A single dose, BCG-adjuvanted SARS-CoV-2 vaccine induces Th1-polarized immunity and high-titre neutralizing antibodies in mice

AbstractNext-generation vaccines that are safe, effective and with equitable access globally are required to prevent SARS-CoV-2 transmission at a population level. One strategy that has gained significant interest is to ‘repurpose’ existing licensed vaccines for use against COVID-19. In this report, we have exploited the immunostimulatory properties of bacille Calmette-Guérin (BCG), the vaccine for tuberculosis, to develop a SARS-CoV-2-specific and highly immunogenic vaccine candidate. Combination of BCG with a stabilized, trimeric form of the SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the sera of vaccinated mice, which could be further augmented by the addition of alum. This vaccine formulation, termed BCG:CoVac, induced a Th1-biased response both in terms of IgG antibody subclass and cytokine release by vaccine-specific CD4+ and CD8+ T cells. A single dose of BCG:CoVac was sufficient to induce high-titre SARS-CoV-2 neutralizing antibodies (NAbs) that were detectable as early as 2 weeks post-vaccination; NAb levels were greater than that seen in the sera of SARS-CoV-2-infected individuals. Boosting of BCG:CoVac-primed mice with a heterologous vaccine combination (spike protein plus alum) could further increase SARS-CoV-2 spike protein-specific antibody response. BCG:CoVac would be broadly applicable for all populations susceptible to SARS-CoV-2 infection and in particular could be readily incorporated into current vaccine schedules in countries where BCG is currently used.ImportanceEffective distribution of vaccine to low- and middle-income countries is critical for the control of the COVID-19 pandemic. To achieve this, vaccines must offer effective protective immunity yet should be cheap to manufacture and meet cold chain management requirements. This study describes a unique COVID-19 vaccine candidate, termed BCG:CoVac, that when delivered as a single dose induces potent SARS-CoV-2 specific immunity in mice, particularly through generation of high-titre, anti-viral neutralising antibodies. BCG:CoVac is built on safe and well-characterised vaccine components: 1) the BCG vaccine, used for control of tuberculosis since 1921 which also has remarkable ‘off target’ effects, protecting children and the elderly against diverse respiratory viral infections; 2) Alhydrogel adjuvant (Alum), a low cost, globally accessible vaccine adjuvant with an excellent safety record in humans (part of >20 licensed human vaccines and in use >70 years); 3) Stabilized, trimeric SARS-CoV-2 spike protein, which stimulates immune specificity for COVID-19. Further assessment in humans will determine if BCG:CoVac can impart protective immunity against not only SARS-CoV-2, but also other respiratory infections where BCG has known efficacy.

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Single-dose replicating RNA vaccine induces neutralizing antibodies against SARS-CoV-2 in nonhuman primates

10.1101/2020.05.28.121640 ◽

2020 ◽

Cited By ~ 5

Author(s):

Jesse H. Erasmus ◽

Amit P. Khandhar ◽

Alexandra C. Walls ◽

Emily A. Hemann ◽

Megan A. O’Connor ◽

...

Keyword(s):

Single Dose ◽

Neutralizing Antibodies ◽

Global Economy ◽

Nonhuman Primates ◽

Vaccine Candidate ◽

Scale Up ◽

Igg Antibody ◽

Antibody Isotypes ◽

Rna Replicon

AbstractThe ongoing COVID-19 pandemic, caused by infection with SARS-CoV-2, is having a dramatic and deleterious impact on health services and the global economy. Grim public health statistics highlight the need for vaccines that can rapidly confer protection after a single dose and be manufactured using components suitable for scale-up and efficient distribution. In response, we have rapidly developed repRNA-CoV2S, a stable and highly immunogenic vaccine candidate comprised of an RNA replicon formulated with a novel Lipid InOrganic Nanoparticle (LION) designed to enhance vaccine stability, delivery and immunogenicity. We show that intramuscular injection of LION/repRNA-CoV2S elicits robust anti-SARS-CoV-2 spike protein IgG antibody isotypes indicative of a Type 1 T helper response as well as potent T cell responses in mice. Importantly, a single-dose administration in nonhuman primates elicited antibody responses that potently neutralized SARS-CoV-2. These data support further development of LION/repRNA-CoV2S as a vaccine candidate for prophylactic protection from SARS-CoV-2 infection.

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A single dose of recombinant VSV-ΔG-spike vaccine provides protection against SARS-CoV-2 challenge

10.1101/2020.06.18.160655 ◽

2020 ◽

Cited By ~ 10

Author(s):

Yfat Yahalom-Ronen ◽

Hadas Tamir ◽

Sharon Melamed ◽

Boaz Politi ◽

Ohad Shifman ◽

...

Keyword(s):

Single Dose ◽

Neutralizing Antibodies ◽

Rapid Development ◽

Body Weight Loss ◽

Spike Protein ◽

Effective Vaccine ◽

Lung Pathology ◽

Golden Syrian Hamster

AbstractThe COVID-19 pandemic caused by SARS-CoV-2 that emerged in December 2019 in China resulted in over 7.8 million infections and over 430,000 deaths worldwide, imposing an urgent need for rapid development of an efficient and cost-effective vaccine, suitable for mass immunization. Here, we generated a replication competent recombinant VSV-ΔG-spike vaccine, in which the glycoprotein of VSV was replaced by the spike protein of the SARS-CoV-2. In vitro characterization of the recombinant VSV-ΔG-spike indicated expression and presentation of the spike protein on the viral membrane with antigenic similarity to SARS-CoV-2. A golden Syrian hamster in vivo model for COVID-19 was implemented. We show that vaccination of hamsters with recombinant VSV-ΔG-spike results in rapid and potent induction of neutralizing antibodies against SARS-CoV-2. Importantly, single-dose vaccination was able to protect hamsters against SARS-CoV-2 challenge, as demonstrated by the abrogation of body weight loss of the immunized hamsters compared to unvaccinated hamsters. Furthermore, whereas lungs of infected hamsters displayed extensive tissue damage and high viral titers, immunized hamsters’ lungs showed only minor lung pathology, and no viral load. Taken together, we suggest recombinant VSV-ΔG-spike as a safe, efficacious and protective vaccine against SARS-CoV-2 infection.

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A single dose of recombinant VSV-∆G-spike vaccine provides protection against SARS-CoV-2 challenge

Nature Communications ◽

10.1038/s41467-020-20228-7 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Yfat Yahalom-Ronen ◽

Hadas Tamir ◽

Sharon Melamed ◽

Boaz Politi ◽

Ohad Shifman ◽

...

Keyword(s):

Single Dose ◽

Neutralizing Antibodies ◽

Rapid Development ◽

Body Weight Loss ◽

Spike Protein ◽

Effective Vaccine ◽

In Vivo Model ◽

Golden Syrian Hamster

AbstractThe COVID-19 pandemic caused by SARS-CoV-2 imposes an urgent need for rapid development of an efficient and cost-effective vaccine, suitable for mass immunization. Here, we show the development of a replication competent recombinant VSV-∆G-spike vaccine, in which the glycoprotein of VSV is replaced by the spike protein of SARS-CoV-2. In-vitro characterization of this vaccine indicates the expression and presentation of the spike protein on the viral membrane with antigenic similarity to SARS-CoV-2. A golden Syrian hamster in-vivo model for COVID-19 is implemented. We show that a single-dose vaccination results in a rapid and potent induction of SARS-CoV-2 neutralizing antibodies. Importantly, vaccination protects hamsters against SARS-CoV-2 challenge, as demonstrated by the abrogation of body weight loss, and alleviation of the extensive tissue damage and viral loads in lungs and nasal turbinates. Taken together, we suggest the recombinant VSV-∆G-spike as a safe, efficacious and protective vaccine against SARS-CoV-2.

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A single dose, BCG-adjuvanted COVID-19 vaccine provides sterilising immunity against SARS-CoV-2 infection

npj Vaccines ◽

10.1038/s41541-021-00406-4 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Claudio Counoupas ◽

Matt D. Johansen ◽

Alberto O. Stella ◽

Duc H. Nguyen ◽

Angela L. Ferguson ◽

...

Keyword(s):

Single Dose ◽

Protective Immunity ◽

Rapid Development ◽

High Titre ◽

Igg Antibodies ◽

Neutralising Antibodies ◽

Bacille Calmette Guerin ◽

Follicular Helper ◽

Specific Igg ◽

Specific Igg Antibodies

AbstractGlobal control of COVID-19 requires broadly accessible vaccines that are effective against SARS-CoV-2 variants. In this report, we exploit the immunostimulatory properties of bacille Calmette-Guérin (BCG), the existing tuberculosis vaccine, to deliver a vaccination regimen with potent SARS-CoV-2-specific protective immunity. Combination of BCG with a stabilised, trimeric form of SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the blood of vaccinated mice, that was further augmented by the addition of alum. This vaccine formulation, BCG:CoVac, induced high-titre SARS-CoV-2 neutralising antibodies (NAbs) and Th1-biased cytokine release by vaccine-specific T cells, which correlated with the early emergence of T follicular helper cells in local lymph nodes and heightened levels of antigen-specific plasma B cells after vaccination. Vaccination of K18-hACE2 mice with a single dose of BCG:CoVac almost completely abrogated disease after SARS-CoV-2 challenge, with minimal inflammation and no detectable virus in the lungs of infected animals. Boosting BCG:CoVac-primed mice with a heterologous vaccine further increased SARS-CoV-2-specific antibody responses, which effectively neutralised B.1.1.7 and B.1.351 SARS-CoV-2 variants of concern. These findings demonstrate the potential for BCG-based vaccination to protect against major SARS-CoV-2 variants circulating globally.

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Long-term persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific and neutralizing antibodies in recovered COVID-19 patients

10.21203/rs.3.rs-1073046/v1 ◽

2021 ◽

Author(s):

Jira Chansaenroj ◽

Ritthideach Yorsaeng ◽

Nasamon Wanlapakorn ◽

Chintana Chirathaworn ◽

Natthinee Sudhinaraset ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Symptom Onset ◽

Neutralizing Antibodies ◽

Serum Antibody ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Spike Protein ◽

Immunological Study ◽

Igg Antibody ◽

Vaccine Schedule

Abstract Understanding antibody responses after natural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can guide the coronavirus disease 2019 (COVID-19) vaccine schedule. This study aimed to assess the dynamics of SARS-CoV-2 antibodies, including anti-spike protein 1 (S1) immunoglobulin (Ig)G, anti-receptor-binding domain (RBD) total Ig, anti-S1 IgA, and neutralizing antibody against wild-type SARS-CoV-2 in a cohort of patients who were previously infected with SARS-CoV-2. Between March and May 2020, 531 individuals with virologically confirmed cases of SARS-CoV-2 infection were enrolled in our immunological study. The neutralizing titers against SARS-CoV-2 were detected in 95.2%, 86.7%, 85.0%, and 85.4% of recovered COVID-19 patients at 3, 6, 9, and 12 months after symptom onset, respectively. The seropositivity rate of anti-S1 IgG, anti-RBD total Ig, anti-S1 IgA, and neutralizing titers remained at 68.6%, 89.6%, 77.1%, and 85.4%, respectively, at 12 months after symptom onset. The half-life of neutralizing titers was estimated at 100.7 days (95% confidence interval = 44.5 – 327.4 days, R2 = 0.106). These results support that the decline in serum antibody levels over time depends on the symptom severity, and the individuals with high IgG antibody titers experienced a significantly longer persistence of SARS-CoV-2-specific antibody responses than those with lower titers.

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Prediction and evolution of the molecular fitness of SARS-CoV-2 variants: Introducing SpikePro

10.1101/2021.04.11.439322 ◽

2021 ◽

Author(s):

Fabrizio Pucci ◽

Marianne Rooman

Keyword(s):

Immune Response ◽

Neutralizing Antibodies ◽

Molecular Mechanisms ◽

Population Level ◽

Critical Issue ◽

Spike Protein ◽

Human Immune Response ◽

Human Immune ◽

The Stability ◽

The Impact

The understanding of the molecular mechanisms driving the fitness of the SARS-CoV-2 virus and its mutational evolution is still a critical issue. We built a simplified computational model, called SpikePro, to predict the SARS-CoV-2 fitness from the amino acid sequence and structure of the spike protein. It contains three contributions: the viral transmissibility predicted from the stability of the spike protein, the infectivity computed in terms of the affinity of the spike protein for the ACE2 receptor, and the ability of the virus to escape from the human immune response based on the binding affinity of the spike protein for a set of neutralizing antibodies. Our model reproduces well the available experimental, epidemiological and clinical data on the impact of variants on the biophysical characteristics of the virus. For example, it is able to identify circulating viral strains that, by increasing their fitness, recently became dominant at the population level. SpikePro is a useful instrument for the genomic surveillance of the SARS-CoV-2 virus, since it predicts in a fast and accurate way the emergence of new viral strains and their dangerousness. It is freely available in the GitHub repository github.com/3BioCompBio/SpikeProSARS-CoV-2.

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PRAK-03202: A triple antigen VLP vaccine candidate against SARS CoV-2

10.1101/2020.10.30.360115 ◽

2020 ◽

Author(s):

Saumyabrata Mazumder ◽

Ruchir Rastogi ◽

Avinash Undale ◽

Kajal Arora ◽

Nupur Mehrotra Arora ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Candidate ◽

Rapid Development ◽

Humoral Response ◽

T Helper 1 ◽

Cellular Immune Responses ◽

Ifn Γ ◽

Neutralizing Potential ◽

Cellular Immune ◽

Different Doses

AbstractThe rapid development of safe and effective vaccines against SARS CoV-2 is the need of the hour for the coronavirus outbreak. Here, we have developed PRAK-03202, the world’s first triple antigen VLP vaccine candidate in a highly characterized S. cerevisiae-based D-CryptTM platform, which induced SARS CoV-2 specific neutralizing antibodies in BALB/c mice. Immunizations using three different doses of PRAK-03202 induces antigen specific (Spike, envelope and membrane proteins) humoral response and neutralizing potential. PBMCs from convalescent patients, when exposed to PRAK-03202, showed lymphocyte proliferation and elevated IFN-γ levels suggestive of conservation of epitopes and induction of T helper 1 (Th1)–biased cellular immune responses. These data support the clinical development and testing of PRAK-03202 for use in humans.

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Intranasal vaccination with a recombinant protein CTA1-DD-RBF protects mice against hRSV infection

Scientific Reports ◽

10.1038/s41598-021-97535-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hai Li ◽

Hu Ren ◽

Yan Zhang ◽

Lei Cao ◽

Wenbo Xu

Keyword(s):

Recombinant Protein ◽

Neutralizing Antibodies ◽

Protective Immunity ◽

Vaccine Candidate ◽

Human Infection ◽

Mucosal Vaccine ◽

Health Concern ◽

Intranasal Immunization ◽

Cell Immunity ◽

Syncytial Virus

AbstractHuman respiratory syncytial virus (hRSV) infection is a major pediatric health concern worldwide. Despite more than half a century of efforts, there is still no commercially available vaccine. In this study, we constructed and purified the recombinant protein CTA1-DD-RBF composed of a CTA1-DD mucosal adjuvant and prefusion F protein (RBF) using Escherichia coli BL21 cells. We studied the immunogenicity of CTA1-DD-RBF in mice. Intranasal immunization with CTA1-DD-RBF stimulated hRSV F-specific IgG1, IgG2a, sIgA, and neutralizing antibodies as well as T cell immunity without inducing lung immunopathology upon hRSV challenge. Moreover, the protective immunity of CTA1-DD-RBF was superior to that of the RBF protein, as confirmed by the assessment of serum-neutralizing activity and viral clearance after challenge. Compared to formalin-inactivated hRSV (FI-RSV), intranasal immunization with CTA1-DD-RBF induced a Th1 immune response. In summary, intranasal immunization with CTA1-DD-RBF is safe and effective in mice. Therefore, CTA1-DD-RBF represents a potential mucosal vaccine candidate for the prevention of human infection with hRSV.

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Neutralizing antibodies to SARS-CoV-2 Omicron variant after 3rd mRNA vaccination in health care workers and elderly subjects and response to a single dose in previously infected adults

10.1101/2021.12.22.21268273 ◽

2021 ◽

Author(s):

Anu Haveri ◽

Anna Solastie ◽

Nina Ekström ◽

Pamela Österlund ◽

Hanna Nohynek ◽

...

Keyword(s):

Health Care ◽

Health Care Workers ◽

Neutralizing Antibodies ◽

Nursing Home Residents ◽

Vaccine Dose ◽

Spike Protein ◽

Wild Type Virus ◽

Elderly Subjects ◽

Igg Antibody ◽

Care Workers

The emergence of SARS-CoV-2 Omicron variant (B.1.1.529) with major spike protein mutations has raised concern over potential neutralization escape and breakthrough infections among vaccinated and previously SARS-CoV-2 infected subjects. We measured cross-protective antibodies against variants in health care workers (HCW, n=20) and nursing home residents (n=9) from samples collected 1-2 months following the booster (3rd) dose. We also assessed the antibody responses in prior to Omicron era infected subjects (n=38) with subsequent administration of a single mRNA vaccine dose. Following booster vaccination HCWs had high IgG antibody concentrations to the spike protein and neutralizing antibodies (NAb) were detectable against all variants. IgG concentrations among the elderly remained lower, and some lacked NAbs against the Beta and Omicron variants. NAb titers were significantly reduced against Delta, Beta and Omicron compared to wild-type virus regardless of age. Vaccination induced high IgG concentrations and variable titers of cross-reactive NAbs in previously infected subjects, whereas NAb titers against Omicron were barely detectable 1-month post-infection. High IgG concentrations with cross-protective neutralizing activity were detected after three COVID-19 vaccine doses in HCWs. However, lower NAb titers seen in the frail elderly suggest inadequate protection against Omicron breakthrough infections, yet protection against severe COVID-19 is expected.

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Development of a Multi-Antigenic SARS-CoV-2 Vaccine Using a Synthetic Poxvirus Platform

10.21203/rs.3.rs-40198/v1 ◽

2020 ◽

Author(s):

Flavia Chiuppesi ◽

Marcela d’Alincourt Salazar ◽

Heidi Contreras ◽

Vu Nguyen ◽

Joy Martinez ◽

...

Keyword(s):

Immune Responses ◽

Neutralizing Antibodies ◽

Protective Immunity ◽

Vaccine Candidate ◽

Vaccine Platform ◽

Synthetic Dna ◽

Cellular Immune Responses ◽

Global Pandemic ◽

Immunodominant Antigens ◽

Cellular Immune

Abstract Modified Vaccinia Ankara (MVA) is a highly attenuated poxvirus vector that is widely used to develop vaccines for infectious diseases and cancer. We developed a novel vaccine platform based on a unique three-plasmid system to efficiently generate recombinant MVA vectors from chemically synthesized DNA. In response to the ongoing global pandemic caused by SARS coronavirus-2 (SARS-CoV-2), we used this novel vaccine platform to rapidly produce fully synthetic MVA (sMVA) vectors co-expressing SARS-CoV-2 spike and nucleocapsid antigens, two immunodominant antigens implicated in protective immunity. Mice immunized with these sMVA vectors developed robust SARS-CoV-2 antigen-specific humoral and cellular immune responses, including potent neutralizing antibodies. These results demonstrate the potential of a novel vaccine platform based on synthetic DNA to efficiently generate recombinant MVA vectors and to rapidly develop a multi-antigenic poxvirus-based SARS-CoV-2 vaccine candidate.

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