Potent Neutralization Antibodies Induced by a Recombinant Trimeric Spike Protein Vaccine Candidate Containing PIKA Adjuvant for COVID-19.
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ABSTRACT:
SUBMITTER: Tong J
PROVIDER: S-EPMC8004863 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recombinant trimeric SARS-CoV-2 Spike protein with PIKA (polyI:C) adjuvant induces potent and durable neutralizing antibodies that protect against multiple SARS-CoV-2 variants. The immunoglobulin subclasses of viral-specific antibodies remain unknown, as do their glycosylation status on Fc regions. In this study, we analyzed immunoglobulins adsorbed by plate-bound recombinant trimeric SARS-CoV-2 Spike protein from serum of Cynomolgus monkey immunized by recombinant trimeric SARS-CoV-2 Spike protein with PIKA (polyI:C) adjuvant. The results showed that IgG1 was the dominant IgG subclass as revealed by ion mobility mass spectrometry. The average percentage of Spike protein-specific IgG1 increased to 88.3% as compared to pre-immunization. Core fucosylation for Fc glycopeptide of Spike protein-specific IgG1 was found to be higher than 98%. These results indicate that a unique Th1-biased, IgG1-dominant antibody response was responsible for the effectiveness of PIKA (polyI:C) adjuvant. Vaccine-induced core-fucosylation of IgG1 Fc region may reduce incidence of severe COVID-19 disease associated with overstimulation of FCGR3A by afucosylated IgG1.
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Project description:BackgroundA key missing element in the development of a successful human immunodeficiency virus (HIV) vaccine is an immunogen that can generate broadly cross-neutralizing antibodies against primary isolates of the virus.MethodsThis phase 1 clinical trial employed a DNA prime and subunit envelope protein boost in an attempt to generate cellular and humoral immune responses that might be desirable in a protective HIV vaccine. Priming was performed via intramuscular injection with gag and env DNA adsorbed to polylactide coglycolide microspheres, followed by boosting with a recombinant trimeric envelope (Env) glycoprotein delivered in MF59 adjuvant.ResultsThe DNA prime and protein boost were generally safe and well-tolerated. Env-specific CD4(+) cellular responses were generated that were predominantly detected after Env protein boosting. Neutralizing antibody responses against the homologous SF162 viral isolate were remarkably strong and were present in the majority of vaccine recipients, including a strong response against CD4-induced epitopes on gp120. Despite the promising potency of this vaccine approach, neutralization breadth against heterologous tier 2 strains of HIV-1 was minimal.ConclusionsPotent neutralization against neutralization-sensitive strains of HIV is achievable in humans through a DNA prime, recombinant oligomeric Env protein boost regimen. Eliciting substantial breadth of neutralization remains an elusive goal.Clinical trials registrationNCT00073216.
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Project description:In order to create an effective immunization approach for a potential vaccine to heroin, liposomes containing monophosphoryl lipid A [L(MPLA)] were tested as an adjuvant system to induce antibodies to heroin hapten analogs. Four synthetic haptens and two immunization strategies were employed. In the first strategy, a hydrophobic 23 amino acid immunogenic peptide derived from the membrane proximal external region of gp41 from HIV-1 envelope protein was embedded as a carrier in the outer surface of L(MPLA), to which was conjugated a 15 amino acid universal T cell epitope and a terminal heroin hapten analog. In the second strategy, tetanus toxoid (TT) carrier protein was decorated with haptens by conjugation, and the hapten-conjugated protein was mixed with L(MPLA). After immunization of mice, each of the immunization strategies was effective for induction of IgG anti-hapten antibodies. The first immunization strategy induced a mean end-point IgG titer against one of two haptens tested of approximately 12,800; however, no detectable antibodies were induced against the liposome-associated HIV-1 carrier peptide. In the second immunization strategy, depending on the hapten used for decorating the TT, end-point IgG titers ranged from 100,000 to 6,500,000. In this strategy, in which hapten was conjugated to the TT, end-point IgG titers of 400,000 to the TT carrier were observed with each conjugate. However, upon mixing unconjugated TT with L(MPLA), anti-TT titers of 6,500,000 were observed. We conclude that L(MPLA) serves as a potent adjuvant for inducing antibodies to candidate heroin haptens. However, antibodies to the carrier peptide or protein were partly or completed inhibited by the presence of conjugated hapten.
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Project description:The botulinum neurotoxins (BoNTs) cause the paralytic human disease botulism and are one of the highest-risk threat agents for bioterrorism. To generate a pharmaceutical to prevent or treat botulism, monoclonal antibodies (mAbs) were generated by phage display and evaluated for neutralization of BoNT serotype A (BoNT/A) in vivo. Although no single mAb significantly neutralized toxin, a combination of three mAbs (oligoclonal Ab) neutralized 450,000 50% lethal doses of BoNT/A, a potency 90 times greater than human hyperimmune globulin. The potency of oligoclonal Ab was primarily due to a large increase in functional Ab binding affinity. The results indicate that the potency of the polyclonal humoral immune response can be deconvoluted to a few mAbs binding nonoverlapping epitopes, providing a route to drugs for preventing and treating botulism and diseases caused by other pathogens and biologic threat agents.
| S-EPMC123259 | biostudies-literature
Project description:Broadly neutralizing antibodies against highly variable viral pathogens are much sought after to treat or protect against global circulating viruses. Here we probed the neutralizing antibody repertoires of four human immunodeficiency virus (HIV)-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies that neutralize broadly across clades. Many of the new monoclonal antibodies are almost tenfold more potent than the recently described PG9, PG16 and VRC01 broadly neutralizing monoclonal antibodies and 100-fold more potent than the original prototype HIV broadly neutralizing monoclonal antibodies. The monoclonal antibodies largely recapitulate the neutralization breadth found in the corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoprotein gp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement of anti-HIV broadly neutralizing monoclonal antibodies now available reveals that certain combinations of antibodies should offer markedly more favourable coverage of the enormous diversity of global circulating viruses than others and these combinations might be sought in active or passive immunization regimes. Overall, the isolation of multiple HIV broadly neutralizing monoclonal antibodies from several donors that, in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventual design of an effective antibody-based HIV vaccine.
| S-EPMC3393110 | biostudies-literature
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, at the end of 2019, and there are currently no specific antiviral treatments or vaccines available. SARS-CoV-2 has been shown to use the same cell entry receptor as SARS-CoV, angiotensin-converting enzyme 2 (ACE2). In this report, we generate a recombinant protein by connecting the extracellular domain of human ACE2 to the Fc region of the human immunoglobulin IgG1. A fusion protein containing an ACE2 mutant with low catalytic activity is also used in this study. The fusion proteins are then characterized. Both fusion proteins have a high binding affinity for the receptor-binding domains of SARS-CoV and SARS-CoV-2 and exhibit desirable pharmacological properties in mice. Moreover, the fusion proteins neutralize virus pseudotyped with SARS-CoV or SARS-CoV-2 spike proteins in vitro. As these fusion proteins exhibit cross-reactivity against coronaviruses, they have potential applications in the diagnosis, prophylaxis, and treatment of SARS-CoV-2.
| S-EPMC7265355 | biostudies-literature
Project description:Despite significant advances in health care, outbreaks of infections by enteroviruses (EVs) continue to plague the Asia-Pacific region every year. Enterovirus 71 (EV71) causes hand-foot-and-mouth disease (HFMD), for which there are currently no therapeutics. Here, we report two new antibodies, A9 and D6, that potently neutralize EV71. A9 exhibited a 50% neutralizing concentration (neut50) value of 0.1 nM against EV71, which was 10-fold lower than that observed for D6. Investigation into the mechanisms of neutralization revealed that binding of A9 to EV71 blocks receptor binding but also destabilizes and damages the virus capsid structure. In contrast, D6 destabilizes the capsid only slightly but interferes more potently with the attachment of the virus to the host cells. Cryo-electron microscopy (cryo-EM) structures of A9 and D6 bound with EV71 shed light on the locations and nature of the epitopes recognized by the two antibodies. Although some regions of the epitopes recognized by the two antibodies overlap, there are differences that give rise to dissimilarities in potency as well as in the mechanisms of neutralization. Interestingly, the overlapping regions of the epitopes encompass the site that the virus uses to bind SCARB2, explaining the reason for the observed blocking of the virus-receptor interaction by the two antibodies. We also identified structural elements that might play roles in modulating the stability of the EV71 particles, including particle integrity. The molecular features of the A9 and D6 epitopes unveiled in this study open up new avenues for rationally designing antiviral drugs.IMPORTANCE During the course of viral infections, the human body produces neutralizing antibodies which play a defining role in clearing the virus. From this study, we report two new, highly potent neutralizing antibodies, A9 and D6, against enterovirus 71 (EV71), the causative agent of HFMD. Both antibodies prevent the virus from entering the host cell, a step that is important for establishing a successful infection. A9 destabilizes and damages the virus capsid that forms an outer protective covering around the genome of the virus, while also interfering with virus attachment to the host cells. In contrast, D6 only prevents binding of the virus to its receptor(s). The mechanism of neutralization of A9 is unique and has not been observed before for neutralizing antibodies targeting EVs. The two antibodies that we are reporting in this study have potential to be developed into much-needed therapeutic interventions for treatment of HFMD, outbreaks of which are reported every year in the Asia-Pacific region.
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Project description:BACKGROUND:Since 2010, outbreaks of genotype 2 (G2) porcine epidemic diarrhea virus (PEDV) have caused high mortality in neonatal piglets and have had devastating impacts on the swine industry in many countries. A reliable serological assay for evaluating the PEDV-specific humoral and mucosal immune response is important for disease survey, monitoring the efficacy of immunization, and designing strategies for the prevention and control of PED. Two PEDV spike (S) glycoprotein-based indirect enzyme-linked immunosorbent assays (ELISAs) were developed using G2b PEDV-Pintung 52 (PEDV-PT) trimeric full-length S and truncated S1-501 proteins derived from the human embryonic kidney (HEK)-293 cell expression system. The truncated S1-501 protein was selected from a superior expressed stable cell line. The sensitivity and specificity of these two ELISAs were compared to immunostaining of G2b PEDV-PT infected cells and to a commercial nucleocapsid (N)-based indirect ELISA kit using a panel of PEDV negative and hyperimmune sera. RESULTS:The commercial N-based ELISA exhibited a sensitivity of 37%, a specificity of 100%, and a fair agreement (kappa?=?0.37) with the immunostaining result. In comparison, the full-length S-based ELISA showed a sensitivity of 97.8%, a specificity of 94%, and an almost perfect agreement (kappa?=?0.90) with the immunostaining result. Interestingly, the S1-501-based ELISA had even higher sensitivity of 98.9% and specificity of 99.1%, and an almost perfect agreement (kappa?=?0.97) with the immunostaining result. A fair agreement (kappa<?0.4) was seen between the commercial N-based ELISA and either of our S-based ELISAs. However, the results of the full-length S-based ELISA shared an almost perfect agreement (kappa?=?0.92) with that of S1-501-based ELISA. CONCLUSIONS:Both full-length S-based and S1-501-based ELISAs exhibit high sensitivity and high specificity for detecting antibodies against PEDVs. Considering the high protein yield and cost-effectiveness, the S1-501-based ELISA could be used as a reliable, sensitive, specific, and economic serological test for PEDV.
| S-EPMC6880432 | biostudies-literature
Project description:Severe acute respiratory syndrome (SARS) is a newly emerging infectious disease, and an effective vaccine is not available. In this study, we compared the immunogenicity and protection efficacy of recombinant proteins corresponding to different domains of the SARS-coronavirus spike protein. Trimeric recombinant proteins were created by fusing the foldon domain derived from T4 bacteriophage to the carboxy-termini of individual domains of the spike protein. While the full-length ectodomain (S) of the spike protein, the full-length ectodomain fused to foldon (S-foldon), the S1 domain (S1), S1-foldon, and the S2 domain(S2) antigens all elicited comparable antibody titers as measured by ELISA, S-foldon induced a significantly higher titer of neutralizing antibody and S2 protein did not elicit virus neutralizing antibodies. When tested in a mouse virus replication model, all the mice vaccinated with the S1, S1-foldon, S, or S-foldon were completely protected.
| S-EPMC3624630 | biostudies-literature
Project description:The severe acute respiratory syndrome coronavirus (SARS-CoV) caused a worldwide epidemic in late 2002/early 2003 and a second outbreak in the winter of 2003/2004 by an independent animal-to-human transmission. The GD03 strain, which was isolated from an index patient of the second outbreak, was reported to resist neutralization by the human monoclonal antibodies (hmAbs) 80R and S3.1, which can potently neutralize isolates from the first outbreak. Here we report that two hmAbs, m396 and S230.15, potently neutralized GD03 and representative isolates from the first SARS outbreak (Urbani, Tor2) and from palm civets (SZ3, SZ16). These antibodies also protected mice challenged with the Urbani or recombinant viruses bearing the GD03 and SZ16 spike (S) glycoproteins. Both antibodies competed with the SARS-CoV receptor, ACE2, for binding to the receptor-binding domain (RBD), suggesting a mechanism of neutralization that involves interference with the SARS-CoV-ACE2 interaction. Two putative hot-spot residues in the RBD (Ile-489 and Tyr-491) were identified within the SARS-CoV spike that likely contribute to most of the m396-binding energy. Residues Ile-489 and Tyr-491 are highly conserved within the SARS-CoV spike, indicating a possible mechanism of the m396 cross-reactivity. Sequence analysis and mutagenesis data show that m396 might neutralize all zoonotic and epidemic SARS-CoV isolates with known sequences, except strains derived from bats. These antibodies exhibit cross-reactivity against isolates from the two SARS outbreaks and palm civets and could have potential applications for diagnosis, prophylaxis, and treatment of SARS-CoV infections.
| S-EPMC1924550 | biostudies-literature