An Alphavirus-derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates

The coronavirus disease 2019 (COVID-19) pandemic, caused by infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is having a deleterious impact on health services and the global economy, highlighting the urgent need for an effective vaccine. Such a vaccine would need to rapidly confer protection after one or two doses and would need to be manufactured using components suitable for scale up. Here, we developed an Alphavirus-derived replicon RNA vaccine candidate, repRNA-CoV2S, encoding the SARS-CoV-2 spike (S) protein. The RNA replicons were formulated with lipid inorganic nanoparticles (LIONs) that were designed to enhance vaccine stability, delivery, and immunogenicity. We show that a single intramuscular injection of the LION/repRNA-CoV2S vaccine in mice elicited robust production of anti–SARS-CoV-2 S protein IgG antibody isotypes indicative of a type 1 T helper cell response. A prime/boost regimen induced potent T cell responses in mice including antigen-specific responses in the lung and spleen. Prime-only immunization of aged (17 months old) mice induced smaller immune responses compared to young mice, but this difference was abrogated by booster immunization. In nonhuman primates, prime-only immunization in one intramuscular injection site or prime/boost immunizations in five intramuscular injection sites elicited modest T cell responses and robust antibody responses. The antibody responses persisted for at least 70 days and neutralized SARS-CoV-2 at titers comparable to those in human serum samples collected from individuals convalescing from COVID-19. These data support further development of LION/repRNA-CoV2S as a vaccine candidate for prophylactic protection against SARS-CoV-2 infection.

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Soluble Spike DNA Vaccine Provides Long-Term Protective Immunity against SARS-CoV-2 in Mice and Nonhuman Primates

Vaccines ◽

10.3390/vaccines9040307 ◽

2021 ◽

Vol 9 (4) ◽

pp. 307

Author(s):

Yong Bok Seo ◽

You Suk Suh ◽

Ji In Ryu ◽

Hwanhee Jang ◽

Hanseul Oh ◽

...

Keyword(s):

T Cell ◽

Nonhuman Primates ◽

Vaccine Candidate ◽

T Cell Responses ◽

Neutralizing Antibody ◽

Dependent Manner ◽

Viral Loads ◽

Cell Responses ◽

Rapid Spread

The unprecedented and rapid spread of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) has motivated the need for a rapidly producible and scalable vaccine. Here, we developed a synthetic soluble SARS-CoV-2 spike (S) DNA-based vaccine candidate, GX-19. In mice, immunization with GX-19 elicited not only S-specific systemic and pulmonary antibody responses but also Th1-biased T cell responses in a dose-dependent manner. GX-19-vaccinated nonhuman primates seroconverted rapidly and exhibited a detectable neutralizing antibody response as well as multifunctional CD4+ and CD8+ T cell responses. Notably, when the immunized nonhuman primates were challenged at 10 weeks after the last vaccination with GX-19, they had reduced viral loads in contrast to non-vaccinated primates as a control. These findings indicate that GX-19 vaccination provides a durable protective immune response and also support further development of GX-19 as a vaccine candidate for SARS-CoV-2.

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Soluble Spike DNA vaccine provides long-term protective immunity against SAR-CoV-2 in mice and nonhuman primates

10.1101/2020.10.09.334136 ◽

2020 ◽

Author(s):

Yong Bok Seo ◽

You Suk Suh ◽

Ji In Ryu ◽

Hwanhee Jang ◽

Hanseul Oh ◽

...

Keyword(s):

T Cell ◽

Nonhuman Primates ◽

Vaccine Candidate ◽

T Cell Responses ◽

Neutralizing Antibody ◽

Dependent Manner ◽

Viral Loads ◽

Cell Responses ◽

Rapid Spread

SummaryThe unprecedented and rapid spread of SARS-CoV-2 has motivated the need for a rapidly producible and scalable vaccine. Here, we developed a synthetic soluble SARS-CoV-2 spike (S) DNA-based vaccine candidate, GX-19. In mice, immunization with GX-19 elicited not only S-specific systemic and pulmonary antibody responses but also Th1-biased T cell responses in a dose-dependent manner. GX-19 vaccinated nonhuman primate seroconverted rapidly and exhibited detectable neutralizing antibody response as well as multifunctional CD4+ and CD8+ T cell responses. Notably, when the immunized nonhuman primates were challenged at 10 weeks after the last vaccination with GX-19, they did not develop fever and reduced viral loads in contrast to non-vaccinated primates as a control. These findings indicate that GX-19 vaccination provides durable protective immune response and also support further development of GX-19 as a vaccine candidate for SARS-CoV-2 in human clinical trials.

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OMIP 075: A 22‐color panel for the measurement of antigen‐specific T‐cell responses in human and nonhuman primates

Cytometry Part A ◽

10.1002/cyto.a.24460 ◽

2021 ◽

Author(s):

Takuto Nogimori ◽

Eiko Moriishi ◽

Mami Ikeda ◽

Shokichi Takahama ◽

Takuya Yamamoto

Keyword(s):

T Cell ◽

Nonhuman Primates ◽

T Cell Responses ◽

Cell Responses

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Polyinosinic-Polycytidylic Acid Is the Most Effective TLR Adjuvant for SIV Gag Protein–Induced T Cell Responses In Nonhuman Primates

The Journal of Immunology ◽

10.4049/jimmunol.1202958 ◽

2013 ◽

Vol 190 (8) ◽

pp. 4103-4115 ◽

Cited By ~ 39

Author(s):

Haesun Park ◽

Lauren Adamson ◽

Tae Ha ◽

Karl Mullen ◽

Shoko I. Hagen ◽

...

Keyword(s):

T Cell ◽

Nonhuman Primates ◽

T Cell Responses ◽

Gag Protein ◽

Cell Responses ◽

Polycytidylic Acid ◽

Polyinosinic Polycytidylic Acid

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Marburg virus survivor immune responses are Th1 skewed with limited neutralizing antibody responses

Journal of Experimental Medicine ◽

10.1084/jem.20170161 ◽

2017 ◽

Vol 214 (9) ◽

pp. 2563-2572 ◽

Cited By ~ 9

Author(s):

Spencer W. Stonier ◽

Andrew S. Herbert ◽

Ana I. Kuehne ◽

Ariel Sobarzo ◽

Polina Habibulin ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Ebola Virus ◽

T Cell Responses ◽

Neutralizing Antibody ◽

Cd8 T Cell ◽

Marburg Virus ◽

Antibody Responses ◽

Cd4 T Cell ◽

Cell Responses

Until recently, immune responses in filovirus survivors remained poorly understood. Early studies revealed IgM and IgG responses to infection with various filoviruses, but recent outbreaks have greatly expanded our understanding of filovirus immune responses. Immune responses in survivors of Ebola virus (EBOV) and Sudan virus (SUDV) infections have provided the most insight, with T cell responses as well as detailed antibody responses having been characterized. Immune responses to Marburg virus (MARV), however, remain almost entirely uncharacterized. We report that immune responses in MARV survivors share characteristics with EBOV and SUDV infections but have some distinct differences. MARV survivors developed multivariate CD4+ T cell responses but limited CD8+ T cell responses, more in keeping with SUDV survivors than EBOV survivors. In stark contrast to SUDV survivors, rare neutralizing antibody responses in MARV survivors diminished rapidly after the outbreak. These results warrant serious consideration for any vaccine or therapeutic that seeks to be broadly protective, as different filoviruses may require different immune responses to achieve immunity.

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Human T cell responses to the antigen ESAT-6 characterize vaccine candidate and potential diagnostic test for tuberculosis

Journal of Infection ◽

10.1016/s0163-4453(99)90139-1 ◽

1999 ◽

Vol 39 (1) ◽

pp. A9

Author(s):

A. Lalvani ◽

A. Pathan ◽

R. Brookes ◽

H. Pritchard ◽

R. Wilkinson ◽

...

Keyword(s):

T Cell ◽

Diagnostic Test ◽

Vaccine Candidate ◽

T Cell Responses ◽

Cell Responses ◽

Human T Cell

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Systems Vaccinology for a Live Attenuated Tularemia Vaccine Reveals Unique Transcriptional Signatures That Predict Humoral and Cellular Immune Responses

Vaccines ◽

10.3390/vaccines8010004 ◽

2019 ◽

Vol 8 (1) ◽

pp. 4 ◽

Cited By ~ 9

Author(s):

Muktha S. Natrajan ◽

Nadine Rouphael ◽

Lilin Lai ◽

Dmitri Kazmin ◽

Travis L. Jensen ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Innate Immune ◽

Antibody Responses ◽

Cytokine Signaling ◽

Cell Responses ◽

Viral Vaccine ◽

Tularemia Vaccine

Background: Tularemia is a potential biological weapon due to its high infectivity and ease of dissemination. This study aimed to characterize the innate and adaptive responses induced by two different lots of a live attenuated tularemia vaccine and compare them to other well-characterized viral vaccine immune responses. Methods: Microarray analyses were performed on human peripheral blood mononuclear cells (PBMCs) to determine changes in transcriptional activity that correlated with changes detected by cellular phenotyping, cytokine signaling, and serological assays. Transcriptional profiles after tularemia vaccination were compared with yellow fever [YF-17D], inactivated [TIV], and live attenuated [LAIV] influenza. Results: Tularemia vaccine lots produced strong innate immune responses by Day 2 after vaccination, with an increase in monocytes, NK cells, and cytokine signaling. T cell responses peaked at Day 14. Changes in gene expression, including upregulation of STAT1, GBP1, and IFIT2, predicted tularemia-specific antibody responses. Changes in CCL20 expression positively correlated with peak CD8+ T cell responses, but negatively correlated with peak CD4+ T cell activation. Tularemia vaccines elicited gene expression signatures similar to other replicating vaccines, inducing early upregulation of interferon-inducible genes. Conclusions: A systems vaccinology approach identified that tularemia vaccines induce a strong innate immune response early after vaccination, similar to the response seen after well-studied viral vaccines, and produce unique transcriptional signatures that are strongly correlated to the induction of T cell and antibody responses.

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Immunodominant T-Cell Epitopes in the VP1 Capsid Protein of Rhinovirus Species A and C

Journal of Virology ◽

10.1128/jvi.01701-16 ◽

2016 ◽

Vol 90 (23) ◽

pp. 10459-10471 ◽

Cited By ~ 13

Author(s):

Cibele M. Gaido ◽

Shane Stone ◽

Abha Chopra ◽

Wayne R. Thomas ◽

Peter N. Le Souëf ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Antibody Responses ◽

T Cell Proliferation ◽

T Cell Epitopes ◽

Future Studies ◽

Cell Responses ◽

Asthma Exacerbations ◽

Antibody Titers ◽

Vp1 Capsid Protein

ABSTRACTRhinovirus (RV) species A and C are the most frequent cause of respiratory viral illness worldwide, and RV-C has been linked to more severe exacerbations of asthma in young children. Little is known about the immune responses to the different RV species, although studies comparing IgG1 antibody titers found impaired antibody responses to RV-C. Therefore, the aim of this study was to assess whether T-cell immunity to RV-C is similarly impaired. We measured T-cell proliferation to overlapping synthetic peptides covering the entire VP1 capsid protein of an RV-A and RV-C genotype for 20 healthy adult donors. Human leukocyte antigen (HLA) was typed in all the donors in order to investigate possible associations between the HLA type and RV peptide recognition. Total and specific IgG1 antibody titers to the VP1 proteins of both RV-A and RV-C were also measured to examine associations between the antibody and T-cell responses. We identified T-cell epitopes that are specific to and representative of each RV-A and RV-C species. These epitopes stimulated CD4+-specific T-cell proliferation, with similar magnitudes of response for both RV species. All the donors, independent of their HLA-DR or -DQ type, were able to recognize the immunodominant RV-A and -C regions of VP1. Furthermore, the presence or absence of specific antibody titers was not related to changes in T-cell recognition. Our results indicate a dissociation between the antibody and T-cell responses to rhinoviruses. The species-representative T-cell epitopes identified in this study are valuable tools for future studies investigating T-cell responses to the different RV species.IMPORTANCERhinoviruses (RVs) are mostly associated with the common cold and asthma exacerbations, although their contributions to most upper and lower respiratory tract diseases have increasingly been reported. Species C (RV-C) has been associated with more frequent and severe asthma exacerbations in young children and, along with RV-A, is the most clinically relevant species. Little is known about how our immune system responds to rhinoviruses, and there are limited tools to study specific adaptive immunity against each rhinovirus species. In this study, we identified immunodominant T-cell epitopes of the VP1 proteins of RV-A and RV-C, which are representative of each species. The study found that T-cell responses to RV-A and RV-C were of similar magnitudes, in contrast with previous findings showing RV-C-specific antibody responses were low. These findings will provide the basis for future studies on the immune response to rhinoviruses and can help elucidate the mechanisms of severity of rhinovirus-induced infections.

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