Janina Gergen

CureVac (Germany)

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Benjamin Petsch

CureVac (Germany)

Susanne Rauch

CureVac (Germany)

Nicole Roth

CureVac (Germany)

Stefan O. Mueller

Stadtspital Waid

Kristina Kovacikova

CureVac (Germany)

Anca Dorhoi

Universität Greifswald

Björn Corleis

Friedrich-Loeffler-Institut

Charlie Fricke

Friedrich-Loeffler-Institut

Lorenz Ulrich

Friedrich-Loeffler-Institut

Donata Hoffmann

Friedrich-Loeffler-Institut

Cooperative Institutions

Friedrich-Loeffler-Institut

Inserm

National Cancer Institute

CureVac (Germany)

Center for Cancer Research

Frederick National Laboratory for Cancer Research

Nantes Université

Institut de Transplantation Urologie en Nephrologie

Harvard University

Center for Research in Transplantation and Translational Immunology

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Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models

Nature Communications (2023)

Björn Corleis Donata Hoffmann Susanne Rauch Charlie Fricke Nicole Roth

Abstract Combining optimized spike (S) protein-encoding mRNA vaccines to target multiple SARS-CoV-2 variants could improve control of the COVID-19 pandemic. We compare monovalent and bivalent mRNA vaccines encoding B.1.351 (Beta) and/or B.1.617.2 (Delta) SARS-CoV-2 S-protein in a transgenic mouse and a Wistar rat model. The blended low-dose bivalent mRNA vaccine contains half the mRNA of each respective monovalent vaccine, but induces comparable neutralizing antibody titres, enrichment of lung-resident memory CD8 + T cells, antigen-specific CD4 + and CD8 + responses, and protects transgenic female mice from SARS-CoV-2 lethality. The bivalent mRNA vaccine significantly reduces viral replication in both Beta- and Delta-challenged mice. Sera from bivalent mRNA vaccine immunized female Wistar rats also contain neutralizing antibodies against the B.1.1.529 (Omicron BA.1 and BA.5) variants. These data suggest that low-dose and fit-for-purpose multivalent mRNA vaccines encoding distinct S-proteins are feasible approaches for extending the coverage of vaccines for emerging and co-circulating SARS-CoV-2 variants.

Bivalent (engine)

10.1038/s41467-023-36110-1

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Citations (17)

Multiplex CRISPR/Cas9 system impairs HCMV replication by excising an essential viral gene

PLoS ONE (2018)

Janina Gergen Flora Coulon Alison Crénéguy Nathan Elain-Duret Alejandra Gutierrez

Anti-HCMV treatments used in immunosuppressed patients reduce viral replication, but resistant viral strains can emerge. Moreover, these drugs do not target latently infected cells. We designed two anti-viral CRISPR/Cas9 strategies to target the UL122/123 gene, a key regulator of lytic replication and reactivation from latency. The singleplex strategy contains one gRNA to target the start codon. The multiplex strategy contains three gRNAs to excise the complete UL122/123 gene. Primary fibroblasts and U-251 MG cells were transduced with lentiviral vectors encoding Cas9 and one or three gRNAs. Both strategies induced mutations in the target gene and a concomitant reduction of immediate early (IE) protein expression in primary fibroblasts. Further detailed analysis in U-251 MG cells showed that the singleplex strategy induced 50% of indels in the viral genome, leading to a reduction in IE protein expression. The multiplex strategy excised the IE gene in 90% of all viral genomes and thus led to the inhibition of IE protein expression. Consequently, viral genome replication and late protein expression were reduced by 90%. Finally, the production of new viral particles was nearly abrogated. In conclusion, the multiplex anti-UL122/123 CRISPR/Cas9 system can target the viral genome efficiently enough to significantly prevent viral replication.

Lytic cycle

Virus latency

10.1371/journal.pone.0192602

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Citations (31)

768. The CRISPR/Cas9 System as an Anti-Viral Treatment to Prevent Primary Infection by HCMV Positive Hematopoietic Stem Cells

Molecular Therapy (2016)

Janina Gergen Flora Coulon Alison Crénéguy Jean‐Marie Heslan Ignacio Anegón

HCMV is a beta-herpes virus, which induces a life long latency in hematopoietic stem cells after an asymptomatic primary infection. In hematopoietic stem cell transplantation, donor hematopoietic stem cells will engraft and differentiate in the recipient. This differentiation induces the reactivation of HCMV in the myeloid compartment and the release of new virions from the donor cells. The HCMV spread leads a primary infection of the immunocompromised HCMV negative recipient and can cause severe end organ diseases. The common treatments of HCMV in immunosuppressed patients are viral DNA replication inhibitors, which cause strong side effects, such as inhibition of hematopoiesis, kidney toxicity, and are likely to promote resistant strain emergence. As a consequence, none of the available drugs can target the HCMV in latent state. To circumvent this, we aim to directly alter the HCMV genome by using the CRIPSR/Cas9 system to knock-out the immediate early gene (IE) encoding essential viral proteins for lytic replication as well as the end of latency. We transduced the low HCMV-permissive U373-MG cells with a lentiviral vector encoding the Cas9 and tree different single gRNA targeting the IE gene. We FACS sorted those cell lines based on their Cas-9-GFP expression and then infected them with a HCMV laboratory strain. We detected mutations at the target site in up to 70% of the viral genomes. We observed a concomitant reduction of 50% less infected cell by FACS staining of the IE protein. Moreover, we set up an assay to analyze the virion release of infected U373-MG cells, which will allow us to address the decrease or inability to release new virions form U373-MG-gRNA-Cas9 HCMV infected cells. We are currently investigating a multiplex strategy with 3 gRNA targeting different parts of the IE gene which are delivered within the same lentiviral vector. The multiplex strategy is auspicious to show higher efficiency than a single gRNA. This strategy will be also tested on HCMV latently infected CD34+ hematopoietic stem cells to prevent viral reactivation. The CRISPR/Cas9 system anti-HCMV is a promising tool to block viral replication. With this anti-HCMV tool we will be able to treat HCMV positive donor cells in order to prevent the primary infection of the immunosuppressed recipient.

Lytic cycle

Virus latency

Hematopoietic stem cell

10.1016/s1525-0016(16)33576-6

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mRNA Vaccines Induce Rapid Antibody Responses in Mice

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Makda S. Gebre Susanne Rauch Nicole Roth Janina Gergen Jingyou Yu

mRNA vaccines can be developed and produced quickly, making them attractive for immediate outbreak responses. Furthermore, clinical trials have demonstrated rapid protection following mRNA vaccination. We sought to investigate how quickly mRNA vaccines elicit antibody responses compared to other vaccine modalities. We first examined immune kinetics of mRNA and DNA vaccines expressing SARS-CoV-2 spike in mice. We observed rapid induction of antigen-specific binding and neutralizing antibodies by day 5 following mRNA, but not DNA, immunization. The mRNA vaccine also induced increased levels of IL-5, IL-6 and MCP-1. We then evaluated immune kinetics of an HIV-1 mRNA vaccine in comparison to DNA, protein, and rhesus adenovirus 52 (RhAd52) vaccines with the same HIV-1 envelope antigen in mice. Induction of envelope-specific antibodies was observed by day 5 following mRNA vaccination, whereas antibodies were detected by day 7-14 following DNA, protein, and RhAd52 vaccination. Eliciting rapid humoral immunity may be an advantageous property of mRNA vaccines for controlling infectious disease outbreaks.

Vaccine failure

10.1101/2021.11.01.466863

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Citations (4)

Assessment of Immunogenicity and Efficacy of CV0501 mRNA-based Omicron COVID-19 Vaccination in Small Animal Models

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Nicole Roth Janina Gergen Kristina Kovacikova Stefan O. Mueller Lorenz Ulrich

Abstract Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron and its subvariants (BA.2, BA.4, BA.5) represent the most commonly circulating variants of concern (VOC) in the coronavirus disease 2019 (COVID-19) pandemic in 2022. Despite high vaccination rates with approved SARS-CoV-2 vaccines encoding the ancestral spike (S) protein, these Omicron subvariants have collectively resulted in increased viral transmission and disease incidence. This necessitates the development and characterization of vaccines incorporating later emerging S proteins to enhance protection against VOC. In this context, bivalent vaccine formulations may induce broad protection against VOC and potential future SARS-CoV-2 variants. Here, we report preclinical data for a lipid nanoparticle (LNP)-formulated RNActive® N1-methylpseudouridine (N1mΨ) modified mRNA vaccine (CV0501) based on our second-generation SARS-CoV-2 vaccine CV2CoV, encoding the S protein of Omicron BA.1. The immunogenicity of CV0501, alone or in combination with a corresponding vaccine encoding the ancestral S protein (ancestral N1mΨ), was first measured in dose-response and booster immunization studies performed in Wistar rats. Both monovalent CV0501 and bivalent CV0501/ancestral N1mΨ immunization induced robust neutralizing antibody titers against the BA.1, BA.2 and BA.5 Omicron subvariants, in addition to other SARS-CoV-2 variants in a booster immunization study. The protective efficacy of monovalent CV0501 against live SARS-CoV-2 BA.2 infection was then assessed in hamsters. Monovalent CV0501 significantly reduced SARS-CoV-2 BA.2 viral loads in the airways, demonstrating protection induced by CV0501 vaccination. CV0501 has now advanced into human Phase 1 clinical trials ( ClinicalTrials.gov Identifier: NCT05477186 ).

Pandemic

Vaccine efficacy

10.1101/2023.01.04.521629

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Citations (2)

mRNA-Based Vaccines and Mode of Action

Current topics in microbiology and immunology (2020)

Janina Gergen Benjamin Petsch

Pandemic

10.1007/82_2020_230

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Citations (24)

mRNA vaccine-induced IgG mediates nasal SARS-CoV-2 clearance in mice

Molecular Therapy — Nucleic Acids (2024)

Charlie Fricke Lorenz Ulrich Jana Kochmann Janina Gergen Kristina Kovacikova

Coronavirus disease 2019 (COVID-19) mRNA vaccines that have contributed to controlling the SARS-CoV-2 pandemic induce specific serum antibodies, which correlate with protection. However, the neutralizing capacity of antibodies for emerging SARS-CoV-2 variants is altered. Suboptimal antibody responses are observed in patients with humoral immunodeficiency diseases, ongoing B cell depletion therapy, and aging. Common experimental mouse models with altered B cell compartments, such as B cell depletion or deficiency, do not fully recapitulate scenarios of declining or suboptimal antibody levels as observed in humans. We report on SARS-CoV-2 immunity in a transgenic mouse model with restricted virus-specific antibodies. Vaccination of C57BL/6-Tg(IghelMD4)4Ccg/J mice with unmodified or N1mΨ-modified mRNA encoding for ancestral spike (S) protein and subsequent challenge with mouse-adapted SARS-CoV-2 provided insights into antibody-independent immunity and the impact of antibody titers on mucosal immunity. Protection against fatal disease was independent of seroconversion following mRNA vaccination, suggesting that virus-specific T cells can compensate for suboptimal antibody levels. In contrast, mRNA-induced IgG in the nasal conchae limited the local viral load and disease progression. Our results indicate that parenteral mRNA immunization can elicit nasal IgG antibodies that effectively suppress local viral replication, highlighting the potential of vaccines in controlling SARS-CoV-2 transmission and epidemiology.

10.1016/j.omtn.2024.102360

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Citations (1)

mRNA vaccines induce rapid antibody responses in mice

npj Vaccines (2022)

Makda S. Gebre Susanne Rauch Nicole Roth Janina Gergen Jingyou Yu

mRNA vaccines can be developed and produced quickly, making them prime candidates for immediate outbreak responses. Furthermore, clinical trials have demonstrated rapid protection following mRNA vaccination. Thus, we sought to investigate how quickly mRNA vaccines elicit antibody responses compared to other vaccine modalities. We first compared the immune kinetics of mRNA and DNA vaccines expressing SARS-CoV-2 spike in mice. We observed rapid induction of antigen-specific binding and neutralizing antibodies by day 5 following mRNA (4 µg/mouse), but not DNA (50 µg/mouse), immunization. Comparing innate responses hours post immunization, the mRNA vaccine induced increased levels of IL-5, IL-6, and MCP-1 cytokines which maybe promoting humoral responses downstream. We then evaluated the immune kinetics of an HIV-1 mRNA vaccine in comparison to DNA, protein, and rhesus adenovirus 52 (RhAd52) vaccines of the same HIV-1 envelope antigen in mice. Again, induction of envelope-specific antibodies was observed by day 5 following mRNA vaccination, whereas antibodies were detected by day 7-14 following DNA, protein, and RhAd52 vaccination. Thus, eliciting rapid humoral immunity may be a unique and advantageous property of mRNA vaccines for controlling infectious disease outbreaks.

10.1038/s41541-022-00511-y

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Citations (22)

Assessment of Immunogenicity and Efficacy of CV0501 mRNA-Based Omicron COVID-19 Vaccination in Small Animal Models

Vaccines (2023)

Nicole Roth Janina Gergen Kristina Kovacikova Stefan O. Mueller Lorenz Ulrich

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron and its subvariants (BA.2, BA.4, BA.5) represented the most commonly circulating variants of concern (VOC) in the coronavirus disease 2019 (COVID-19) pandemic in 2022. Despite high vaccination rates with approved SARS-CoV-2 vaccines encoding the ancestral spike (S) protein, these Omicron subvariants have collectively resulted in increased viral transmission and disease incidence. This necessitates the development and characterization of vaccines incorporating later emerging S proteins to enhance protection against VOC. In this context, bivalent vaccine formulations may induce broad protection against VOC and potential future SARS-CoV-2 variants. Here, we report preclinical data for a lipid nanoparticle (LNP)-formulated RNActive® N1-methylpseudouridine (N1mΨ) modified mRNA vaccine (CV0501) based on our second-generation SARS-CoV-2 vaccine CV2CoV, encoding the S protein of Omicron BA.1. The immunogenicity of CV0501, alone or in combination with a corresponding vaccine encoding the ancestral S protein (ancestral N1mΨ), was first measured in dose-response and booster immunization studies performed in Wistar rats. Both monovalent CV0501 and bivalent CV0501/ancestral N1mΨ immunization induced robust neutralizing antibody titers against the BA.1, BA.2 and BA.5 Omicron subvariants, in addition to other SARS-CoV-2 variants in a booster immunization study. The protective efficacy of monovalent CV0501 against live SARS-CoV-2 BA.2 infection was then assessed in hamsters. Monovalent CV0501 significantly reduced SARS-CoV-2 BA.2 viral loads in the airways, demonstrating protection induced by CV0501 vaccination. CV0501 has now advanced into human Phase 1 clinical trials (ClinicalTrials.gov Identifier: NCT05477186).

Pandemic

Bivalent (engine)

10.3390/vaccines11020318

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Citations (7)

Comparative immunogenicity of an mRNA/LNP and a DNA vaccine targeting HIV gag conserved elements in macaques

Frontiers in Immunology (2022)

Antonio Valentin Cristina Bergamaschi Margherita Rosati Matthew Angel Robert Burns

Immunogenicity of HIV-1 mRNA vaccine regimens was analyzed in a non-human primate animal model. Rhesus macaques immunized with mRNA in lipid nanoparticle (mRNA/LNP) formulation expressing HIV-1 Gag and Gag conserved regions (CE) as immunogens developed robust, durable antibody responses but low adaptive T-cell responses. Augmentation of the dose resulted in modest increases in vaccine-induced cellular immunity, with no difference in humoral responses. The gag mRNA/lipid nanoparticle (LNP) vaccine provided suboptimal priming of T cell responses for a heterologous DNA booster vaccination regimen. In contrast, a single immunization with gag mRNA/LNP efficiently boosted both humoral and cellular responses in macaques previously primed by a gag DNA-based vaccine. These anamnestic cellular responses were mediated by activated CD8 + T cells with a phenotype of differentiated T-bet + cytotoxic memory T lymphocytes. The heterologous prime/boost regimens combining DNA and mRNA/LNP vaccine modalities maximized vaccine-induced cellular and humoral immune responses. Analysis of cytokine responses revealed a transient systemic signature characterized by the release of type I interferon, IL-15 and IFN-related chemokines. The pro-inflammatory status induced by the mRNA/LNP vaccine was also characterized by IL-23 and IL-6, concomitant with the release of IL-17 family of cytokines. Overall, the strong boost of cellular and humoral immunity induced by the mRNA/LNP vaccine suggests that it could be useful as a prophylactic vaccine in heterologous prime/boost modality and in immune therapeutic interventions against HIV infection or other chronic human diseases.

10.3389/fimmu.2022.945706

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Citations (18)