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1.
Cell Rep ; : 111729, 2022 Nov 10.
Article in English | MEDLINE | ID: covidwho-2177160

ABSTRACT

Since the initial emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.1, several Omicron sublineages have emerged, leading to BA.5 as the current dominant sublineage. Here, we report the neutralization of different Omicron sublineages by human sera collected from individuals who had distinct mRNA vaccination and/or BA.1 infection. Four-dose-vaccine sera neutralize the original USA-WA1/2020, Omicron BA.1, BA.2, BA.2.12.1, BA.3, and BA.4/5 viruses with geometric mean titers (GMTs) of 1,554, 357, 236, 236, 165, and 95, respectively; two-dose-vaccine-plus-BA.1-infection sera exhibit GMTs of 2,114, 1,705, 730, 961, 813, and 274, respectively; and three-dose-vaccine-plus-BA.1-infection sera show GMTs of 2,962, 2,038, 983, 1,190, 1,019, and 297, respectively. Thus, the four-dose vaccine elicits the lowest neutralization against BA.5; the two-dose vaccine plus BA.1 infection elicits significantly higher GMTs against Omicron sublineages than the four-dose-vaccine; and the three-dose vaccine plus BA.1 infection elicits slightly higher GMTs (statistically insignificant) than the two-dose vaccine plus BA.1 infection. Finally, the BA.2.75 is more susceptible than BA.5 to four-dose-vaccine-elicited neutralization and three-dose-vaccine-plus-BA.1-infection-elicited neutralization.

2.
Cell Rep ; 39(13): 110989, 2022 06 28.
Article in English | MEDLINE | ID: covidwho-2121651

ABSTRACT

The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon ß (IFNß) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNß as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNß-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNß in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection.


Subject(s)
Interferon-beta , Interleukin-12 , Toll-Like Receptor 4 , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Cytokines/immunology , Cytokines/metabolism , Humans , Interferon-beta/immunology , Interferon-beta/metabolism , Interleukin-12/immunology , Interleukin-12/metabolism , Lipopolysaccharides/pharmacology , Proteomics , SARS-CoV-2/immunology
3.
Cell Rep ; 39(5): 110754, 2022 05 03.
Article in English | MEDLINE | ID: covidwho-2113939

ABSTRACT

Rapid spread of SARS-CoV-2 variants C.1.2 and B.1.621 (Mu variant) in Africa and the Americas, respectively, as well as a high number of mutations in the viral spike proteins raised concerns that these variants might pose an elevated threat to human health. Here, we show that C.1.2 and B.1.621 spike proteins mediate increased entry into certain cell lines but do not exhibit increased ACE2 binding. Further, we demonstrate that C.1.2 and B.1.621 are resistant to neutralization by bamlanivimab but remain sensitive to inhibition by antibody cocktails used for COVID-19 therapy. Finally, we show that C.1.2 and B.1.621 partially escape neutralization by antibodies induced upon infection and vaccination, with escape of vaccine-induced antibodies being as potent as that measured for B.1.351 (Beta variant), which is known to be highly neutralization resistant. Collectively, C.1.2 and B.1.621 partially evade control by vaccine-induced antibodies, suggesting that close monitoring of these variants is warranted.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , Humans , Spike Glycoprotein, Coronavirus , Vaccination
4.
Cell Rep ; 41(4): 111554, 2022 10 25.
Article in English | MEDLINE | ID: covidwho-2104502

ABSTRACT

Due to the recrudescence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections worldwide, mainly caused by the Omicron variant of concern (VOC) and its sub-lineages, several jurisdictions are administering an mRNA vaccine boost. Here, we analyze humoral responses induced after the second and third doses of an mRNA vaccine in naive and previously infected donors who received their second dose with an extended 16-week interval. We observe that the extended interval elicits robust humoral responses against VOCs, but this response is significantly diminished 4 months after the second dose. Administering a boost to these individuals brings back the humoral responses to the same levels obtained after the extended second dose. Interestingly, we observe that administering a boost to individuals that initially received a short 3- to 4-week regimen elicits humoral responses similar to those observed in the long interval regimen. Nevertheless, humoral responses elicited by the boost in naive individuals do not reach those present in previously infected vaccinated individuals.


Subject(s)
COVID-19 , Viral Vaccines , Humans , SARS-CoV-2 , BNT162 Vaccine , COVID-19/prevention & control , Antibodies, Viral , COVID-19 Vaccines , Vaccination
5.
Cell Rep ; 41(4): 111544, 2022 10 25.
Article in English | MEDLINE | ID: covidwho-2104501

ABSTRACT

Each severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant renews concerns about decreased vaccine neutralization weakening efficacy. However, while prevention of infection varies, protection from disease remains and implicates immunity beyond neutralization in vaccine efficacy. Polyclonal antibodies function through Fab domains that neutralize virus and Fc domains that induce non-neutralizing responses via engagement of Fc receptors on immune cells. To understand how vaccines promote protection, we leverage sera from 51 SARS-CoV-2 uninfected individuals after two doses of the BNT162b2 mRNA vaccine. We show that neutralizing activities against clinical isolates of wild-type and five SARS-CoV-2 variants, including Omicron BA.2, link to FcγRIIIa/CD16 non-neutralizing effector functions. This is associated with post-translational afucosylation and sialylation of vaccine-specific antibodies. Further, polyfunctional neutralizing and non-neutralizing breadth, magnitude, and coordination diminish with age. Thus, studying Fc functions in addition to Fab-mediated neutralization provides greater insight into vaccine efficacy for vulnerable populations, such as the elderly, against SARS-CoV-2 and novel variants.


Subject(s)
COVID-19 , Viral Vaccines , Humans , Aged , SARS-CoV-2 , Antibodies, Viral , BNT162 Vaccine , Receptors, Fc , Antibodies, Neutralizing
6.
Cell Rep ; 41(8): 111708, 2022 Nov 22.
Article in English | MEDLINE | ID: covidwho-2095146

ABSTRACT

Genome-wide association studies (GWASs) show that genetic factors contribute to the risk of severe coronavirus disease 2019 (COVID-19) and blood analyte levels. Here, we utilize GWAS summary statistics to study the shared genetic influences (pleiotropy) between severe COVID-19 and 344 blood analytes at the genome, gene, and single-nucleotide polymorphism (SNP) levels. Our pleiotropy analyses genetically link blood levels of 71 analytes to severe COVID-19 in at least one of the three levels of investigation-suggesting shared biological mechanisms or causal relationships. Six analytes (alanine aminotransferase, alkaline phosphatase, apolipoprotein B, C-reactive protein, triglycerides, and urate) display evidence of pleiotropy with severe COVID-19 at all three levels. Causality analyses indicate that higher triglycerides levels causally increase the risk of severe COVID-19, thereby providing important support for the use of lipid-lowering drugs such as statins and fibrates to prevent severe COVID-19.


Subject(s)
COVID-19 , Humans , COVID-19/blood , COVID-19/genetics , Genome-Wide Association Study , Polymorphism, Single Nucleotide , Triglycerides/blood , Risk Factors
7.
Cell Rep ; 41(7): 111650, 2022 Nov 15.
Article in English | MEDLINE | ID: covidwho-2086004

ABSTRACT

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concerns (VOCs) continue to emerge, cross-neutralizing antibody responses become key toward next-generation design of a more universal COVID-19 vaccine. By analyzing published data from the literature, we report here that the combination of germline genes IGHV2-5/IGLV2-14 represents a public antibody response to the receptor-binding domain (RBD) that potently cross-neutralizes a broad range of VOCs, including Omicron and its sub-lineages. Detailed molecular analysis shows that the complementarity-determining region H3 sequences of IGHV2-5/IGLV2-14-encoded RBD antibodies have a preferred length of 11 amino acids and a conserved HxIxxI motif. In addition, these antibodies have a strong allelic preference due to an allelic polymorphism at amino acid residue 54 of IGHV2-5, which is located at the paratope. These findings have important implications for understanding cross-neutralizing antibody responses to SARS-CoV-2 and its heterogenicity at the population level as well as the development of a universal COVID-19 vaccine.


Subject(s)
Antibodies, Viral , Broadly Neutralizing Antibodies , COVID-19 , Humans , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , COVID-19 Vaccines , Receptors, Virus/metabolism , SARS-CoV-2
8.
Cell Rep ; 41(3): 111496, 2022 10 18.
Article in English | MEDLINE | ID: covidwho-2075981

ABSTRACT

It is important to determine if severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and SARS-CoV-2 mRNA vaccinations elicit different types of antibodies. Here, we characterize the magnitude and specificity of SARS-CoV-2 spike-reactive antibodies from 10 acutely infected health care workers with no prior SARS-CoV-2 exposure history and 23 participants who received SARS-CoV-2 mRNA vaccines. We found that infection and primary mRNA vaccination elicit S1- and S2-reactive antibodies, while secondary vaccination boosts mostly S1 antibodies. Using absorption assays, we found that SARS-CoV-2 infections elicit a large proportion of original antigenic sin-like antibodies that bind efficiently to the spike of common seasonal human coronaviruses but poorly to the spike of SARS-CoV-2. In converse, vaccination modestly boosts antibodies reactive to the spike of common seasonal human coronaviruses, and these antibodies cross-react more efficiently to the spike of SARS-CoV-2. Our data indicate that SARS-CoV-2 infections and mRNA vaccinations elicit fundamentally different antibody responses.


Subject(s)
COVID-19 , Humans , COVID-19/prevention & control , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Antibodies, Viral , Vaccination , RNA, Messenger/genetics
9.
Cell Rep ; 41(5): 111528, 2022 Nov 01.
Article in English | MEDLINE | ID: covidwho-2060517

ABSTRACT

The emergence and global spread of the SARS-CoV-2 Omicron variants, which carry an unprecedented number of mutations, raise serious concerns due to the reduced efficacy of current vaccines and resistance to therapeutic antibodies. Here, we report the generation and characterization of two potent human monoclonal antibodies, NA8 and NE12, against the receptor-binding domain of the SARS-CoV-2 spike protein. NA8 interacts with a highly conserved region and has a breadth of neutralization with picomolar potency against the Beta variant and the Omicron BA.1 and BA.2 sublineages and nanomolar potency against BA.2.12.1 and BA.4. Combination of NA8 and NE12 retains potent neutralizing activity against the major SARS-CoV-2 variants of concern. Cryo-EM analysis provides the structural basis for the broad and complementary neutralizing activity of these two antibodies. We confirm the in vivo protective and therapeutic efficacies of NA8 and NE12 in the hamster model. These results show that broad and potent human antibodies can overcome the continuous immune escape of evolving SARS-CoV-2 variants.


Subject(s)
Antineoplastic Agents, Immunological , COVID-19 , Humans , SARS-CoV-2 , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/genetics , Neutralization Tests , Antibodies, Viral/therapeutic use , Viral Envelope Proteins , Membrane Glycoproteins/genetics , Antibodies, Neutralizing/therapeutic use
10.
Cell Rep ; 41(3): 111512, 2022 10 18.
Article in English | MEDLINE | ID: covidwho-2060516

ABSTRACT

The SARS-CoV-2 Omicron variant evades most neutralizing vaccine-induced antibodies and is associated with lower antibody titers upon breakthrough infections than previous variants. However, the mechanism remains unclear. Here, we find using a geometric deep-learning model that Omicron's extensively mutated receptor binding site (RBS) features reduced antigenicity compared with previous variants. Mice immunization experiments with different recombinant receptor binding domain (RBD) variants confirm that the serological response to Omicron is drastically attenuated and less potent. Analyses of serum cross-reactivity and competitive ELISA reveal a reduction in antibody response across both variable and conserved RBD epitopes. Computational modeling confirms that the RBS has a potential for further antigenicity reduction while retaining efficient receptor binding. Finally, we find a similar trend of antigenicity reduction over decades for hCoV229E, a common cold coronavirus. Thus, our study explains the reduced antibody titers associated with Omicron infection and reveals a possible trajectory of future viral evolution.


Subject(s)
COVID-19 , Viral Vaccines , Mice , Animals , Spike Glycoprotein, Coronavirus , Neutralization Tests , Antibodies, Viral/chemistry , SARS-CoV-2 , Antibodies, Neutralizing/chemistry , Epitopes/chemistry
11.
Cell Rep ; 41(1): 111441, 2022 10 04.
Article in English | MEDLINE | ID: covidwho-2031186

ABSTRACT

Biologically active small molecules can impart modulatory effects, in some cases providing extended long-term memory. In a screen of biologically active small molecules for regulators of tumor necrosis factor (TNF) induction, we identify several compounds with the ability to induce training effects on human macrophages. Rutaecarpine shows acute and long-term modulation, enhancing lipopolysaccharide (LPS)-induced pro-inflammatory cytokine secretion and relieving LPS tolerance in human macrophages. Rutaecarpine inhibits ß-glucan-induced H3K4Me3 marks at the promoters of several pro-inflammatory cytokines, highlighting the potential of this molecule to modulate chromosomal topology. Syk kinase inhibitor (SYKi IV), another screen hit, promotes an enhanced response to LPS similar to that previously reported for ß-glucan-induced training. Macrophages trained with SYKi IV show a high degree of resistance to influenza A, multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and OC43 coronavirus infection, highlighting a potential application of this molecule and other SYKis as prophylactic treatments for viral susceptibility.


Subject(s)
COVID-19 , beta-Glucans , COVID-19/drug therapy , Cytokines , Humans , Indole Alkaloids , Lipopolysaccharides , Macrophages , Quinazolinones , SARS-CoV-2 , Syk Kinase , Tumor Necrosis Factor-alpha
12.
Cell Rep ; 40(11): 111335, 2022 09 13.
Article in English | MEDLINE | ID: covidwho-1996065

ABSTRACT

Although thousands of anti-SARS-CoV-2 monoclonal neutralizing antibodies (nAbs) have been identified and well characterized, some crucial events in the development of these nAbs during viral infection remain unclear. Using deep sequencing, we explore the dynamics of antibody repertoire in a SARS-CoV-2-infected donor, from whom the potent and broad nAb P2C-1F11 (the parent version of Brii-196) was previously isolated. Further analysis shows a rapid clonal expansion of some SARS-CoV-2-specific antibodies in early infection. Longitudinal tracing of P2C-1F11 lineage antibodies reveals that these elite nAbs were rare. Using sequence alignment, structure modeling, and bioactivity analysis based on site-mutated assay, we demonstrate that a key substitution F27I in heavy chain contributes significantly to the maturation of P2C-1F11-like antibodies. Overall, our findings elucidate the developmental process and maturation pathway of P2C-1F11, providing some important information for the design of novel immunogens to elicit more potent nAbs against SARS-CoV-2 infection.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal , Antibodies, Neutralizing , Antibodies, Viral , Humans
13.
Cell Rep ; 40(9): 111299, 2022 08 30.
Article in English | MEDLINE | ID: covidwho-1982704

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has led to the development of a large number of vaccines, several of which are now approved for use in humans. Understanding vaccine-elicited antibody responses against emerging SARS-CoV-2 variants of concern (VOCs) in real time is key to inform public health policies. Serum neutralizing antibody titers are the current best correlate of protection from SARS-CoV-2 challenge in non-human primates and a key metric to understand immune evasion of VOCs. We report that vaccinated BALB/c mice do not recapitulate faithfully the breadth and potency of neutralizing antibody responses elicited by various vaccine platforms against VOCs, compared with non-human primates or humans, suggesting caution should be exercised when interpreting data obtained with this animal model.


Subject(s)
COVID-19 , Viral Vaccines , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Humans , Mice , Mice, Inbred BALB C , Primates , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
14.
Cell Rep ; 40(9): 111284, 2022 08 30.
Article in English | MEDLINE | ID: covidwho-1982703

ABSTRACT

Preexisting immunity cross-reactive to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in SARS-CoV-1 survivors suggests that a coronavirus disease 2019 vaccine may boost such preexisting cross-reactive memory T cells. We measure SARS-CoV-2 and SARS-CoV-1 spike-specific neutralizing antibody and T cell responses in a single dose of Ad5-nCoV-immunized SARS-CoV-1 survivors 6 months after vaccination. Compared with Ad5-nCoV-immunized naive healthy individuals (NHIs), vaccination of Ad5-nCoV in SARS-CoV-1 survivors boosts the antibody response against SARS-CoV-1 but induces a limited neutralizing antibody that is capable of neutralizing SARS-CoV-2 variants of concern, and nearly all serum samples lose neutralization to Omicron subvariants. Immunized SARS-CoV-1 survivors produce a T cell response to SARS-CoV-2 comparable with that of Ad5-nCoV-immunized NHIs. However, a robust cross-reactive T cell response to SARS-CoV-1 is identified in immunized SARS-CoV-1 survivors compared with Ad5-nCoV-immunized NHIs. These findings suggest that vaccination with Ad5-nCoV elicits a stronger neutralizing antibody and cross-reactive T cell responses against SARS-CoV-1 in SARS-CoV-1 survivors.


Subject(s)
COVID-19 , Viral Vaccines , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Survivors , Vaccination
15.
Cell Rep ; 40(8): 111276, 2022 08 23.
Article in English | MEDLINE | ID: covidwho-1982702

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is the target for neutralizing antibodies elicited following both infection and vaccination. While extensive research has shown that the receptor binding domain (RBD) and, to a lesser extent, the N-terminal domain (NTD) are the predominant targets for neutralizing antibodies, identification of neutralizing epitopes beyond these regions is important for informing vaccine development and understanding antibody-mediated immune escape. Here, we identify a class of broadly neutralizing antibodies that bind an epitope on the spike subdomain 1 (SD1) and that have arisen from infection or vaccination. Using cryo-electron microscopy (cryo-EM) and hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS), we show that SD1-specific antibody P008_60 binds an epitope that is not accessible within the canonical prefusion states of the SARS-CoV-2 spike, suggesting a transient conformation of the viral glycoprotein that is vulnerable to neutralization.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , Cryoelectron Microscopy , Epitopes , Humans , Neutralization Tests , Spike Glycoprotein, Coronavirus , Syndactyly , Vaccination
16.
Cell Rep ; 40(7): 111214, 2022 08 16.
Article in English | MEDLINE | ID: covidwho-1966424

ABSTRACT

Vaccine-associated enhanced respiratory disease (VAERD) is a severe complication for some respiratory infections. To investigate the potential for VAERD induction in coronavirus disease 2019 (COVID-19), we evaluate two vaccine leads utilizing a severe hamster infection model: a T helper type 1 (TH1)-biased measles vaccine-derived candidate and a TH2-biased alum-adjuvanted, non-stabilized spike protein. The measles virus (MeV)-derived vaccine protects the animals, but the protein lead induces VAERD, which can be alleviated by dexamethasone treatment. Bulk transcriptomic analysis reveals that our protein vaccine prepares enhanced host gene dysregulation in the lung, exclusively up-regulating mRNAs encoding the eosinophil attractant CCL-11, TH2-driving interleukin (IL)-19, or TH2 cytokines IL-4, IL-5, and IL-13. Single-cell RNA sequencing (scRNA-seq) identifies lung macrophages or lymphoid cells as sources, respectively. Our findings imply that VAERD is caused by the concerted action of hyperstimulated macrophages and TH2 cytokine-secreting lymphoid cells and potentially links VAERD to antibody-dependent enhancement (ADE). In summary, we identify the cytokine drivers and cellular contributors that mediate VAERD after TH2-biased vaccination.


Subject(s)
COVID-19 , Vaccines , Animals , Antibodies, Viral , Cricetinae , Cytokines/metabolism , Immunization , Lung/pathology , Mice , Mice, Inbred BALB C , Th1 Cells , Th2 Cells , Vaccination
17.
Cell Rep ; 40(4): 111138, 2022 07 26.
Article in English | MEDLINE | ID: covidwho-1944467

ABSTRACT

COVID-19 vaccines elicit humoral and cellular immune responses. Durable maintenance of vaccine-induced immunity is required for long-term protection of the host. Here, we examine activation and differentiation of vaccine-induced CD8+ T cells using MHC class I (MHC-I) multimers and correlations between early differentiation and the durability of CD8+ T cell responses among healthcare workers immunized with two doses of BNT162b2. The frequency of MHC-I multimer+ cells is robustly increased by BNT162b2 but decreases 6 months post-second vaccination to 2.4%-65.6% (23.0% on average) of the peak. MHC-I multimer+ cells dominantly exhibit phenotypes of activated effector cells 1-2 weeks post-second vaccination and gradually acquire phenotypes of long-term memory cells, including stem cell-like memory T (TSCM) cells. Importantly, the frequency of TSCM cells 1-2 weeks post-second vaccination significantly correlates with the 6-month durability of CD8+ T cells, indicating that early generation of TSCM cells determines the longevity of vaccine-induced memory CD8+ T cell responses.


Subject(s)
CD8-Positive T-Lymphocytes , COVID-19 , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Stem Cells , Vaccination
18.
Cell Rep ; 39(13): 111004, 2022 06 28.
Article in English | MEDLINE | ID: covidwho-1944462

ABSTRACT

Vaccine boosters and infection can facilitate the development of SARS-CoV-2 antibodies with improved potency and breadth. Here, we observe superimmunity in a camelid extensively immunized with the SARS-CoV-2 receptor-binding domain (RBD). We rapidly isolate a large repertoire of specific ultra-high-affinity nanobodies that bind strongly to all known sarbecovirus clades using integrative proteomics. These pan-sarbecovirus nanobodies (psNbs) are highly effective against SARS-CoV and SARS-CoV-2 variants, including Omicron, with the best median neutralization potency at single-digit nanograms per milliliter. A highly potent, inhalable, and bispecific psNb (PiN-31) is also developed. Structural determinations of 13 psNbs with the SARS-CoV-2 spike or RBD reveal five epitope classes, providing insights into the mechanisms and evolution of their broad activities. The highly evolved psNbs target small, flat, and flexible epitopes that contain over 75% of conserved RBD surface residues. Their potencies are strongly and negatively correlated with the distance of the epitopes from the receptor binding sites.


Subject(s)
COVID-19 , SARS Virus , Single-Domain Antibodies , Antibodies, Neutralizing , Antibodies, Viral , Epitopes , Humans , SARS-CoV-2
19.
Cell Rep ; 40(5): 111160, 2022 08 02.
Article in English | MEDLINE | ID: covidwho-1936138

ABSTRACT

Although COVID-19 vaccines have been developed, multiple pathogenic coronavirus species exist, urging on development of multispecies coronavirus vaccines. Here we develop prototype lipid nanoparticle (LNP)-mRNA vaccine candidates against SARS-CoV-2 Delta, SARS-CoV, and MERS-CoV, and we test how multiplexing LNP-mRNAs can induce effective immune responses in animal models. Triplex and duplex LNP-mRNA vaccinations induce antigen-specific antibody responses against SARS-CoV-2, SARS-CoV, and MERS-CoV. Single-cell RNA sequencing profiles the global systemic immune repertoires and respective transcriptome signatures of vaccinated animals, revealing a systemic increase in activated B cells and differential gene expression across major adaptive immune cells. Sequential vaccination shows potent antibody responses against all three species, significantly stronger than simultaneous vaccination in mixture. These data demonstrate the feasibility, antibody responses, and single-cell immune profiles of multispecies coronavirus vaccination. The direct comparison between simultaneous and sequential vaccination offers insights into optimization of vaccination schedules to provide broad and potent antibody immunity against three major pathogenic coronavirus species.


Subject(s)
COVID-19 , Middle East Respiratory Syndrome Coronavirus , Viral Vaccines , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Liposomes , Middle East Respiratory Syndrome Coronavirus/genetics , Nanoparticles , RNA, Messenger/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Vaccination , Vaccines, Synthetic , mRNA Vaccines
20.
Cell Rep ; 40(4): 111148, 2022 07 26.
Article in English | MEDLINE | ID: covidwho-1926273

ABSTRACT

Plasmacytoid dendritic cells (pDCs) are specialized cells of the immune system that are thought to be the main cellular source of type I interferon alpha (IFNα) in response to viral infections. IFNs are powerful antivirals, whereas defects in their function or induction lead to impaired resistance to virus infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. IFN production needs to be controlled, because sustained IFN production can also have detrimental effects on disease outcome. As such, pDCs are likely important for acute antiviral protection against SARS-CoV-2 infection but could potentially also contribute to chronic IFN levels. Here, we provide a historical overview of pDC biology and summarize existing literature addressing their involvement and importance during viral infections of the airways. Furthermore, we outline recent reports focused on the potential role of pDCs during SARS-CoV-2 infection, as well as the potential for this cellular subset to impact COVID-19 disease outcome.


Subject(s)
COVID-19 , Interferon Type I , Antiviral Agents/pharmacology , Dendritic Cells , Humans , SARS-CoV-2
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