scholarly journals Glycosylation of HIV Env Impacts IgG Subtype Responses to Vaccination

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 153 ◽  
Author(s):  
Rebecca Heß ◽  
Michael Storcksdieck genannt Bonsmann ◽  
Dennis Lapuente ◽  
Andre Maaske ◽  
Carsten Kirschning ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Surface Protein ◽  
T Cell Response ◽  
Specific Antibodies ◽  
Lectin Receptor ◽  
Hiv Antigen ◽  
Syncytial Virus ◽  
Antibody Class ◽  
Antigen Presenting ◽  
The Impact

The envelope protein (Env) is the only surface protein of the human immunodeficiency virus (HIV) and as such the exclusive target for protective antibody responses. Experimental evidences from mouse models suggest a modulating property of Env to steer antibody class switching towards the less effective antibody subclass IgG1 accompanied with strong TH2 helper responses. By simple physical linkage we were able to imprint this bias, exemplified by a low IgG2a/IgG1 ratio of antigen-specific antibodies, onto an unrelated antigen, namely the HIV capsid protein p24. Here, our results indicate the glycan moiety of Env as the responsible immune modulating activity. Firstly, in Card9−/− mice lacking specific C-Type lectin responsiveness, DNA immunization significantly increased the IgG2a/IgG1 ratio for the Env-specific antibodies while the antibody response against the F-protein of the respiratory syncytial virus (RSV) serving as control antigen remained unchanged. Secondly, sequential shortening of the Env encoding sequence revealed the C2V3 domain as responsible for the strong IgG1 responses and TH2 cytokine production. Removing all potential N-glycosylation sites from the C2V3 domain by site-specific mutagenesis reversed the vaccine-induced immune response towards a Th1-dominated T-cell response and a balanced IgG2a/IgG1 ratio. Accordingly, the stretch of oligomannose glycans in the C2V3 domain of Env might mediate a specific uptake and/or signaling modus in antigen presenting cells by involving interaction with an as yet unknown C-type lectin receptor. Our results contribute to a deeper understanding of the impact of Env glycosylation on HIV antigen-specific immune responses, which will further support HIV vaccine development.

scholarly journals Induction of Functional Specific Antibodies, IgG-Secreting Plasmablasts and Memory B Cells Following BCG Vaccination

2022 ◽  
Vol 12 ◽  
Author(s):  
Julia Bitencourt ◽  
Marco Polo Peralta-Álvarez ◽  
Morven Wilkie ◽  
Ashley Jacobs ◽  
Daniel Wright ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Response ◽  
Vaccine Development ◽  
T Cell Response ◽  
Bcg Vaccine ◽  
Human Populations ◽  
Vaccine Candidates ◽  
Specific Antibodies ◽  
Bcg Vaccination ◽  
Macrophage Phagocytosis

Tuberculosis (TB) is a major global health problem and the only currently-licensed vaccine, BCG, is inadequate. Many TB vaccine candidates are designed to be given as a boost to BCG; an understanding of the BCG-induced immune response is therefore critical, and the opportunity to relate this to circumstances where BCG does confer protection may direct the design of more efficacious vaccines. While the T cell response to BCG vaccination has been well-characterized, there is a paucity of literature on the humoral response. We demonstrate BCG vaccine-mediated induction of specific antibodies in different human populations and macaque species which represent important preclinical models for TB vaccine development. We observe a strong correlation between antibody titers in serum versus plasma with modestly higher titers in serum. We also report for the first time the rapid and transient induction of antibody-secreting plasmablasts following BCG vaccination, together with a robust and durable memory B cell response in humans. Finally, we demonstrate a functional role for BCG vaccine-induced specific antibodies in opsonizing mycobacteria and enhancing macrophage phagocytosis in vitro, which may contribute to the BCG vaccine-mediated control of mycobacterial growth observed. Taken together, our findings indicate that the humoral immune response in the context of BCG vaccination merits further attention to determine whether TB vaccine candidates could benefit from the induction of humoral as well as cellular immunity.

scholarly journals Conjugation of Mannans to Enhance the Potency of Liposome Nanoparticles for the Delivery of RNA Vaccines

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 240
Author(s):  
Roshan Goswami ◽  
Derek T. O’Hagan ◽  
Roberto Adamo ◽  
Barbara C. Baudner
Keyword(s):  
Respiratory Syncytial Virus ◽  
Enzymatic Degradation ◽  
Booster Dose ◽  
Lipid Nanoparticles ◽  
Delivery Vehicle ◽  
Intradermal Delivery ◽  
Liposomal Delivery ◽  
Syncytial Virus ◽  
Antigen Presenting ◽  
The Impact

Recent approval of mRNA vaccines to combat COVID-19 have highlighted the potential of this platform. Lipid nanoparticles (LNP) is the delivery vehicle of choice for mRNA as they prevent its enzymatic degradation by encapsulation. We have recently shown that surface exposition of mannose, incorporated in LNPs as stable cholesterol-amine conjugate, enhances the potency of self-amplifying RNA (SAM) replicon vaccines through augmented uptake by antigen presenting cells (APCs). Here, we generated a new set of LNPs whose surface was modified with mannans of different length (from mono to tetrasaccharide), in order to study the effect on antibody response of model SAM replicon encoding for the respiratory syncytial virus fusion F protein. Furthermore, the impact of the mannosylated liposomal delivery through intradermal as well as intramuscular routes was investigated. The vaccine priming response showed to improve consistently with increase in the chain length of mannoses; however, the booster dose response plateaued above the length of disaccharide. An increase in levels of IgG1 and IgG2a was observed for mannnosylated lipid nanoparticles (MLNPs) as compared to LNPs. This work confirms the potential of mannosylated SAM LNPs for both intramuscular and intradermal delivery, and highlights a disaccharide length as sufficient to ensure improved immunogenicity compared to the un-glycosylated delivery system.

scholarly journals Structure-Based Vaccine Antigen Design

2019 ◽  
Vol 70 (1) ◽  
pp. 91-104 ◽  
Author(s):  
Barney S. Graham ◽  
Morgan S.A. Gilman ◽  
Jason S. McLellan
Keyword(s):  
Vaccine Development ◽  
Structural Information ◽  
Protein Structures ◽  
Surface Protein ◽  
Surface Proteins ◽  
Vaccine Antigen ◽  
Viral Fusion ◽  
Emerging Pathogens ◽  
Syncytial Virus ◽  
Viral Surface

Enabled by new approaches for rapid identification and selection of human monoclonal antibodies, atomic-level structural information for viral surface proteins, and capacity for precision engineering of protein immunogens and self-assembling nanoparticles, a new era of antigen design and display options has evolved. While HIV-1 vaccine development has been a driving force behind these technologies and concepts, clinical proof-of-concept for structure-based vaccine design may first be achieved for respiratory syncytial virus (RSV), where conformation-dependent access to neutralization-sensitive epitopes on the fusion glycoprotein determines the capacity to induce potent neutralizing activity. Success with RSV has motivated structure-based stabilization of other class I viral fusion proteins for use as immunogens and demonstrated the importance of structural information for developing vaccines against other viral pathogens, particularly difficult targets that have resisted prior vaccine development efforts. Solving viral surface protein structures also supports rapid vaccine antigen design and application of platform manufacturing approaches for emerging pathogens.

scholarly journals Immunization with cDNA Expressed by Amastigotes of Trypanosoma cruzi Elicits Protective Immune Response against Experimental Infection

2003 ◽  
Vol 71 (5) ◽  
pp. 2744-2757 ◽  
Author(s):  
Silvia B. Boscardin ◽  
Sheila S. Kinoshita ◽  
Adriana E. Fujimura ◽  
Mauricio M. Rodrigues
Keyword(s):  
Trypanosoma Cruzi ◽  
Vaccine Development ◽  
Surface Protein ◽  
Dna Vaccination ◽  
Eukaryotic Expression ◽  
Host Cells ◽  
Specific Antibodies ◽  
C Terminus ◽  
Lethal Infection ◽  
Genes Encoding

ABSTRACT Immunization of mice with plasmids containing Trypanosoma cruzi genes induced specific antibodies, CD4+ Th1 and CD8+ Tc1 cells, and protective immunity against infection. In most cases, plasmids used for DNA vaccination contained genes encoding antigens expressed by trypomastigotes, the nonreplicative forms of the parasite. In this study, we explored the possibility of using genes expressed by amastigotes, the form of the parasite which replicates inside host cells, for experimental DNA vaccination. For that purpose, we selected a gene related to the amastigote surface protein 2 (ASP-2), an antigen recognized by antibodies and T cells from infected mice and humans, for our study. Using primers specific for the asp-2 gene, four distinct groups of genes were amplified from cDNA from amastigotes of the Y strain of T. cruzi. At the nucleotide level, they shared 82.3 to 89.9% identity with the previously described asp-2 gene. A gene named clone 9 presented the highest degree of identity with the asp-2 gene and was selected for immunological studies. Polyclonal antisera raised against the C terminus of the recombinant protein expressed by the clone 9 gene reacted with an antigen of approximately 83 kDa expressed in amastigotes of T. cruzi. Immunization of BALB/c mice with eukaryotic expression plasmids containing the clone 9 gene elicited specific antibodies and CD4+ T-cell-dependent gamma interferon secretion. Upon challenge with trypomastigotes, mice immunized with plasmids harboring the clone 9 gene displayed reduced parasitemia and survived lethal infection. We concluded that amastigote cDNA is an interesting source of antigens that can be used for immunological studies, as well as for vaccine development.

scholarly journals Plasmodium falciparum 19-Kilodalton Merozoite Surface Protein 1 (MSP1)-Specific Antibodies That Interfere with Parasite GrowthIn VitroCan Inhibit MSP1 Processing, Merozoite Invasion, and Intracellular Parasite Development

2011 ◽  
Vol 80 (3) ◽  
pp. 1280-1287 ◽  
Author(s):  
David K. Moss ◽  
Edmond J. Remarque ◽  
Bart W. Faber ◽  
David R. Cavanagh ◽  
David E. Arnot ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Significant Inhibition ◽  
Parasite Growth ◽  
Proteolytic Processing ◽  
Parasite Development ◽  
Intracellular Parasite ◽  
Specific Antibodies ◽  
Merozoite Surface Protein 1

Merozoite surface protein 1 (MSP1) is a target for malaria vaccine development. Antibodies to the 19-kDa carboxy-terminal region referred to as MSP119inhibit erythrocyte invasion and parasite growth, with some MSP1-specific antibodies shown to inhibit the proteolytic processing of MSP1 that occurs at invasion. We investigated a series of antibodies purified from rabbits immunized with MSP119and AMA1 recombinant proteins for their ability to inhibit parasite growth, initially looking at MSP1 processing. Although significant inhibition of processing was mediated by several of the antibody samples, there was no clear relationship with overall growth inhibition by the same antibodies. However, no antibody samples inhibited processing but not invasion, suggesting that inhibition of MSP1 processing contributes to but is not the only mechanism of antibody-mediated inhibition of invasion and growth. Examining other mechanisms by which MSP1-specific antibodies inhibit parasite growth, we show that MSP119-specific antibodies are taken up into invaded erythrocytes, where they persist for significant periods and result in delayed intracellular parasite development. This delay may result from antibody interference with coalescence of MSP119-containing vesicles with the food vacuole. Antibodies raised against a modified recombinant MSP119sequence were more efficient at delaying intracellular growth than those to the wild-type protein. We propose that antibodies specific for MSP119can mediate inhibition of parasite growth by at least three mechanisms: inhibition of MSP1 processing, direct inhibition of invasion, and inhibition of parasite development following invasion. The balance between mechanisms may be modulated by modifying the immunogen used to induce the antibodies.

scholarly journals Immunization with C5a Peptidase or Peptidase-Type III Polysaccharide Conjugate Vaccines Enhances Clearance of Group B Streptococci from Lungs of Infected Mice

2002 ◽  
Vol 70 (11) ◽  
pp. 6409-6415 ◽  
Author(s):  
Qi Cheng ◽  
Steven Debol ◽  
Hong Lam ◽  
Ron Eby ◽  
Lorri Edwards ◽  
...  
Keyword(s):  
Tetanus Toxoid ◽  
Capsular Polysaccharide ◽  
Vaccine Development ◽  
Surface Protein ◽  
Histological Evaluation ◽  
Group B Streptococci ◽  
Type Iii ◽  
Rapid Clearance ◽  
Group B ◽  
The Impact

ABSTRACT Group B streptococci (GBS) are among the most common causes of life-threatening neonatal infections. Vaccine development since the late 1970s has focused on the capsular polysaccharides, but a safe, effective product is still not available. Our quest for a vaccine turned to the streptococcal C5a peptidase (SCPB). This surface protein is antigenically conserved across most if not all serotypes. A murine model was used to assess the impact of SCPB on clearance of GBS from the lungs of intranasally infected animals. Mutational inactivation of SCPB resulted in more-rapid clearance of streptococci from the lung. Immunization with recombinant SCPB alone or SCPB conjugated to type III capsular polysaccharide produced serotype-independent protection, which was evidenced by more-rapid clearance of the serotype VI strain from the lungs. Immunization of mice with tetanus toxoid-type III polysaccharide conjugate did not produce protection, confirming that protection induced by SCPB conjugates was independent of type III polysaccharide antigen. Histological evaluation of lungs from infected mice revealed that pathology in animals immunized with SCPB or SCPB conjugates was significantly less than that in animals immunized with a tetanus toxoid-polysaccharide conjugate. These experiments suggest that inclusion of C5a peptidase in a vaccine will both add another level to and broaden the spectrum of the protection of a polysaccharide vaccine.

scholarly journals Impaired Dendritic Cell Homing in COVID-19

2021 ◽  
Vol 8 ◽  
Author(s):  
Lukas Borcherding ◽  
Alime Sema Teksen ◽  
Bianca Grosser ◽  
Tina Schaller ◽  
Klaus Hirschbühl ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lymph Nodes ◽  
Diffuse Alveolar Damage ◽  
Antigen Presenting Cells ◽  
High Viral Load ◽  
T Cell Response ◽  
Myeloid Dendritic Cells ◽  
Peripheral Cell ◽  
Antigen Presenting ◽  
The Impact

The high mortality of COVID-19 is mostly attributed to acute respiratory distress syndrome (ARDS), whose histopathological correlate is diffuse alveolar damage (DAD). Furthermore, severe COVID-19 is often accompanied by a cytokine storm and a disrupted response of the adaptive immune system. Studies aiming to depict this dysregulation have mostly investigated the peripheral cell count as well as the functionality of immune cells. We investigated the impact of SARS-CoV-2 on antigen-presenting cells using multiplexed immunofluorescence. Similar to MERS-CoV and SARS-CoV, SARS-CoV-2 appears to be impairing the maturation of dendritic cells (DCs). DC maturation involves a switch in surface antigen expression, which enables the cells' homing to lymph nodes and the subsequent activation of T-cells. As quantitative descriptions of the local inflammatory infiltrate are still scarce, we compared the cell population of professional antigen-presenting cells (APC) in the lungs of COVID-19 autopsy cases in different stages of DAD. We found an increased count of myeloid dendritic cells (mDCs) in later stages. Interestingly, mDCs also showed no significant upregulation of maturation markers in DAD-specimens with high viral load. Accumulation of immature mDCs, which are unable to home to lymph nodes, ultimately results in an inadequate T-cell response.

Prospects for new viral vaccines

1980 ◽  
Vol 290 (1040) ◽  
pp. 395-407 ◽  
Keyword(s):  
Hepatitis B ◽  
Vaccine Development ◽  
Cost Benefit Analysis ◽  
Cost Benefit ◽  
Growth Potential ◽  
Viral Genetics ◽  
E Coli ◽  
Syncytial Virus ◽  
Herpes Group ◽  
The Impact

Animal virology has made outstanding contributions to preventive medicine by the development of vaccines for the control of infectious disease in man and animals. Cost-benefit analysis indicates substantial savings in health care costs from the control of diseases such as smallpox, poliomyelitis, yellow fever and measles. Areas for further development include vaccines for influenza (living, attenuated virus), the herpes group (varicella:cytomegalovirus), respiratory syncytial virus, rotavirus and hepatitis A, B, and non A/non B. The general options for vaccine formulation are discussed with particular emphasis on approaches with the use of viral genetics to ‘tailor make’ vaccine viruses with defined growth potential in laboratory systems, low pathogenicity, and defined antigens. Current progress with the development of an inactivated hepatitis B vaccine is reviewed as a case study in vaccine development. The impact of recent experiments in cloning hepatitis B virus DNA in E. coli on the production of a purified viral polypeptide vaccine is assessed.

scholarly journals Considerations for a Respiratory Syncytial Virus Vaccine Targeting an Elderly Population

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 624
Author(s):  
Laura M. Stephens ◽  
Steven M. Varga
Keyword(s):  
Respiratory Syncytial Virus ◽  
Disease Burden ◽  
Elderly Population ◽  
Vaccine Development ◽  
The Elderly ◽  
The United States ◽  
Susceptible Population ◽  
Age Related ◽  
Syncytial Virus ◽  
Tract Infections

Respiratory syncytial virus (RSV) is most commonly associated with acute lower respiratory tract infections in infants and children. However, RSV also causes a high disease burden in the elderly that is often under recognized. Adults >65 years of age account for an estimated 80,000 RSV-associated hospitalizations and 14,000 deaths in the United States annually. RSV infection in aged individuals can result in more severe disease symptoms including pneumonia and bronchiolitis. Given the large disease burden caused by RSV in the aged, this population remains an important target for vaccine development. Aging results in lowered immune responsiveness characterized by impairments in both innate and adaptive immunity. This immune senescence poses a challenge when developing a vaccine targeting elderly individuals. An RSV vaccine tailored towards an elderly population will need to maximize the immune response elicited in order to overcome age-related defects in the immune system. In this article, we review the hurdles that must be overcome to successfully develop an RSV vaccine for use in the elderly, and discuss the vaccine candidates currently being tested in this highly susceptible population.

scholarly journals 1719. Respiratory Syncytial Virus-Associated Hospitalization Rates among US Infants: A Systematic Review and Meta-Analysis

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S843-S843
Author(s):  
John M McLaughlin ◽  
Farid L Khan ◽  
Heinz-Josef Schmitt ◽  
Yasmeen Agosti ◽  
Luis Jodar ◽  
...  
Keyword(s):  
Public Health ◽  
Respiratory Syncytial Virus ◽  
Active Surveillance ◽  
Meta Analysis ◽  
The United States ◽  
Administrative Claims ◽  
Prevention Strategies ◽  
Hospitalization Rates ◽  
Syncytial Virus ◽  
The Impact

Abstract Background Understanding the true magnitude of infant respiratory syncytial virus (RSV) burden is critical for determining the potential public-health benefit of RSV prevention strategies. Although global reviews of infant RSV burden exist, none have summarized data from the United States or evaluated how RSV burden estimates are influenced by variations in study design. Methods We performed a systematic literature review and meta-analysis of studies describing RSV-associated hospitalization rates among US infants. We also examined the impact of key study characteristics on these estimates. Results After review of 3058 articles through January 2020, we identified 25 studies with 31 unique estimates of RSV-associated hospitalization rates. Among US infants < 1 year of age, annual rates ranged from 8.4 to 40.8 per 1000 with a pooled rate= 19.4 (95%CI= 17.9–20.9). Study type was associated with RSV hospitalization rates (P =.003), with active surveillance studies having pooled rates per 1000 (11.1; 95%CI: 9.8–12.3) that were half that of studies based on administrative claims (21.4; 95%CI: 19.5–23.3) or modeling approaches (23.2; 95%CI: 20.2–26.2). Conclusion Applying the pooled rates identified in our review to the 2020 US birth cohort suggests that 73,680 to 86,020 RSV-associated infant hospitalizations occur each year. To date, public-health officials have used conservative estimates from active surveillance as the basis for defining US infant RSV burden. The full range of RSV-associated hospitalization rates identified in our review better characterizes the true RSV burden in infants and can better inform future evaluations of RSV prevention strategies. Disclosures John M. McLaughlin, PhD, Pfizer (Employee, Shareholder) Farid L. Khan, MPH, Pfizer (Employee, Shareholder) Heinz-Josef Schmitt, MD, Pfizer (Employee, Shareholder) Yasmeen Agosti, MD, Pfizer (Employee, Shareholder) Luis Jodar, PhD, Pfizer (Employee, Shareholder) Eric Simões, MD, Pfizer (Consultant, Research Grant or Support) David L. Swerdlow, MD, Pfizer (Employee, Shareholder)

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