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1.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-324099

ABSTRACT

Background: SARS-CoV-2 has caused a global pandemic, infecting millions of people. A safe, effective vaccine is urgently needed and remains a global health priority. Subunit vaccines are used successfully against other viruses when administered in the presence of an effective adjuvant. Methods: We evaluated three different clinically tested adjuvant systems in combination with the SARS-CoV-2 pre-fusion stabilized (S-2P) spike protein using a one-dose regimen in mice.Findings: Whilst spike protein alone was only weakly immunogenic, the addition of either Aluminum hydroxide, a squalene based oil-in-water emulsion system (SE) or a cationic liposome-based adjuvant significantly enhanced antibody responses against the spike receptor binding domain (RBD). Kinetics of antibody responses differed, with SE providing the most rapid response. Neutralizing antibodies developed after a single immunization in all adjuvanted groups with ID 50 titers ranging from 86 - 4063. Spike-specific CD4 T helper responses were also elicited, comprising mainly of IFN-g and IL-17 producing cells in the cationic liposome adjuvanted group, and more IL-5- and IL-10-secreting cells in the AH group.Interpretation: These results demonstrate that adjuvanted spike protein subunit vaccine is a viable strategy for rapidly eliciting SARS-CoV-2 neutralizing antibodies and CD4 T cell responses of various qualities depending on the adjuvant used, which can be explored in further vaccine development against COVID-19.Funding: This work was supported by the European Union Horizon 2020 research and innovation program under grant agreement no. 101003653.Declaration of Interests: D.C. is co-inventor on patents on the cationic adjuvant formulations (CAF). All rights have been turned over to Statens Serum Institut, which is a non-profit government research facility. The rest of the authors declare that there are no competing interests.Ethics Approval Statement: Mouse studies were conducted in accordance with the regulations set forth by the National Committee for the Protection of Animals used for Scientific Purposes and in accordance with European Community Directive 86/609. The experiments have been approved by the governmental Animal Experiments Inspectorate under license 2017-15- 0201-01363.

2.
Int J Mol Sci ; 23(3)2022 Feb 06.
Article in English | MEDLINE | ID: covidwho-1674673

ABSTRACT

The SARS-CoV-2 pandemic caused a massive health and societal crisis, although the fast development of effective vaccines reduced some of the impact. To prepare for future respiratory virus pandemics, a pan-viral prophylaxis could be used to control the initial virus outbreak in the period prior to vaccine approval. The liposomal vaccine adjuvant CAF®09b contains the TLR3 agonist polyinosinic:polycytidylic acid, which induces a type I interferon (IFN-I) response and an antiviral state in the affected tissues. When testing CAF09b liposomes as a potential pan-viral prophylaxis, we observed that intranasal administration of CAF09b liposomes to mice resulted in an influx of innate immune cells into the nose and lungs and upregulation of IFN-I-related gene expression. When CAF09b liposomes were administered prior to challenge with mouse-adapted influenza A/Puerto Rico/8/1934 virus, it protected from severe disease, although the virus was still detectable in the lungs. However, when CAF09b liposomes were administered after influenza challenge, the mice had a similar disease course to controls. In conclusion, CAF09b may be a suitable candidate as a pan-viral prophylactic treatment for epidemic viruses, but must be administered prior to virus exposure to be effective.


Subject(s)
/therapeutic use , Influenza Vaccines/therapeutic use , Influenza, Human/prevention & control , Orthomyxoviridae Infections/prevention & control , /methods , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/therapeutic use , /chemistry , Administration, Intranasal , Animals , COVID-19/prevention & control , COVID-19 Vaccines/chemical synthesis , COVID-19 Vaccines/therapeutic use , Cells, Cultured , Chick Embryo , Gene Expression Regulation/drug effects , Humans , Influenza Vaccines/administration & dosage , Influenza Vaccines/chemistry , Influenza Vaccines/pharmacology , Interferon Type I/genetics , Liposomes/chemistry , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Primary Prevention/methods , SARS-CoV-2/immunology
3.
J Control Release ; 342: 388-399, 2022 02.
Article in English | MEDLINE | ID: covidwho-1562303

ABSTRACT

The efficacy of RNA-based vaccines has been recently demonstrated, leading to the use of mRNA-based COVID-19 vaccines. The application of self-amplifying mRNA within these formulations may offer further enhancement to these vaccines, as self-amplifying mRNA replicons enable longer expression kinetics and more potent immune responses compared to non-amplifying mRNAs. To investigate the impact of administration route on RNA-vaccine potency, we investigated the immunogenicity of a self-amplifying mRNA encoding the rabies virus glycoprotein encapsulated in different nanoparticle platforms (solid lipid nanoparticles (SLNs), polymeric nanoparticles (PNPs) and lipid nanoparticles (LNPs)). These were administered via three different routes: intramuscular, intradermal and intranasal. Our studies in a mouse model show that the immunogenicity of our 4 different saRNA vaccine formulations after intramuscular or intradermal administration was initially comparable; however, ionizable LNPs gave higher long-term IgG responses. The clearance of all 4 of the nanoparticle formulations from the intramuscular or intradermal administration site was similar. In contrast, immune responses generated after intranasal was low and coupled with rapid clearance for the administration site, irrespective of the formulation. These results demonstrate that both the administration route and delivery system format dictate self-amplifying RNA vaccine efficacy.


Subject(s)
COVID-19 , Nanoparticles , Animals , COVID-19 Vaccines , Humans , Liposomes , Mice , RNA, Messenger , SARS-CoV-2 , Vaccine Potency , Vaccines, Synthetic
4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-296458

ABSTRACT

ABSTRACT The SARS-CoV-2 pandemic caused a massive health and societal crisis, although the fast development of effective vaccines reduced some of the impact. To prepare for future pandemics, a pan-viral prophylaxis could be used to control the initial virus outbreak in the period prior to vaccine approval. The liposomal vaccine adjuvant CAF ® 09b contains the TLR3 agonist polyinosinic:polycytidylic acid, which induces a type I interferon (IFN-I) response and an antiviral state in the affected tissues. When testing CAF09b as a potential pan-viral prophylaxis, we observed that intranasal administration of CAF09b to mice resulted in an influx of innate immune cells into the nose and lungs and upregulation of IFN-I related gene expression. When CAF09b was administered prior to challenge with mouse-adapted influenza A/Puerto Rico/8/1934 virus, it protected from severe disease, although virus was still detectable in the lungs. However, when CAF09b was administered after influenza challenge, the mice had a similar disease course to controls. In conclusion, CAF09b may be a suitable candidate as a pan-viral prophylactic treatment for epidemic viruses, but must be administered prior to virus exposure to be effective.

5.
EBioMedicine ; 63: 103197, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1014450

ABSTRACT

BACKGROUND: SARS-CoV-2 has caused a global pandemic, infecting millions of people. A safe, effective vaccine is urgently needed and remains a global health priority. Subunit vaccines are used successfully against other viruses when administered in the presence of an effective adjuvant. METHODS: We evaluated three different clinically tested adjuvant systems in combination with the SARS-CoV-2 pre-fusion stabilized (S-2P) spike protein using a one-dose regimen in mice. FINDINGS: Whilst spike protein alone was only weakly immunogenic, the addition of either Aluminum hydroxide, a squalene based oil-in-water emulsion system (SE) or a cationic liposome-based adjuvant significantly enhanced antibody responses against the spike receptor binding domain (RBD). Kinetics of antibody responses differed, with SE providing the most rapid response. Neutralizing antibodies developed after a single immunization in all adjuvanted groups with ID50 titers ranging from 86-4063. Spike-specific CD4 T helper responses were also elicited, comprising mainly of IFN-γ and IL-17 producing cells in the cationic liposome adjuvanted group, and more IL-5- and IL-10-secreting cells in the AH group. INTERPRETATION: These results demonstrate that adjuvanted spike protein subunit vaccine is a viable strategy for rapidly eliciting SARS-CoV-2 neutralizing antibodies and CD4 T cell responses of various qualities depending on the adjuvant used, which can be explored in further vaccine development against COVID-19. FUNDING: This work was supported by the European Union Horizon 2020 research and innovation program under grant agreement no. 101003653.


Subject(s)
Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , CD4-Positive T-Lymphocytes/immunology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/immunology , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/chemistry , Aluminum Hydroxide/chemistry , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , COVID-19/pathology , COVID-19/virology , Female , Immunization , Interferon-gamma/metabolism , Interleukin-17/metabolism , Liposomes/chemistry , Mice , Mice, Inbred C57BL , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Squalene/chemistry , Vaccines, Subunit/immunology
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