◽

Neil R. Hackett ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Protective Immunity ◽

Vaccine Candidate ◽

Wild Type ◽

Cell Responses ◽

Rgd Sequence ◽

Hexon Protein ◽

Repeat Administration ◽

Antigen Presenting ◽

Fiber Gene

ABSTRACT This study focuses on the development of a new clinical vaccine candidate (AdOprF.RGD.Epi8) against Pseudomonas aeruginosa using an E1− E3− adenovirus (Ad) vector expressing OprF (AdOprF.RGD.Epi8) and modifications of the Ad genome providing two capsid changes: (i) modification of the Ad hexon gene to incorporate an immune-dominant OprF epitope (Epi8) into loop 1 of the hexon, enabling repeat administration to boost the anti-OprF immune response, and (ii) modification of the fiber gene to incorporate an integrin-binding RGD sequence to enhance gene delivery to antigen-presenting cells. Western analysis confirmed that AdOprF.RGD.Epi8 expresses OprF, contains Epi8 in the hexon protein, and enhances gene transfer to dendritic cells compared to AdOprF, a comparable Ad vector expressing OprF with an unmodified capsid. Intramuscular immunization of C57BL/6 mice with AdOprF.RGD.Epi8 resulted in the generation of anti-OprF antibodies at comparable levels to those induced following immunization with AdOprF, but immunization with AdOprF.RGD.Epi8 was associated with increased CD4 and CD8 gamma interferon T-cell responses against OprF as well as increased survival against lethal pulmonary challenge with agar-encapsulated P. aeruginosa. Importantly, repeat administration of AdOprF.RGD.Epi8 resulted in boosting of the humoral anti-OprF response as well as increased protection, whereas no boosting could be achieved with repeat administration of AdOprF. This suggests that the capsid-modified AdOprF.RGD.Epi8 vector is a more effective immunogen compared to a comparable wild-type Ad capsid, making it a good candidate for an anti-P. aeruginosa vaccine.

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Naturally Occurring Clostridium perfringens Nontoxic Alpha-Toxin Variant as a Potential Vaccine Candidate against Alpha-Toxin-Associated Diseases

Infection and Immunity ◽

10.1128/iai.69.11.7194-7196.2001 ◽

2001 ◽

Vol 69 (11) ◽

pp. 7194-7196 ◽

Cited By ~ 15

Author(s):

Heike Schoepe ◽

Christian Pache ◽

Axel Neubauer ◽

Heidrun Potschka ◽

Tobias Schlapp ◽

...

Keyword(s):

Phospholipase C ◽

Mutant Strain ◽

Clostridium Perfringens ◽

Hemolytic Activity ◽

Vaccine Candidate ◽

Alpha Toxin ◽

Wild Type ◽

Potential Vaccine Candidate ◽

Naturally Occurring ◽

Potential Vaccine

ABSTRACT Clostridium perfringens mutant strain 121A/91 shows neither enzymatic (phospholipase C) nor hemolytic activity. Nevertheless, the cpa gene and the corresponding alpha-toxin variant are detectable. Vaccination with this genetically constructed alpha-toxin variant, rAT121/91, induces antibodies capable of significantly reducing activities induced by wild-type toxin. Thus, rAT121/91 could be a useful vaccine candidate.

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Infection with “Escaped” Virus Variants Impairs Control of Simian Immunodeficiency Virus SIVmac239 Replication in Mamu-B*08-Positive Macaques

Journal of Virology ◽

10.1128/jvi.01298-09 ◽

2009 ◽

Vol 83 (22) ◽

pp. 11514-11527 ◽

Cited By ~ 50

Author(s):

Laura E. Valentine ◽

John T. Loffredo ◽

Alex T. Bean ◽

Enrique J. León ◽

Caitlin E. MacNair ◽

...

Keyword(s):

T Cell ◽

Viral Replication ◽

Simian Immunodeficiency Virus ◽

Mhc Class I ◽

T Cell Responses ◽

Class I ◽

Wild Type ◽

Viral Loads ◽

Cell Responses ◽

Immunodeficiency Virus

ABSTRACT An understanding of the mechanism(s) by which some individuals spontaneously control human immunodeficiency virus (HIV)/simian immunodeficiency virus replication may aid vaccine design. Approximately 50% of Indian rhesus macaques that express the major histocompatibility complex (MHC) class I allele Mamu-B*08 become elite controllers after infection with simian immunodeficiency virus SIVmac239. Mamu-B*08 has a binding motif that is very similar to that of HLA-B27, a human MHC class I allele associated with the elite control of HIV, suggesting that SIVmac239-infected Mamu-B*08-positive (Mamu-B*08+ ) animals may be a good model for the elite control of HIV. The association with MHC class I alleles implicates CD8+ T cells and/or natural killer cells in the control of viral replication. We therefore introduced point mutations into eight Mamu-B*08-restricted CD8+ T-cell epitopes to investigate the contribution of epitope-specific CD8+ T-cell responses to the development of the control of viral replication. Ten Mamu-B*08 + macaques were infected with this mutant virus, 8X-SIVmac239. We compared immune responses and viral loads of these animals to those of wild-type SIVmac239-infected Mamu-B*08 + macaques. The five most immunodominant Mamu-B*08-restricted CD8+ T-cell responses were barely detectable in 8X-SIVmac239-infected animals. By 48 weeks postinfection, 2 of 10 8X-SIVmac239-infected Mamu-B*08+ animals controlled viral replication to <20,000 viral RNA (vRNA) copy equivalents (eq)/ml plasma, while 10 of 15 wild-type-infected Mamu-B*08+ animals had viral loads of <20,000 vRNA copy eq/ml (P = 0.04). Our results suggest that these epitope-specific CD8+ T-cell responses may play a role in establishing the control of viral replication in Mamu-B*08 + macaques.

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A core-shell structured COVID-19 mRNA vaccine with favorable biodistribution pattern and promising immunity

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00634-z ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Ren Yang ◽

Yao Deng ◽

Baoying Huang ◽

Lei Huang ◽

Ang Lin ◽

...

Keyword(s):

Large Scale ◽

Colloidal Stability ◽

Vaccine Candidate ◽

Vaccine Uptake ◽

Core Shell ◽

Wild Type ◽

Cell Responses ◽

Targeting Effect ◽

Unique Core ◽

Promising Vaccine Candidate

AbstractAlthough inoculation of COVID-19 vaccines has rolled out globally, there is still a critical need for safe and effective vaccines to ensure fair and equitable supply for all countries. Here, we report on the development of a highly efficacious mRNA vaccine, SW0123 that is composed of sequence-modified mRNA encoding the full-length SARS-CoV-2 Spike protein packaged in core–shell structured lipopolyplex (LPP) nanoparticles. SW0123 is easy to produce using a large-scale microfluidics-based apparatus. The unique core–shell structured nanoparticle facilitates vaccine uptake and demonstrates a high colloidal stability, and a desirable biodistribution pattern with low liver targeting effect upon intramuscular administration. Extensive evaluations in mice and nonhuman primates revealed strong immunogenicity of SW0123, represented by induction of Th1-polarized T cell responses and high levels of antibodies that were capable of neutralizing not only the wild-type SARS-CoV-2, but also a panel of variants including D614G and N501Y variants. In addition, SW0123 conferred effective protection in both mice and non-human primates upon SARS-CoV-2 challenge. Taken together, SW0123 is a promising vaccine candidate that holds prospects for further evaluation in humans.

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An Effective Live Vaccine Strain Of Trypanosoma Cruzi Prevents Chagas Disease In The Mouse Model

10.21203/rs.3.rs-92241/v1 ◽

2020 ◽

Author(s):

Bijay Jha ◽

Sanjay Varikuti ◽

Nicholas Bishop ◽

Gregory dos Santos ◽

Jacquelyn McDonald ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Chagas Disease ◽

Vaccine Candidate ◽

Etiologic Agent ◽

Live Vaccine ◽

Parasite Line ◽

Wild Type ◽

Knock Out ◽

Cell Responses ◽

Deficient Mice

Abstract Trypanosoma cruzi is the etiologic agent of Chagas disease for which there are no prophylactic vaccines. Cyclophilin 19 is a secreted cis-trans peptidyl isomerase expressed in all life stages of Trypanosoma cruzi, which in the insect stage leads to the inactivation of insect anti-parasitic peptides and parasite transformation and in intracellular amastigotes participates in generating ROS enhancing parasite growth. We have generated a parasite knock-out mutant of Cyp19 which fails to replicate in cell culture or in mice indicating that lack of Cyp19 is critical for infectivity. Knock-out parasites fail to replicate in or cause clinical disease in immune-deficient mice further validating their lack of virulence. Repeated inoculation of knock-out parasites into immuno-competent mice elicits parasite-specific antibodies and T-cell responses. Challenge of immunized mice with wild-type parasites is 100% effective at preventing disease. These results indicate that the knock-out parasite line is a live vaccine candidate for Chagas disease.

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Intranasal plus subcutaneous prime vaccination with a dual antigen COVID-19 vaccine elicits T-cell and antibody responses in mice

Scientific Reports ◽

10.1038/s41598-021-94364-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Adrian Rice ◽

Mohit Verma ◽

Annie Shin ◽

Lise Zakin ◽

Peter Sieling ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Human Adenovirus ◽

Wild Type ◽

T Helper ◽

Cell Responses ◽

Antigen Vaccine ◽

Serotype 5 ◽

Humoral Responses ◽

Delivery Approach

AbstractWe have developed a COVID-19 vaccine, hAd5 S-Fusion + N-ETSD, that expresses SARS-CoV-2 spike (S) and nucleocapsid (N) proteins with modifications to increase immune responses delivered using a human adenovirus serotype 5 (hAd5) platform. Here, we demonstrate subcutaneous (SC) prime and SC boost vaccination of CD-1 mice with this dual-antigen vaccine elicits T-helper cell 1 (Th1) biased T-cell and humoral responses to both S and N that are greater than those seen with hAd5 S wild type delivering only unmodified S. We then compared SC to intranasal (IN) prime vaccination with SC or IN boosts and show that an IN prime with an IN boost is as effective at generating Th1 biased humoral responses as the other combinations tested, but an SC prime with an IN or SC boost elicits greater T cell responses. Finally, we used a combined SC plus IN (SC + IN) prime with or without a boost and found the SC + IN prime alone to be as effective in generating humoral and T-cell responses as the SC + IN prime with a boost. The finding that SC + IN prime-only delivery has the potential to provide broad immunity—including mucosal immunity—against SARS-CoV-2 supports further testing of this vaccine and delivery approach in animal models of viral challenge.

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CV2CoV, an enhanced mRNA-based SARS-CoV-2 vaccine candidate, supports higher protein expression and improved immunogenicity in rats

10.1101/2021.05.13.443734 ◽

2021 ◽

Author(s):

Nicole Roth ◽

Jacob Schoen ◽

Donata Hoffmann ◽

Moritz Thran ◽

Andreas Thess ◽

...

Keyword(s):

Cell Culture ◽

Protein Expression ◽

First Generation ◽

Vaccine Candidate ◽

Antibody Responses ◽

Neutralising Antibodies ◽

Vaccination Programs ◽

Human Host ◽

Novel Variants ◽

Clinical Candidate

More than a year after emergence of the SARS-CoV-2 pandemic, multiple first-generation vaccines are approved and available for vaccination. Still, many challenges remain. The ongoing vaccination programs across the globe suffer from insufficient vaccine supply. The virus is adapting to the human host and novel variants are circulating that are neutralised less efficiently by antibodies raised against ancestral SARS-CoV-2 variants. Here, we describe CV2CoV, a second-generation mRNA vaccine developed for enhanced protein expression and immunogenicity. CV2CoV supports increased levels of protein expression in cell culture compared to our clinical candidate CVnCoV. Vaccination with CV2CoV induces high levels of virus neutralising antibodies with accelerated kinetics in rats. Robust antibody responses are reflected in significant cross-neutralisation of circulating SARS-CoV-2 variants of concern, i.e. B.1.1.7 and B.1.351. Together, these results underline the value of CV2CoV as next-generation SARS-CoV-2 mRNA vaccine

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Breadth and function of antibody response to acute SARS-CoV-2 infection in humans

10.1101/2020.08.28.267526 ◽

2020 ◽

Cited By ~ 5

Author(s):

Kuan-Ying A. Huang ◽

Tiong Kit Tan ◽

Ting-Hua Chen ◽

Chung-Guei Huang ◽

Ruth Harvey ◽

...

Keyword(s):

Monoclonal Antibodies ◽

B Cells ◽

Antibody Response ◽

Somatic Mutations ◽

Therapeutic Agents ◽

Memory B Cells ◽

Wild Type ◽

Neutralising Antibodies ◽

And Function ◽

Humoral Responses

AbstractSerological and plasmablast responses and plasmablast-derived IgG monoclonal antibodies (MAbs) have been analysed in three COVID-19 patients with different clinical severities. Potent humoral responses were detected within 3 weeks of onset of illness in all patients and the serological titre was elicited soon after or concomitantly with peripheral plasmablast response. An average of 13.7% and 13.0% of plasmablast-derived MAbs were reactive with virus spike glycoprotein or nucleocapsid, respectively. A subset of anti-spike (10 of 32) and over half of anti-nucleocapsid (19 of 35) antibodies cross-reacted with other betacoronaviruses tested and harboured extensive somatic mutations, indicative of an expansion of memory B cells upon SARS-CoV-2 infection. Fourteen of 32 anti-spike MAbs, including five anti-RBD, three anti-non-RBD S1 and six anti-S2, neutralised wild-type SARS-CoV-2 in independent assays. Anti-RBD MAbs were further grouped into four cross-inhibiting clusters, of which six antibodies from three separate clusters blocked the binding of RBD to ACE2 and five were neutralising. All ACE2-blocking anti-RBD antibodies were isolated from two patients with prolonged fever, which is compatible with substantial ACE2-blocking response in their sera. At last, the identification of non-competing pairs of neutralising antibodies would offer potential templates for the development of prophylactic and therapeutic agents against SARS-CoV-2.

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Breadth and function of antibody response to acute SARS-CoV-2 infection in humans

PLoS Pathogens ◽

10.1371/journal.ppat.1009352 ◽

2021 ◽

Vol 17 (2) ◽

pp. e1009352 ◽

Cited By ~ 1

Author(s):

Kuan-Ying A. Huang ◽

Tiong Kit Tan ◽

Ting-Hua Chen ◽

Chung-Guei Huang ◽

Ruth Harvey ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Antibody Response ◽

Somatic Mutations ◽

Therapeutic Agents ◽

Memory B Cells ◽

Receptor Binding Domain ◽

Wild Type ◽

Neutralising Antibodies ◽

And Function ◽

Humoral Responses

Serological and plasmablast responses and plasmablast-derived IgG monoclonal antibodies (MAbs) have been analysed in three COVID-19 patients with different clinical severities. Potent humoral responses were detected within 3 weeks of onset of illness in all patients and the serological titre was elicited soon after or concomitantly with peripheral plasmablast response. An average of 13.7% and 13.0% of plasmablast-derived MAbs were reactive with virus spike glycoprotein or nucleocapsid, respectively. A subset of anti-spike (10 of 32) and over half of anti-nucleocapsid (19 of 35) antibodies cross-reacted with other betacoronaviruses tested and harboured extensive somatic mutations, indicative of an expansion of memory B cells upon SARS-CoV-2 infection. Fourteen of 32 anti-spike MAbs, including five anti-receptor-binding domain (RBD), three anti-non-RBD S1 and six anti-S2, neutralised wild-type SARS-CoV-2 in independent assays. Anti-RBD MAbs were further grouped into four cross-inhibiting clusters, of which six antibodies from three separate clusters blocked the binding of RBD to ACE2 and five were neutralising. All ACE2-blocking anti-RBD antibodies were isolated from two recovered patients with prolonged fever, which is compatible with substantial ACE2-blocking response in their sera. At last, the identification of non-competing pairs of neutralising antibodies would offer potential templates for the development of prophylactic and therapeutic agents against SARS-CoV-2.

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An adjuvanted subunit SARS-CoV-2 spike protein vaccine provides protection against Covid-19 infection and transmission

10.21203/rs.3.rs-902649/v1 ◽

2021 ◽

Author(s):

Kairat Tabynov ◽

Nurkeldi Turebekov ◽

Meruert Babayeva ◽

Gleb Fomin ◽

Toktasyn Yerubaev ◽

...

Keyword(s):

T Cell ◽

Neutralizing Antibodies ◽

Vaccine Candidate ◽

T Cell Responses ◽

Spike Protein ◽

Effective Vaccine ◽

Protein Vaccine ◽

Wild Type ◽

Cell Responses ◽

Ongoing Development

Abstract Recombinant protein approaches offer major promise for safe and effective vaccine prevention of SARS-CoV-2 infection. We developed a recombinant spike protein vaccine (called NARUVAX-C19) and characterized its ability when formulated with a nanoemulsion adjuvant to induce anti-spike antibody and T-cell responses and provide protection including against viral transmission in rodent. In mice, NARUVAX-C19 vaccine administered intramuscularly twice at 21-day interval elicited balanced Th1/Th2 humoral and T-cell responses with high titers of neutralizing antibodies against wild-type (D614G) and delta (B.1.617.2) variants. In Syrian hamsters, NARUVAX-C19 provided complete protection against wild-type (D614G) infection and prevented its transmission to naïve animals placed in the same cage as challenged animals. The results contrasted with only weak protection seen with a monomeric spike receptor binding domain (RBD) vaccine even when formulated with the same adjuvant. These encouraging results warrant ongoing development of this Covid-19 vaccine candidate.

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