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1.
Vaccine ; 40(26): 3655-3663, 2022 Jun 09.
Article in English | MEDLINE | ID: covidwho-1821522

ABSTRACT

We conducted preclinical studies in mice using a yeast-produced SARS-CoV-2 RBD subunit vaccine candidate formulated with aluminum hydroxide (alum) and CpG deoxynucleotides. This formulation is equivalent to the CorbevaxTM vaccine that recently received emergency use authorization by the Drugs Controller General ofIndia. We compared the immune response of mice vaccinated with RBD/alum to mice vaccinated with RBD/alum + CpG. We also evaluated mice immunized with RBD/alum + CpG and boosted with RBD/alum. Mice were immunized twice intramuscularly at a 21-day interval. Compared to two doses of the /alum formulation, the RBD/alum + CpG vaccine induced a stronger and more balanced Th1/Th2 cellular immune response, with high levels of neutralizing antibodies against the original Wuhan isolate of SARS-CoV-2 as well as the B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 and (Delta) variants. Neutralizing antibody titers against the B.1.1.529 (BA.1, Omicron) variant exceeded those in human convalescent plasma after Wuhan infection but were lower than against the other variants. Interestingly, the second dose did not benefit from the addition of CpG, possibly allowing dose-sparing of the adjuvant in the future. The data reported here reinforces that the RBD/alum + CpG vaccine formulation is suitable for inducing broadly neutralizing antibodies against SARS-CoV-2, including variants of concern.


Subject(s)
COVID-19 , SARS-CoV-2 , Alum Compounds , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19/therapy , COVID-19 Vaccines , Humans , Immunization, Passive , Mice , Recombinant Proteins , Spike Glycoprotein, Coronavirus
2.
Front Immunol ; 13: 844837, 2022.
Article in English | MEDLINE | ID: covidwho-1809397

ABSTRACT

In this work, we evaluated recombinant receptor binding domain (RBD)-based vaccine formulation prototypes with potential for further clinical development. We assessed different formulations containing RBD plus alum, AddaS03, AddaVax, or the combination of alum and U-Omp19: a novel Brucella spp. protease inhibitor vaccine adjuvant. Results show that the vaccine formulation composed of U-Omp19 and alum as adjuvants has a better performance: it significantly increased mucosal and systemic neutralizing antibodies in comparison to antigen plus alum, AddaVax, or AddaS03. Antibodies induced with the formulation containing U-Omp19 and alum not only increased their neutralization capacity against the ancestral virus but also cross-neutralized alpha, lambda, and gamma variants with similar potency. Furthermore, the addition of U-Omp19 to alum vaccine formulation increased the frequency of RBD-specific geminal center B cells and plasmablasts. Additionally, U-Omp19+alum formulation induced RBD-specific Th1 and CD8+ T-cell responses in spleens and lungs. Finally, this vaccine formulation conferred protection against an intranasal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge of K18-hACE2 mice.


Subject(s)
Adjuvants, Immunologic/metabolism , B-Lymphocytes/immunology , Bacterial Outer Membrane Proteins/metabolism , Brucella/metabolism , COVID-19 Vaccines/immunology , COVID-19/immunology , Germinal Center/immunology , SARS-CoV-2/physiology , Alum Compounds/metabolism , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral , Antibody Formation , Bacterial Outer Membrane Proteins/immunology , Brucella/immunology , Disease Resistance , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Spike Glycoprotein, Coronavirus/immunology
3.
Chem Commun (Camb) ; 58(24): 3925-3928, 2022 Mar 22.
Article in English | MEDLINE | ID: covidwho-1730326

ABSTRACT

Adjuvants are important components in vaccines to increase the immunogenicity of proteins and induce optimal immunity. In this study, we designed a novel ternary adjuvant system Alum + c-GAMP + poly(I:C) with STING agonist 3,3'-c-GAMP (c-GAMP) and TLR3 agonist poly(I:C) co-adsorbed on the conventional adjuvant aluminum gel (Alum), and further constructed an S1 protein vaccine. Two doses of vaccination with the ternary adjuvant vaccine were sufficient to induce a balanced Th1/Th2 immune response and robust humoral and cellular immunity. Additionally, the ternary adjuvant group had effective neutralizing activity against live virus SARS-CoV-2 and pseudovirus of all variants of concern (alpha, beta, gamma, delta and omicron). These results indicate that the ternary adjuvants have a significant synergistic effect and can rapidly trigger potent immune responses; the combination of the ternary adjuvant system with S1 protein is a promising COVID-19 vaccine candidate.


Subject(s)
COVID-19 , SARS-CoV-2 , Adjuvants, Immunologic/pharmacology , Alum Compounds , Aluminum , Animals , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/pharmacology , Humans , Immunity, Cellular , Mice , Mice, Inbred BALB C , Poly I
4.
J Med Virol ; 94(5): 2250-2258, 2022 05.
Article in English | MEDLINE | ID: covidwho-1664418

ABSTRACT

Waning antibodies and rapidly emerging variants are challenges for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine development. Adjusting existing immunization schedules and further boosting strategies are under consideration. Here, the immune responses induced by an alum-adjuvanted inactivated SARS-CoV-2 vaccine in mice were compared among immunization schedules with two or three doses. For the two-dose schedule, a 0-28-day schedule induced 5-fold stronger spike-specific IgG responses than a 0-14-day schedule, with only a slight elevation of spike-specific cellular immunity 14 days after the last immunization. A third homologous boost 2 or 5 months after the second dose for the 0-28-day schedule slightly strengthened humoral responses (1.3-fold for the 0-1-3-month schedule, and 1.8-fold for the 0-1-6-month schedule) 14 days after the last immunization. Additionally, a third homologous boost (especially with the 0-1-3-month schedule) induced significantly stronger cell-mediated immunity than both two-dose immunization schedules for all indexes tested, with a response similar to that induced by a one-dose heterologous boost with BNT162b2 in clinical trials, according to cellular immunity analysis (1.5-fold). These T cell responses were Th2 oriented, with good CD4+ and CD8+ memory. These results may offer clues for applying a homologous boosting strategy for alum-adjuvanted inactivated SARS-CoV-2 vaccines.


Subject(s)
COVID-19 Vaccines , COVID-19 , Alum Compounds , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Humans , Immunity, Cellular , Immunoglobulin G , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
5.
Lancet ; 399(10323): 461-472, 2022 01 29.
Article in English | MEDLINE | ID: covidwho-1641748

ABSTRACT

BACKGROUND: A range of safe and effective vaccines against SARS CoV 2 are needed to address the COVID 19 pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccine SCB-2019. METHODS: This ongoing phase 2 and 3 double-blind, placebo-controlled trial was done in adults aged 18 years and older who were in good health or with a stable chronic health condition, at 31 sites in five countries (Belgium, Brazil, Colombia, Philippines, and South Africa). The participants were randomly assigned 1:1 using a centralised internet randomisation system to receive two 0·5 mL intramuscular doses of SCB-2019 (30 µg, adjuvanted with 1·50 mg CpG-1018 and 0·75 mg alum) or placebo (0·9% sodium chloride for injection supplied in 10 mL ampoules) 21 days apart. All study staff and participants were masked, but vaccine administrators were not. Primary endpoints were vaccine efficacy, measured by RT-PCR-confirmed COVID-19 of any severity with onset from 14 days after the second dose in baseline SARS-CoV-2 seronegative participants (the per-protocol population), and the safety and solicited local and systemic adverse events in the phase 2 subset. This study is registered on EudraCT (2020-004272-17) and ClinicalTrials.gov (NCT04672395). FINDINGS: 30 174 participants were enrolled from March 24, 2021, until the cutoff date of Aug 10, 2021, of whom 30 128 received their first assigned vaccine (n=15 064) or a placebo injection (n=15 064). The per-protocol population consisted of 12 355 baseline SARS-CoV-2-naive participants (6251 vaccinees and 6104 placebo recipients). Most exclusions (13 389 [44·4%]) were because of seropositivity at baseline. There were 207 confirmed per-protocol cases of COVID-19 at 14 days after the second dose, 52 vaccinees versus 155 placebo recipients, and an overall vaccine efficacy against any severity COVID-19 of 67·2% (95·72% CI 54·3-76·8), 83·7% (97·86% CI 55·9-95·4) against moderate-to-severe COVID-19, and 100% (97·86% CI 25·3-100·0) against severe COVID-19. All COVID-19 cases were due to virus variants; vaccine efficacy against any severity COVID-19 due to the three predominant variants was 78·7% (95% CI 57·3-90·4) for delta, 91·8% (44·9-99·8) for gamma, and 58·6% (13·3-81·5) for mu. No safety issues emerged in the follow-up period for the efficacy analysis (median of 82 days [IQR 63-103]). The vaccine elicited higher rates of mainly mild-to-moderate injection site pain than the placebo after the first (35·7% [287 of 803] vs 10·3% [81 of 786]) and second (26·9% [189 of 702] vs 7·4% [52 of 699]) doses, but the rates of other solicited local and systemic adverse events were similar between the groups. INTERPRETATION: Two doses of SCB-2019 vaccine plus CpG and alum provides notable protection against the entire severity spectrum of COVID-19 caused by circulating SAR-CoV-2 viruses, including the predominating delta variant. FUNDING: Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.


Subject(s)
Adjuvants, Immunologic/therapeutic use , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Spike Glycoprotein, Coronavirus/therapeutic use , Adolescent , Adult , Aged , Alum Compounds/therapeutic use , Belgium , Brazil , Colombia , Double-Blind Method , Female , Humans , Male , Middle Aged , Oligodeoxyribonucleotides/therapeutic use , Philippines , Protein Multimerization , Recombinant Proteins/therapeutic use , Risk , SARS-CoV-2 , South Africa , Young Adult
6.
Oxid Med Cell Longev ; 2022: 5397733, 2022.
Article in English | MEDLINE | ID: covidwho-1635531

ABSTRACT

The infection of coronavirus disease (COVID-19) seriously threatens human life. It is urgent to generate effective and safe specific antibodies (Abs) against the pathogenic elements of COVID-19. Mice were immunized with SARS-CoV-2 spike protein antigens: S ectodomain-1 (CoV, in short) mixed in Alum adjuvant for 2 times and boosted with CoV weekly for 6 times. A portion of mice were treated with Maotai liquor (MTL, in short) or/and heat stress (HS) together with CoV boosting. We observed that the anti-CoV Ab was successfully induced in mice that received the CoV/Alum immunization for 2 times. However, upon boosting with CoV, the CoV Ab production diminished progressively; spleen CoV Ab-producing plasma cell counts reduced, in which substantial CoV-specific Ab-producing plasma cells (sPC) were apoptotic. Apparent oxidative stress signs were observed in sPCs; the results were reproduced by exposing sPCs to CoV in the culture. The presence of MTL or/and HS prevented the CoV-induced oxidative stress in sPCs and promoted and stabilized the CoV Ab production in mice in re-exposure to CoV. In summary, CoV/Alum immunization can successfully induce CoV Ab production in mice that declines upon reexposure to CoV. Concurrent administration of MTL/HS stabilizes and promotes the CoV Ab production in mice.


Subject(s)
Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Apoptosis , COVID-19/immunology , Plasma Cells/immunology , SARS-CoV-2/physiology , Superoxide Dismutase-1/physiology , Adjuvants, Immunologic , Alcoholic Beverages , Alum Compounds , Angiotensin-Converting Enzyme 2/physiology , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/enzymology , COVID-19 Vaccines/immunology , Heat-Shock Response , Immunization, Secondary , Immunogenicity, Vaccine , Janus Kinase 2/physiology , Male , Mice , Mice, Inbred C57BL , Oxidative Stress , Plasma Cells/drug effects , Plasma Cells/pathology , Reactive Oxygen Species/metabolism , STAT1 Transcription Factor/physiology , Signal Transduction , Specific Pathogen-Free Organisms , Spike Glycoprotein, Coronavirus/immunology , Vaccination
7.
Vaccine ; 39(48): 7001-7011, 2021 11 26.
Article in English | MEDLINE | ID: covidwho-1488001

ABSTRACT

COVID-19 pandemic has severely impacted the public health and social economy worldwide. A safe, effective, and affordable vaccine against SARS-CoV-2 infections/diseases is urgently needed. We have been developing a recombinant vaccine based on a prefusion-stabilized spike trimer of SARS-CoV-2 and formulated with aluminium hydroxide and CpG 7909. The spike protein was expressed in Chinese hamster ovary (CHO) cells, purified, and prepared as a stable formulation with the dual adjuvant. Immunogenicity studies showed that candidate vaccines elicited robust neutralizing antibody responses and substantial CD4+ T cell responses in both mice and non-human primates. And vaccine-induced neutralizing antibodies persisted at high level for at least 6 months. Challenge studies demonstrated that candidate vaccine reduced the viral loads and inflammation in the lungs of SARS-CoV-2 infected golden Syrian hamsters significantly. In addition, the vaccine-induced antibodies showed cross-neutralization activity against B.1.1.7 and B.1.351 variants. These data suggest candidate vaccine is efficacious in preventing SARS-CoV-2 infections and associated pneumonia, thereby justifying ongoing phase I/II clinical studies in China (NCT04982068 and NCT04990544).


Subject(s)
COVID-19 Vaccines , COVID-19 , Alum Compounds , Aluminum Hydroxide , Animals , Antibodies, Neutralizing , Antibodies, Viral , CHO Cells , Cricetinae , Cricetulus , Humans , Mice , Pandemics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics
8.
Nat Commun ; 12(1): 3587, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1387350

ABSTRACT

There is a great need for the development of vaccines that induce potent and long-lasting protective immunity against SARS-CoV-2. Multimeric display of the antigen combined with potent adjuvant can enhance the potency and longevity of the antibody response. The receptor binding domain (RBD) of the spike protein is a primary target of neutralizing antibodies. Here, we developed a trimeric form of the RBD and show that it induces a potent neutralizing antibody response against live virus with diverse effector functions and provides protection against SARS-CoV-2 challenge in mice and rhesus macaques. The trimeric form induces higher neutralizing antibody titer compared to monomer with as low as 1µg antigen dose. In mice, adjuvanting the protein with a TLR7/8 agonist formulation alum-3M-052 induces 100-fold higher neutralizing antibody titer and superior protection from infection compared to alum. SARS-CoV-2 infection causes significant loss of innate cells and pathology in the lung, and vaccination protects from changes in innate cells and lung pathology. These results demonstrate RBD trimer protein as a suitable candidate for vaccine against SARS-CoV-2.


Subject(s)
Adjuvants, Immunologic/administration & dosage , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Heterocyclic Compounds, 3-Ring/administration & dosage , Stearic Acids/administration & dosage , Alum Compounds/administration & dosage , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Formation/immunology , COVID-19 Vaccines/administration & dosage , Disease Models, Animal , Heterocyclic Compounds, 3-Ring/immunology , Humans , Macaca mulatta , Mice , Protein Binding , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/immunology , Stearic Acids/immunology
9.
Proc Natl Acad Sci U S A ; 118(34)2021 08 24.
Article in English | MEDLINE | ID: covidwho-1345645

ABSTRACT

Alum, used as an adjuvant in injected vaccines, promotes T helper 2 (Th2) and serum antibody (Ab) responses. However, it fails to induce secretory immunoglobulin (Ig) A (SIgA) in mucosal tissues and is poor in inducing Th1 and cell-mediated immunity. Alum stimulates interleukin 1 (IL-1) and the recruitment of myeloid cells, including neutrophils. We investigated whether neutrophil elastase regulates the adjuvanticity of alum, and whether a strategy targeting neutrophil elastase could improve responses to injected vaccines. Mice coadministered a pharmacological inhibitor of elastase, or lacking elastase, developed high-affinity serum IgG and IgA antibodies after immunization with alum-adsorbed protein vaccines, including the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). These mice also developed broader antigen-specific CD4+ T cell responses, including high Th1 and T follicular helper (Tfh) responses. Interestingly, in the absence of elastase activity, mucosal SIgA responses were induced after systemic immunization with alum as adjuvant. Importantly, lack or suppression of elastase activity enhanced the magnitude of anti-SARS-CoV-2 spike subunit 1 (S1) antibodies, and these antibodies reacted with the same epitopes of spike 1 protein as sera from COVID-19 patients. Therefore, suppression of neutrophil elastase could represent an attractive strategy for improving the efficacy of alum-based injected vaccines for the induction of broad immunity, including mucosal immunity.


Subject(s)
Adjuvants, Immunologic/pharmacology , Alum Compounds/pharmacology , COVID-19/immunology , COVID-19/therapy , Enzyme Inhibitors/pharmacology , Leukocyte Elastase/antagonists & inhibitors , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Formation/drug effects , COVID-19/drug therapy , COVID-19/metabolism , HEK293 Cells , Humans , Immunity, Innate/drug effects , Immunity, Innate/immunology , Immunity, Mucosal/drug effects , Immunity, Mucosal/immunology , Immunoglobulin A/immunology , Leukocyte Elastase/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/immunology , Swine , Th1 Cells/immunology
10.
Sci Immunol ; 6(61)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1315792

ABSTRACT

Ongoing SARS-CoV-2 vaccine development is focused on identifying stable, cost-effective, and accessible candidates for global use, specifically in low and middle-income countries. Here, we report the efficacy of a rapidly scalable, novel yeast expressed SARS-CoV-2 specific receptor-binding domain (RBD) based vaccine in rhesus macaques. We formulated the RBD immunogen in alum, a licensed and an emerging alum adsorbed TLR-7/8 targeted, 3M-052-alum adjuvants. The RBD+3M-052-alum adjuvanted vaccine promoted better RBD binding and effector antibodies, higher CoV-2 neutralizing antibodies, improved Th1 biased CD4+T cell reactions, and increased CD8+ T cell responses when compared to the alum-alone adjuvanted vaccine. RBD+3M-052-alum induced a significant reduction of SARS-CoV-2 virus in respiratory tract upon challenge, accompanied by reduced lung inflammation when compared with unvaccinated controls. Anti-RBD antibody responses in vaccinated animals inversely correlated with viral load in nasal secretions and BAL. RBD+3M-052-alum blocked a post SARS-CoV-2 challenge increase in CD14+CD16++ intermediate blood monocytes, and Fractalkine, MCP-1, and TRAIL in the plasma. Decreased plasma analytes and intermediate monocyte frequencies correlated with reduced nasal and BAL viral loads. Lastly, RBD-specific plasma cells accumulated in the draining lymph nodes and not in the bone marrow, contrary to previous findings. Together, these data show that a yeast expressed, RBD-based vaccine+3M-052-alum provides robust immune responses and protection against SARS-CoV-2, making it a strong and scalable vaccine candidate.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Alum Compounds/administration & dosage , COVID-19 Vaccines , COVID-19/prevention & control , SARS-CoV-2 , Saccharomycetales/genetics , Spike Glycoprotein, Coronavirus/genetics , Administration, Inhalation , Administration, Intranasal , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Cell Line , Cytokines/immunology , Humans , Immunoglobulin G/immunology , Lung/pathology , Macaca mulatta , Male , Protein Binding , Protein Domains , Spike Glycoprotein, Coronavirus/immunology , Viral Load
11.
J Med Virol ; 93(2): 892-898, 2021 02.
Article in English | MEDLINE | ID: covidwho-1206802

ABSTRACT

Since its emergence in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed into a global pandemic within a matter of months. While subunit vaccines are one of the prominent options for combating coronavirus disease 2019 (COVID-19), the immunogenicity of spike protein-based antigens remains unknown. When immunized in mice, the S1 domain induced much higher IgG and IgA antibody levels than the receptor-binding domain (RBD) and more efficiently neutralized SARS-CoV-2 when adjuvanted with alum. It is inferred that a large proportion of these neutralization epitopes are located in the S1 domain but outside the RBD and that some of these are spatial epitopes. This finding indicates that expression systems with posttranslational modification abilities are important to maintain the natural configurations of recombinant spike protein antigens and are critical for effective COVID-19 vaccines. Further, adjuvants prone to a Th1 response should be considered for S1-based subunit COVID-19 vaccines to reduce the potential risk of antibody-dependent enhancement of infection.


Subject(s)
Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Antigens, Viral/immunology , COVID-19 Vaccines/biosynthesis , COVID-19/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adjuvants, Immunologic/administration & dosage , Alum Compounds/administration & dosage , Animals , Antigens, Viral/genetics , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Female , HEK293 Cells , Humans , Immunity, Humoral/drug effects , Immunization , Immunization Schedule , Immunogenicity, Vaccine , Immunoglobulin A/biosynthesis , Immunoglobulin G/biosynthesis , Mice , Mice, Inbred BALB C , Protein Domains/immunology , Recombinant Proteins/administration & dosage , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Spike Glycoprotein, Coronavirus/genetics , Th1 Cells/drug effects , Th1 Cells/immunology , Th2 Cells/drug effects , Th2 Cells/immunology
12.
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
13.
Turk J Med Sci ; 50(8): 1771-1780, 2020 12 17.
Article in English | MEDLINE | ID: covidwho-976378

ABSTRACT

Background/aim: Based on the antiviral and antibacterial properties of aluminum salts, we aimed to find out the influence of aluminum salts on COVID-19 infected patients. Materials and methods: We performed an observational retrospective cohort study which includes the patients diagnosed as COVID-19 and received aluminum salts in addition to actual treatments during hospitalization as the treatment group (Alum Group). Patients who received standard COVID-19 treatment protocols in the Infectious Diseases Clinics were included as the Control Group. Clinical findings, laboratory parameters, length of stay, survival, radiological follow-up, intensive care and mechanical ventilation needs, the presence of comorbidity, polymerase chain reaction (PCR) tests, symptoms, symptom recovery times, hospital stay times, treatment protocols, and clinical presence of pneumonia were examined in all patients. Advanced chemical composition analyzes of existing aluminum salts were also performed. Results: A total of 109 patients, 54 in the alum group and 55 in the control group, were included in the study. None of the patients in the aluminum group developed side effects due to the intake of aluminum salt. Survival status was significantly different between the two groups as there were 5 loss in the Control Group and none in the Alum Group (P = 0.023). The symptom recovery time was significantly shorter in the Alum Group; 2 (1­3) vs. 1 (1­2) days, P = 0.003. According to the paired samples analyses of the comparison between hospitalization and discharge, CRP levels significantly drops in the Alum Group (from 54.09 to 27, P = 0.001) but not in the Control Group. The drop was significantly same for the lactate dehydrogenase (LDH) and procalcitonin levels with P = 0.001. Conclusion: It has been observed that aluminum salts have beneficial effects in COVID-19 infected cases. Considering the low systemic toxicity of intermittent oral intake of aluminum salts as food supplements and the fact that pandemic control is still not achieved, the use of aluminum salts is promising.


Subject(s)
Alum Compounds , COVID-19 , Hospitalization/statistics & numerical data , Recovery of Function/drug effects , Alum Compounds/administration & dosage , Alum Compounds/adverse effects , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/physiopathology , COVID-19 Testing/methods , Critical Care/methods , Critical Care/statistics & numerical data , Female , Humans , Male , Middle Aged , Respiration, Artificial/statistics & numerical data , Retrospective Studies , SARS-CoV-2/drug effects , Survival Analysis , Treatment Outcome , Turkey/epidemiology
14.
Semin Immunol ; 50: 101426, 2020 08.
Article in English | MEDLINE | ID: covidwho-951436

ABSTRACT

In the last decade there have been some significant advances in vaccine adjuvants, particularly in relation to their inclusion in licensed products. This was proceeded by several decades in which such advances were very scarce, or entirely absent, but several novel adjuvants have now been included in licensed products, including in the US. These advances have relied upon several key technological insights that have emerged in this time period, which have finally allowed an in depth understanding of how adjuvants work. These advances include developments in systems biology approaches which allow the hypotheses first advanced in pre-clinical studies to be critically evaluated in human studies. This review highlights these recent advances, both in relation to the adjuvants themselves, but also the technologies that have enabled their successes. Moreover, we critically appraise what will come next, both in terms of new adjuvant molecules, and the technologies needed to allow them to succeed. We confidently predict that additional adjuvants will emerge in the coming years that will reach approval in licensed products, but that the components might differ significantly from those which are currently used. Gradually, the natural products that were originally used to build adjuvants, since they were readily available at the time of initial development, will come to be replaced by synthetic or biosynthetic materials, with more appealing attributes, including more reliable and robust supply, along with reduced heterogeneity. The recent advance in vaccine adjuvants is timely, given the need to create novel vaccines to deal with the COVID-19 pandemic. Although, we must ensure that the rigorous safety evaluations that allowed the current adjuvants to advance are not 'short-changed' in the push for new vaccines to meet the global challenge as quickly as possible, we must not jeopardize what we have achieved, by pushing less established technologies too quickly, if the data does not fully support it.


Subject(s)
Adjuvants, Immunologic/therapeutic use , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Alum Compounds/pharmacology , COVID-19/immunology , COVID-19 Vaccines/therapeutic use , Humans , SARS-CoV-2/immunology , Systems Biology , Vaccinology/methods
15.
Adv Mater ; 32(40): e2004210, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-734755

ABSTRACT

For rapid response against the prevailing COVID-19 (coronavirus disease 19), it is a global imperative to exploit the immunogenicity of existing formulations for safe and efficient vaccines. As the most accessible adjuvant, aluminum hydroxide (alum) is still the sole employed adjuvant in most countries. However, alum tends to attach on the membrane rather than entering the dendritic cells (DCs), leading to the absence of intracellular transfer and process of the antigens, and thus limits T-cell-mediated immunity. To address this, alum is packed on the squalene/water interphase is packed, forming an alum-stabilized Pickering emulsion (PAPE). "Inheriting" from alum and squalene, PAPE demonstrates a good biosafety profile. Intriguingly, with the dense array of alum on the oil/water interphase, PAPE not only adsorbs large quantities of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antigens, but also harbors a higher affinity for DC uptake, which provokes the uptake and cross-presentation of the delivered antigens. Compared with alum-treated groups, more than six times higher antigen-specific antibody titer and three-fold more IFN-γ-secreting T cells are induced, indicating the potent humoral and cellular immune activations. Collectively, the data suggest that PAPE may provide potential insights toward a safe and efficient adjuvant platform for the enhanced COVID-19 vaccinations.


Subject(s)
Adjuvants, Immunologic/chemistry , Viral Vaccines/chemistry , Alum Compounds/chemistry , Animals , Antigens, Viral/chemistry , Antigens, Viral/immunology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Emulsions , HEK293 Cells , Humans , Interferon-gamma/metabolism , Mice, Inbred BALB C , Pandemics , Pneumonia, Viral/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology
16.
J Med Virol ; 93(2): 892-898, 2021 02.
Article in English | MEDLINE | ID: covidwho-661060

ABSTRACT

Since its emergence in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed into a global pandemic within a matter of months. While subunit vaccines are one of the prominent options for combating coronavirus disease 2019 (COVID-19), the immunogenicity of spike protein-based antigens remains unknown. When immunized in mice, the S1 domain induced much higher IgG and IgA antibody levels than the receptor-binding domain (RBD) and more efficiently neutralized SARS-CoV-2 when adjuvanted with alum. It is inferred that a large proportion of these neutralization epitopes are located in the S1 domain but outside the RBD and that some of these are spatial epitopes. This finding indicates that expression systems with posttranslational modification abilities are important to maintain the natural configurations of recombinant spike protein antigens and are critical for effective COVID-19 vaccines. Further, adjuvants prone to a Th1 response should be considered for S1-based subunit COVID-19 vaccines to reduce the potential risk of antibody-dependent enhancement of infection.


Subject(s)
Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Antigens, Viral/immunology , COVID-19 Vaccines/biosynthesis , COVID-19/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adjuvants, Immunologic/administration & dosage , Alum Compounds/administration & dosage , Animals , Antigens, Viral/genetics , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Female , HEK293 Cells , Humans , Immunity, Humoral/drug effects , Immunization , Immunization Schedule , Immunogenicity, Vaccine , Immunoglobulin A/biosynthesis , Immunoglobulin G/biosynthesis , Mice , Mice, Inbred BALB C , Protein Domains/immunology , Recombinant Proteins/administration & dosage , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Spike Glycoprotein, Coronavirus/genetics , Th1 Cells/drug effects , Th1 Cells/immunology , Th2 Cells/drug effects , Th2 Cells/immunology
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