scholarly journals Potential Mechanisms of Age Related Severity of COVID-19 Infection: Implications for Development of Vaccines, Convalescent Serum, and Antibody Therapies

2020 ◽  
Author(s):  
Martin Zand ◽  
Jiong Wang
Keyword(s):  
Viral Entry ◽  
Vaccine Development ◽  
Surface Proteins ◽  
Igg Antibodies ◽  
Dengue Virus Infection ◽  
Younger Adults ◽  
High Affinity ◽  
Age Related ◽  
Coronavirus Infection ◽  
Viral Surface

There is an urgent need for vaccines to induce immunity to the 2019 coronavirus strain (COVID-19; CoV-SARS-2). Vaccine development may not be straightforward, in part due to the the phenomenon of antibody-dependent enhancement (ADE). The immune response to coronavirus infection or vaccination generates a mixture of IgG antibodies against viral surface proteins. Many of these antibodies block viral infection. However, in some cases IgG:virus complexes can facilitate viral entry and infection of cells by ADE, increasing the the risk and severity of infection. This phenomenon occurs in SARS, MERS, HIV, Zika and dengue virus infection and vaccination; it has been a serious barrier to vaccine development for these infections. Lack of high-affinity anti-COVID-19 IgG antibodies in children and younger adults may explain, in part, the decreased severity of infection in these groups. Here, we discuss the evidence for ADE in the context of COVID-19 infection, and how it may affect development of a vaccine and convalescent serum therapies. Here we discuss ADE in the context of COVID-19 infection, and how this may affect vaccine development, convalescent serum, and targeted monoclonal antibody therapies. We caution that this work is a hypothesis, and should be taken as such.

scholarly journals The potential for antibody-dependent enhancement of SARS-CoV-2 infection: Translational implications for vaccine development

2020 ◽  
pp. 1-4 ◽  
Author(s):  
Jiong Wang ◽  
Martin S. Zand
Keyword(s):  
Monoclonal Antibody ◽  
Virus Infection ◽  
Dengue Virus ◽  
Vaccine Development ◽  
Surface Proteins ◽  
Dengue Virus Infection ◽  
Antibody Dependent Enhancement ◽  
High Affinity ◽  
Viral Surface

Abstract There is an urgent need for vaccines to the 2019 coronavirus (COVID19; SARS-CoV-2). Vaccine development may not be straightforward, due to antibody-dependent enhancement (ADE). Antibodies against viral surface proteins can, in some cases, increase infection severity by ADE. This phenomenon occurs in SARS-CoV-1, MERS, HIV, Zika, and dengue virus infection and vaccination. Lack of high-affinity anti-SARS-CoV-2 IgG in children may explain the decreased severity of infection in these groups. Here, we discuss the evidence for ADE in the context of SARS-CoV-2 infection and how to address this potential translational barrier to vaccine development, convalescent plasma, and targeted monoclonal antibody therapies.

scholarly journals Application of Viral Vectors for Vaccine Development with a Special Emphasis on COVID-19

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1324
Author(s):  
Kenneth Lundstrom
Keyword(s):  
Neutralizing Antibodies ◽  
Viral Vectors ◽  
Vaccine Development ◽  
Viral Vector ◽  
Recombinant Protein Expression ◽  
Surface Proteins ◽  
Viral Particles ◽  
Preclinical Animal Models ◽  
Viral Surface ◽  
Lethal Doses

Viral vectors can generate high levels of recombinant protein expression providing the basis for modern vaccine development. A large number of different viral vector expression systems have been utilized for targeting viral surface proteins and tumor-associated antigens. Immunization studies in preclinical animal models have evaluated the elicited humoral and cellular responses and the possible protection against challenges with lethal doses of infectious pathogens or tumor cells. Several vaccine candidates for both infectious diseases and various cancers have been subjected to a number of clinical trials. Human immunization trials have confirmed safe application of viral vectors, generation of neutralizing antibodies and protection against challenges with lethal doses. A special emphasis is placed on COVID-19 vaccines based on viral vectors. Likewise, the flexibility and advantages of applying viral particles, RNA replicons and DNA replicon vectors of self-replicating RNA viruses for vaccine development are presented.

A proof of concept for structure-based vaccine design targeting RSV in humans

Science ◽  
2019 ◽  
Vol 365 (6452) ◽  
pp. 505-509 ◽  
Author(s):  
Michelle C. Crank ◽  
Tracy J. Ruckwardt ◽  
Man Chen ◽  
Kaitlyn M. Morabito ◽  
Emily Phung ◽  
...  
Keyword(s):  
Subunit Vaccine ◽  
Vaccine Development ◽  
Vaccine Candidate ◽  
Level Structure ◽  
Vaccine Design ◽  
Atomic Level ◽  
Surface Proteins ◽  
Proof Of Concept ◽  
Syncytial Virus ◽  
Viral Surface

Technologies that define the atomic-level structure of neutralization-sensitive epitopes on viral surface proteins are transforming vaccinology and guiding new vaccine development approaches. Previously, iterative rounds of protein engineering were performed to preserve the prefusion conformation of the respiratory syncytial virus (RSV) fusion (F) glycoprotein, resulting in a stabilized subunit vaccine candidate (DS-Cav1), which showed promising results in mice and macaques. Here, phase I human immunogenicity data reveal a more than 10-fold boost in neutralizing activity in serum from antibodies targeting prefusion-specific surfaces of RSV F. These findings represent a clinical proof of concept for structure-based vaccine design, suggest that development of a successful RSV vaccine will be feasible, and portend an era of precision vaccinology.

scholarly journals A widespread viral entry mechanism: The C-end Rule motif–neuropilin receptor interaction

2021 ◽  
Vol 118 (49) ◽  
pp. e2112457118
Author(s):  
Giuseppe Balistreri ◽  
Yohei Yamauchi ◽  
Tambet Teesalu
Keyword(s):  
Cell Surface ◽  
Viral Entry ◽  
Surface Proteins ◽  
Receptor Interaction ◽  
Growth Factor Signaling ◽  
Surface Receptors ◽  
Viral Particles ◽  
Carboxy Terminal ◽  
Viral Surface ◽  
Entry Mechanism

Many phylogenetically distant animal viruses, including the new coronavirus severe acute respiratory syndrome coronavirus 2, have surface proteins with polybasic sites that are cleaved by host furin and furin-like proteases. Other than priming certain viral surface proteins for fusion, cleavage generates a carboxy-terminal RXXR sequence. This C-end Rule (CendR) motif is known to bind to neuropilin (NRP) receptors on the cell surface. NRPs are ubiquitously expressed, pleiotropic cell surface receptors with important roles in growth factor signaling, vascular biology, and neurobiology, as well as immune homeostasis and activation. The CendR–NRP receptor interaction promotes endocytic internalization and tissue spreading of different cargo, including viral particles. We propose that the interaction between viral surface proteins and NRPs plays an underappreciated and prevalent role in the transmission and pathogenesis of diverse viruses and represents a promising broad-spectrum antiviral target.

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 Map of SARS-CoV-2 spike epitopes not shielded by glycans

2020 ◽  
Author(s):  
Mateusz Sikora ◽  
Sören von Bülow ◽  
Florian E. C. Blanc ◽  
Michael Gecht ◽  
Roberto Covino ◽  
...  
Keyword(s):  
Viral Entry ◽  
Vaccine Development ◽  
Protein S ◽  
Antibody Binding ◽  
Structural Rigidity ◽  
Steric Accessibility ◽  
Dynamics Simulations ◽  
Viral Surface ◽  
Atom System ◽  
Immunological Target

The severity of the COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, calls for the urgent development of a vaccine. The primary immunological target is the SARS-CoV-2 spike (S) protein. S is exposed on the viral surface to mediate viral entry into the host cell. To identify possible antibody binding sites not shielded by glycans, we performed multi-microsecond molecular dynamics simulations of a 4.1 million atom system containing a patch of viral membrane with four full-length, fully glycosylated and palmitoylated S proteins. By mapping steric accessibility, structural rigidity, sequence conservation and generic antibody binding signatures, we recover known epitopes on S and reveal promising epitope candidates for vaccine development. We find that the extensive and inherently flexible glycan coat shields a surface area larger than expected from static structures, highlighting the importance of structural dynamics in epitope mapping.

Age-Related Differences in Motivational Integration and Cognitive Control

2019 ◽  
Author(s):  
Debbie Marianne Yee ◽  
Sarah L Adams ◽  
Asad Beck ◽  
Todd Samuel Braver
Keyword(s):  
Older Adults ◽  
Decision Making ◽  
Cognitive Control ◽  
Task Performance ◽  
Cognitive Task ◽  
Monetary Reward ◽  
Potential Candidate ◽  
Younger Adults ◽  
Age Related ◽  
Cognitive Task Performance

Motivational incentives play an influential role in value-based decision-making and cognitive control. A compelling hypothesis in the literature suggests that the brain integrates the motivational value of diverse incentives (e.g., motivational integration) into a common currency value signal that influences decision-making and behavior. To investigate whether motivational integration processes change during healthy aging, we tested older (N=44) and younger (N=54) adults in an innovative incentive integration task paradigm that establishes dissociable and additive effects of liquid (e.g., juice, neutral, saltwater) and monetary incentives on cognitive task performance. The results reveal that motivational incentives improve cognitive task performance in both older and younger adults, providing novel evidence demonstrating that age-related cognitive control deficits can be ameliorated with sufficient incentive motivation. Additional analyses revealed clear age-related differences in motivational integration. Younger adult task performance was modulated by both monetary and liquid incentives, whereas monetary reward effects were more gradual in older adults and more strongly impacted by trial-by-trial performance feedback. A surprising discovery was that older adults shifted attention from liquid valence toward monetary reward throughout task performance, but younger adults shifted attention from monetary reward toward integrating both monetary reward and liquid valence by the end of the task, suggesting differential strategic utilization of incentives. Together these data suggest that older adults may have impairments in incentive integration, and employ different motivational strategies to improve cognitive task performance. The findings suggest potential candidate neural mechanisms that may serve as the locus of age-related change, providing targets for future cognitive neuroscience investigations.

Sources of cognitive conflict and their relevance to Theory of Mind proficiency in healthy ageing. A preregistered study.

2018 ◽  
Author(s):  
Foyzul Rahman ◽  
Sabrina Javed ◽  
Ian Apperly ◽  
Peter Hansen ◽  
Carol Holland ◽  
...  
Keyword(s):  
Theory Of Mind ◽  
Executive Control ◽  
Spatial Working Memory ◽  
Age Groups ◽  
Response Speed ◽  
Cognitive Conflict ◽  
Mental States ◽  
Younger Adults ◽  
Age Related ◽  
Outcome Knowledge

Age-related decline in Theory of Mind (ToM) may be due to waning executive control, which is necessary for resolving conflict when reasoning about others’ mental states. We assessed how older (OA; n=50) versus younger adults (YA; n=50) were affected by three theoretically relevant sources of conflict within ToM: competing Self-Other perspectives; competing cued locations and outcome knowledge. We examined which best accounted for age-related difficulty with ToM. Our data show unexpected similarity between age groups when representing a belief incongruent with one’s own. Individual differences in attention and motor response speed best explained the degree of conflict experienced through conflicting Self-Other perspectives. However, OAs were disproportionately affected by managing conflict between cued locations. Age and spatial working memory were most relevant for predicting the magnitude of conflict elicited by conflicting cued locations. We suggest that previous studies may have underestimated OA’s ToM proficiency by including unnecessary conflict in ToM tasks.

Internet Navigation Skills for Financial Management: Associations with Age, Neurocognitive Performance, and Functional Capacity

2020 ◽  
Author(s):  
Samina Rahman ◽  
Victoria Kordovski ◽  
Savanna Tierney ◽  
Steven Paul Woods
Keyword(s):  
Older Adults ◽  
Functional Capacity ◽  
Financial Management ◽  
Internet Banking ◽  
Online Banking ◽  
Neurocognitive Performance ◽  
Younger Adults ◽  
Neurocognitive Functions ◽  
Age Related ◽  
Use Factors

Objective: Online banking is becoming increasingly common among older adults, whomay experience difficulties effectively navigating this instrumental technology. Thisstudy examined age effects on a performance-based Internet banking task and itsassociation with neurocognitive ability and functional capacity in older and youngeradults. Method: Thirty-five older adults and 50 younger adults completed anexperimenter-controlled online banking measure in which they independentlyperformed a series of naturalistic financial tasks (e.g., account transfers, bill paying).Participants also completed a standardized battery of neuropsychological tests andmeasures of functional capacity. Results: Older adults were markedly slower and lessaccurate in completing the Internet-based banking task, which was not confounded byother demographic, mood, or computer use factors. Higher scores on measures ofneurocognition and financial functional capacity were both strongly associated withhigher Internet-based banking task accuracy scores and quicker completion times inthe older, but not the younger adults. Conclusions: Findings suggest that older adultsexperience difficultly quickly and accurately navigating online banking platforms, whichmay be partly related to age-related declines in neurocognitive functions and basicfinancial capacity. Future studies might examine whether neurocognitive approaches toremediation and compensation can be used to improve online banking capacity inolder adults.

SARS-CoV-2 Biology Insights, Part IV.Antibody-Dependent Enhancement (ADE) and the tricky “Herd Immunity”: narrative review (Preprint)

2020 ◽  
Author(s):  
Laura Lafon-Hughes
Keyword(s):  
Viral Infection ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Whooping Cough ◽  
Common Knowledge ◽  
Herd Immunity ◽  
Life Quality ◽  
Host Cells ◽  
System P

BACKGROUND It is common knowledge that vaccination has improved our life quality and expectancy since it succeeded in achieving almost eradication of several diseases including chickenpox (varicella), diphtheria, hepatitis A and B, measles, meningococcal, mumps, pneumococcal, polio, rotavirus, rubella, tetanus and whooping cough (pertussis) Vaccination success is based on vaccine induction of neutralizing antibodies that help fight the infection (e.g. by a virus), preventing the disease. Conversely, Antibody-dependent enhancement (ADE) of a viral infection occurs when anti-viral antibodies facilitate viral entry into host cells and enhance viral infection in these cells. ADE has been previously studied in Dengue and HIV viruses and explains why a second infection with Dengue can be lethal. As already reviewed in Part I and Part II, SARS-Cov-2 shares with HIV not only 4 sequences in the Spike protein but also the capacity to attack the immune system. OBJECTIVE As HIV presents ADE, we wondered whether this was also the case regarding SARS-CoV-2. METHODS A literature review was done through Google. RESULTS SARS-CoV-2 presents ADE. As SARS, which does not have the 4 HIV-like inserts, has the same property, ADE would not be driven by the HIV-like spike sequences. CONCLUSIONS ADE can explain the failure of herd immunity-based strategies and will also probably hamper anti-SARS-CoV-2 vaccine development. As reviewed in Part I, there fortunately are promising therapeutic strategies for COVID-19, which should be further developed. In the meantime, complementary countermeasures to protect mainly the youth from this infection are presented to be discussed in Part V Viewpoint.

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