A dual-antigen self-amplifying RNA SARS-CoV-2 vaccine induces potent humoral and cellular immune responses and protects against SARS-CoV-2 variants through T cell-mediated immunity

Cafferty, Séan Mc; Haque, AKM Ashiqul; Vandierendonck, Aster; Weidensee, Brian; Plovyt, Magalie; Stuchlíková, Magdalena; François, Nathalie; Valembois, Sophie; Heyndríckx, Leo; Míchiels, Johan; Ariën, Kevin K.; Vandekerckhove, Linos; Abdelnabi, Rana; Foo, Caroline S.; Neyts, Johan; Sahu, Itishri; Sanders, Niek N.

doi:10.1016/j.ymthe.2022.04.014

Cited by 40 publications

(33 citation statements)

References 47 publications

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“…In the in vivo viral challenge testing paradigm, cell-mediated immunity -not accessed in the pseudovirus assay that tests seraconferred by AdS+N vaccination likely plays a key role in protection, as has been reported for natural infection of patients (44)(45)(46)(47). Others have reported that combination of S and N increased provided enhanced protection against infection by variants with highly mutated spike in a hamster model (48), and thus, in future studies, we plan to assess protection against infection by SARS-CoV-2 variants in vivo by the dual-antigen vaccine as compared to S or N alone. There were limitations to the study performed, including there being a single time interval between prime and boost tested (21 days) and a single time point for sample collection (35 days).…”

Section: Discussionmentioning

confidence: 98%

Heterologous saRNA Prime, DNA Dual-Antigen Boost SARS-CoV-2 Vaccination Elicits Robust Cellular Immunogenicity and Cross-Variant Neutralizing Antibodies

et al. 2022

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We assessed if immune responses are enhanced in CD-1 mice by heterologous vaccination with two different nucleic acid-based COVID-19 vaccines: a next-generation human adenovirus serotype 5 (hAd5)-vectored dual-antigen spike (S) and nucleocapsid (N) vaccine (AdS+N) and a self-amplifying and -adjuvanted S RNA vaccine (AAHI-SC2) delivered by a nanostructured lipid carrier. The AdS+N vaccine encodes S modified with a fusion motif to increase cell-surface expression and an N antigen modified with an Enhanced T-cell Stimulation Domain (N-ETSD) to direct N to the endosomal/lysosomal compartment and increase MHC class I and II stimulation potential. The S sequence in the AAHI-SC2 vaccine comprises the D614G mutation, two prolines to stabilize S in the prefusion conformation, and 3 glutamines in the furin cleavage region to confer protease resistance. CD-1 mice received vaccination by homologous and heterologous prime > boost combinations. Humoral responses to S were the highest with any regimen that included the AAHI-SC2 vaccine, and IgG bound to wild type and Delta (B.1.617.2) variant S1 at similar levels. An AAHI-SC2 prime followed by an AdS+N boost particularly enhanced CD4+ and CD8+ T-cell responses to both wild type and Delta S peptides relative to all other vaccine regimens. Sera from mice receiving AAHI-SC2 homologous or heterologous vaccination were found to be highly neutralizing for all pseudovirus strains tested: Wuhan, Beta, Delta, and Omicron strains. The findings here, taken in consideration with the availability of both vaccines in thermostable formulations, support the testing of heterologous vaccination by an AAHI-SC2 > AdS+N regimen in animal models of SARS-CoV-2 infection to assess its potential to provide increased protection against emerging SARS-CoV-2 variants particularly in regions of the world where the need for cold-chain storage has limited the distribution of other vaccines.

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Section: Discussionmentioning

confidence: 98%

Heterologous saRNA Prime, DNA Dual-Antigen Boost SARS-CoV-2 Vaccination Elicits Robust Cellular Immunogenicity and Cross-Variant Neutralizing Antibodies

et al. 2022

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“…Here, the saRNA encodes the viral glycoproteins as the target for neutralizing antibodies and cellular immune responses. Alphavirus-based saRNAs were successfully tested in animal models as vaccine candidates for SARS-CoV-2 infections [ 68 , 91 , 92 , 93 , 94 ]. Recently, preclinical data for a cross-sarbecovirus saRNA vaccine candidate expressing multiple bat and human coronavirus spike antigens showed that it was able to protect against lethal heterologous infections [ 95 ].…”

Section: Self-amplifying Rna Vaccine Candidatesmentioning

confidence: 99%

Self-Amplifying RNA Vaccine Candidates: Alternative Platforms for mRNA Vaccine Development

Schmidt

Schnierle

2023

Pathogens

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The present use of mRNA vaccines against COVID-19 has shown for the first time the potential of mRNA vaccines for infectious diseases. Here we will summarize the current knowledge about improved mRNA vaccines, i.e., the self-amplifying mRNA (saRNA) vaccines. This approach may enhance antigen expression by amplification of the antigen-encoding RNA. RNA design, RNA delivery, and the innate immune responses induced by RNA will be reviewed.

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“…Moreover, vaccine efficacy at preventing infection declines by six months after full vaccination 6 , and breakthrough infections, especially by novel SARS-CoV-2 variants, have been reported in previously vaccinated individuals 7 . Indeed, current vaccination efforts have largely focussed on humoral immunity, which wanes over time 8,9 , leading experts to postulate that if long lasting protection is to be achieved, an effective memory T-cell response must be generated against COVID-19 and its variants 10,11 . In addition, there is an urgent need to provide equitable access to affordable and effective vaccines amongst developing nations to prevent the ongoing morbidity and mortality as well as reduce the risk of novel variants emerging.…”

Section: Introductionmentioning

confidence: 99%

BCG administration promotes the long-term protection afforded by a single-dose intranasal adenovirus-based SARS-CoV-2 vaccine

Perera

Domenech

Babuadze

et al. 2023

Preprint

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Despite medical interventions and several approved vaccines, the COVID-19 pandemic is continuing into its third year. Recent publications have explored single-dose intranasal (i.n.) adenovirus-based vaccines as an effective strategy for curbing SARS-CoV-2 in naive animal models. However, the effects of prior immunizations and infections have yet to be considered within these models. Here, we investigate the immunomodulatory effects of Mycobacterium bovis BCG pre-immunization on a subsequent S-protein expressing i.n. Ad vaccination, termed Ad(Spike). We found that Ad(Spike) alone conferred long-term protection from severe SARS-CoV-2 pathology within a mouse model, yet it was unable to limit initial infection 6 months post-vaccination. While i.n. Ad(Spike) retains some protective effect after 6 months, a single administration of BCG-Danish prior to Ad(Spike) vaccination potentiates its ability to control viral replication of the B.1.351 SARS-CoV-2 variant within the respiratory tract. Though BCG-Danish had no effect on the ability of Ad(Spike) to generate and maintain humoral immunity, it promoted the generation of cytotoxic and Th1 responses over suppressive FoxP3+ TREG cells in the lungs of infected mice. These data demonstrate a novel vaccination strategy that may prove useful in limiting future viral pandemics by potentiating the long-term efficacy of next generation mucosal vaccines within the context of the safe and widely distributed BCG vaccine.

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A dual-antigen self-amplifying RNA SARS-CoV-2 vaccine induces potent humoral and cellular immune responses and protects against SARS-CoV-2 variants through T cell-mediated immunity

Cited by 40 publications

References 47 publications

Heterologous saRNA Prime, DNA Dual-Antigen Boost SARS-CoV-2 Vaccination Elicits Robust Cellular Immunogenicity and Cross-Variant Neutralizing Antibodies

Heterologous saRNA Prime, DNA Dual-Antigen Boost SARS-CoV-2 Vaccination Elicits Robust Cellular Immunogenicity and Cross-Variant Neutralizing Antibodies

Self-Amplifying RNA Vaccine Candidates: Alternative Platforms for mRNA Vaccine Development

BCG administration promotes the long-term protection afforded by a single-dose intranasal adenovirus-based SARS-CoV-2 vaccine

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