scholarly journals Circulating SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity

2021 ◽  
Author(s):  
Wilfredo F. Garcia-Beltran ◽  
Evan C. Lam ◽  
Kerri St. Denis ◽  
Adam D. Nitido ◽  
Zeidy H. Garcia ◽  
...  
Keyword(s):  
Immune Responses ◽  
Humoral Immunity ◽  
Neutralizing Antibodies ◽  
Wild Type ◽  
Vaccine Responses ◽  
Main Target ◽  
Cross Neutralization ◽  
Ongoing Surveillance ◽  
Multiple Strains ◽  
The Impact

SUMMARYVaccination elicits immune responses capable of potently neutralizing SARS-CoV-2. However, ongoing surveillance has revealed the emergence of variants harboring mutations in spike, the main target of neutralizing antibodies. To understand the impact of globally circulating variants, we evaluated the neutralization potency of 48 sera from BNT162b2 and mRNA-1273 vaccine recipients against pseudoviruses bearing spike proteins derived from 10 strains of SARS-CoV-2. While multiple strains exhibited vaccine-induced cross-neutralization comparable to wild-type pseudovirus, 5 strains harboring receptor-binding domain mutations, including K417N/T, E484K, and N501Y, were highly resistant to neutralization. Cross-neutralization of B.1.351 variants was weak and comparable to SARS-CoV and bat-derived WIV1-CoV, suggesting that a relatively small number of mutations can mediate potent escape from vaccine responses. While the clinical impact of neutralization resistance remains uncertain, these results highlight the potential for variants to escape from neutralizing humoral immunity and emphasize the need to develop broadly protective interventions against the evolving pandemic.

scholarly journals Cross-Protection against MERS-CoV by Prime-Boost Vaccination Using Viral Spike DNA and Protein

2020 ◽  
Vol 94 (24) ◽  
Author(s):  
Jung-ah Choi ◽  
Junghyun Goo ◽  
Eunji Yang ◽  
Dae-Im Jung ◽  
Sena Lee ◽  
...  
Keyword(s):  
Immune Responses ◽  
Recombinant Proteins ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Respiratory Illness ◽  
Cross Protection ◽  
Effective Vaccine ◽  
Wild Type ◽  
Boost Vaccination ◽  
Cross Neutralization

ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory illness and has a high mortality of ∼34%. However, since its discovery in 2012, an effective vaccine has not been developed for it. To develop a vaccine against multiple strains of MERS-CoV, we targeted spike glycoprotein (S) using prime-boost vaccination with DNA and insect cell-expressed recombinant proteins for the receptor-binding domain (RBD), S1, S2, SΔTM, or SΔER. Our S subunits were generated using an S sequence derived from the MERS-CoV EMC/2012 strain. We examined humoral and cellular immune responses of various combinations with DNA plasmids and recombinant proteins in mice. Mouse sera immunized with SΔER DNA priming/SΔTM protein boosting showed cross-neutralization against 15 variants of S-pseudovirions and the wild-type KOR/KNIH/002 strain. In addition, these immunizations provided full protection against the KOR/KNIH/002 strain challenge in human DPP4 knock-in mice. These findings suggest that vaccination with the S subunits derived from one viral strain can provide cross-protection against variant MERS-CoV strains with mutations in S. DNA priming/protein boosting increased gamma interferon production, while protein-alone immunization did not. The RBD subunit alone was insufficient to induce neutralizing antibodies, suggesting the importance of structural conformation. In conclusion, heterologous DNA priming with protein boosting is an effective way to induce both neutralizing antibodies and cell-mediated immune responses for MERS-CoV vaccine development. This study suggests a strategy for selecting a suitable platform for developing vaccines against MERS-CoV or other emerging coronaviruses. IMPORTANCE Coronavirus is an RNA virus with a higher mutation rate than DNA viruses. Therefore, a mutation in S-protein, which mediates viral infection by binding to a human cellular receptor, is expected to cause difficulties in vaccine development. Given that DNA-protein vaccines promote stronger cell-mediated immune responses than protein-only vaccination, we immunized mice with various combinations of DNA priming and protein boosting using the S-subunit sequences of the MERS-CoV EMC/2012 strain. We demonstrated a cross-protective effect against wild-type KOR/KNIH/002, a strain with two mutations in the S amino acids, including one in its RBD. The vaccine also provided cross-neutralization against 15 different S-pseudotyped viruses. These suggested that a vaccine targeting one variant of S can provide cross-protection against multiple viral strains with mutations in S. The regimen of DNA priming/Protein boosting can be applied to the development of other coronavirus vaccines.

scholarly journals Persistence of the immune responses and cross-neutralizing activity with Variants of Concern following two doses of adjuvanted SCB-2019 COVID-19 vaccine

2021 ◽  
Author(s):  
Peter C Richmond ◽  
Lara Hatchuel ◽  
Filippo Pacciarini ◽  
Branda Hu ◽  
Igor Smolenov ◽  
...  
Keyword(s):  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Protein S ◽  
Competitive Binding ◽  
Igg Antibodies ◽  
Wild Type ◽  
Phase 1 Study ◽  
Cross Neutralization ◽  
Dose Dependent

Abstract Background We have previously reported the safety and immunogenicity four weeks after two doses of the Clover COVID-19 vaccine candidate, SCB-2019, a stabilized pre-fusion form of the SARS-CoV-2 S-protein (S-trimer). We now report persistence of antibodies up to 6 months after vaccination, and cross-neutralization titers against three Variants of Concern (VoC). Methods In a phase 1 study adult (18–54 years) and elderly (55–75 years) volunteers received two vaccinations 21 days apart with 3, 9 or 30µg doses of SCB-2019 adjuvanted with CpG-1018/alum or placebo. We measured IgG antibodies against SCB-2019, ACE2-competitive-binding antibodies, and neutralizing antibodies against wild type SARS-CoV-2 (Wuhan-Hu-1) at Days 101 and 184, and neutralizing antibodies against three VoC, Alpha (B.1.1.7), Beta (B.1.351) and Gamma (P.1) in Day 36 sera. Results Titers waned from their peak at Days 36–50, but SCB-2019 IgG antibodies, ACE2-competitive binding antibodies and neutralizing antibodies against wild type SARS-CoV-2 persisted at 25–35% of their observed peak levels at Day 184. Day 36 sera also demonstrated dose-dependent increases in neutralizing titers against the three VoC. Conclusions SCB-2019 dose-dependently induced immune responses against wild-type SARS-CoV-2 which persisted up to Day 184. Neutralizing antibodies were cross-reactive against three of the most prevalent VoC.

TLR4 regulates rabies virus-induced humoral immunity through recruitment of cDC2 to lymph organs

2021 ◽  
Author(s):  
Chen Chen ◽  
Chengguang Zhang ◽  
Haoqi Li ◽  
Zongmei Wang ◽  
Yueming Yuan ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Rabies Virus ◽  
Humoral Immunity ◽  
Humoral Immune Response ◽  
Critical Role ◽  
Wild Type ◽  
Humoral Immune ◽  
Specific Igg ◽  
Molecular Patterns

Rabies, caused by rabies virus (RABV), is fatal to both humans and animals around the world. Effective clinical therapy for rabies has not been achieved, and vaccination is the most effective means of preventing and controlling rabies. Although different vaccines, such as live attenuated and inactivated vaccines, can induce different immune responses, different expression of pattern recognition receptors (PRRs) also causes diverse immune responses. Toll-like receptor 4 (TLR4) is a pivotal PRR that induces cytokine production and bridges innate and adaptive immunity. Importantly, TLR4 recognizes various virus-derived pathogen-associated molecular patterns (PAMPs) and virus-induced damage-associated molecular patterns (DAMPs), usually leading to the activation of immune cells. However, the role of TLR4 in the humoral immune response induced by RABV has not been revealed yet. Based on TLR4-deficient ( TLR4 -/- ) and wild-type (WT) mouse models, we report that TLR4-dependent recruitment of the conventional type-2 dendritic cells (CD8α - CD11b + cDC2) into secondary lymph organs (SLOs) is critical for antigen presentation. cDC2-initiated differentiation of Tfh cells promotes the proliferation of germinal centre (GC) B cells, the formation of GCs, and the production of plasma cells (PCs), all of which contribute to the production of RABV-specific IgG and virus-neutralizing antibodies (VNAs). Collectively, our work demonstrates that TLR4 is necessary for the recruitment of cDC2 and for the induction of RABV-induced humoral immunity, which is regulated by the cDC2-Tfh-GC B axis. IMPORTANCE Vaccination is the most efficient method to prevent rabies. TLR4, a well-known immune sensor, plays a critical role in initiating innate immune response. Here, we found that TLR4 deficiency ( TLR4 -/- ) mice suppressed the induction of humoral immune response after immunization with rabies virus (RABV), including reduced production of VNAs and RABV-specific IgG, compared with that occurred in wild-type (WT) mice. As a consequence, TLR4 -/- mice exhibited higher mortality than WT mice after challenge with virulent RABV. Importantly, further investigation found that TLR4 signaling promoted the recruitment of cDC2 (CD8α + CD11b - ), a subset of cDCs known to induce CD4 + T cell immunity through their MHC-II presentation machinery. Our results imply that TLR4 is indispensable for an efficient humoral response to rabies vaccine, which provides new insight into the development of novel rabies vaccines.

scholarly journals A Common Food Glycan, Pectin, Shares an Antigen with Streptococcus pneumoniae Capsule

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Moon H. Nahm ◽  
Jigui Yu ◽  
Jiri Vlach ◽  
Maor Bar-Peled
Keyword(s):  
Immune Response ◽  
Streptococcus Pneumoniae ◽  
Immune Responses ◽  
Pneumococcal Vaccine ◽  
Cross Reactivity ◽  
Food Plants ◽  
Content Type ◽  
Plant Foods ◽  
Vaccine Responses ◽  
The Impact

ABSTRACT We are exposed daily to many glycans from bacteria and food plants. Bacterial glycans are generally antigenic and elicit antibody responses. It is unclear if food glycans’ sharing of antigens with bacterial glycans influences our immune responses to bacteria. We studied 14 different plant foods for cross-reactivity with monoclonal antibodies (MAbs) against 24 pneumococcal serotypes which commonly cause infections and are included in pneumococcal vaccines. Serotype 15B-specific MAb cross-reacts with fruit peels, and serotype 10A MAb cross-reacts with many natural and processed plant foods. The serotype 10A cross-reactive epitope is 1,6-β-galactosidase [βGal(1-6)], present in the rhamno-galacturonan I (RG-I) domain of pectin. Despite wide consumption of pectin, the immune response to 10A is comparable to the responses to other serotypes. An antipectin antibody can opsonize serotype 10A pneumococci, and the shared βGal(1-6) may be useful as a simple vaccine against 10A. Impact of food glycans should be considered in host-pathogen interactions and future vaccine designs. IMPORTANCE The impact of food consumption on vaccine responses is unknown. Streptococcus pneumoniae (the pneumococcus) is an important human pathogen, and its polysaccharide capsule is used as a vaccine. We show that capsule type 10A in a pneumococcal vaccine shares an antigenic epitope, βGal(1-6), with pectin, which is in many plant foods and is widely consumed. Immune response to 10A is comparable to that seen with other capsule types, and pectin ingestion may have little impact on vaccine responses. However, antibody to pectin can kill serotype 10A pneumococci and this shared epitope may be considered in pneumococcal vaccine designs.

scholarly journals Epistasis at the SARS-CoV-2 RBD Interface and the Propitiously Boring Implications for Vaccine Escape

2021 ◽  
Author(s):  
Nash D. Rochman ◽  
Guilhem Faure ◽  
Yuri I. Wolf ◽  
Peter L. Freddolino ◽  
Feng Zhang ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Protein Structure Modeling ◽  
Escape Mutants ◽  
Small Set ◽  
Global Concern ◽  
The Impact

AbstractAt the time of this writing, August 2021, potential emergence of vaccine escape variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a grave global concern. The interface between the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein and the host receptor (ACE2) overlap with the binding site of principal neutralizing antibodies (NAb), limiting the repertoire of viable mutations. Nonetheless, variants with multiple mutations in the RBD have rose to dominance. Non-additive, epistatic relationships among RBD mutations are apparent, and assessing the impact of such epistasis on the mutational landscape is crucial. Epistasis can substantially increase the risk of vaccine escape and cannot be completely characterized through the study of the wild type (WT) alone. We employed protein structure modeling using Rosetta to compare the effects of all single mutants at the RBD-NAb and RBD-ACE2 interfaces for the WT, Gamma (417T, 484K, 501Y), and Delta variants (452R, 478K). Overall, epistasis at the RBD surface appears to be limited and the effects of most multiple mutations are additive. Epistasis at the Delta variant interface weakly stabilizes NAb interaction relative to ACE2, whereas in the Gamma variant, epistasis more substantially destabilizes NAb interaction. These results suggest that the repertoire of potential escape mutations for the Delta variant is not substantially different from that of the WT, whereas Gamma poses a moderately greater risk for enhanced vaccine escape. Thus, the modest ensemble of mutations relative to the WT shown to reduce vaccine efficacy might constitute the majority of all possible escape mutations.SignificancePotential emergence of vaccine escape variants of SARS-CoV-2 is arguably the most pressing problem during the COVID-19 pandemic as vaccines are distributed worldwide. We employed a computational approach to assess the risk of antibody escape resulting from mutations in the receptor-binding domain of the spike protein of the wild type SARS-CoV-2 virus as well as the Gamma and Delta variants. The results indicate that emergence of escape mutants is somewhat less likely for the Delta variant than for the wild type and moderately more likely for the Gamma variant. We conclude that the small set of escape-enhancing mutations already identified for the wild type is likely to include the majority of all possible mutations with this effect, a welcome finding.

scholarly journals Activated PIK3CD drives innate B cell expansion yet limits B cell–intrinsic immune responses

2018 ◽  
Vol 215 (10) ◽  
pp. 2485-2496 ◽  
Author(s):  
Michelle N. Wray-Dutra ◽  
Fahd Al Qureshah ◽  
Genita Metzler ◽  
Mohamed Oukka ◽  
Richard G. James ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Plasma Cells ◽  
Recurrent Infection ◽  
Vaccine Responses ◽  
And Function ◽  
Natural Igm ◽  
The Impact

Activated PI3K-delta syndrome (APDS) is an immunodeficiency caused by gain-of-function mutations in PIK3CD. This disease exhibits complex immune phenotypes including increased IgM, recurrent infection, and impaired vaccine responses. To better understand the impact of B cells in this disease, we generated an inducible model of the common APDS mutation (hPIK3CD-E1021K; referred to as aPIK3CD) and intercrossed these mice with B cell–specific Cre models. Mb1-aPIK3CD mice exhibited bone marrow B lymphopenia and, conversely, expansion of the peripheral innate B1a and MZ B cell compartments. aPIK3CD B cells manifest increased pS6 and increased survival at several stages, without alterations in cycling, and baseline increases in plasma cells, natural IgM, and IgG3. Finally, Mb1-aPIK3CD mice exhibited blunted T cell–independent immune responses, and both AID- and CD21-aPIK3CD mice displayed reduced class-switched antibodies following T cell–dependent immunization. Thus, aPIK3CD alters B cell development and function and is counter-productive during immune responses, providing insight into B cell–intrinsic contributions to the APDS phenotype.

scholarly journals Host Immune Responses to Chronic Adenovirus Infections in Human and Nonhuman Primates

2008 ◽  
Vol 83 (6) ◽  
pp. 2623-2631 ◽  
Author(s):  
Roberto Calcedo ◽  
Luk H. Vandenberghe ◽  
Soumitra Roy ◽  
Suryanarayan Somanathan ◽  
Lili Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Peripheral Blood ◽  
Neutralizing Antibodies ◽  
Potential Role ◽  
Low Frequencies ◽  
Host Immune Responses ◽  
Virus Genomes ◽  
The Impact

ABSTRACT Recent studies indicate that great apes and macaques chronically shed adenoviruses in the stool. Shedding of adenovirus in the stool of humans is less prevalent, although virus genomes persist in gut-associated lymphoid tissue in the majority of individual samples. Chimpanzees have high levels of broadly reactive neutralizing antibodies to adenoviruses in serum, with very low frequencies of adenovirus-specific T cells in peripheral blood. A similar situation exists in macaques; sampling of guts from macaques demonstrated adenovirus-specific T cells in lamina propria. Humans show intermediate levels of serum neutralizing antibodies, with adenovirus-specific T cells in peripheral blood of all individuals sampled and about 20% of samples from the gut, suggesting a potential role of T cells in better controlling virus replication in the gut. The overall structure of the E3 locus, which is involved in modulating the host's response to infection, is degenerate in humans compared to that in apes, which may contribute to diminished evasion of host immunity. The impact of adenovirus persistence and immune responses should be considered when using adenoviral vectors in gene therapy and genetic vaccines.

scholarly journals Construction, characterization, and immunization of nanoparticles that display a diverse array of influenza HA trimers

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0247963 ◽  
Author(s):  
Alexander A. Cohen ◽  
Zhi Yang ◽  
Priyanthi N. P. Gnanapragasam ◽  
Susan Ou ◽  
Kim-Marie A. Dam ◽  
...  
Keyword(s):  
Immune Responses ◽  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Electron Tomography ◽  
Covalent Attachment ◽  
Humoral Immune ◽  
Group 2 ◽  
Multiple Strains ◽  
Universal Influenza Vaccine

Current influenza vaccines do not elicit broadly protective immune responses against multiple strains. New strategies to focus the humoral immune response to conserved regions on influenza antigens are therefore required for recognition by broadly neutralizing antibodies. It has been suggested that B-cells with receptors that recognize conserved epitopes would be preferentially stimulated through avidity effects by mosaic particles presenting multiple forms of a variable antigen. We adapted SpyCatcher-based platforms, AP205 virus-like particles (VLPs) and mi3 nanoparticles (NPs), to covalently co-display SpyTagged hemagglutinin (HA) trimers from group 1 and group 2 influenza A strains. Here we show successful homotypic and heterotypic conjugation of up to 8 different HA trimers to both VLPs and NPs. We characterized the HA-VLPs and HA-NPs by cryo-electron tomography to derive the average number of conjugated HAs and their separation distances on particles, and compared immunizations of mosaic and homotypic particles in wild-type mice. Both types of HA particles elicited strong antibody responses, but the mosaic particles did not consistently elicit broader immune responses than mixtures of homotypic particles. We conclude that covalent attachment of HAs from currently-circulating influenza strains represents a viable alternative to current annual influenza vaccine strategies, but in the absence of further modifications, is unlikely to represent a method for making a universal influenza vaccine.

scholarly journals Biology of E1-Deleted Adenovirus Vectors in Nonhuman Primate Muscle

2001 ◽  
Vol 75 (11) ◽  
pp. 5222-5229 ◽  
Author(s):  
Philip W. Zoltick ◽  
Narendra Chirmule ◽  
Michael A. Schnell ◽  
Guang-ping Gao ◽  
Joseph V. Hughes ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Transgene Expression ◽  
Adenovirus Vector ◽  
T Cell Response ◽  
Intramuscular Administration ◽  
Cytotoxic T Cell ◽  
Adenovirus Vectors ◽  
The Impact

ABSTRACT Adenovirus vectors have been studied as vehicles for gene transfer to skeletal muscle, an attractive target for gene therapies for inherited and acquired diseases. In this setting, immune responses to viral proteins and/or transgene products cause inflammation and lead to loss of transgene expression. A few studies in murine models have suggested that the destructive cell-mediated immune response to virally encoded proteins of E1-deleted adenovirus may not contribute to the elimination of transgene-expressing cells. However, the impact of immune responses following intramuscular administration of adenovirus vectors on transgene stability has not been elucidated in larger animal models such as nonhuman primates. Here we demonstrate that intramuscular administration of E1-deleted adenovirus vector expressing rhesus monkey erythropoietin or growth hormone to rhesus monkeys results in generation of a Th1-dependent cytotoxic T-cell response to adenovirus proteins. Transgene expression dropped significantly over time but was still detectable in some animals after 6 months. Systemic levels of adenovirus-specific neutralizing antibodies were generated, which blocked vector readministration. These studies indicate that the cellular and humoral immune response generated to adenovirus proteins, in the context of transgenes encoding self-proteins, hinders long-term transgene expression and readministration with first-generation vectors.

scholarly journals Construction, characterization, and immunization of nanoparticles that display a diverse array of influenza HA trimers

2020 ◽  
Author(s):  
Alexander A. Cohen ◽  
Zhi Yang ◽  
Priyanthi NP Gnanapragasam ◽  
Susan Ou ◽  
Kim-Marie A. Dam ◽  
...  
Keyword(s):  
Immune Responses ◽  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Electron Tomography ◽  
Covalent Attachment ◽  
Humoral Immune ◽  
Group 2 ◽  
Multiple Strains ◽  
Universal Influenza Vaccine

AbstractCurrent influenza vaccines do not elicit broadly protective immune responses against multiple strains. New strategies to focus the humoral immune response to conserved regions on influenza antigens are therefore required for recognition by broadly neutralizing antibodies. It has been suggested that B-cells with receptors that recognize conserved epitopes would be preferentially stimulated through avidity effects by mosaic particles presenting multiple forms of a variable antigen. We adapted SpyCatcher-based platforms, AP205 virus-like particles (VLPs) and mi3 nanoparticles (NPs), to covalently co-display SpyTagged hemagglutinin (HA) trimers from group 1 and group 2 influenza A strains. Here we show successful homotypic and heterotypic conjugation of up to 8 different HA trimers to both VLPs and NPs. We characterized the HA-VLPs and HA-NPs by cryo-electron tomography to derive the average number of conjugated HAs and their separation distances on particles, and compared immunizations of mosaic and homotypic particles in wild-type mice. Both types of HA particles elicited strong antibody responses, but the mosaic particles did not consistently elicit broader immune responses than mixtures of homotypic particles. We conclude that covalent attachment of HAs from currently-circulating influenza strains represents a viable alternative to current annual influenza vaccine strategies, but in the absence of further modifications, is unlikely to represent a method for making a universal influenza vaccine.

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