Novel virus-like nanoparticle vaccine effectively protects animal model from SARS-CoV-2 infection

The key to battling the COVID-19 pandemic and its potential aftermath is to develop a variety of vaccines that are efficacious and safe, elicit lasting immunity, and cover a range of SARS-CoV-2 variants. Recombinant viral receptor-binding domains (RBDs) are safe vaccine candidates but often have limited efficacy due to the lack of virus-like immunogen display pattern. Here we have developed a novel virus-like nanoparticle (VLP) vaccine that displays 120 copies of SARS-CoV-2 RBD on its surface. This VLP-RBD vaccine mimics virus-based vaccines in immunogen display, which boosts its efficacy, while maintaining the safety of protein-based subunit vaccines. Compared to the RBD vaccine, the VLP-RBD vaccine induced five times more neutralizing antibodies in mice that efficiently blocked SARS-CoV-2 from attaching to its host receptor and potently neutralized the cell entry of variant SARS-CoV-2 strains, SARS-CoV-1, and SARS-CoV-1-related bat coronavirus. These neutralizing immune responses induced by the VLP-RBD vaccine did not wane during the two-month study period. Furthermore, the VLP-RBD vaccine effectively protected mice from SARS-CoV-2 challenge, dramatically reducing the development of clinical signs and pathological changes in immunized mice. The VLP-RBD vaccine provides one potentially effective solution to controlling the spread of SARS-CoV-2.

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The immunodominant and neutralization linear epitopes for SARS-CoV-2

10.1101/2020.08.27.267716 ◽

2020 ◽

Cited By ~ 1

Author(s):

Shuai Lu ◽

Xi-xiu Xie ◽

Lei Zhao ◽

Bin Wang ◽

Jie Zhu ◽

...

Keyword(s):

Neutralizing Antibodies ◽

High Performance ◽

Three Dimensional ◽

Cell Entry ◽

Linear Epitopes ◽

Almost All ◽

Bat Coronavirus ◽

Shed Light ◽

Immunodominant Epitopes ◽

N Proteins

ABSTRACTThe coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) becomes a tremendous threat to global health. Although vaccines against the virus are under development, the antigen epitopes on the virus and their immunogenicity are poorly understood. Here, we simulated the three-dimensional structures of SARS-CoV-2 proteins with high performance computer, predicted the B cell epitopes on spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins of SARS-CoV-2 using structure-based approaches, and then validated the epitope immunogenicity by immunizing mice. Almost all 33 predicted epitopes effectively induced antibody production, six of which were immunodominant epitopes in patients identified via the binding of epitopes with the sera from domestic and imported COVID-19 patients, and 23 were conserved within SARS-CoV-2, SARS-CoV and bat coronavirus RaTG13. We also found that the immunodominant epitopes of domestic SARS-CoV-2 were different from that of the imported, which may be caused by the mutations on S (G614D) and N proteins. Importantly, we validated that eight epitopes on S protein elicited neutralizing antibodies that blocked the cell entry of both D614 and G614 pseudo-virus of SARS-CoV-2, three and nine epitopes induced D614 or G614 neutralizing antibodies, respectively. Our present study shed light on the immunodominance, neutralization, and conserved epitopes on SARS-CoV-2 which are potently used for the diagnosis, virus classification and the vaccine design tackling inefficiency, virus mutation and different species of coronaviruses.

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Soft plastron, soft carapace with skeletal abnormality in juvenile tortoises

Tierärztliche Praxis Ausgabe K Kleintiere / Heimtiere ◽

10.1055/s-0038-1623777 ◽

2014 ◽

Vol 42 (05) ◽

pp. 310-320 ◽

Cited By ~ 10

Author(s):

W. Heuser ◽

H. Pendl ◽

N. J. Knowles ◽

G. Keil ◽

W. Herbst ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Clinical Signs ◽

Biological Properties ◽

Testudo Graeca ◽

Metabolic Bone ◽

Viral Aetiology ◽

Novel Virus ◽

Geochelone Elegans ◽

Th 1

Summary Objective: A disease is described in juvenile tortoises (Testudo graeca and Geochelone elegans) consisting mainly of a soft carapace, soft plastron and deformed skeleton. The aim of this study was to determine histopathological lesions and the biological properties of the isolated viruses. Materials and methods: Clinical signs and gross pathology were determined on diseased and healthy appearing tortoises. Paraffin sections were stained with HE, PAS and Prussian Blue and histologically examined. Terrapene heart (TH-1) cell cultures served for virus isolations from 64 tissues and 104 swabs. One isolate (isolate 1243/37 tongue) was used in neutralization tests on 19 sera. Results: Retarded growth and increasingly soft plastron and carapace were the prominent signs in diseased tortoises. Pathological lesions consisted of dilated urinary sac, enlarged kidneys and livers. Histopathologically, hepatic hemosiderosis, hypoplastic anaemia, congestive glomerulonephrosis and osteodystrophy were seen. A novel virus (“virus X”) was isolated from 64 organs and 79 of 104 swabs. The isolated viruses were identified as a novel chelonid picornavirus based on cytopathic effect, resistance to chloroform and stability at low pH. Co-cultivation with 5-iodo-2’-deoxyuridine and actinomycin D did not reduce virus titres. Electron microscopically, round, non-enveloped particles (25–30 nm) were detected. Neutralizing antibodies to the isolate 1243/37tongue were present in 17 of 19 sera from seven species of tortoises. Conclusion and clinical relevance: Nephropathy, osteodystrophy and virus isolations suggest a viral aetiology. Metabolic bone disease is the major differential diagnosis. Further investigations in vivo are needed to evaluate the likely effects of the picornavirus on tortoises.

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Recovery from acute SARS-CoV-2 infection and development of anamnestic immune responses in T cell-depleted rhesus macaques

10.1101/2021.04.02.438262 ◽

2021 ◽

Author(s):

Kim J Hasenkrug ◽

Friederike Feldmann ◽

Lara Myers ◽

Mario L Santiago ◽

Kejun Guo ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Neutralizing Antibodies ◽

Causal Effect ◽

Rhesus Macaques ◽

High Titer ◽

Clinical Signs ◽

T Cell Subsets ◽

Natural Resistance

Severe COVID-19 has been associated with T cell lymphopenia 1,2, but no causal effect of T cell deficiency on disease severity has been established. To investigate the specific role of T cells in recovery from SARS-CoV-2 infections we studied rhesus macaques that were depleted of either CD4+, CD8+ or both T cell subsets prior to infection. Peak virus loads were similar in all groups, but the resolution of virus in the T cell-depleted animals was slightly delayed compared to controls. The T cell-depleted groups developed virus-neutralizing antibody responses and also class-switched to IgG. When re-infected six weeks later, the T cell-depleted animals showed anamnestic immune responses characterized by rapid induction of high-titer virus-neutralizing antibodies, faster control of virus loads and reduced clinical signs. These results indicate that while T cells play a role in the recovery of rhesus macaques from acute SARS-CoV-2 infections, their depletion does not induce severe disease, and T cells do not account for the natural resistance of rhesus macaques to severe COVID-19. Neither primed CD4+ or CD8+ T cells appeared critical for immunoglobulin class switching, the development of immunological memory or protection from a second infection.

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A Single Shot Pre-fusion-Stabilized Bovine RSV F Vaccine is Safe and Effective in Newborn Calves with Maternally Derived Antibodies

Vaccines ◽

10.3390/vaccines8020231 ◽

2020 ◽

Vol 8 (2) ◽

pp. 231

Author(s):

Sabine Riffault ◽

Sara Hägglund ◽

Efrain Guzman ◽

Katarina Näslund ◽

Luc Jouneau ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Clinical Signs ◽

Single Shot ◽

Upper Respiratory Tract ◽

Native Form ◽

Subunit Vaccines ◽

Virus Particles ◽

Immune Parameters ◽

Single Intramuscular Injection ◽

Syncytial Virus

Achieving safe and protective vaccination against respiratory syncytial virus (RSV) in infants and in calves has proven a challenging task. The design of recombinant antigens with a conformation close to their native form in virus particles is a major breakthrough. We compared two subunit vaccines, the bovine RSV (BRSV) pre-fusion F (preF) alone or with nanorings formed by the RSV nucleoprotein (preF+N). PreF and N proteins are potent antigenic targets for neutralizing antibodies and T cell responses, respectively. To tackle the challenges of neonatal immunization, three groups of six one-month-old calves with maternally derived serum antibodies (MDA) to BRSV received a single intramuscular injection of PreF, preF+N with MontanideTM ISA61 VG (ISA61) as adjuvant or only ISA61 (control). One month later, all calves were challenged with BRSV and monitored for virus replication in the upper respiratory tract and for clinical signs of disease over one week, and then post-mortem examinations of their lungs were performed. Both preF and preF+N vaccines afforded safe, clinical, and virological protection against BRSV, with little difference between the two subunit vaccines. Analysis of immune parameters pointed to neutralizing antibodies and antibodies to preF as being significant correlates of protection. Thus, a single shot vaccination with preF appears sufficient to reduce the burden of BRSV disease in calves with MDA.

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Chapter 2b: The molecular antigenic structure of the TBEV

Tick-borne encephalitis - The Book ◽

10.33442/26613980_2b-3 ◽

2020 ◽

Keyword(s):

Conformational Changes ◽

Neutralizing Antibodies ◽

Lipid Membrane ◽

Cell Entry ◽

Antigenic Structure ◽

E Proteins ◽

Amino Acid Sequence Level ◽

Endosomal Membrane ◽

E Protein ◽

Golgi Network

TBEV-particles are assembled in an immature, noninfectious form in the endoplasmic reticulum by the envelopment of the viral core (containing the viral RNA) by a lipid membrane associated with two viral proteins, prM and E. Immature particles are transported through the cellular exocytic pathway and conformational changes induced by acidic pH in the trans-Golgi network allow the proteolytic cleavage of prM by furin, a cellular protease, resulting in the release of mature and infectious TBE-virions. The E protein controls cell entry by mediating attachment to as yet ill-defined receptors as well as by low-pH-triggered fusion of the viral and endosomal membrane after uptake by receptor-mediated endocytosis. Because of its key functions in cell entry, the E protein is the primary target of virus neutralizing antibodies, which inhibit these functions by different mechanisms. Although all flavivirus E proteins have a similar overall structure, divergence at the amino acid sequence level is up to 60 percent (e.g. between TBE and dengue viruses), and therefore cross-neutralization as well as (some degree of) cross-protection are limited to relatively closely related flaviviruses, such as those constituting the tick-borne encephalitis serocomplex.

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Principles and Challenges in anti-COVID-19 Vaccine Development

International Archives of Allergy and Immunology ◽

10.1159/000514225 ◽

2021 ◽

pp. 1-11

Author(s):

Zuzana Strizova ◽

Jitka Smetanova ◽

Jirina Bartunkova ◽

Tomas Milota

Keyword(s):

Clinical Trials ◽

Immune Responses ◽

Vaccine Development ◽

Viral Vector ◽

Health It ◽

Therapeutic Approaches ◽

Clinical Phase ◽

Adaptive Immune ◽

Limited Efficacy ◽

Safe Vaccine

The number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients keeps rising in most of the European countries despite the pandemic precaution measures. The current antiviral and anti-inflammatory therapeutic approaches are only supportive, have limited efficacy, and the prevention in reducing the transmission of SARS-CoV-2 virus is the best hope for public health. It is presumed that an effective vaccination against SARS-CoV-2 infection could mobilize the innate and adaptive immune responses and provide a protection against severe forms of coronavirus disease 2019 (COVID-19) disease. As the race for the effective and safe vaccine has begun, different strategies were introduced. To date, viral vector-based vaccines, genetic vaccines, attenuated vaccines, and protein-based vaccines are the major vaccine types tested in the clinical trials. Over 80 clinical trials have been initiated; however, only 18 vaccines have reached the clinical phase II/III or III, and 4 vaccine candidates are under consideration or have been approved for the use so far. In addition, the protective effect of the off-target vaccines, such as <i>Bacillus</i> Calmette-Guérin and measles vaccine, is being explored in randomized prospective clinical trials with SARS-CoV-2-infected patients. In this review, we discuss the most promising anti-COVID-19 vaccine clinical trials and different vaccination strategies in order to provide more clarity into the ongoing clinical trials.

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Immune Responses Elicited by Live Attenuated Influenza Vaccines as Correlates of Universal Protection against Influenza Viruses

Vaccines ◽

10.3390/vaccines9040353 ◽

2021 ◽

Vol 9 (4) ◽

pp. 353

Author(s):

Yo Han Jang ◽

Baik L. Seong

Keyword(s):

Immune Responses ◽

Neutralizing Antibodies ◽

Influenza Virus Infection ◽

Influenza Viruses ◽

Influenza Vaccines ◽

Immune Correlates ◽

Protection Efficacy ◽

Public Health Challenge ◽

Efficient Protection ◽

Universal Influenza Vaccine

Influenza virus infection remains a major public health challenge, causing significant morbidity and mortality by annual epidemics and intermittent pandemics. Although current seasonal influenza vaccines provide efficient protection, antigenic changes of the viruses often significantly compromise the protection efficacy of vaccines, rendering most populations vulnerable to the viral infection. Considerable efforts have been made to develop a universal influenza vaccine (UIV) able to confer long-lasting and broad protection. Recent studies have characterized multiple immune correlates required for providing broad protection against influenza viruses, including neutralizing antibodies, non-neutralizing antibodies, antibody effector functions, T cell responses, and mucosal immunity. To induce broadly protective immune responses by vaccination, various strategies using live attenuated influenza vaccines (LAIVs) and novel vaccine platforms are under investigation. Despite superior cross-protection ability, very little attention has been paid to LAIVs for the development of UIV. This review focuses on immune responses induced by LAIVs, with special emphasis placed on the breadth and the potency of individual immune correlates. The promising prospect of LAIVs to serve as an attractive and reliable vaccine platforms for a UIV is also discussed. Several important issues that should be addressed with respect to the use of LAIVs as UIV are also reviewed.

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Rapid seroconversion and persistent functional IgG antibodies in severe COVID-19 patients correlates with an IL-12p70 and IL-33 signature

Scientific Reports ◽

10.1038/s41598-021-83019-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ariel Munitz ◽

L. Edry-Botzer ◽

M. Itan ◽

R. Tur-Kaspa ◽

D. Dicker ◽

...

Keyword(s):

Nucleocapsid Protein ◽

Neutralizing Antibodies ◽

Host Response ◽

Humoral Response ◽

Rapid Onset ◽

Response Analysis ◽

Receptor Binding Domain ◽

Igg Antibodies ◽

Viral Receptor ◽

Iga Antibodies

AbstractDespite ongoing efforts to characterize the host response toward SARS-CoV-2, a major gap in our knowledge still exists regarding the magnitude and duration of the humoral response. Analysis of the antibody response in mild versus moderate/severe patients, using our new developed quantitative electrochemiluminescent assay for detecting IgM/IgA/IgG antibodies toward SARS-CoV-2 antigens, revealed a rapid onset of IgG/IgA antibodies, specifically in moderate/severe patients. IgM antibodies against the viral receptor binding domain, but not against nucleocapsid protein, were detected at early stages of the disease. Furthermore, we observed a marked reduction in IgM/IgA antibodies over-time. Adapting our assay for ACE2 binding-competition, demonstrated that the presence of potentially neutralizing antibodies is corelated with IgG/IgA. Finally, analysis of the cytokine profile in COVID-19 patients revealed unique correlation of an IL-12p70/IL33 and IgG seroconversion, which correlated with disease severity. In summary, our comprehensive analysis has major implications on the understanding and monitoring of SARS-CoV-2 infections.

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COVID-19: Mechanisms of Vaccination and Immunity

Vaccines ◽

10.3390/vaccines8030404 ◽

2020 ◽

Vol 8 (3) ◽

pp. 404 ◽

Cited By ~ 1

Author(s):

Daniel E. Speiser ◽

Martin F. Bachmann

Keyword(s):

Immune Responses ◽

Clinical Management ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Public Life ◽

High Affinity ◽

Vaccination Strategies ◽

Detailed Evaluation ◽

Pros And Cons

Vaccines are needed to protect from SARS-CoV-2, the virus causing COVID-19. Vaccines that induce large quantities of high affinity virus-neutralizing antibodies may optimally prevent infection and avoid unfavorable effects. Vaccination trials require precise clinical management, complemented with detailed evaluation of safety and immune responses. Here, we review the pros and cons of available vaccine platforms and options to accelerate vaccine development towards the safe immunization of the world’s population against SARS-CoV-2. Favorable vaccines, used in well-designed vaccination strategies, may be critical for limiting harm and promoting trust and a long-term return to normal public life and economy.

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Characterization of Lassa Virus Cell Entry and Neutralization with Lassa Virus Pseudoparticles

Journal of Virology ◽

10.1128/jvi.01711-08 ◽

2009 ◽

Vol 83 (7) ◽

pp. 3228-3237 ◽

Cited By ~ 34

Author(s):

François-Loic Cosset ◽

Philippe Marianneau ◽

Geraldine Verney ◽

Fabrice Gallais ◽

Noel Tordo ◽

...

Keyword(s):

Immune Response ◽

Humoral Immune Response ◽

Neutralizing Antibodies ◽

Cell Attachment ◽

Low Ph ◽

Cell Entry ◽

Lassa Virus ◽

Ph Optimum ◽

Humoral Immune

ABSTRACT The cell entry and humoral immune response of the human pathogen Lassa virus (LV), a biosafety level 4 (BSL4) Old World arenavirus, are not well characterized. LV pseudoparticles (LVpp) are a surrogate model system that has been used to decipher factors and routes involved in LV cell entry under BSL2 conditions. Here, we describe LVpp, which are highly infectious, with titers approaching those obtained with pseudoparticles displaying G protein of vesicular stomatitis virus and their the use for the characterization of LV cell entry and neutralization. Upon cell attachment, LVpp utilize endocytic vesicles for cell entry as described for many pH-dependent viruses. However, the fusion of the LV glycoproteins is activated at unusually low pH values, with optimal fusion occurring between pH 4.5 and 3, a pH range at which fusion characteristics of viral glycoproteins have so far remained largely unexplored. Consistent with a shifted pH optimum for fusion activation, we found wild-type LV and LVpp to display a remarkable resistance to exposure to low pH. Finally, LVpp allow the fast and quantifiable detection of neutralizing antibodies in human and animal sera and will thus facilitate the study of the humoral immune response in LV infections.

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