scholarly journals Interferon-armed RBD dimer enhances the immunogenicity of RBD for sterilizing immunity against SARS-CoV-2

Cell Research ◽  
2021 ◽  
Author(s):  
Shiyu Sun ◽  
Yueqi Cai ◽  
Tian-Zhang Song ◽  
Yang Pu ◽  
Lin Cheng ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Antigen Processing ◽  
Rhesus Macaques ◽  
Low Cost ◽  
High Dose ◽  
Cross Presentation ◽  
Cell Responses ◽  
Generation Vaccine ◽  
Sterilizing Immunity ◽  
Dose Vaccine

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global crisis, urgently necessitating the development of safe, efficacious, convenient-to-store, and low-cost vaccine options. A major challenge is that the receptor-binding domain (RBD)-only vaccine fails to trigger long-lasting protective immunity if used alone for vaccination. To enhance antigen processing and cross-presentation in draining lymph nodes (DLNs), we developed an interferon (IFN)-armed RBD dimerized by an immunoglobulin fragment (I-R-F). I-R-F efficiently directs immunity against RBD to DLNs. A low dose of I-R-F induces not only high titers of long-lasting neutralizing antibodies (NAbs) but also more comprehensive T cell responses than RBD. Notably, I-R-F provides comprehensive protection in the form of a one-dose vaccine without an adjuvant. Our study shows that the pan-epitope modified human I-R-F (I-P-R-F) vaccine provides rapid and complete protection throughout the upper and lower respiratory tracts against a high-dose SARS-CoV-2 challenge in rhesus macaques. Based on these promising results, we have initiated a randomized, placebo-controlled, phase I/II trial of the human I-P-R-F vaccine (V-01) in 180 healthy adults, and the vaccine appears safe and elicits strong antiviral immune responses. Due to its potency and safety, this engineered vaccine may become a next-generation vaccine candidate in the global effort to overcome COVID-19.

scholarly journals Interferon-armed RBD dimer enhances the immunogenicity of RBD for sterilizing immunity against SARS-CoV-2

2021 ◽  
Author(s):  
Shiyu Sun ◽  
Yueqi Cai ◽  
Tian-Zhang Song ◽  
Yang Pu ◽  
Lin Cheng ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Antigen Processing ◽  
Rhesus Macaques ◽  
High Titer ◽  
Low Cost ◽  
High Dose ◽  
Cross Presentation ◽  
Cell Responses ◽  
Generation Vaccine ◽  
Sterilizing Immunity

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global crisis, urgently necessitating the development of safe, efficacious, convenient-to-store, and low-cost vaccine options. A major challenge is that the receptor-binding domain (RBD)-only vaccine fails to trigger long-lasting protective immunity if used solely for vaccination. To enhance antigen processing and cross-presentation in draining lymph nodes (DLNs), we developed an interferon (IFN)-armed RBD dimerized by immunoglobulin fragment (I-R-F). I-R-F efficiently directs immunity against RBD to DLN. A low dose of I-R-F induces not only high titer long-lasting neutralizing antibodies but also comprehensive T cell responses than RBD, and even provides comprehensive protection in one dose without adjuvant. This study shows that the I-R-F vaccine provides rapid and complete protection throughout upper and lower respiratory tracts against high dose SARS-CoV-2 challenge in rhesus macaques. Due to its potency and safety, this engineered vaccine may become one of the next-generation vaccine candidates in the global race to defeat COVID-19.

scholarly journals A single intranasal dose of chimpanzee adenovirus-vectored vaccine protects against SARS-CoV-2 infection in rhesus macaques

2021 ◽  
Author(s):  
Ahmed O. Hassan ◽  
Friederike Feldmann ◽  
Haiyan Zhao ◽  
David T. Curiel ◽  
Atsushi Okumura ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Neutralizing Antibodies ◽  
Lower Respiratory Tract ◽  
Protective Efficacy ◽  
Rhesus Macaques ◽  
Angiotensin Converting Enzyme 2 ◽  
Cell Responses ◽  
Vectored Vaccine ◽  
Dose Vaccine ◽  
Intranasal Dose

SUMMARYThe deployment of a vaccine that limits transmission and disease likely will be required to end the Coronavirus Disease 2019 (COVID-19) pandemic. We recently described the protective activity of an intranasally-administered chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized spike (S) protein (ChAd-SARS-CoV-2-S) in the upper and lower respiratory tract of mice expressing the human angiotensin-converting enzyme 2 (ACE2) receptor. Here, we show the immunogenicity and protective efficacy of this vaccine in non-human primates. Rhesus macaques were immunized with ChAd-Control or ChAd-SARS-CoV-2-S and challenged one month later by combined intranasal and intrabronchial routes with SARS-CoV-2. A single intranasal dose of ChAd-SARS-CoV-2-S induced neutralizing antibodies and T cell responses and limited or prevented infection in the upper and lower respiratory tract after SARS-CoV-2 challenge. As this single intranasal dose vaccine confers protection against SARS-CoV-2 in non-human primates, it is a promising candidate for limiting SARS-CoV-2 infection and transmission in humans.

scholarly journals Control of SARS-CoV-2 infection after Spike DNA or Spike DNA+Protein co-immunization in rhesus macaques

2021 ◽  
Author(s):  
Margherita Rosati ◽  
Mahesh Agarwal ◽  
Xintao Hu ◽  
Santhi Devasundaram ◽  
Dimitris Stellas ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Anatomical Site ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Antibody Titers ◽  
Cellular Immune

The speed of development, versatility and efficacy of mRNA-based vaccines have been amply demonstrated in the case of SARS-CoV-2. DNA vaccines represent an important alternative since they induce both humoral and cellular immune responses in animal models and in human trials. We tested the immunogenicity and protective efficacy of DNA-based vaccine regimens expressing different prefusion-stabilized SARS-CoV-2 Spike antigens upon intramuscular injection followed by electroporation in rhesus macaques. Different Spike DNA vaccine regimens induced antibodies that potently neutralized SARS-CoV-2 in vitro and elicited robust T cell responses. The DNA-only vaccine regimens were compared to a regimen that included co-immunization of Spike DNA and protein in the same anatomical site, the latter of which showed significant higher antibody responses. All vaccine regimens led to control of SARS-CoV-2 intranasal/intratracheal challenge and absence of virus dissemination to the lower respiratory tract. Vaccine-induced binding and neutralizing antibody titers and antibody-dependent cellular phagocytosis inversely correlated with transient virus levels in the nasal mucosa. Importantly, the Spike DNA+Protein co-immunization regimen induced the highest binding and neutralizing antibodies and showed the strongest control against SARS-CoV-2 challenge in rhesus macaques.

scholarly journals Plasmacytoid dendritic cells efficiently cross-prime naive T cells in vivo after TLR activation

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3713-3722 ◽  
Author(s):  
Juliette Mouriès ◽  
Gabriel Moron ◽  
Géraldine Schlecht ◽  
Nicolas Escriou ◽  
Gilles Dadaglio ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Antigen Processing ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cross Presentation ◽  
Cell Responses

Abstract Cross-presentation is a crucial mechanism in tumoral and microbial immunity because it allows internalized cell associated or exogenous antigens (Ags) to be delivered into the major histocompatibility complex I pathway. This pathway is important for the development of CD8+ T-cell responses and for the induction of tolerance. In mice, cross-presentation is considered to be a unique property of CD8α+ conventional dendritic cells (DCs). Here we show that splenic plasmacytoid DCs (pDCs) efficiently capture exogenous Ags in vivo but are not able to cross-present these Ags at steady state. However, in vitro and in vivo stimulation by Toll-like receptor-7, or -9 or viruses licenses pDCs to cross-present soluble or particulate Ags by a transporter associated with antigen processing-dependent mechanism. Induction of cross-presentation confers to pDCs the ability to generate efficient effector CD8+ T-cell responses against exogenous Ags in vivo, showing that pDCs may play a crucial role in induction of adaptive immune responses against pathogens that do not infect tissues of hemopoietic origin. This study provides the first evidence for an in vivo role of splenic pDCs in Ag cross-presentation and T-cell cross-priming and suggests that pDCs may constitute an attractive target to boost the efficacy of vaccines based on cytotoxic T lymphocyte induction.

scholarly journals Comparative Immunogenicity of Several Enhanced Influenza Vaccine Options for Older Adults: A Randomized, Controlled Trial

2019 ◽  
Vol 71 (7) ◽  
pp. 1704-1714 ◽  
Author(s):  
Benjamin J Cowling ◽  
Ranawaka A P M Perera ◽  
Sophie A Valkenburg ◽  
Nancy H L Leung ◽  
A Danielle Iuliano ◽  
...  
Keyword(s):  
Older Adults ◽  
Immune Responses ◽  
Standard Dose ◽  
Community Dwelling ◽  
Quadrivalent Vaccine ◽  
High Dose ◽  
Cell Responses ◽  
Trivalent Vaccine ◽  
Community Dwelling Older Adults ◽  
Dose Vaccine

Abstract Background Enhanced influenza vaccines may improve protection for older adults, but comparative immunogenicity data are limited. Our objective was to examine immune responses to enhanced influenza vaccines, compared to standard-dose vaccines, in community-dwelling older adults. Methods Community-dwelling older adults aged 65–82 years in Hong Kong were randomly allocated (October 2017–January 2018) to receive 2017–2018 Northern hemisphere formulations of a standard-dose quadrivalent vaccine, MF59-adjuvanted trivalent vaccine, high-dose trivalent vaccine, or recombinant-hemagglutinin (rHA) quadrivalent vaccine. Sera collected from 200 recipients of each vaccine before and at 30-days postvaccination were assessed for antibodies to egg-propagated vaccine strains by hemagglutination inhibition (HAI) and to cell-propagated A/Hong Kong/4801/2014(H3N2) virus by microneutralization (MN). Influenza-specific CD4+ and CD8+ T cell responses were assessed in 20 participants per group. Results Mean fold rises (MFR) in HAI titers to egg-propagated A(H1N1) and A(H3N2) and the MFR in MN to cell-propagated A(H3N2) were statistically significantly higher in the enhanced vaccine groups, compared to the standard-dose vaccine. The MFR in MN to cell-propagated A(H3N2) was highest among rHA recipients (4.7), followed by high-dose (3.4) and MF59-adjuvanted (2.9) recipients, compared to standard-dose recipients (2.3). Similarly, the ratio of postvaccination MN titers among rHA recipients to cell-propagated A(H3N2) recipients was 2.57-fold higher than the standard-dose vaccine, which was statistically higher than the high-dose (1.33-fold) and MF59-adjuvanted (1.43-fold) recipient ratios. Enhanced vaccines also resulted in the boosting of T-cell responses. Conclusions In this head-to-head comparison, older adults receiving enhanced vaccines showed improved humoral and cell-mediated immune responses, compared to standard-dose vaccine recipients. Clinical Trials Registration NCT03330132.

scholarly journals The role of cDC1s in vivo: CD8 T cell priming through cross-presentation

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 98 ◽  
Author(s):  
Derek Theisen ◽  
Kenneth Murphy
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Processing ◽  
Molecular Mechanisms ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cross Presentation ◽  
Cell Responses

The cDC1 subset of classical dendritic cells is specialized for priming CD8 T cell responses through the process of cross-presentation. The molecular mechanisms of cross-presentation remain incompletely understood because of limited biochemical analysis of rare cDC1 cells, difficulty in their genetic manipulation, and reliance onin vitrosystems based on monocyte- and bone-marrow-derived dendritic cells. This review will discuss cross-presentation from the perspective of studies with monocyte- or bone-marrow-derived dendritic cells while highlighting the need for future work examining cDC1 cells. We then discuss the role of cDC1s as a cellular platform to combine antigen processing for class I and class II MHC presentation to allow the integration of “help” from CD4 T cells during priming of CD8 T cell responses.

scholarly journals Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates

2010 ◽  
Vol 207 (9) ◽  
pp. 2003-2017 ◽  
Author(s):  
Christopher Sundling ◽  
Mattias N.E. Forsell ◽  
Sijy O'Dell ◽  
Yu Feng ◽  
Bimal Chakrabarti ◽  
...  
Keyword(s):  
B Cell ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Neutralization Capacity ◽  
Cell Responses ◽  
Specific Memory ◽  
Pathogenic Factors ◽  
B Cell Responses ◽  
Immunogenic Properties ◽  
Hiv 1

Broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoproteins (Envs) have proven difficult to elicit by immunization. Therefore, to identify effective Env neutralization targets, efforts are underway to define the specificities of bNAbs in chronically infected individuals. For a prophylactic vaccine, it is equally important to define the immunogenic properties of the heavily glycosylated Env in healthy primates devoid of confounding HIV-induced pathogenic factors. We used rhesus macaques to investigate the magnitude and kinetics of B cell responses stimulated by Env trimers in adjuvant. Robust Env-specific memory B cell responses and high titers of circulating antibodies developed after trimer inoculation. Subsequent immunizations resulted in significant expansion of Env-specific IgG-producing plasma cell populations and circulating Abs that displayed increasing avidity and neutralization capacity. The neutralizing activity elicited with the regimen used was, in most aspects, superior to that elicited by a regimen based on monomeric Env immunization in humans. Despite the potency and breadth of the trimer-elicited response, protection against heterologous rectal simian-HIV (SHIV) challenge was modest, illustrating the challenge of eliciting sufficient titers of cross-reactive protective NAbs in mucosal sites. These data provide important information for the design and evaluation of vaccines aimed at stimulating protective HIV-1 immune responses in humans.

scholarly journals Vaccination of Rhesus Macaques with Recombinant Mycobacterium bovis Bacillus Calmette-Guérin Env V3 Elicits Neutralizing Antibody-Mediated Protection against Simian-Human Immunodeficiency Virus with a Homologous but Not a Heterologous V3 Motif

2005 ◽  
Vol 79 (3) ◽  
pp. 1452-1462 ◽  
Author(s):  
Kenji Someya ◽  
Dayaraj Cecilia ◽  
Yasushi Ami ◽  
Tadashi Nakasone ◽  
Kazuhiro Matsuo ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
Mycobacterium Bovis ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
High Dose ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Although the correlates of vaccine-induced protection against human immunodeficiency virus type 1 (HIV-1) are not fully known, it is presumed that neutralizing antibodies (NAb) play a role in controlling virus infection. In this study, we examined immune responses elicited in rhesus macaques following vaccination with recombinant Mycobacterium bovis bacillus Calmette-Guérin expressing an HIV-1 Env V3 antigen (rBCG Env V3). We also determined the effect of vaccination on protection against challenge with either a simian-human immunodeficiency virus (SHIV-MN) or a highly pathogenic SHIV strain (SHIV-89.6PD). Immunization with rBCG Env V3 elicited significant levels of NAb for the 24 weeks tested that were predominantly HIV-1 type specific. Sera from the immunized macaques neutralized primary HIV-1 isolates in vitro, including HIV-1BZ167/X4, HIV-1SF2/X4, HIV-1CI2/X4, and, to a lesser extent, HIV-1MNp/X4, all of which contain a V3 sequence homologous to that of rBCG Env V3. In contrast, neutralization was not observed against HIV-1SF33/X4, which has a heterologous V3 sequence, nor was it found against primary HIV-1 R5 isolates from either clade A or B. Furthermore, the viral load in the vaccinated macaques was significantly reduced following low-dose challenge with SHIV-MN, and early plasma viremia was markedly decreased after high-dose SHIV-MN challenge. In contrast, replication of pathogenic SHIV-89.6PD was not affected by vaccination in any of the macaques. Thus, we have shown that immunization with an rBCG Env V3 vaccine elicits a strong, type-specific V3 NAb response in rhesus macaques. While this response was not sufficient to provide protection against a pathogenic SHIV challenge, it was able to significantly reduce the viral load in macaques following challenge with a nonpathogenic SHIV. These observations suggest that rBCG vectors have the potential to deliver an appropriate virus immunogen for desirable immune elicitations.

scholarly journals Protective activity of mRNA vaccines against ancestral and variant SARS-CoV-2 strains

2021 ◽  
Author(s):  
Baoling Ying ◽  
Bradley Whitener ◽  
Laura A. VanBlargan ◽  
Ahmed O. Hassan ◽  
Swathi Shrihari ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Low Dose ◽  
High Dose ◽  
Lung Pathology ◽  
Protective Activity ◽  
Breakthrough Infection ◽  
Cell Responses ◽  
Waning Immunity ◽  
Lower Magnitude ◽  
Delta Virus

SUMMARYAlthough mRNA vaccines prevent COVID-19, variants jeopardize their efficacy as immunity wanes. Here, we assessed the immunogenicity and protective activity of historical (mRNA-1273, designed for Wuhan-1 spike) or modified (mRNA-1273.351, designed for B.1.351 spike) preclinical Moderna mRNA vaccines in 129S2 and K18-hACE2 mice. Immunization with high or low dose formulations of mRNA vaccines induced neutralizing antibodies in serum against ancestral SARS-CoV-2 and several variants, although levels were lower particularly against the B.1.617.2 (Delta) virus. Protection against weight loss and lung pathology was observed with all high-dose vaccines against all viruses. Nonetheless, low-dose formulations of the vaccines, which produced lower magnitude antibody and T cell responses, and serve as a possible model for waning immunity, showed breakthrough lung infection and pneumonia with B.1.617.2. Thus, as levels of immunity induced by mRNA vaccines decline, breakthrough infection and disease likely will occur with some SARS-CoV-2 variants, suggesting a need for additional booster regimens.

scholarly journals SARS-CoV-2 protein subunit vaccination elicits potent neutralizing antibody responses

2020 ◽  
Author(s):  
Marco Mandolesi ◽  
Daniel J Sheward ◽  
Leo Hanke ◽  
Junjie Ma ◽  
Pradeepa Pushparaj ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Host Cells ◽  
High Dose ◽  
Protein Subunit ◽  
High Dose Regimen ◽  
Antibody Titers ◽  
Protein Immunization

The outbreak and spread of SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2), the cause of coronavirus disease 2019 (COVID-19), is a current global health emergency and a prophylactic vaccine is needed urgently. The spike glycoprotein of SARS-CoV-2 mediates entry into host cells, and thus is a target for neutralizing antibodies and vaccine design. Here we show that adjuvanted protein immunization with SARS-CoV-2 spike trimers, stabilized in prefusion conformation, results in potent antibody responses in mice and rhesus macaques with neutralizing antibody titers orders of magnitude greater than those typically measured in serum from SARS-CoV-2 seropositive humans. Neutralizing antibody responses were observed after a single dose, with exceptionally high titers achieved after boosting. Furthermore, neutralizing antibody titers elicited by a dose-sparing regimen in mice were similar to those obtained from a high dose regimen. Taken together, these data strongly support the development of adjuvanted SARS-CoV-2 prefusion-stabilized spike protein subunit vaccines.

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