Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 14 de 14
Filter
1.
Virology ; 576: 61-68, 2022 11.
Article in English | MEDLINE | ID: covidwho-2086825

ABSTRACT

SARS-CoV-2 variants have posed significant challenges to the hopes of using ancestral strain-based vaccines to address the risk of breakthrough infection by variants. We designed and developed a bivalent vaccine based on SARS-CoV-2 Alpha and Beta variants (named SCTV01C). SCTV01C antigens were stable at 25 oC for at least 6 months. In the presence of a squalene-based oil-in-water adjuvant SCT-VA02B, SCTV01C showed significant protection efficacy against antigen-matched Beta variant, with favorable safety profiles in rodents. Notably, SCTV01C exhibited cross-neutralization capacity against Omicron subvariants (BA.1, BA.1.1, BA.2, BA.3, and BA.4/5) in mice, superior to a WT (D614G)-based vaccine, which reinforced our previously published findings that SCTV01C exhibited broad-spectrum neutralizing potencies against over a dozen pre-Omicron variants and the Omicron BA.1 variant. In summary, variant-based multivalent protein vaccine could be a platform approach to address the challenging issues of emerging variants, vaccine hesitancy and the needs of affordable and thermal stable vaccines.


Subject(s)
COVID-19 , Viral Vaccines , Mice , Humans , Animals , SARS-CoV-2/genetics , Vaccines, Combined , Viral Vaccines/genetics , Squalene , COVID-19/prevention & control , Antibodies, Viral , Water , Antibodies, Neutralizing
2.
PLoS One ; 17(8): e0269823, 2022.
Article in English | MEDLINE | ID: covidwho-2002298

ABSTRACT

COVID-19 pandemic has accelerated the development of vaccines against its etiologic agent, SARS-CoV-2. However, the emergence of new variants of the virus lead to the generation of new alternatives to improve the current sub-unit vaccines in development. In the present report, the immunogenicity of the Spike RBD of SARS-CoV-2 formulated with an oil-in-water emulsion and a water-in-oil emulsion with squalene was evaluated in mice and hamsters. The RBD protein was expressed in insect cells and purified by chromatography until >95% purity. The protein was shown to have the appropriate folding as determined by ELISA and flow cytometry binding assays to its receptor, as well as by its detection by hamster immune anti-S1 sera under non-reducing conditions. In immunization assays, although the cellular immune response elicited by both adjuvants were similar, the formulation based in water-in-oil emulsion and squalene generated an earlier humoral response as determined by ELISA. Similarly, this formulation was able to stimulate neutralizing antibodies in hamsters. The vaccine candidate was shown to be safe, as demonstrated by the histopathological analysis in lungs, liver and kidney. These results have shown the potential of this formulation vaccine to be evaluated in a challenge against SARS-CoV-2 and determine its ability to confer protection.


Subject(s)
COVID-19 , Viral Vaccines , Adjuvants, Immunologic , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Cricetinae , Emulsions , Humans , Immunogenicity, Vaccine , Mice , Mice, Inbred BALB C , Models, Animal , Pandemics/prevention & control , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Squalene , Water
3.
mSphere ; 7(4): e0024322, 2022 08 31.
Article in English | MEDLINE | ID: covidwho-1992945

ABSTRACT

The ongoing COVID-19 pandemic has contributed largely to the global vaccine disparity. Development of protein subunit vaccines can help alleviate shortages of COVID-19 vaccines delivered to low-income countries. Here, we evaluated the efficacy of a three-dose virus-like particle (VLP) vaccine composed of hepatitis B surface antigen (HBsAg) decorated with the receptor binding domain (RBD) from the Wuhan or Beta SARS-CoV-2 strain adjuvanted with either aluminum hydroxide (alum) or squalene in water emulsion (SWE). RBD HBsAg vaccines were compared to the standard two doses of Pfizer mRNA vaccine. Alum-adjuvanted vaccines were composed of either HBsAg conjugated with Beta RBD alone (ß RBD HBsAg+Al) or a combination of both Beta RBD HBsAg and Wuhan RBD HBsAg (ß/Wu RBD HBsAg+Al). RBD vaccines adjuvanted with SWE were formulated with Beta RBD HBsAg (ß RBD HBsAg+SWE) or without HBsAg (ß RBD+SWE). Both alum-adjuvanted RBD HBsAg vaccines generated functional RBD IgG against multiple SARS-CoV-2 variants of concern (VOC), decreased viral RNA burden, and lowered inflammation in the lung against Alpha or Beta challenge in K18-hACE2 mice. However, only ß/Wu RBD HBsAg+Al was able to afford 100% survival to mice challenged with Alpha or Beta VOC. Furthermore, mice immunized with ß RBD HBsAg+SWE induced cross-reactive neutralizing antibodies against major VOC of SARS-CoV-2, lowered viral RNA burden in the lung and brain, and protected mice from Alpha or Beta challenge similarly to mice immunized with Pfizer mRNA. However, RBD+SWE immunization failed to protect mice from VOC challenge. Our findings demonstrate that RBD HBsAg VLP vaccines provided similar protection profiles to the approved Pfizer mRNA vaccines used worldwide and may offer protection against SARS-CoV-2 VOC. IMPORTANCE Global COVID-19 vaccine distribution to low-income countries has been a major challenge of the pandemic. To address supply chain issues, RBD virus-like particle (VLP) vaccines that are cost-effective and capable of large-scale production were developed and evaluated for efficacy in preclinical mouse studies. We demonstrated that RBD-VLP vaccines protected K18-hACE2 mice against Alpha or Beta challenge similarly to Pfizer mRNA vaccination. Our findings showed that the VLP platform can be utilized to formulate immunogenic and efficacious COVID-19 vaccines.


Subject(s)
COVID-19 , Vaccines, Virus-Like Particle , Alum Compounds , Animals , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Emulsions , Hepatitis B Surface Antigens/genetics , Humans , Melphalan , Mice , Mice, Inbred BALB C , Pandemics , RNA, Messenger , RNA, Viral , SARS-CoV-2 , Squalene , Vaccines, Synthetic , Water , gamma-Globulins , mRNA Vaccines
4.
Vaccine ; 40(23): 3098-3102, 2022 05 20.
Article in English | MEDLINE | ID: covidwho-1825027

ABSTRACT

In older adults, the serum antibody response to inactivated influenza vaccine (IIV) is often lower than in adolescents and non-elderly adults which may translate into suboptimal protection against influenza. To counteract this expression of immunosenescence, the use of adjuvanted IIV formulations has been explored. Four recent studies (three meta-analyses and one clinical trial) found an antibody increase of up to 1.5-fold in older adults, when a squalene-adjuvanted (MF59™) IIV was used. The clinical relevance of this increase may well continue to be a matter of debate. We would favour a threshold of 1.5 to consider an adjuvanted vaccine formulation superior to standard aqueous IIV because it exceeds the inevitable variation of antibody responses to non-adjuvanted IIV. It is also the same as the upper FDA equivalence limit for IIV lot-to-lot consistency. A corresponding threshold for the seroresponse rate difference could then be +5%.


Subject(s)
Influenza Vaccines , Influenza, Human , Adjuvants, Immunologic , Adolescent , Aged , Antibodies, Viral , Hemagglutination Inhibition Tests , Humans , Influenza, Human/prevention & control , Middle Aged , Polysorbates , Squalene , Vaccination , Vaccines, Inactivated
5.
Lancet Infect Dis ; 21(10): 1383-1394, 2021 10.
Article in English | MEDLINE | ID: covidwho-1621119

ABSTRACT

BACKGROUND: Given the scale of the ongoing COVID-19 pandemic, the development of vaccines based on different platforms is essential, particularly in light of emerging viral variants, the absence of information on vaccine-induced immune durability, and potential paediatric use. We aimed to assess the safety and immunogenicity of an MF59-adjuvanted subunit vaccine for COVID-19 based on recombinant SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a novel molecular clamp (spike glycoprotein-clamp [sclamp]). METHODS: We did a phase 1, double-blind, placebo-controlled, block-randomised trial of the sclamp subunit vaccine in a single clinical trial site in Brisbane, QLD, Australia. Healthy adults (aged ≥18 to ≤55 years) who had tested negative for SARS-CoV-2, reported no close contact with anyone with active or previous SARS-CoV-2 infection, and tested negative for pre-existing SARS-CoV-2 immunity were included. Participants were randomly assigned to one of five treatment groups and received two doses via intramuscular injection 28 days apart of either placebo, sclamp vaccine at 5 µg, 15 µg, or 45 µg, or one dose of sclamp vaccine at 45 µg followed by placebo. Participants and study personnel, except the dose administration personnel, were masked to treatment. The primary safety endpoints included solicited local and systemic adverse events in the 7 days after each dose and unsolicited adverse events up to 12 months after dosing. Here, data are reported up until day 57. Primary immunogenicity endpoints were antigen-specific IgG ELISA and SARS-CoV-2 microneutralisation assays assessed at 28 days after each dose. The study is ongoing and registered with ClinicalTrials.gov, NCT04495933. FINDINGS: Between June 23, 2020, and Aug 17, 2020, of 314 healthy volunteers screened, 120 were randomly assigned (n=24 per group), and 114 (95%) completed the study up to day 57 (mean age 32·5 years [SD 10·4], 65 [54%] male, 55 [46%] female). Severe solicited reactions were infrequent and occurred at similar rates in participants receiving placebo (two [8%] of 24) and the SARS-CoV-2 sclamp vaccine at any dose (three [3%] of 96). Both solicited reactions and unsolicited adverse events occurred at a similar frequency in participants receiving placebo and the SARS-CoV-2 sclamp vaccine. Solicited reactions occurred in 19 (79%) of 24 participants receiving placebo and 86 (90%) of 96 receiving the SARS-CoV-2 sclamp vaccine at any dose. Unsolicited adverse events occurred in seven (29%) of 24 participants receiving placebo and 35 (36%) of 96 participants receiving the SARS-CoV-2 sclamp vaccine at any dose. Vaccination with SARS-CoV-2 sclamp elicited a similar antigen-specific response irrespective of dose: 4 weeks after the initial dose (day 29) with 5 µg dose (geometric mean titre [GMT] 6400, 95% CI 3683-11 122), with 15 µg dose (7492, 4959-11 319), and the two 45 µg dose cohorts (8770, 5526-13 920 in the two-dose 45 µg cohort; 8793, 5570-13 881 in the single-dose 45 µg cohort); 4 weeks after the second dose (day 57) with two 5 µg doses (102 400, 64 857-161 676), with two 15 µg doses (74 725, 51 300-108 847), with two 45 µg doses (79 586, 55 430-114 268), only a single 45 µg dose (4795, 2858-8043). At day 57, 67 (99%) of 68 participants who received two doses of sclamp vaccine at any concentration produced a neutralising immune response, compared with six (25%) of 24 who received a single 45 µg dose and none of 22 who received placebo. Participants receiving two doses of sclamp vaccine elicited similar neutralisation titres, irrespective of dose: two 5 µg doses (GMT 228, 95% CI 146-356), two 15 µg doses (230, 170-312), and two 45 µg doses (239, 187-307). INTERPRETATION: This first-in-human trial shows that a subunit vaccine comprising mammalian cell culture-derived, MF59-adjuvanted, molecular clamp-stabilised recombinant spike protein elicits strong immune responses with a promising safety profile. However, the glycoprotein 41 peptide present in the clamp created HIV diagnostic assay interference, a possible barrier to widespread use highlighting the criticality of potential non-spike directed immunogenicity during vaccine development. Studies are ongoing with alternative molecular clamp trimerisation domains to ameliorate this response. FUNDING: Coalition for Epidemic Preparedness Innovations, National Health and Medical Research Council, Queensland Government, and further philanthropic sources listed in the acknowledgments.


Subject(s)
Adjuvants, Immunologic/pharmacology , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Spike Glycoprotein, Coronavirus/immunology , Squalene/immunology , Adult , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Australia , Female , Healthy Volunteers , Humans , Male , Pandemics/prevention & control , Polysorbates , Vaccination/adverse effects , Young Adult
6.
Cell Mol Immunol ; 19(2): 222-233, 2022 02.
Article in English | MEDLINE | ID: covidwho-1607212

ABSTRACT

Although antivirals are important tools to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, effective vaccines are essential to control the current coronavirus disease 2019 (COVID-19) pandemic. Plant-derived virus-like particle (VLP) vaccine candidates have previously demonstrated immunogenicity and efficacy against influenza. Here, we report the immunogenicity and protection induced in rhesus macaques by intramuscular injections of a VLP bearing a SARS-CoV-2 spike protein (CoVLP) vaccine candidate formulated with or without Adjuvant System 03 (AS03) or cytidine-phospho-guanosine (CpG) 1018. Although a single dose of the unadjuvanted CoVLP vaccine candidate stimulated humoral and cell-mediated immune responses, booster immunization (at 28 days after priming) and adjuvant administration significantly improved both responses, with higher immunogenicity and protection provided by the AS03-adjuvanted CoVLP. Fifteen micrograms of CoVLP adjuvanted with AS03 induced a polyfunctional interleukin-2 (IL-2)-driven response and IL-4 expression in CD4 T cells. Animals were challenged by multiple routes (i.e., intratracheal, intranasal, and ocular) with a total viral dose of 106 plaque-forming units of SARS-CoV-2. Lower viral replication in nasal swabs and bronchoalveolar lavage fluid (BALF) as well as fewer SARS-CoV-2-infected cells and immune cell infiltrates in the lungs concomitant with reduced levels of proinflammatory cytokines and chemotactic factors in the BALF were observed in animals immunized with the CoVLP adjuvanted with AS03. No clinical, pathologic, or virologic evidence of vaccine-associated enhanced disease was observed in vaccinated animals. The CoVLP adjuvanted with AS03 was therefore selected for vaccine development and clinical trials.


Subject(s)
Adjuvants, Immunologic/adverse effects , COVID-19 Vaccines/adverse effects , COVID-19/immunology , COVID-19/prevention & control , Immunogenicity, Vaccine/immunology , Pandemics/prevention & control , Polysorbates/adverse effects , SARS-CoV-2/immunology , Squalene/adverse effects , Tobacco/metabolism , Vaccination/methods , Vaccines, Virus-Like Particle/adverse effects , alpha-Tocopherol/adverse effects , Adjuvants, Immunologic/administration & dosage , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/epidemiology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Disease Models, Animal , Drug Combinations , Drug Compounding/methods , Immunity, Humoral , Macaca mulatta , Male , Polysorbates/administration & dosage , Recombinant Proteins/immunology , Recombinant Proteins/metabolism , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Squalene/administration & dosage , Treatment Outcome , Vaccines, Virus-Like Particle/administration & dosage , alpha-Tocopherol/administration & dosage
7.
Reprod Toxicol ; 107: 69-80, 2022 01.
Article in English | MEDLINE | ID: covidwho-1531737

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulting in the coronavirus disease 2019 (COVID-19) has afflicted tens of millions of people in a worldwide pandemic. A recently developed recombinant Plant-Derived Virus-Like Particle Vaccine candidate for COVID-19 (CoVLP) formulated with AS03 has been shown to be well-tolerated and highly immunogenic in healthy adults. Since the target population for the vaccine includes women of childbearing potential, the objective of the study was to evaluate any untoward prenatal and postnatal effects of AS03-adjuvanted CoVLP administered intramuscularly to Sprague-Dawley female rats before cohabitation for mating (22 and 8 days prior) and during gestation (Gestation Days [GD] 6 and 19). The embryo-fetal development (EFD) cohort was subjected to cesarean on GD 21 and the pre/post-natal (PPN) cohort was allowed to naturally deliver. Effects of AS03-adjuvanted CoVLP was evaluated on pregnant rats, embryo-fetal development (EFD), during parturition, lactation and the development of the F1 offspring up to weaning Vaccination with AS03-adjuvanted CoVLP induced an antibody response in F0 females and anti-SARS-CoV-2 spike-specific maternal antibodies were detected in the offspring at the end of the gestation and lactation periods. Overall, there was no evidence of untoward effects of AS03-adjuvanted CoVLP on the fertility or reproductive performance of the vaccinated F0 females. There was no evidence of untoward effects on embryo-fetal development (including teratogenicity), or early (pre-weaning) development of the F1 offspring. These results support the acceptable safety profile of the AS03-adjuvanted CoVLP vaccine for administration to women of childbearing potential.


Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , Embryonic Development/drug effects , Fertility/drug effects , Fetal Development/drug effects , Polysorbates/administration & dosage , Squalene/administration & dosage , Vaccines, Virus-Like Particle/administration & dosage , alpha-Tocopherol/administration & dosage , Animals , Animals, Newborn , Antibodies, Viral/blood , Drug Combinations , Female , Immunoglobulin G/blood , Maternal-Fetal Exchange , Pregnancy , Rats, Sprague-Dawley , Recombinant Proteins/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Tobacco/genetics
8.
Int J Pharm ; 607: 121024, 2021 Sep 25.
Article in English | MEDLINE | ID: covidwho-1364121

ABSTRACT

Vaccination is regarded as the most effective intervention for controlling the coronavirus disease 2019 (COVID-19) pandemic. The objective of this study is to provide comprehensive information on lipid squalene nanoparticle (SQ@NP)-adjuvanted COVID-19 vaccines regarding modulating immune response and enhancing vaccine efficacy. After being adjuvanted with SQ@NP, the SARS-CoV-2 spike (S) subunit protein was intramuscularly (i.m.) administered to mice. Serum samples investigated by ELISA and virus neutralizing assay showed that a single-dose SQ@NP-adjuvanted S-protein vaccine can induce antigen-specific IgG and protective antibodies comparable with those induced by two doses of nonadjuvanted protein vaccine. When the mice received a boosting vaccine injection, anamnestic response was observed in the groups of adjuvanted vaccine. Furthermore, the secretion of cytokines in splenocytes, such as interferon (IFN)-γ, interleukin (IL)-5 and IL-10, was significantly enhanced after adjuvantation of S-protein vaccine with SQ@NP; however, this was not the case for the vaccine adjuvanted with conventional aluminum mineral salts. Histological examination of injection sites showed that the SQ@NP-adjuvanted vaccine was considerably well tolerated following i.m. injection in mice. These results pave the way for the performance tuning of optimal vaccine formulations against COVID-19.


Subject(s)
COVID-19 , Nanoparticles , Adjuvants, Immunologic , Animals , Antibodies, Viral , COVID-19 Vaccines , Humans , Lipids , Mice , SARS-CoV-2 , Squalene
9.
J Med Virol ; 94(1): 119-130, 2022 01.
Article in English | MEDLINE | ID: covidwho-1359797

ABSTRACT

This study investigates the effect of the nanostructure of squalene in the form of microemulsion on COVID-19 patients. In this blinded clinical trial, a comparison was made between the efficacy of squalene treatment and controls. A total of 30 COVID-19 patients admitted to the emergency department, and the infection ward was equally allocated to case (n = 15) and control (n = 15) groups according to their age and underlying diseases. The baseline characteristics of subjects, including age, gender, time of treatment onset, underlying condition, white blood cells count, and lymphocyte count were similar (p < 0.05). Baseline laboratory tests and computed tomography (CT) scans were performed for the study groups. The treatment group received 5 mg of intravenous squalene twice a day and standard treatment for 6 days, while controls received only standard treatment. After 6 days of treatment, clinical and CT scan changes were evaluated and compared in intervention and control groups. The need for oxygen therapy (p = 0.020), 2 days of no fever (p = 0.025), cough alleviation (p = 0.010), and lung high-resolution computed tomography improvement (p = 0.033) were significantly different between cases and controls within 7 days of admission. No adverse effects were observed in the treatment group. Our data suggest that squalene could be considered as a potential treatment for COVID-19, and further studies are required to confirm the results.


Subject(s)
COVID-19/drug therapy , Squalene/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Emulsions , Female , Humans , Male , Middle Aged , Plant Oils/chemistry , Squalene/administration & dosage , Squalene/adverse effects , Squalene/chemistry , Treatment Outcome
10.
Cell ; 184(15): 3915-3935.e21, 2021 07 22.
Article in English | MEDLINE | ID: covidwho-1283262

ABSTRACT

Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at interferon response factor (IRF) loci in monocytes and mDCs. This was associated with elevated expression of antiviral genes and heightened resistance to the unrelated Zika and Dengue viruses. These results demonstrate that vaccination stimulates persistent epigenomic remodeling of the innate immune system and reveal AS03's potential as an epigenetic adjuvant.


Subject(s)
Epigenomics , Immunity/genetics , Influenza Vaccines/genetics , Influenza Vaccines/immunology , Single-Cell Analysis , Transcription, Genetic , Vaccination , Adolescent , Adult , Anti-Bacterial Agents/pharmacology , Antigens, CD34/metabolism , Antiviral Agents/pharmacology , Cellular Reprogramming , Chromatin/metabolism , Cytokines/biosynthesis , Drug Combinations , Female , Gene Expression Regulation , Histones/metabolism , Humans , Immunity, Innate/genetics , Influenza A Virus, H5N1 Subtype/drug effects , Influenza A Virus, H5N1 Subtype/immunology , Interferon Type I/metabolism , Male , Myeloid Cells/metabolism , Polysorbates/pharmacology , Squalene/pharmacology , Toll-Like Receptors/metabolism , Transcription Factor AP-1/metabolism , Transcriptome/genetics , Young Adult , alpha-Tocopherol/pharmacology
11.
Nature ; 594(7862): 253-258, 2021 06.
Article in English | MEDLINE | ID: covidwho-1192479

ABSTRACT

The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative1. Here we demonstrate the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (hereafter designated RBD-NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD-NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD-NP in AS03 (RBD-NP-AS03), and correlated with protection from infection. RBD-NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD-NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD-NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD-NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343).


Subject(s)
Adjuvants, Immunologic , Antibodies, Neutralizing/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Vaccines, Subunit/immunology , Alum Compounds , Animals , Antibodies, Viral/immunology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , COVID-19/virology , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Disease Models, Animal , Immunity, Cellular , Immunity, Humoral , Macaca mulatta/immunology , Male , Oligodeoxyribonucleotides , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Squalene
12.
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
13.
Immunity ; 53(6): 1281-1295.e5, 2020 12 15.
Article in English | MEDLINE | ID: covidwho-967679

ABSTRACT

The deployment of effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical to eradicate the coronavirus disease 2019 (COVID-19) pandemic. Many licensed vaccines confer protection by inducing long-lived plasma cells (LLPCs) and memory B cells (MBCs), cell types canonically generated during germinal center (GC) reactions. Here, we directly compared two vaccine platforms-mRNA vaccines and a recombinant protein formulated with an MF59-like adjuvant-looking for their abilities to quantitatively and qualitatively shape SARS-CoV-2-specific primary GC responses over time. We demonstrated that a single immunization with SARS-CoV-2 mRNA, but not with the recombinant protein vaccine, elicited potent SARS-CoV-2-specific GC B and T follicular helper (Tfh) cell responses as well as LLPCs and MBCs. Importantly, GC responses strongly correlated with neutralizing antibody production. mRNA vaccines more efficiently induced key regulators of the Tfh cell program and influenced the functional properties of Tfh cells. Overall, this study identifies SARS-CoV-2 mRNA vaccines as strong candidates for promoting robust GC-derived immune responses.


Subject(s)
Antibodies, Neutralizing/metabolism , B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Germinal Center/immunology , SARS-CoV-2/physiology , T-Lymphocytes, Helper-Inducer/immunology , Vaccines, Synthetic/immunology , Antigens, Viral/genetics , Antigens, Viral/immunology , Cells, Cultured , Epitopes , Humans , Lymphocyte Activation , Polysorbates , RNA, Viral/immunology , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Squalene , Vaccination
14.
Sci Adv ; 6(23): eaaz5466, 2020 06.
Article in English | MEDLINE | ID: covidwho-602279

ABSTRACT

Uncontrolled inflammatory processes are at the root of numerous pathologies. Most recently, studies on confirmed COVID-19 cases have suggested that mortality might be due to virally induced hyperinflammation. Uncontrolled pro-inflammatory states are often driven by continuous positive feedback loops between pro-inflammatory signaling and oxidative stress, which cannot be resolved in a targeted manner. Here, we report on the development of multidrug nanoparticles for the mitigation of uncontrolled inflammation. The nanoparticles are made by conjugating squalene, a natural lipid, to adenosine, an endogenous immunomodulator, and then encapsulating α-tocopherol, as antioxidant. This resulted in high drug loading, biocompatible, multidrug nanoparticles. By exploiting the endothelial dysfunction at sites of acute inflammation, these multidrug nanoparticles delivered the therapeutic agents in a targeted manner, conferring survival advantage to treated animals in models of endotoxemia. Selectively delivering adenosine and antioxidants together could serve as a novel therapeutic approach for safe treatment of acute paradoxal inflammation.


Subject(s)
Drug Delivery Systems/methods , Endotoxemia/drug therapy , Nanoparticles/chemistry , Squalene/chemistry , Systemic Inflammatory Response Syndrome/drug therapy , Adenosine/administration & dosage , Adenosine/chemistry , Animals , Antioxidants/administration & dosage , Antioxidants/chemistry , Betacoronavirus , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Coronavirus Infections/virology , Disease Models, Animal , Endotoxemia/chemically induced , Female , Immunologic Factors/administration & dosage , Immunologic Factors/chemistry , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Nanoparticles/administration & dosage , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Squalene/administration & dosage , Systemic Inflammatory Response Syndrome/chemically induced , Treatment Outcome , alpha-Tocopherol/administration & dosage , alpha-Tocopherol/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL