scholarly journals Immunogenicity and In vivo protection of a variant nanoparticle vaccine that confers broad protection against emerging SARS-CoV-2 variants

2021 ◽  
Author(s):  
James Logue ◽  
Robert Johnson ◽  
Nita Patel ◽  
Bin Zhou ◽  
Sonia Maciejewski ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Neutralizing Antibodies ◽  
Virus Titer ◽  
Cellular Responses ◽  
Risk Of Infection ◽  
Post Challenge ◽  
Anamnestic Response ◽  
Transmission Rates ◽  
One Year

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to spread globally. As SARS-CoV-2 has transmitted from person to person, variant viruses have emerged with elevated transmission rates and higher risk of infection for vaccinees. We present data showing that a recombinant prefusion-stabilized Spike (rS) protein based on the B.1.351 sequence (rS-B.1.351) was highly immunogenic in mice and produced neutralizing antibodies against SARS-CoV-2/WA1, B.1.1.7, and B.1.351. Mice vaccinated with our prototype vaccine NVX-CoV2373 (rS-WU1) or rS-B.1.351 alone, in combination, or as a heterologous prime boost, were protected when challenged with live SARS-CoV-2/B.1.1.7 or SARS-CoV-2/B.1.351. Virus titer was reduced to undetectable levels in the lungs post-challenge in all vaccinated mice, and Th1-skewed cellular responses were observed. A strong anamnestic response was demonstrated in baboons boosted with rS-B.1.351 approximately one year after immunization with NVX-CoV2373 (rS-WU1). An rS-B.1.351 vaccine alone or in combination with prototype rS-WU1 induced protective antibody- and cell-mediated responses that were protective against challenge with SARS-CoV-2 variant viruses.

scholarly journals Serological response to rabies virus induced by commercial vaccines in cattle

2017 ◽  
Vol 47 (10) ◽  
Author(s):  
Mathias Martins ◽  
João Motta de Quadros ◽  
Eduardo Furtado Flores ◽  
Rudi Weiblen
Keyword(s):  
Rabies Virus ◽  
Neutralizing Antibodies ◽  
Vaccine Dose ◽  
Booster Vaccination ◽  
Serological Response ◽  
Serum Samples ◽  
Anamnestic Response ◽  
Post Vaccination ◽  
Antibody Titers ◽  
One Year

ABSTRACT: The antibody response to rabies virus (RABV) induced by commercial vaccines in heifers was investigated. For this, 84 heifers were vaccinated twice (30 days interval) with each of four vaccines (G1 = 14 animals; G2 = 24; G3 = 22 and G4 = 24) and received a booster vaccination 360 days later. Serum samples collected at different intervals after vaccination and 30 days after booster were submitted to a virus neutralizing (VN) assay for RABV antibodies. Thirty days after the second vaccine dose, 92% of the immunized animals presented VN titers ≥0.5UI/mL (geometric medium titers [GMT] 1.7 to 3.8UI/mL). At the day of the booster (360 days post-vaccination); however, the percentage of animals harboring antibody titers ≥0.5UI/mL had dropped to 31% (0-80% of the animals, depending on the vaccine), resulting in lower GMT (0.1 to 0.6UI/mL). Booster vaccination at day 360 resulted in a detectable anamnestic response in all groups, resulting in 83% of animals (65 to 100%) harboring VN titers ≥0.5UI/mL thirty days later (GMT 0.6 to 4.3UI/mL). These results indicated that these vaccines were able to induce an adequate anti-RABV response in all animals after prime vaccination (and after booster as well). However, the titers decreased, reaching titers <0.5UI/mL in approximately 70% of animals within the interval before the recommended booster. Thus, booster vaccination for rabies in cattle using the current vaccines should be performed before the recommended one-year interval, as to maintain neutralizing antibodies levels in most vaccinated animals.

scholarly journals Murine monoclonal antibodies against RBD of SARS-CoV-2 neutralize authentic wild type SARS-CoV-2 as well as B.1.1.7 and B.1.351 viruses and protect in vivo in a mouse model in a neutralization dependent manner

2021 ◽  
Author(s):  
Fatima Amanat ◽  
Shirin Strohmeier ◽  
Wen-Hsin Lee ◽  
Sandhya Bangaru ◽  
Andrew B Ward ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Mouse Model ◽  
Neutralizing Antibodies ◽  
Dependent Manner ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Murine Monoclonal Antibodies

After first emerging in December 2019 in China, severe acute respiratory syndrome 2 (SARS-CoV-2) has since caused a pandemic leading to millions of infections and deaths worldwide. Vaccines have been developed and authorized but supply of these vaccines is currently limited. With new variants of the virus now emerging and spreading globally, it is essential to develop therapeutics that are broadly protective and bind conserved epitopes in the receptor binding domain (RBD) or the whole spike of SARS-CoV-2. In this study, we have generated mouse monoclonal antibodies (mAbs) against different epitopes on the RBD and assessed binding and neutralization against authentic SARS-CoV-2. We have demonstrated that antibodies with neutralizing activity, but not non-neutralizing antibodies, lower viral titers in the lungs when administered in a prophylactic setting in vivo in a mouse challenge model. In addition, most of the mAbs cross-neutralize the B.1.351 as well as the B.1.1.7 variants in vitro.

scholarly journals Single Amino Acid Substitutions in the Severe Acute Respiratory Syndrome Coronavirus Spike Glycoprotein Determine Viral Entry and Immunogenicity of a Major Neutralizing Domain

2005 ◽  
Vol 79 (18) ◽  
pp. 11638-11646 ◽  
Author(s):  
Christopher E. Yi ◽  
Lei Ba ◽  
Linqi Zhang ◽  
David D. Ho ◽  
Zhiwei Chen
Keyword(s):  
Amino Acid ◽  
Severe Acute Respiratory Syndrome ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Antiviral Agents ◽  
Single Amino Acid ◽  
Major Mechanism ◽  
The Difference

ABSTRACT Neutralizing antibodies (NAbs) against severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) spike (S) glycoprotein confer protection to animals experimentally infected with the pathogenic virus. We and others previously demonstrated that a major mechanism for neutralizing SARS-CoV was through blocking the interaction between the S glycoprotein and the cellular receptor angiotensin-converting enzyme 2 (ACE2). In this study, we used in vivo electroporation DNA immunization and a pseudovirus-based assay to functionally evaluate immunogenicity and viral entry. We characterized the neutralization and viral entry determinants within the ACE2-binding domain of the S glycoprotein. The deletion of a positively charged region SΔ(422-463) abolished the capacity of the S glycoprotein to induce NAbs in mice vaccinated by in vivo DNA electroporation. Moreover, the SΔ(422-463) pseudovirus was unable to infect HEK293T-ACE2 cells. To determine the specific residues that contribute to related phenotypes, we replaced eight basic amino acids with alanine. We found that a single amino acid substitution (R441A) in the full-length S DNA vaccine failed to induce NAbs and abolished viral entry when pseudoviruses were generated. However, another substitution (R453A) abolished viral entry while retaining the capacity for inducing NAbs. The difference between R441A and R453A suggests that the determinants for immunogenicity and viral entry may not be identical. Our findings provide direct evidence that these basic residues are essential for immunogenicity of the major neutralizing domain and for viral entry. Our data have implications for the rational design of vaccine and antiviral agents as well as for understanding viral tropism.

scholarly journals The Dynamics of Neutralizing Antibody Level in One Year After SARS-CoV-2 Infection

2021 ◽  
Author(s):  
Dan Liang ◽  
Guanting Zhang ◽  
Mingxing Huang ◽  
Wenshan Hong ◽  
An'an Li ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Antibody Level ◽  
Diagnostic Tests ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Neutralization Assay ◽  
Blood Samples ◽  
Immune Ability ◽  
One Year

Abstract Background: A lot of recent researches have focused on the duration of the nature immunity elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. An improved understanding of the immunity offered by the antibodies developed against SARS-CoV-2 in recovered patients is critical for the development of diagnostic tests and vaccines. Methods: We enrolled 114 donors, which providing blood samples after discharge for half a year and one year. Neutralizing antibodies (NAbs) were tested using a micro-neutralization assay. Results: In two tests, 82 of 114 recovered patients completed the first test half a year after discharge and NAbs remained detectable in the vast majority of patients (75/82, 91.46%). In the comparison of the two intervals, 50% (27/54) of individuals had increased NAbs titers. when 31.48% (17/54) of patients remained unchanged. Conclusion: Our results suggest that immune ability is acquired in most individuals infected with SARS-CoV-2 and is sustained in a majority of patients for up to a year after recovery.

scholarly journals Human neutralizing antibodies for SARS-CoV-2 prevention and immunotherapy

2021 ◽  
Author(s):  
Dongyan Zhou ◽  
Runhong Zhou ◽  
Zhiwei Chen
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Passive Immunization ◽  
Clinical Development ◽  
Vaccine Research ◽  
Breakthrough Infection ◽  
Clinical Benefits

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). SARS-CoV-2 has been spreading worldwide since December 2019, resulting in the ongoing COVID-19 pandemic with 237 million infections and 4.8 million deaths by 11 October 2021. While there are great efforts of global vaccination, ending this pandemic has been challenged by issues of exceptionally high viral transmissibility, re-infection, vaccine-breakthrough infection, and immune escape variants of concerns. Besides the record-breaking speed of vaccine research and development, antiviral drugs including SARS-CoV-2-specific human neutralizing antibodies (HuNAbs) have been actively explored for passive immunization. In support of HuNAb-based immunotherapy, passive immunization using convalescent patients’ plasma have generated promising evidence on clinical benefits for both mild and severe COVID-19 patients. Since the source of convalescent plasma is limited, the discovery of broadly reactive HuNAbs may have significant impacts on the fight against the COVID-19 pandemic. In this review, therefore, we discuss the current technologies of gene cloning, modes of action, in vitro and in vivo potency and breadth, and clinical development for potent SARS-CoV-2-specific HuNAbs.

scholarly journals Identification and Characterization of Dominant Helper T-Cell Epitopes in the Nucleocapsid Protein of Severe Acute Respiratory Syndrome Coronavirus

2007 ◽  
Vol 81 (11) ◽  
pp. 6079-6088 ◽  
Author(s):  
Jincun Zhao ◽  
Qianrong Huang ◽  
Wei Wang ◽  
Yan Zhang ◽  
Ping Lv ◽  
...  
Keyword(s):  
T Cell ◽  
Severe Acute Respiratory Syndrome ◽  
Synthetic Peptides ◽  
Nucleocapsid Protein ◽  
Neutralizing Antibodies ◽  
High Titer ◽  
Delayed Type Hypersensitivity ◽  
T Cell Epitopes ◽  
Helper T Cell

ABSTRACT By using a series of overlapping synthetic peptides covering 98% of the amino acid sequence of the nucleocapsid protein (NP) of severe acute respiratory syndrome coronavirus (SARS-CoV), four helper T-cell (Th) epitopes (NP11, residues 11 to 25; NP51, residues 51 to 65; NP61, residues 61 to 75; and NP111, residues 111 to 125) in C57BL mice (H-2b), four (NP21, residues 21 to 35; NP91, residues 91 to 105; NP331, residues 331 to 345; and NP351, residues 351 to 365) in C3H mice (H-2k), and two (NP81, residues 81 to 95; and NP351, residues 351 to 365) in BALB/c mice (H-2d) have been identified. All of these peptides were able to stimulate the proliferation of NP-specific T-cell lines or freshly isolated lymph node cells from mice immunized with recombinant NP. Immunization of mice with synthetic peptides containing appropriate Th epitopes elicited strong cellular immunity in vivo, as evidenced by delayed-type hypersensitivity. Priming with the helper peptides (e.g., NP111 and NP351) significantly accelerated the immune response induced by recombinant NP, as determined by the production of NP-specific antibodies. When fused with a conserved neutralizing epitope (SP1143-1157) from the spike protein of SARS-CoV, NP111 and NP351 assisted in the production of high-titer neutralizing antibodies in vivo. These data provide useful insights regarding immunity against SARS-CoV and have the potential to help guide the design of peptide-based vaccines.

scholarly journals Metabolic, humoral, and cellular responses in adult volunteers immunized with the genetically inactivated pertussis toxin mutant PT-9K/129G.

1990 ◽  
Vol 172 (3) ◽  
pp. 861-868 ◽  
Author(s):  
A Podda ◽  
L Nencioni ◽  
M T De Magistris ◽  
A Di Tommaso ◽  
P Bossù ◽  
...  
Keyword(s):  
T Cells ◽  
Pertussis Toxin ◽  
Neutralizing Antibodies ◽  
Cellular Response ◽  
Genetic Manipulation ◽  
Whooping Cough ◽  
Cellular Responses ◽  
Adult Volunteers

PT-9K/129G, a nontoxic mutant of pertussis toxin (PT) obtained by genetic manipulation, has been shown in animal models to be a promising candidate for new vaccines against whooping cough. To assess the safety and the immunogenicity of PT-9K/129G in humans, a pilot study has been performed in adult volunteers. The protein was found to be safe, capable of inducing high titers of toxin-neutralizing antibodies, and capable of generating immunological memory. In fact, vaccination caused an increase of cell-mediated response to PT, PT-9K/129G, S1 subunit, and B oligomer, indicating that memory T cells are induced by the vaccine. Since PT-9K/129G is mitogenic for T lymphocytes in vitro, it was investigated whether this activity is also present in vivo. No variation was observed in the proportion of T cells (CD3+), T helper cells (CD4+), and cytotoxic T cells (CD8+), as well as in that of other lymphoid populations, by FACS analysis. Interestingly, no thorough correlation was found between humoral and cellular responses. In one case, a very high cellular response was present in absence of detectable antibodies, suggesting that the antibody response, which is the only parameter measured in most clinical trials, may not give a complete picture of the response induced by a vaccine.

scholarly journals Vaccination with B.1.1.7, B.1.351 and P.1 variants protects mice from challenge with wild type SARS-CoV-2

2021 ◽  
Author(s):  
Fatima Amanat ◽  
Shirin Strohmeier ◽  
Philip Meade ◽  
Nicholas Dambrauskas ◽  
Barbara Mühlemann ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Recombinant Protein ◽  
Mouse Model ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Wild Type ◽  
Fold Reduction ◽  
Reactive Antibody

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been highly efficient in protecting against coronavirus disease 2019 (COVID-19). However, the emergence of viral variants that are more transmissible and, in some cases, escape from neutralizing antibody responses has raised concerns. Here, we evaluated recombinant protein spike antigens derived from wild type SARS-CoV-2 and from variants B.1.1.7, B.1.351 and P.1 for their immunogenicity and protective effect in vivo against challenge with wild type SARS-CoV-2 in the mouse model. All proteins induced high neutralizing antibodies against the respective viruses but also induced high cross-neutralizing antibody responses. The decline in neutralizing titers between variants was moderate, with B.1.1.7 vaccinated animals having a maximum fold reduction of 4.8 against B.1.351 virus. P.1 induced the most cross-reactive antibody responses but was also the least immunogenic in terms of homologous neutralization titers. However, all antigens protected from challenge with wild type SARS-CoV-2 in a mouse model.

scholarly journals Protective humoral responses to severe acute respiratory syndrome-associated coronavirus: implications for the design of an effective protein-based vaccine

2004 ◽  
Vol 85 (10) ◽  
pp. 3109-3113 ◽  
Author(s):  
Hai Pang ◽  
Yinggang Liu ◽  
Xueqing Han ◽  
Yanhui Xu ◽  
Fuguo Jiang ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Structural Proteins ◽  
Effective Vaccine ◽  
S Protein ◽  
M Proteins ◽  
Humoral Responses

Some of the structural proteins of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) carry major epitopes involved in virus neutralization and are essential for the induction of protective humoral responses and the development of an effective vaccine. Rabbit antisera were prepared using full-length N and M proteins and eight expressed fragments covering the S protein. Antisera to S and M proteins were found to have different neutralizing titres towards SARS-CoV infection in vivo, ranging from 1 : 35 to 1 : 128. Antiserum to the N protein did not contain neutralizing antibodies. Epitopes inducing protective humoral responses to virus infection were located mainly in the M protein and a region spanning residues 13–877 of the S protein. The neutralizing ability of antisera directed against the expressed structural proteins was greater than that of convalescent patient antisera, confirming that, as immunogens, the former induce strong, SARS-CoV-specific neutralizing antibody responses. The in vitro neutralization assay has important implications for the design of an effective, protein-based vaccine preventing SARS-CoV infection.

scholarly journals SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected hospitalized COVID-19 patients

2020 ◽  
Vol 101 (11) ◽  
pp. 1156-1169 ◽  
Author(s):  
William B. Klimstra ◽  
Natasha L. Tilston-Lunel ◽  
Sham Nambulli ◽  
James Boslett ◽  
Cynthia M. McMillen ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Serum Samples ◽  
Furin Cleavage ◽  
Furin Cleavage Site ◽  
Antibody Titres ◽  
Low Passage

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), emerged at the end of 2019 and by mid-June 2020 the virus had spread to at least 215 countries, caused more than 8 000 000 confirmed infections and over 450 000 deaths, and overwhelmed healthcare systems worldwide. Like severe acute respiratory syndrome coronavirus (SARS-CoV), which emerged in 2002 and caused a similar disease, SARS-CoV-2 is a betacoronavirus. Both viruses use human angiotensin-converting enzyme 2 (hACE2) as a receptor to enter cells. However, the SARS-CoV-2 spike (S) glycoprotein has a novel insertion that generates a putative furin cleavage signal and this has been postulated to expand the host range. Two low-passage (P) strains of SARS-CoV-2 (Wash1 : P4 and Munich : P1) were cultured twice in Vero E6 cells and characterized virologically. Sanger and MinION sequencing demonstrated significant deletions in the furin cleavage signal of Wash1 : P6 and minor variants in the Munich : P3 strain. Cleavage of the S glycoprotein in SARS-CoV-2-infected Vero E6 cell lysates was inefficient even when an intact furin cleavage signal was present. Indirect immunofluorescence demonstrated that the S glycoprotein reached the cell surface. Since the S protein is a major antigenic target for the development of neutralizing antibodies, we investigated the development of neutralizing antibody titres in serial serum samples obtained from COVID-19 human patients. These were comparable regardless of the presence of an intact or deleted furin cleavage signal. These studies illustrate the need to characterize virus stocks meticulously prior to performing either in vitro or in vivo pathogenesis studies.

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