scholarly journals Immunogenicity of prime-boost protein subunit vaccine strategies against SARS-CoV-2 in mice and macaques

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hyon-Xhi Tan ◽  
Jennifer A. Juno ◽  
Wen Shi Lee ◽  
Isaac Barber-Axthelm ◽  
Hannah G. Kelly ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Subunit Vaccine ◽  
Cell Activity ◽  
Receptor Binding Domain ◽  
Protein Subunit ◽  
Neutralising Antibodies ◽  
Subunit Vaccines ◽  
Vaccine Candidates ◽  
Follicular Helper ◽  
T Follicular Helper Cell

AbstractSARS-CoV-2 vaccines are advancing into human clinical trials, with emphasis on eliciting high titres of neutralising antibodies against the viral spike (S). However, the merits of broadly targeting S versus focusing antibody onto the smaller receptor binding domain (RBD) are unclear. Here we assess prototypic S and RBD subunit vaccines in homologous or heterologous prime-boost regimens in mice and non-human primates. We find S is highly immunogenic in mice, while the comparatively poor immunogenicity of RBD is associated with limiting germinal centre and T follicular helper cell activity. Boosting S-primed mice with either S or RBD significantly augments neutralising titres, with RBD-focussing driving moderate improvement in serum neutralisation. In contrast, both S and RBD vaccines are comparably immunogenic in macaques, eliciting serological neutralising activity that generally exceed levels in convalescent humans. These studies confirm recombinant S proteins as promising vaccine candidates and highlight multiple pathways to achieving potent serological neutralisation.

scholarly journals Prime-boost protein subunit vaccines against SARS-CoV-2 are highly immunogenic in mice and macaques

2020 ◽  
Author(s):  
Hyon-Xhi Tan ◽  
Jennifer A Juno ◽  
Wen Shi Lee ◽  
Isaac Barber-Axthelm ◽  
Hannah G Kelly ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Receptor Binding ◽  
Cell Activity ◽  
Receptor Binding Domain ◽  
Protein Subunit ◽  
Neutralising Antibodies ◽  
Subunit Vaccines ◽  
Vaccine Candidates ◽  
Follicular Helper ◽  
T Follicular Helper Cell

SummarySARS-CoV-2 vaccines are advancing into human clinical trials, with emphasis on eliciting high titres of neutralising antibodies against the viral spike (S). However, the merits of broadly targeting S versus focusing antibody onto the smaller receptor binding domain (RBD) are unclear. Here we assessed prototypic S and RBD subunit vaccines in homologous or heterologous prime-boost regimens in mice and non-human primates. We find S is highly immunogenic in mice, while the comparatively poor immunogenicity of RBD was associated with limiting germinal centre and T follicular helper cell activity. Boosting S-primed mice with either S or RBD significantly augmented neutralising titres, with RBD-focussing driving moderate improvement in serum neutralisation. In contrast, both S and RBD vaccines were comparably immunogenic in macaques, eliciting serological neutralising activity that generally exceed levels in convalescent humans. These studies confirm recombinant S proteins as promising vaccine candidates and highlight multiple pathways to achieving potent serological neutralisation.

scholarly journals COVID-19: Insights into Potential Vaccines

2021 ◽  
Vol 9 (3) ◽  
pp. 605
Author(s):  
Ke-Yan Loo ◽  
Vengadesh Letchumanan ◽  
Hooi-Leng Ser ◽  
Siew Li Teoh ◽  
Jodi Woan-Fei Law ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Viral Vector ◽  
Phase Iii ◽  
Effective Vaccine ◽  
Pharmaceutical Companies ◽  
Protein Subunit ◽  
Subunit Vaccines ◽  
Vaccine Candidates ◽  
Phase Iii Clinical Trials ◽  
Positive Results

People around the world ushered in the new year 2021 with a fear of COVID-19, as family members have lost their loved ones to the disease. Millions of people have been infected, and the livelihood of many has been jeopardized due to the pandemic. Pharmaceutical companies are racing against time to develop an effective vaccine to protect against COVID-19. Researchers have developed various types of candidate vaccines with the release of the genetic sequence of the SARS-CoV-2 virus in January. These include inactivated viral vaccines, protein subunit vaccines, mRNA vaccines, and recombinant viral vector vaccines. To date, several vaccines have been authorized for emergency use and they have been administered in countries across the globe. Meanwhile, there are also vaccine candidates in Phase III clinical trials awaiting results and approval from authorities. These candidates have shown positive results in the previous stages of the trials, whereby they could induce an immune response with minimal side effects in the participants. This review aims to discuss the different vaccine platforms and the clinical trials of the candidate vaccines.

scholarly journals A single immunization with spike-functionalized ferritin vaccines elicits neutralizing antibody responses against SARS-CoV-2 in mice

2020 ◽  
Author(s):  
Abigail E. Powell ◽  
Kaiming Zhang ◽  
Mrinmoy Sanyal ◽  
Shaogeng Tang ◽  
Payton A. Weidenbacher ◽  
...  
Keyword(s):  
Single Dose ◽  
Neutralizing Antibodies ◽  
Subunit Vaccine ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Receptor Binding Domain ◽  
Amino Acid Deletion ◽  
Vaccine Candidates ◽  
Self Assembling ◽  
Antibody Titers

AbstractDevelopment of a safe and effective SARS-CoV-2 vaccine is a public health priority. We designed subunit vaccine candidates using self-assembling ferritin nanoparticles displaying one of two multimerized SARS-CoV-2 spikes: full-length ectodomain (S-Fer) or a C-terminal 70 amino-acid deletion (SΔC-Fer). Ferritin is an attractive nanoparticle platform for production of vaccines and ferritin-based vaccines have been investigated in humans in two separate clinical trials. We confirmed proper folding and antigenicity of spike on the surface of ferritin by cryo-EM and binding to conformation-specific monoclonal antibodies. After a single immunization of mice with either of the two spike ferritin particles, a lentiviral SARS-CoV-2 pseudovirus assay revealed mean neutralizing antibody titers at least 2-fold greater than those in convalescent plasma from COVID-19 patients. Additionally, a single dose of SΔC-Fer elicited significantly higher neutralizing responses as compared to immunization with the spike receptor binding domain (RBD) monomer or spike ectodomain trimer alone. After a second dose, mice immunized with SΔC-Fer exhibited higher neutralizing titers than all other groups. Taken together, these results demonstrate that multivalent presentation of SARS-CoV-2 spike on ferritin can notably enhance elicitation of neutralizing antibodies, thus constituting a viable strategy for single-dose vaccination against COVID-19.

scholarly journals A first-in-human evaluation of the safety and immunogenicity of SCB-2019, an adjuvanted, recombinant SARS-CoV-2 trimeric S-protein subunit vaccine for COVID-19 in healthy adults; a phase 1, randomised, double-blind, placebo-controlled trial

2020 ◽  
Author(s):  
Peter Richmond ◽  
Lara Hatchuel ◽  
Min Dong ◽  
Brenda Ma ◽  
Branda Hu ◽  
...  
Keyword(s):  
Older Adults ◽  
Immune Responses ◽  
Subunit Vaccine ◽  
Phase 1 ◽  
Intracellular Cytokine Staining ◽  
High Dose ◽  
Protein Subunit ◽  
Neutralising Antibodies ◽  
S Protein ◽  
Human Dose

ABSTRACTBackgroundAs part of the accelerated development of prophylactic vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) we report a first-in-human dose-finding and adjuvant justification study of SCB-2019, a novel protein subunit vaccine candidate composed of a stabilised trimeric form of the spike (S)-protein produced in CHO-cells, combined with two different adjuvants.MethodsThis phase 1 study was done in one centre in Western Australia in 151 healthy adult volunteers in two age groups (18–54 and 55–75 years), allocated to 15 groups (nine young and six older adults) to receive two doses, 21 days apart, of placebo, or 3 μg, 9 μg or 30 μg SCB-2019, alone or adjuvanted with AS03 or CpG/Alum. Reactogenicity was assessed for 7 days after each vaccination. Humoral responses were measured as SCB-2019 binding and ACE2-competitive binding IgG antibodies by ELISA, and as neutralising antibodies by wild-type SARS-CoV-2 microneutralisation assay; cellular responses to pooled S-protein peptides were measured by flow-cytometric intracellular cytokine staining.FindingsWe report on 148 participants with at least 4 weeks follow-up post dose 2. Three participants withdrew, two for personal reasons and one with an unrelated SAE (pituitary adenoma). Vaccination was well tolerated, with few Grade 3 solicited adverse events (AE). Most local AEs were mild injection site pain, which were more frequent with formulations containing AS03 than CpG/Alum or unadjuvanted SCB-2019. Systemic AEs, mostly transient headache, fatigue or myalgia, were more frequent in young adults than older adults after the first dose, but similar after second doses. Unadjuvanted SCB-2019 elicited minimal immune responses, but SCB-2019 with fixed doses of AS03 or CpG/Alum induced high titres and seroconversion rates of binding and neutralising antibodies in both young and older adults. Titres were higher than those observed in a panel of COVID-19 convalescent sera in all AS03 groups and high dose CpG/Alum groups. Both adjuvanted formulations elicited Th1-biased CD4+ T cell responses.InterpretationSCB-2019 trimeric protein formulated with AS03 or CpG/Alum adjuvants elicited robust humoral and cellular immune responses against SARS-CoV-2 with high viral neutralising activity. Both adjuvanted formulations were well tolerated and are suitable for further clinical development.Clinical trial registrationClinicalTrials.gov identifier NCT04405908.

scholarly journals SARS-CoV-2 preS dTM vaccine booster candidates increase functional antibody responses and cross-neutralization against SARS-CoV-2 variants of concern in non-human primates

2021 ◽  
Author(s):  
Vincent Pavot ◽  
Catherine Berry ◽  
Michael Kishko ◽  
Natalie Anosova ◽  
Dean Huang ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Protein Vaccine ◽  
Preclinical Models ◽  
Protein Subunit ◽  
Vaccine Candidates ◽  
Vaccine Booster ◽  
Cross Neutralization

Abstract The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that partly evade neutralizing antibodies has raised concerns of reduced vaccine effectiveness and increased infection. We previously demonstrated in preclinical models and in human clinical trials that our SARS-CoV-2 recombinant spike protein vaccine adjuvanted with AS03 (CoV2 preS dTM-AS03) elicits robust neutralizing antibody responses in naïve subjects. Here, the objective was to document the potency of various booster vaccine formulations in macaques previously vaccinated with mRNA or protein subunit vaccine candidates. We show that one booster dose of AS03-adjuvanted CoV2 preS dTM, D614 (parental) or B.1.351 (Beta), in monovalent or bivalent (D614 + B.1.351) formulations, significantly boosted pre-existing neutralizing antibodies and elicited high and stable cross-neutralizing antibodies covering the four known SARS-CoV-2 variants of concern (Alpha, Beta, Gamma and Delta) and, unexpectedly, SARS-CoV-1, in primed macaques. Interestingly, the non-adjuvanted CoV2 preS dTM B.1.351 vaccine formulation also significantly boosted and broadened the neutralizing antibody responses. Our findings show that these vaccine candidates used as a booster have the potential to offer cross-protection against a broad spectrum of variants. This has important implications for vaccine control of SARS-CoV-2 variants of concern and informs on the benefit of a booster with our vaccine candidates currently under evaluation in phase 2 and 3 clinical trials (NCT04762680 and NCT04904549).

scholarly journals Rabies virus glycoprotein produced in Nicotiana benthamiana is an immunogenic antigen in mice

2021 ◽  
Vol 57 (No. 1) ◽  
pp. 26-35
Author(s):  
Youngmin Park ◽  
Hyangju Kang ◽  
Kyungmin Min ◽  
Nam Hyung Kim ◽  
Minhee Park ◽  
...  
Keyword(s):  
Rabies Virus ◽  
Nicotiana Benthamiana ◽  
Subunit Vaccine ◽  
Transient Transfection ◽  
Effective Vaccine ◽  
Neutralising Antibodies ◽  
Subunit Vaccines ◽  
The Third ◽  
C Terminus ◽  
A Subunit

Rabies remains an infectious disease among humans and animals, and requires the development of an effective vaccine essential to prevent rabies. Advances in molecular biology and biotechnology have led to the development and improvement of many rabies vaccines. Before the third-generation of the vaccine, rabies vaccines were based on the virus itself. Thus, even if effective, these vaccines may not be completely safe, resulting in a strong demand for the development of effective subunit vaccines that do not raise concerns about virus replication and infection in the host. This study investigated the ability of the glycoprotein of the rabies virus to be expressed in tobacco plants (Nicotiana benthamiana) and to induce an immune response in mice. Using a transient transfection, a soluble glycoprotein was successfully expressed in N. benthamiana. Fusing of five histidine residues at the C-terminus enabled the glycoprotein to be easily purified by affinity chromatography. The glycoprotein expressed in the plants was found to be N-glycosylated post-translationally, and the mice immunised with this glycoprotein generated neutralising antibodies against the rabies virus. These results suggest that a glycoprotein produced in the endoplasmic reticulum of N. benthamiana is bioactive, and might be used to generate a subunit vaccine against the rabies virus.

scholarly journals Immunogenicity and Protection Efficacy of Monomeric and Trimeric Recombinant SARS Coronavirus Spike Protein Subunit Vaccine Candidates

2013 ◽  
Vol 26 (2) ◽  
pp. 126-132 ◽  
Author(s):  
Jie Li ◽  
Laura Ulitzky ◽  
Erica Silberstein ◽  
Deborah R. Taylor ◽  
Raphael Viscidi
Keyword(s):  
Subunit Vaccine ◽  
Spike Protein ◽  
Sars Coronavirus ◽  
Protein Subunit ◽  
Vaccine Candidates ◽  
Protection Efficacy

scholarly journals SARS-CoV-2 preS dTM vaccine booster candidates increase functional antibody responses and cross-neutralization against SARS-CoV-2 variants of concern in non-human primates

2021 ◽  
Author(s):  
Vincent Pavot ◽  
Catherine Berry ◽  
Michael Kishko ◽  
Natalie G. Anosova ◽  
Dean Huang ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Protein Vaccine ◽  
Protein Subunit ◽  
Vaccine Candidates ◽  
Link Type ◽  
Vaccine Booster ◽  
Cross Neutralization

AbstractThe emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that partly evade neutralizing antibodies has raised concerns of reduced vaccine effectiveness and increased infection. We previously demonstrated in preclinical models and in human clinical trials that our SARS-CoV-2 recombinant spike protein vaccine adjuvanted with AS03 (CoV2 preS dTM-AS03) elicits robust neutralizing antibody responses in naïve subjects. Here, the objective was to document the potency of various booster vaccine formulations in macaques previously vaccinated with mRNA or protein subunit vaccine candidates.We show that one booster dose of AS03-adjuvanted CoV2 preS dTM, D614 (parental) or B.1.351 (Beta), in monovalent or bivalent (D614 + B.1.351) formulations, significantly boosted pre-existing neutralizing antibodies and elicited high and stable cross-neutralizing antibodies covering the four known SARS-CoV-2 variants of concern (Alpha, Beta, Gamma and Delta) and, unexpectedly, SARS-CoV-1, in primed macaques. Interestingly, the non-adjuvanted CoV2 preS dTM B.1.351 vaccine formulation also significantly boosted and broadened the neutralizing antibody responses.Our findings show that these vaccine candidates used as a booster have the potential to offer cross-protection against a broad spectrum of variants. This has important implications for vaccine control of SARS-CoV-2 variants of concern and informs on the benefit of a booster with our vaccine candidates currently under evaluation in phase 2 and 3 clinical trials (NCT04762680 and NCT04904549).

scholarly journals Subunit Vaccines Using TLR Triagonist Combination Adjuvants Provide Protection Against Coxiella burnetii While Minimizing Reactogenic Responses

2021 ◽  
Vol 12 ◽  
Author(s):  
Alycia P. Fratzke ◽  
Sharon Jan ◽  
Jiin Felgner ◽  
Li Liang ◽  
Rie Nakajima ◽  
...  
Keyword(s):  
Coxiella Burnetii ◽  
Q Fever ◽  
Protective Efficacy ◽  
Cell Vaccine ◽  
Protein Subunit ◽  
Subunit Vaccines ◽  
Whole Cell ◽  
Vaccine Candidates ◽  
Route Of Transmission ◽  
Whole Cell Vaccine

Q fever is caused by the obligate intracellular bacterium, Coxiella burnetii, a designated potential agent of bioterrorism because of its route of transmission, resistance to disinfectants, and low infectious dose. The only vaccine licensed for human use is Q-VAX® (Seqirus, licensed in Australia), a formalin-inactivated whole-cell vaccine, which produces severe local and systemic reactogenic responses in previously sensitized individuals. Accordingly, the U.S. Food and Drug Administration and other regulatory bodies around the world, have been reluctant to approve Q-VAX for widespread use. To obviate these adverse reactions, we prepared recombinant protein subunit vaccine candidates containing purified CBU1910, CBU0307, CBU0545, CBU0612, CBU0891, and CBU1398 proteins and TLR triagonist adjuvants. TLR triagonist adjuvants combine different TLR agonists to enhance immune responses to vaccine antigens. We tested both the protective efficacy and reactogenicity of our vaccine candidates in Hartley guinea pigs using intratracheal infection with live C. burnetii. While all of our candidates showed varying degrees of protection during challenge, local reactogenic responses were significantly reduced for one of our vaccine candidates when compared with a formalin-inactivated whole-cell vaccine. Our findings show that subunit vaccines combined with novel TLR triagonist adjuvants can generate protective immunity to C. burnetii infection while reducing reactogenic responses.

scholarly journals Current Progress in Developing Subunit Vaccines against Enterotoxigenic Escherichia coli-Associated Diarrhea

2015 ◽  
Vol 22 (9) ◽  
pp. 983-991 ◽  
Author(s):  
Weiping Zhang ◽  
David A. Sack
Keyword(s):  
Escherichia Coli ◽  
Subunit Vaccine ◽  
Vaccine Development ◽  
Enterotoxigenic Escherichia Coli ◽  
Cell Vaccine ◽  
Virulence Determinants ◽  
Subunit Vaccines ◽  
Content Type ◽  
Vaccine Candidates ◽  
Colonization Factor

ABSTRACTDiarrhea continues to be a leading cause of death in children <5 years of age, and enterotoxigenicEscherichia coli(ETEC) is the most common bacterial cause of children's diarrhea. Currently, there are no available vaccines against ETEC-associated diarrhea. Whole-cell vaccine candidates have been under development but require further improvements because they provide inadequate protection and produce unwanted adverse effects. Meanwhile, a newer approach using polypeptide or subunit vaccine candidates focusing on ETEC colonization factor antigens (CFAs) and enterotoxins, the major virulence determinants of ETEC diarrhea, shows substantial promise. A conservative CFA/I adhesin tip antigen and a CFA MEFA (multiepitope fusion antigen) were shown to induce cross-reactive antiadhesin antibodies that protected against adherence by multiple important CFAs. Genetic fusion of toxoids derived from ETEC heat-labile toxin (LT) and heat-stable toxin (STa) induced antibodies neutralizing both enterotoxins. Moreover, CFA-toxoid MEFA polypeptides, generated by fusing CFA MEFA to an STa-LT toxoid fusion, induced antiadhesin antibodies that broadly inhibited adherence of the seven most important ETEC CFAs associated with about 80% of the diarrhea cases caused by ETEC strains with known CFAs. This same antigen preparation also induced antitoxin antibodies that neutralized both toxins that are associated with all cases of ETEC diarrhea. Results from these studies suggest that polypeptide or subunit vaccines have the potential to effectively protect against ETEC diarrhea. In addition, novel adhesins and mucin proteases have been investigated as potential alternatives or, more likely, additional antigens for ETEC subunit vaccine development.

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