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1
Willis, Elinor, Norbert Pardi, Kaela Parkhouse, Barbara L. Mui, Ying K. Tam, Drew Weissman, and Scott E. Hensley. "Nucleoside-modified mRNA vaccination partially overcomes maternal antibody inhibition of de novo immune responses in mice." Science Translational Medicine 12, no. 525 (January 8, 2020): eaav5701. http://dx.doi.org/10.1126/scitranslmed.aav5701.
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Maternal antibodies provide short-term protection to infants against many infections. However, they can inhibit de novo antibody responses in infants elicited by infections or vaccination, leading to increased long-term susceptibility to infectious diseases. Thus, there is a need to develop vaccines that are able to elicit protective immune responses in the presence of antigen-specific maternal antibodies. Here, we used a mouse model to demonstrate that influenza virus–specific maternal antibodies inhibited de novo antibody responses in mouse pups elicited by influenza virus infection or administration of conventional influenza vaccines. We found that a recently developed influenza vaccine, nucleoside-modified mRNA encapsulated in lipid nanoparticles (mRNA-LNP), partially overcame this inhibition by maternal antibodies. The mRNA-LNP influenza vaccine established long-lived germinal centers in the mouse pups and elicited stronger antibody responses than did a conventional influenza vaccine approved for use in humans. Vaccination with mRNA-LNP vaccines may offer a promising strategy for generating robust immune responses in infants in the presence of maternal antibodies.
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Gupta, Rajesh K., David N. Taylor, Dolores A. Bryla, John B. Robbins, and Shousun C. Szu. "Phase 1 Evaluation of Vibrio choleraeO1, Serotype Inaba, Polysaccharide-Cholera Toxin Conjugates in Adult Volunteers." Infection and Immunity 66, no. 7 (July 1, 1998): 3095–99. http://dx.doi.org/10.1128/iai.66.7.3095-3099.1998.
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ABSTRACT Conjugate vaccines were prepared by binding hydrazine-treated lipopolysaccharide (DeALPS) from Vibrio cholerae O1, serotype Inaba, to cholera toxin (CT) variants CT-1 and CT-2. Volunteers (n = 75) were injected with either 25 μg of DeALPS, alone or as a conjugate, or the licensed cellular vaccine containing 4 × 109 organisms each of serotypes Inaba and Ogawa per ml. No serious adverse reactions were observed. DeALPS alone did not elicit serum LPS or vibriocidal antibodies in mice and only low levels of immunoglobulin M (IgM) anti-LPS in the volunteers. Recipients of the cellular vaccine had the highest IgM anti-LPS levels, but the difference was not statistically significant from that elicited by the conjugates. The conjugates elicited the highest levels of IgG anti-LPS (DeALPS-CT-2 > DeALPS-CT-1 > cellular vaccine). Both conjugates and the cellular vaccine elicited vibriocidal antibodies: after 8 months, recipients of cellular vaccine had the highest geometric mean titer (1,249), followed by DeALPS-CT-2 (588) and DeALPS-CT-1 (330). The correlation coefficient between IgG anti-LPS and 2-mercaptoethanol (2-ME)-resistant vibriocidal antibodies was 0.81 (P = 0.0004). Convalescent sera from cholera patients had a mean vibriocidal titer of 2,525 that was removed by treatment with 2-ME. The vibriocidal activities of sera from all vaccine groups and from the patients were absorbed (>75%) by LPS but not by either CT-1 or CT-2. Conjugate-induced IgG vibriocidal antibodies persisted longer than those elicited by the whole-cell vaccine. Both conjugates, but not the cellular vaccine, elicited IgG anti-CT.
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Greaney, Allison J., Andrea N. Loes, Lauren E. Gentles, Katharine H. D. Crawford, Tyler N. Starr, Keara D. Malone, Helen Y. Chu, and Jesse D. Bloom. "Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection." Science Translational Medicine 13, no. 600 (June 8, 2021): eabi9915. http://dx.doi.org/10.1126/scitranslmed.abi9915.
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The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with mutations in key antibody epitopes has raised concerns that antigenic evolution could erode adaptive immunity elicited by prior infection or vaccination. The susceptibility of immunity to viral evolution is shaped in part by the breadth of epitopes targeted by antibodies elicited by vaccination or natural infection. To investigate how human antibody responses to vaccines are influenced by viral mutations, we used deep mutational scanning to compare the specificity of polyclonal antibodies elicited by either two doses of the mRNA-1273 COVID-19 vaccine or natural infection with SARS-CoV-2. The neutralizing activity of vaccine-elicited antibodies was more targeted to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein compared to antibodies elicited by natural infection. However, within the RBD, binding of vaccine-elicited antibodies was more broadly distributed across epitopes compared to infection-elicited antibodies. This greater binding breadth means that single RBD mutations have less impact on neutralization by vaccine sera compared to convalescent sera. Therefore, antibody immunity acquired by natural infection or different modes of vaccination may have a differing susceptibility to erosion by SARS-CoV-2 evolution.
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Harris, Shannon L., Adam Finn, and Dan M. Granoff. "Disparity in Functional Activity between Serum Anticapsular Antibodies Induced in Adults by Immunization with an Investigational Group A and C Neisseria meningitidis-Diphtheria Toxoid Conjugate Vaccine and by a Polysaccharide Vaccine." Infection and Immunity 71, no. 6 (June 2003): 3402–8. http://dx.doi.org/10.1128/iai.71.6.3402-3408.2003.
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ABSTRACT Polysaccharide-protein conjugate vaccines elicit higher concentrations of serum anticapsular antibody in infants and children than do unconjugated polysaccharide vaccines. The conjugate-induced antibodies also have higher avidity and complement-mediated bactericidal activity. Similar vaccine-related differences in the magnitude or functional activity of antibody are observed infrequently in immunized adults. We compared the antibody responses of adults immunized with an investigational group A and C meningococcal conjugate vaccine to those elicited by an unconjugated meningococcal polysaccharide vaccine. Although there were no significant differences between the respective geometric mean bactericidal titers of the two vaccine groups, it took, on average, three- to fourfold higher concentrations of polysaccharide-induced serum anticapsular antibody to achieve 50% complement-mediated bacteriolysis than conjugate-induced antibody (P < 0.001 for groups A and C). At limiting doses, the polysaccharide-induced anticapsular antibodies also were less effective in conferring passive protection against meningococcal bacteremia in infant rats challenged with a group C strain (P < 0.04). The avidity index of the group C antibodies was higher in the conjugate vaccine group than in the polysaccharide vaccine group (P < 0.005). The disparities in the functional activity of the anticapsular antibodies elicited in adults by the two vaccines imply fundamental differences in the respective B-cell populations stimulated.
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Nuñez, Ivette A., Ying Huang, and Ted M. Ross. "Next-Generation Computationally Designed Influenza Hemagglutinin Vaccines Protect against H5Nx Virus Infections." Pathogens 10, no. 11 (October 20, 2021): 1352. http://dx.doi.org/10.3390/pathogens10111352.
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H5N1 COBRA hemagglutinin (HA) sequences, termed human COBRA-2 HA, were constructed through layering of HA sequences from viruses isolated from humans collected between 2004–2007 using only clade 2 strains. These COBRA HA proteins, when expressed on the surface of virus-like particles (VLP), elicited protective immune responses in mice, ferrets, and non-human primates. However, these vaccines were not as effective at inducing neutralizing antibodies against newly circulating viruses. Therefore, COBRA HA-based vaccines were updated in order to elicit protective antibodies against the current circulating clades of H5Nx viruses. Next-generation COBRA HA vaccines were designed to encompass the newly emerging viruses circulating in wild avian populations. HA amino acid sequences from avian and human H5 influenza viruses isolated between 2011–2017 were downloaded from the GISAID (Global Initiative on Sharing All Influenza Data). Mice were vaccinated with H5 COBRA rHA that elicited antibodies with hemagglutinin inhibition (HAI) activity against H5Nx viruses from five clades. The H5 COBRA rHA vaccine, termed IAN8, elicited protective immune responses against mice challenged with A/Sichuan/26621/2014 and A/Vietnam/1203/2004. This vaccine elicited antibodies with HAI activity against viruses from clades 2.2, 2.3.2.1, 2.3.4.2, 2.2.1 and 2.2.2. Lungs from vaccinated mice had decreased viral titers and the levels of cellular infiltration in mice vaccinated with IAN-8 rHA were similar to mice vaccinated with wild-type HA comparator vaccines or mock vaccinated controls. Overall, these next-generation H5 COBRA HA vaccines elicited protective antibodies against both historical H5Nx influenza viruses, as well as currently circulating clades of H5N1, H5N6, and H5N8 influenza viruses.
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Koeberling, Oliver, Isabel Delany, and Dan M. Granoff. "A Critical Threshold of Meningococcal Factor H Binding Protein Expression Is Required for Increased Breadth of Protective Antibodies Elicited by Native Outer Membrane Vesicle Vaccines." Clinical and Vaccine Immunology 18, no. 5 (March 2, 2011): 736–42. http://dx.doi.org/10.1128/cvi.00542-10.
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ABSTRACTNative outer membrane vesicles (NOMV) (not detergent treated), which are prepared from recombinant strains with attenuated endotoxin activity and overexpressed factor H binding protein (fHbp), elicited broad serum bactericidal antibody responses in mice. The amount of overexpressed fHbp required for optimal immunogenicity is not known. In this study we prepared NOMV vaccines from LpxL1 knockout (ΔLpxL1) mutants with penta-acylated lipooligosaccharide and attenuated endotoxin activity. The recombinant strains had wild-type (1×) fHbp expression or were engineered for 3-fold- or 10-fold-increased fHbp expression (3× or 10× fHbp). Control vaccines included NOMV from ΔLpxL1/ΔfHbp mutants or recombinant fHbp. In mice, only the 10× fHbp NOMV vaccine elicited significantly higher serum IgG anti-fHbp antibody titers than the corresponding 1× fHbp NOMV or recombinant fHbp vaccine. The 10× fHbp NOMV vaccine also elicited higher bactericidal responses (P< 0.05) against five group B strains with heterologous PorA than the recombinant fHbp or 1× fHbp NOMV vaccine. The 3× fHbp NOMV vaccine gave higher bactericidal titers against only one strain. Serum bactericidal titers in mice immunized with the control ΔfHbp NOMV vaccines were <1:10, and bactericidal titers in mice immunized with the 10× fHbp NOMV vaccine were <1:10 after adsorption of anti-fHbp antibodies. Mixing antiserum to NOMV vaccines from fHbp knockout mutants with antiserum to recombinant fHbp did not increase anti-fHbp bactericidal titers. Thus, a critical threshold of increased fHbp expression is required for NOMV vaccines to elicit broad serum bactericidal responses, and the antibodies conferring protection are directed primarily at fHbp.
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Salat, Jiri, Petra Strakova, and Daniel Ruzek. "Dynamics of Whole Virus and Non-Structural Protein 1 (NS1) IgG Response in Mice Immunized with Two Commercial Tick-Borne Encephalitis Vaccines." Vaccines 10, no. 7 (June 23, 2022): 1001. http://dx.doi.org/10.3390/vaccines10071001.
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The presence of a non-structural protein 1 (NS1) in tick-borne encephalitis (TBE) vaccines and the possible induction of an NS1-specific immune response in vaccinated individuals remains a somewhat controversial topic. Previously, we detected the presence of NS1 in the Encepur TBE vaccine by mass spectrometry and found the induction of NS1-specific IgG antibodies in mice vaccinated with the FSME-Immun TBE vaccine. Here, in this follow-up study, we examined the dynamics and extent of the NS1-specific IgG response in mice vaccinated with these two vaccines in more detail and compared it with the IgG response to the whole virus (WV). Mice were vaccinated at two-week intervals with a total of six doses of each vaccine, and levels of IgG antibodies to TBE virus WV and NS1 were measured by ELISA after each dose. Both vaccines elicited a robust anti-WV IgG response after two doses. The Encepur vaccine did not elicit NS1-specific IgG even after all six doses. In contrast, the FSME-Immun vaccine triggered the production of NS1-specific IgG after four doses. The results indicate that FSME-Immun is the only vaccine that elicits an NS1-specific antibody response in mice. However, compared to WV-specific IgG, the NS1-specific response is weaker, and a higher number of doses is required to induce detectable levels of NS1-specific IgG antibodies.
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Dapporto, Francesca, Serena Marchi, Margherita Leonardi, Pietro Piu, Piero Lovreglio, Nicola Decaro, Nicola Buonvino, et al. "Antibody Avidity and Neutralizing Response against SARS-CoV-2 Omicron Variant after Infection or Vaccination." Journal of Immunology Research 2022 (August 31, 2022): 1–9. http://dx.doi.org/10.1155/2022/4813199.
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Background. The recently emerged SARS-CoV-2 Omicron variant exhibits several mutations on the spike protein, enabling it to escape the immunity elicited by natural infection or vaccines. Avidity is the strength of binding between an antibody and its specific epitope. The SARS-CoV-2 spike protein binds to its cellular receptor with high affinity and is the primary target of neutralizing antibodies. Therefore, protective antibodies should show high avidity. This study aimed at investigating the avidity of receptor-binding domain (RBD) binding antibodies and their neutralizing activity against the Omicron variant in SARS-CoV-2 infected patients and vaccinees. Methods. Samples were collected from 42 SARS-CoV-2 infected patients during the first pandemic wave, 50 subjects who received 2 doses of mRNA vaccine before the Omicron wave, 44 subjects who received 3 doses of mRNA vaccine, and 35 subjects who received heterologous vaccination (2 doses of adenovirus-based vaccine plus mRNA vaccine) during the Omicron wave. Samples were tested for the avidity of RBD-binding IgG and neutralizing antibodies against the wild-type SARS-CoV-2 virus and the Omicron variant. Results. In patients, RBD-binding IgG titers against the wild-type virus increased with time, but remained low. High neutralizing titers against the wild-type virus were not matched by high avidity or neutralizing activity against the Omicron variant. Vaccinees showed higher avidity than patients. Two vaccine doses elicited the production of neutralizing antibodies, but low avidity for the wild-type virus; antibody levels against the Omicron variant were even lower. Conversely, 3 doses of vaccine elicited high avidity and high neutralizing antibodies against both the wild-type virus and the Omicron variant. Conclusions. Repeated vaccination increases antibody avidity against the spike protein of the Omicron variant, suggesting that antibodies with high avidity and high neutralizing potential increase cross-protection against variants that carry several mutations on the RBD.
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Warner, Nikole L., and Kathryn M. Frietze. "Development of Bacteriophage Virus-Like Particle Vaccines Displaying Conserved Epitopes of Dengue Virus Non-Structural Protein 1." Vaccines 9, no. 7 (July 2, 2021): 726. http://dx.doi.org/10.3390/vaccines9070726.
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Dengue virus (DENV) is a major global health problem, with over half of the world’s population at risk of infection. Despite over 60 years of efforts, no licensed vaccine suitable for population-based immunization against DENV is available. Here, we describe efforts to engineer epitope-based vaccines against DENV non-structural protein 1 (NS1). NS1 is present in DENV-infected cells as well as secreted into the blood of infected individuals. NS1 causes disruption of endothelial cell barriers, resulting in plasma leakage and hemorrhage. Immunizing against NS1 could elicit antibodies that block NS1 function and also target NS1-infected cells for antibody-dependent cell cytotoxicity. We identified highly conserved regions of NS1 from all four DENV serotypes. We generated synthetic peptides to these regions and chemically conjugated them to bacteriophage Qβ virus-like particles (VLPs). Mice were immunized two times with the candidate vaccines and sera were tested for the presence of antibodies that bound to the cognate peptide, recombinant NS1 from all four DENV serotypes, and DENV-2-infected cells. We found that two of the candidate vaccines elicited antibodies that bound to recombinant NS1, and one candidate vaccine elicited antibodies that bound to DENV-infected cells. These results show that an epitope-specific vaccine against conserved regions of NS1 could be a promising approach for DENV vaccines or therapeutics to bind circulating NS1 protein.
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Giles, Brendan M., Stephanie J. Bissel, Dilhari R. DeAlmeida, Clayton A. Wiley, and Ted M. Ross. "Antibody Breadth and Protective Efficacy Are Increased by Vaccination with Computationally Optimized Hemagglutinin but Not with Polyvalent Hemagglutinin-Based H5N1 Virus-Like Particle Vaccines." Clinical and Vaccine Immunology 19, no. 2 (December 21, 2011): 128–39. http://dx.doi.org/10.1128/cvi.05533-11.
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ABSTRACTOne of the challenges for developing an H5N1 influenza vaccine is the diversity of antigenically distinct isolates within this subtype. Previously, our group described a novel hemagglutinin (HA) derived from a methodology termed computationally optimized broadly reactive antigen (COBRA). This COBRA HA, when used as an immunogen, elicits a broad antibody response against H5N1 isolates from different clades. In this report, the immune responses elicited by the COBRA HA virus-like particle (VLP) vaccine were compared to responses elicited by a mixture of VLPs expressing representative HA molecules from clade 2.1, 2.2, and 2.3 primary H5N1 isolates (polyvalent). The COBRA HA VLP vaccine elicited higher-titer antibodies to a panel of H5N1 HA proteins than did the other VLPs. Both COBRA and polyvalent vaccines protected vaccinated mice and ferrets from experimental infection with highly lethal H5N1 influenza viruses, but COBRA-vaccinated animals had decreased viral replication, less inflammation in the lungs of mice, and reduced virus recovery in ferret nasal washes. Both vaccines had similar cellular responses postchallenge, indicating that higher-titer serum antibodies likely restrict the duration of viral replication. Furthermore, passively transferred immune serum from the COBRA HA VLP-vaccinated mice protected recipient animals more efficiently than immune serum from polyvalent-vaccinated mice. This is the first report comparing these two vaccine strategies. The single COBRA HA antigen elicited a broader antibody response and reduced morbidity and viral titers more effectively than a polyvalent mixture of primary H5N1 HA antigens.
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Visciano, Maria Luisa, Aakash Mahant Mahant, Carl Pierce, Richard Hunte, and Betsy C. Herold. "Antibodies Elicited in Response to a Single Cycle Glycoprotein D Deletion Viral Vaccine Candidate Bind C1q and Activate Complement Mediated Neutralization and Cytolysis." Viruses 13, no. 7 (June 30, 2021): 1284. http://dx.doi.org/10.3390/v13071284.
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Herpes simplex virus (HSV) prevention is a global health priority but, despite decades of research, there is no effective vaccine. Prior efforts focused on generating glycoprotein D (gD) neutralizing antibodies, but clinical trial outcomes were disappointing. The deletion of gD yields a single-cycle candidate vaccine (∆gD-2) that elicits high titer polyantigenic non-gD antibodies that exhibit little complement-independent neutralization but mediate antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Active or passive immunization with ΔgD-2 completely protects mice from lethal disease and latency following challenge with clinical isolates of either serotype. The current studies evaluated the role of complement in vaccine-elicited protection. The immune serum from the ΔgD-2 vaccinated mice exhibited significantly greater C1q binding compared to the serum from the gD protein vaccinated mice with infected cell lysates from either serotype as capture antigens. The C1q-binding antibodies recognized glycoprotein B. This resulted in significantly greater antibody-mediated complement-dependent cytolysis and neutralization. Notably, complete protection was preserved when the ΔgD-2 immune serum was passively transferred into C1q knockout mice, suggesting that ADCC and ADCP are sufficient in mice. We speculate that the polyfunctional responses elicited by ΔgD-2 may prove more effective in preventing HSV, compared to the more restrictive responses elicited by adjuvanted gD protein vaccines.
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Heile, Jens M., Yiu-Lian Fong, Domenico Rosa, Kim Berger, Giulietta Saletti, Susanna Campagnoli, Giuliano Bensi, et al. "Evaluation of Hepatitis C Virus Glycoprotein E2 for Vaccine Design: an Endoplasmic Reticulum-Retained Recombinant Protein Is Superior to Secreted Recombinant Protein and DNA-Based Vaccine Candidates." Journal of Virology 74, no. 15 (August 1, 2000): 6885–92. http://dx.doi.org/10.1128/jvi.74.15.6885-6892.2000.
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ABSTRACT Hepatitis C virus (HCV) is the leading causative agent of blood-borne chronic hepatitis and is the target of intensive vaccine research. The virus genome encodes a number of structural and nonstructural antigens which could be used in a subunit vaccine. The HCV envelope glycoprotein E2 has recently been shown to bind CD81 on human cells and therefore is a prime candidate for inclusion in any such vaccine. The experiments presented here assessed the optimal form of HCV E2 antigen from the perspective of antibody generation. The quality of recombinant E2 protein was evaluated by both the capacity to bind its putative receptor CD81 on human cells and the ability to elicit antibodies that inhibited this binding (NOB antibodies). We show that truncated E2 proteins expressed in mammalian cells bind with high efficiency to human cells and elicit NOB antibodies in guinea pigs only when purified from the core-glycosylated intracellular fraction, whereas the complex-glycosylated secreted fraction does not bind and elicits no NOB antibodies. We also show that carbohydrate moieties are not necessary for E2 binding to human cells and that only the monomeric nonaggregated fraction can bind to CD81. Moreover, comparing recombinant intracellular E2 protein to several E2-encoding DNA vaccines in mice, we found that protein immunization is superior to DNA in both the quantity and quality of the antibody response elicited. Together, our data suggest that to elicit antibodies aimed at blocking HCV binding to CD81 on human cells, the antigen of choice is a mammalian cell-expressed, monomeric E2 protein purified from the intracellular fraction.
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Waickman, Adam T., Joseph Lu, Corey Chase, Hengsheng Fang, Erinn McDowell, Erin Bingham, Jeffrey Bogart, Stephen Graziano, Stephen J. Thomas, and Teresa Gentile. "Systemic Cancer Therapy Does Not Significantly Impact Early Vaccine-Elicited SARS-CoV-2 Immunity in Patients with Solid Tumors." Vaccines 10, no. 5 (May 9, 2022): 738. http://dx.doi.org/10.3390/vaccines10050738.
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mRNA vaccines have been shown to be safe and effective in individuals with cancer. It is unclear, however, if systemic anti-cancer therapy impacts the coordinated cellular and humoral immune responses elicited by SARS-CoV-2 mRNA vaccines. To fill this knowledge gap, we assessed SARS-CoV-2 mRNA vaccine-elicited immunity in a cohort of patients with advanced solid tumors either under observation or receiving systemic anti-cancer therapy. This analysis revealed that SARS-CoV-2 mRNA vaccine-elicited cellular and humoral immunity was not significantly different in individuals with cancer receiving systemic anti-cancer therapy relative to individuals under observation. Furthermore, even though some patients exhibited suboptimal antibody titers after vaccination, SARS-CoV-2 specific cellular immune responses were still detected. These data suggest that antibody titers offer an incomplete picture of vaccine-elicited SARS-CoV-2 immunity in cancer patients undergoing active systemic anti-cancer therapy, and that vaccine-elicited cellular immunity exists even in the absence of significant quantities of SARS-CoV-2 specific antibodies.
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Hu, Mary C., Michael A. Walls, Steven D. Stroop, Mark A. Reddish, Bernard Beall, and James B. Dale. "Immunogenicity of a 26-Valent Group A Streptococcal Vaccine." Infection and Immunity 70, no. 4 (April 2002): 2171–77. http://dx.doi.org/10.1128/iai.70.4.2171-2177.2002.
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ABSTRACT A multivalent vaccine containing amino-terminal M protein fragments from 26 different serotypes of group A streptococci was constructed by recombinant techniques. The vaccine consisted of four different recombinant proteins that were formulated with alum to contain 400 μg of protein per dose. Rabbits were immunized via the intramuscular route at 0, 4, and 16 weeks. Immune sera were assayed for the presence of type-specific antibodies against the individual recombinant M peptides by enzyme-linked immunosorbent assay and for opsonic antibodies by in vitro opsonization tests and indirect bactericidal tests. The 26-valent vaccine was highly immunogenic and elicited fourfold or greater increases in antibody levels against 25 of the 26 serotypes represented in the vaccine. The immune sera were broadly opsonic and were bactericidal against the majority of the 26 different serotypes. Importantly, none of the immune sera cross-reacted with human tissues. Our results indicate that type-specific, protective M protein epitopes can be incorporated into complex, multivalent vaccines designed to elicit broadly protective opsonic antibodies in the absence of tissue-cross-reactive antibodies.
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Basha, Saleem, Staci Hazenfeld, Rebecca Brady, and Ramu Subbramanian. "Domain-specific variation in hemagglutinin-specific T-cell responses elicited by licensed seasonal influenza vaccines (106.11)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 106.11. http://dx.doi.org/10.4049/jimmunol.186.supp.106.11.
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Abstract Persistent antigenic drift in influenza hemagglutinin (HA) results in the emergence of serologically novel influenza viruses that result in seasonal epidemics globally. While the globular domain of the HA antigen is the primary repository of drift mutations, the viral-fusion domain is highly conserved. T cells are being increasingly recognized as a significant component of influenza immunity in humans and may target variant regions of HA that are not effectively targeted by type-specific antibodies. While a trivalent inactivated influenza vaccine (TIV) and a live-attenuated influenza vaccine (LAIV) are now licensed for use in humans, their comparative ability to elicit T cell responses against influenza HA is not well understood: specifically, the relative magnitude of T cell responses elicited by TIV and LAIV and their domain-specificity toward HA regions is unknown. In this study, we systematically compare immune responses elicited by TIV and LAIV in a cohort of healthy adults (18 to 49 years old) against the rapidly evolving H3N2 HA antigen. Data suggests TIV elicits higher geometric mean antibody titers than LAIV; whereas, LAIV elicits superior T cell responses. Importantly, the two vaccines vary significantly in their ability to elicit T cell responses targeting the variant and conserved regions of HA. These results have important implications for the deployment of influenza vaccines in years of antigenic mismatch and shift.
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Ching, Lance K., Giorgos Vlachogiannis, Katherine A. Bosch, and Leonidas Stamatatos. "The First Hypervariable Region of the gp120 Env Glycoprotein Defines the Neutralizing Susceptibility of Heterologous Human Immunodeficiency Virus Type 1 Isolates to Neutralizing Antibodies Elicited by the SF162gp140 Immunogen." Journal of Virology 82, no. 2 (November 14, 2007): 949–56. http://dx.doi.org/10.1128/jvi.02143-07.
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ABSTRACT Current vaccine efforts to elicit cross-reactive neutralizing antibodies (NAbs) against human immunodeficiency virus (HIV) focus on the engineering of soluble mimetics of the trimeric HIV Env glycoprotein (commonly termed gp140 immunogens). Such immunogens are thought to be more effective than previously tested monomeric gp120 immunogens at eliciting cross-reactive NAbs. Still, the breadth of neutralizing antibody responses elicited by gp140 immunogens is narrow. Understanding why antibodies elicited by gp140 immunogens fail to neutralize a wide range of heterologous primary HIV isolates is necessary for improving the design of such immunogens. We previously reported that antibodies elicited in macaques by SF162 Env-derived gp140 immunogens fail to neutralize several heterologous “neutralization-resistant” primary HIV type 1 isolates, such as JRFL, ADA, and YU2. Here we show that by replacing the V1 region of Env on these heterologous viruses with that of SF162, we render them highly susceptible to neutralization by the SF162gp140-elicited antibodies. We observed that viral neutralization was mediated not only by vaccine-elicited anti-V1 but also by anti-V3 antibodies and antibodies directed against as yet unidentified Env regions, depending on the heterologous Env background. Our study indicates that common neutralization epitopes are differentially exposed on diverse primary HIV isolates and that the V1 loop contributes to this differential exposure. Therefore, the antibody responses elicited by soluble gp140 immunogens will have to overcome several distinct obstacles in order to neutralize diverse primary HIV isolates.
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Chandrasekar, Shaswath S., Yashdeep Phanse, Rachel E. Hildebrand, Mostafa Hanafy, Chia-Wei Wu, Chungyi H. Hansen, Jorge E. Osorio, M. Suresh, and Adel M. Talaat. "Localized and Systemic Immune Responses against SARS-CoV-2 Following Mucosal Immunization." Vaccines 9, no. 2 (February 6, 2021): 132. http://dx.doi.org/10.3390/vaccines9020132.
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The rapid transmission of SARS-CoV-2 in the USA and worldwide necessitates the development of multiple vaccines to combat the COVID-19 global pandemic. Previously, we showed that a particulate adjuvant system, quil-A-loaded chitosan (QAC) nanoparticles, can elicit robust immunity combined with plasmid vaccines when used against avian coronavirus. Here, we report on the immune responses elicited by mucosal homologous plasmid and a heterologous immunization strategy using a plasmid vaccine and a Modified Vaccinia Ankara (MVA) expressing SARS-CoV-2 spike (S) and nucleocapsid (N) antigens. Only the heterologous intranasal immunization strategy elicited neutralizing antibodies against SARS-CoV-2 in serum and bronchoalveolar lavage of mice, suggesting a protective vaccine. The same prime/boost strategy led to the induction of type 1 and type 17 T-cell responses and polyfunctional T-cells expressing multiple type 1 cytokines (e.g., IFN-γ, TNFα, IL-2) in the lungs and spleens of vaccinated mice. In contrast, the plasmid homologous vaccine strategy led to the induction of local mono and polyfunctional T-cells secreting IFN-γ. Outcomes of this study support the potential of QAC-nano vaccines to elicit significant mucosal immune responses against respiratory coronaviruses.
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Turner, Hannah L., Raiees Andrabi, Christopher A. Cottrell, Sara T. Richey, Ge Song, Sean Callaghan, Fabio Anzanello, et al. "Disassembly of HIV envelope glycoprotein trimer immunogens is driven by antibodies elicited via immunization." Science Advances 7, no. 31 (July 2021): eabh2791. http://dx.doi.org/10.1126/sciadv.abh2791.
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Rationally designed protein subunit vaccines are being developed for a variety of viruses including influenza, RSV, SARS-CoV-2, and HIV. These vaccines are based on stabilized versions of the primary targets of neutralizing antibodies on the viral surface, namely, viral fusion glycoproteins. While these immunogens display the epitopes of potent neutralizing antibodies, they also present epitopes recognized by non-neutralizing or weakly neutralizing (“off-target”) antibodies. Using our recently developed electron microscopy polyclonal epitope mapping approach, we have uncovered a phenomenon wherein off-target antibodies elicited by HIV trimer subunit vaccines cause the otherwise highly stabilized trimeric proteins to degrade into cognate protomers. Further, we show that these protomers expose an expanded suite of off-target epitopes, normally occluded inside the prefusion conformation of trimer, that subsequently elicit further off-target antibody responses. Our study provides critical insights for further improvement of HIV subunit trimer vaccines for future rounds of the iterative vaccine design process.
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Madani, Navid, Amy M. Princiotto, David Easterhoff, Todd Bradley, Kan Luo, Wilton B. Williams, Hua-Xin Liao, et al. "Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds." Journal of Virology 90, no. 10 (March 9, 2016): 5031–46. http://dx.doi.org/10.1128/jvi.03211-15.
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ABSTRACTThe human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines.IMPORTANCEPreventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.
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Murji, Amyn A., Juliana S. Qin, Tandile Hermanus, Lynn Morris, and Ivelin S. Georgiev. "Elicitation of Neutralizing Antibody Responses to HIV-1 Immunization with Nanoparticle Vaccine Platforms." Viruses 13, no. 7 (July 2, 2021): 1296. http://dx.doi.org/10.3390/v13071296.
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A leading strategy for developing a prophylactic HIV-1 vaccine is the elicitation of antibodies that can neutralize a large fraction of circulating HIV-1 variants. However, a major challenge that has limited the effectiveness of current vaccine candidates is the extensive global diversity of the HIV-1 envelope protein (Env), the sole target for HIV-neutralizing antibodies. To address this challenge, various strategies incorporating Env diversity into the vaccine formulation have been proposed. Here, we assessed the potential of two such strategies that utilize a nanoparticle-based vaccine platform to elicit broadly neutralizing antibody responses. The nanoparticle immunogens developed here consisted of different formulations of Envs from strains BG505 (clade A) and CZA97 (clade C), attached to the N-termini of bacterial ferritin. Single—antigen nanoparticle cocktails, as well as mosaic nanoparticles bearing both Env trimers, elicited high antibody titers in mice and guinea pigs. Furthermore, serum from guinea pigs immunized with nanoparticle immunogens achieved autologous, and in some cases heterologous, tier 2 neutralization, although significant differences between mosaic and single—antigen nanoparticles were not observed. These results provide insights into the ability of different vaccine strategies for incorporating Env sequence diversity to elicit neutralizing antibodies, with implications for the development of broadly protective HIV-1 vaccines.
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Lian, Ying, Indresh Srivastava, V. Rául Gómez-Román, Jan zur Megede, Yide Sun, Elaine Kan, Susan Hilt, et al. "Evaluation of Envelope Vaccines Derived from the South African Subtype C Human Immunodeficiency Virus Type 1 TV1 Strain." Journal of Virology 79, no. 21 (November 1, 2005): 13338–49. http://dx.doi.org/10.1128/jvi.79.21.13338-13349.2005.
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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) subtype C infections are on the rise in Sub-Saharan Africa and Asia. Therefore, there is a need to develop an HIV vaccine capable of eliciting broadly reactive immune responses against members of this subtype. We show here that modified HIV envelope (env) DNA vaccines derived from the South African subtype C TV1 strain are able to prime for humoral responses in rabbits and rhesus macaques. Priming rabbits with DNA plasmids encoding V2-deleted TV1 gp140 (gp140TV1ΔV2), followed by boosting with oligomeric protein (o-gp140TV1ΔV2) in MF59 adjuvant, elicited higher titers of env-binding and autologous neutralizing antibodies than priming with DNA vaccines encoding the full-length TV1 env (gp160) or the intact TV1 gp140. Immunization with V2-deleted subtype B SF162 env and V2-deleted TV1 env together using a multivalent vaccine approach induced high titers of oligomeric env-binding antibodies and autologous neutralizing antibodies against both the subtypes B and C vaccine strains, HIV-1 SF162 and TV1, respectively. Low-level neutralizing activity against the heterologous South African subtype C TV2 strain, as well as a small subset of viruses in a panel of 13 heterologous primary isolates, was observed in some rabbits immunized with the V2-deleted vaccines. Immunization of rhesus macaques with the V2-deleted TV1 DNA prime/protein boost also elicited high titers of env-binding antibodies and moderate titers of autologous TV1 neutralizing antibodies. The pilot-scale production of the various TV1 DNA vaccine constructs and env proteins described here should provide an initial platform upon which to improve the immunogenicity of these subtype C HIV envelope vaccines.
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Maciejewski, Sonia, Tracy J. Ruckwardt, Kaitlyn M. Morabito, Bryant M. Foreman, Katherine E. Burgomaster, David N. Gordon, Rebecca S. Pelc, et al. "Distinct neutralizing antibody correlates of protection among related Zika virus vaccines identify a role for antibody quality." Science Translational Medicine 12, no. 547 (June 10, 2020): eaaw9066. http://dx.doi.org/10.1126/scitranslmed.aaw9066.
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The emergence of Zika virus (ZIKV) in the Americas stimulated the development of multiple ZIKV vaccine candidates. We previously developed two related DNA vaccine candidates encoding ZIKV structural proteins that were immunogenic in animal models and humans. We sought to identify neutralizing antibody (NAb) properties induced by each vaccine that correlated with protection in nonhuman primates (NHPs). Despite eliciting equivalent NAb titers in NHPs, these vaccines were not equally protective. The transfer of equivalent titers of vaccine-elicited NAb into AG129 mice also revealed nonequivalent protection, indicating qualitative differences among antibodies (Abs) elicited by these vaccines. Both vaccines elicited Abs with similar binding titers against envelope protein monomers and those incorporated into virus-like particles, as well as a comparable capacity to orchestrate phagocytosis. Functional analysis of vaccine-elicited NAbs from NHPs and humans revealed a capacity to neutralize the structurally mature form of the ZIKV virion that varied in magnitude among vaccine candidates. Conversely, sensitivity to the virion maturation state was not a characteristic of NAbs induced by natural or experimental infection. Passive transfer experiments in mice revealed that neutralization of mature ZIKV virions more accurately predicts protection from ZIKV infection. These findings demonstrate that NAb correlates of protection may differ among vaccine antigens when assayed using standard neutralization platforms and suggest that measurements of Ab quality, including the capacity to neutralize mature virions, will be critical for defining correlates of ZIKV vaccine-induced immunity.
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Bryan, J. T., J. F. Smith, W. Ruiz, M. K. Brownlow, M. J. Brown, and M. T. Esser. "Evaluation of antibodies induced by an HPV vaccine to cross-neutralize pseudovirions of vaccine-related HPV types." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 15008. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.15008.
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15008 Background: Human papillomavirus (HPV) is the causative agent of cervical cancer. The HPV types 6, 11, 16 and 18 quadrivalent L1 virus-like particle (VLP) vaccine has been shown to be highly efficacious in preventing HPV vaccine type-related disease. The HPV A7 species contains types 18, 45 and 59. The A9 species include types 16, 31, 33, 35, 52 and 58. The potential of the vaccine induced antibodies to cross-neutralize infection of pseudovirions (PsV) of HPV types within the A9 and A7 species was evaluated. Methods: Sera from quadrivalent, monovalent HPV 16, or monovalent HPV 18 vaccinees were evaluated. Sera were tested in a multiplexed competitive Luminex Immunoassay (cLIA) against vaccine types to demonstrate HPV type-specific seroconversion. A9 and A7 VLP type cross-reactive binding ability was assessed by a total IgG LIA. HPV L1 and L2 PsV containing secreted alkaline-phosphatase (SEAP) sequences were constructed using native HPV sequences for 16 and 31 and with mammalian codon-optimized sequences for 18 and 45. Demonstrated expression of SEAP was used as an indirect measure of PsV infection of 293TT cells. Results: All subjects seroconverted to high titers against the vaccine HPV types. Cross-reactive antibodies were generated. Quadrivalent vaccinee sera bound to HPV 31, 45, 52 and 58 VLPs. These total IgG titers were 1.5–2 logs lower than the titers to the vaccine types. PsV types 18 and 45 were neutralized using the 18 monovalent and the quadrivalent sera. At month 7, the PsV 18 neutralization titer was ∼1–1.5 logs less than that required for PsV 45 cross-neutralization. Neutralization studies using PsV of the A9 species are in progress. Conclusions: High titers of anti-HPV antibodies are elicited by vaccination with HPV VLP vaccines. These antibodies can prevent in vitro PsV infection of vaccine-HPV types. Cross-reactive, cross-neutralizing antibodies are generated, however at reduced titers compared to the vaccine-specific types. Antibody titers required for cross-protection against non-vaccine types are not known. [Table: see text]
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Dangi, Tanushree, Nicole M. Palacio, Sarah Sanchez, and Pablo Penaloza-MacMaster. "Characterization of cross-reactive immunity following coronavirus vaccination or natural infection." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 103.13. http://dx.doi.org/10.4049/jimmunol.206.supp.103.13.
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Abstract SARS-CoV-2 has infected more than 100 million people worldwide. Several vaccine candidates have been deployed under emergency use authorization, but it is unclear whether a coronavirus (CoV) vaccine can protect against other CoV. To investigate this proof-of-concept, we evaluated cross-reactive immunity following vaccination with a modified vaccinia Ankara expressing SARS-CoV-1 spike protein. We first vaccinated C57BL/6 mice intramuscularly and then measured heterologous antibodies (SARS-CoV-2, OC43 and mouse hepatitis virus, MHV) by ELISA. Interestingly, the SARS-CoV-1 vaccine elicited cross-reactive antibodies that recognize these other CoV. Sera from mice immunized with the SARS-CoV-1 vaccine neutralized SARS-CoV-2 pseudovirus in vitro (5-fold greater than control naïve sera; p=0.007), and transfer of these immune sera into naïve mice provided partial protection after heterologous challenges. Similar cross-reactivity was observed following immunization with a SARS-CoV-2 vaccine, and we mapped a conserved CD8 T cell epitope in both SARS-CoV-1 and CoV-2 spike protein, allowing us to develop an MHC tetramer to track this cross-reactive response. Finally, we interrogated whether a CoV infection could elicit cross-reactive immunity. We show that an OC43 infection generated cross-reactive antibodies against SARS-CoV-2, OC43 and MHV, and conferred partial protection against MHV challenge. In summary, our findings demonstrate that cross-reactive immunity can be elicited by vaccination, providing a framework for the rational design of universal CoV vaccines. Moreover, these data suggest that prior infection with endemic CoV may provide partial protection against other CoVs.
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Zost, Seth J., Kaela Parkhouse, Megan E. Gumina, Kangchon Kim, Sebastian Diaz Perez, Patrick C. Wilson, John J. Treanor, Andrea J. Sant, Sarah Cobey, and Scott E. Hensley. "Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains." Proceedings of the National Academy of Sciences 114, no. 47 (November 6, 2017): 12578–83. http://dx.doi.org/10.1073/pnas.1712377114.
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H3N2 viruses continuously acquire mutations in the hemagglutinin (HA) glycoprotein that abrogate binding of human antibodies. During the 2014–2015 influenza season, clade 3C.2a H3N2 viruses possessing a new predicted glycosylation site in antigenic site B of HA emerged, and these viruses remain prevalent today. The 2016–2017 seasonal influenza vaccine was updated to include a clade 3C.2a H3N2 strain; however, the egg-adapted version of this viral strain lacks the new putative glycosylation site. Here, we biochemically demonstrate that the HA antigenic site B of circulating clade 3C.2a viruses is glycosylated. We show that antibodies elicited in ferrets and humans exposed to the egg-adapted 2016–2017 H3N2 vaccine strain poorly neutralize a glycosylated clade 3C.2a H3N2 virus. Importantly, antibodies elicited in ferrets infected with the current circulating H3N2 viral strain (that possesses the glycosylation site) and humans vaccinated with baculovirus-expressed H3 antigens (that possess the glycosylation site motif) were able to efficiently recognize a glycosylated clade 3C.2a H3N2 virus. We propose that differences in glycosylation between H3N2 egg-adapted vaccines and circulating strains likely contributed to reduced vaccine effectiveness during the 2016–2017 influenza season. Furthermore, our data suggest that influenza virus antigens prepared via systems not reliant on egg adaptations are more likely to elicit protective antibody responses that are not affected by glycosylation of antigenic site B of H3N2 HA.
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Abd Alla, Mohamed D., Gary L. White, Tyson B. Rogers, Max E. Cary, David W. Carey, and Jonathan I. Ravdin. "Adherence-Inhibitory Intestinal Immunoglobulin A Antibody Response in Baboons Elicited by Use of a Synthetic Intranasal Lectin-Based Amebiasis Subunit Vaccine." Infection and Immunity 75, no. 8 (May 25, 2007): 3812–22. http://dx.doi.org/10.1128/iai.00341-07.
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ABSTRACT We designed an amebiasis subunit vaccine that is constructed by using four peptide epitopes of the galactose-inhibitable lectin heavy subunit that were recognized by intestinal secretory immunoglobulin A (IgA) antibodies from immune human subjects. These epitopes are contained in the region encompassing amino acids 758 to 1134 of the lectin heavy subunit, designated LC3. Baboons (Papio anubis) are natural hosts for Entamoeba histolytica; naturally infected baboons raised in captivity possess serum IgA antibodies to the same four LC3 epitopes as humans. Uninfected, seronegative baboons received four intranasal immunizations at 7-day intervals with the synthetic peptide vaccine (400, 800, or 1,600 μg per nostril) with cholera toxin (20 μg) as the adjuvant. As determined by an enzyme-linked immunosorbent assay (ELISA), each dose of the peptide vaccine elicited antipeptide serum IgA and IgG and intestinal IgA antibody responses in all six immunized baboons by day 28, 7 days after the last immunization (P, <0.01 for each dose compared to the cholera toxin control). The peptide vaccine elicited serum IgG and intestinal IgA antibodies that recognized purified recombinant LC3 protein (P, <0.008 and 0.02, respectively) and native lectin protein (P < 0.01). In addition, an indirect immunofluorescence assay with whole trophozoites (P < 0.01) and Western blot analysis confirmed that serum IgG antibodies from vaccinated baboons recognized native lectin protein on the surfaces of axenic E. histolytica trophozoites or from solubilized amebae. All four synthetic peptides were immunogenic; the vaccine elicited dose- and time-dependent responses, as determined by ELISA optical density readings indicating the production of serum and intestinal antibodies (P, <0.02 for antipeptide and antilectin antibodies). As a positive control, intranasal immunization with purified recombinant LC3 protein with cholera toxin as the adjuvant elicited a serum anti-LC3 IgA and IgG antibody response (P, 0.05 and <0.0001, respectively); however, no intestinal anti-LC3 IgA antibody response was observed (P = 0.4). Of interest, serum IgA and IgG antibodies elicited by the recombinant LC3 vaccine did not recognize any of the four putatively protective LC3 peptide epitopes. Both serum and fecal antibodies elicited by the peptide vaccine exhibited neutralizing activity, as determined by their dose-dependent inhibition of the galactose-specific adherence of E. histolytica trophozoites to Chinese hamster ovary cells in vitro (P, <0.001 for each group of antibodies compared to the control). In summary, a lectin-based intranasal polylysine-linked synthetic peptide vaccine was effective in eliciting an adherence-inhibitory, intestinal antilectin IgA antibody response in baboons. Future studies with the baboon model will determine vaccine efficacy against asymptomatic E. histolytica intestinal infection.
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Neerukonda, Sabari Nath, Russell Vassell, Sabrina Lusvarghi, Richard Wang, Fernando Echegaray, Lisa Bentley, Ann E. Eakin, et al. "SARS-CoV-2 Delta Variant Displays Moderate Resistance to Neutralizing Antibodies and Spike Protein Properties of Higher Soluble ACE2 Sensitivity, Enhanced Cleavage and Fusogenic Activity." Viruses 13, no. 12 (December 11, 2021): 2485. http://dx.doi.org/10.3390/v13122485.
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The SARS-CoV-2 B.1.617 lineage variants, Kappa (B.1.617.1) and Delta (B.1.617.2, AY) emerged during the second wave of infections in India, but the Delta variants have become dominant worldwide and continue to evolve. Here, we compared B.1.617 variants for neutralization resistance by convalescent sera, mRNA vaccine-elicited sera, and therapeutic neutralizing antibodies using a pseudovirus neutralization assay. B.1.617.1, B.1.617.2, and AY.1 pseudoviruses showed a modest 1.5- to 4.4-fold reduction in neutralization by convalescent sera and vaccine-elicited sera. In comparison, similar modest reductions were also observed for C.37, P.1, R.1, and B.1.526 pseudoviruses, but 7- and 16-fold reductions for vaccine-elicited and convalescent sera, respectively, were seen for B.1.351 pseudoviruses. Among twenty-three therapeutic antibodies tested, four antibodies showed either complete or partial loss of neutralization against B.1.617.2 pseudoviruses and six antibodies showed either complete or partial loss of neutralization against B.1.617.1 and AY.1 pseudoviruses. Our results indicate that the current mRNA-based vaccines will likely remain effective in protecting against B.1.617 variants. Finally, the P681R substitution confers efficient cleavage of B.1.617 variants’ spike proteins and the spike of Delta variants exhibited greater sensitivity to soluble ACE2 neutralization, as well as fusogenic activity, which may contribute to enhanced spread of Delta variants.
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Nagashima, Kaito A., and Jarrod J. Mousa. "Next-Generation Influenza HA Immunogens and Adjuvants in Pursuit of a Broadly Protective Vaccine." Viruses 13, no. 4 (March 24, 2021): 546. http://dx.doi.org/10.3390/v13040546.
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Influenza virus, a highly mutable respiratory pathogen, causes significant disease nearly every year. Current vaccines are designed to protect against circulating influenza strains of a given season. However, mismatches between vaccine strains and circulating strains, as well as inferior vaccine effectiveness in immunodeficient populations, represent major obstacles. In an effort to expand the breadth of protection elicited by influenza vaccination, one of the major surface glycoproteins, hemagglutinin (HA), has been modified to develop immunogens that display conserved regions from multiple viruses or elicit a highly polyclonal antibody response to broaden protection. These approaches, which target either the head or the stalk domain of HA, or both domains, have shown promise in recent preclinical and clinical studies. Furthermore, the role of adjuvants in bolstering the robustness of the humoral response has been studied, and their effects on the vaccine-elicited antibody repertoire are currently being investigated. This review will discuss the progress made in the universal influenza vaccine field with respect to influenza A viruses from the perspectives of both antigen and adjuvant, with a focus on the elicitation of broadly neutralizing antibodies.
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Luo, Deyan, Bing Ni, Peng Li, Wei Shi, Songle Zhang, Yue Han, Liwei Mao, Yangdong He, Yuzhang Wu, and Xiliang Wang. "Protective Immunity Elicited by a Divalent DNA Vaccine Encoding Both the L7/L12 and Omp16 Genes of Brucella abortus in BALB/c Mice." Infection and Immunity 74, no. 5 (May 2006): 2734–41. http://dx.doi.org/10.1128/iai.74.5.2734-2741.2006.
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ABSTRACT This study was designed to evaluate the immunogenicity and the protective efficacy of a divalent fusion DNA vaccine encoding both the Brucella abortus L7/L12 protein (ribosomal protein) and Omp16 protein (outer membrane lipoprotein), designated pcDNA3.1-L7/L12-Omp16. Intramuscular injection of this divalent DNA vaccine into BALB/c mice elicited markedly both humoral and cellular immune responses. The specific antibodies exhibited a dominance of immunoglobulin G2a (IgG2a) over IgG1. In addition, the dual-gene DNA vaccine elicited a strong T-cell proliferative response and induced a large amount of gamma interferon-producing T cells upon restimulation in vitro with recombinant fusion protein L7/L12-Omp16, suggesting the induction of a typical T-helper-1-dominated immune response in vivo. This divalent DNA vaccine could also induce a significant level of protection against challenge with the virulent strain B. abortus 544 in BALB/c mice. Furthermore, the protection level induced by the divalent DNA vaccine was significantly higher than that induced by the univalent DNA vaccines pcDNA3.1-L7/L12 or pcDNA3.1-Omp16. Taken together, the results of this study verify for the first time that the Omp16 gene can be a candidate target for a DNA vaccine against brucellosis. Additionally, a divalent genetic vaccine based on the L7/L12 and Omp16 genes can elicit a stronger cellular immune response and better immunoprotection than the relevant univalent vaccines can.
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Penezina, Oksana, Neil X. Krueger, Isaac R. Rodriguez-Chavez, Michael P. Busch, John Hural, Jerome H. Kim, Robert J. O'Connell, et al. "Performance of a Redesigned HIV Selectest Enzyme-Linked Immunosorbent Assay Optimized To Minimize Vaccine-Induced Seropositivity in HIV Vaccine Trial Participants." Clinical and Vaccine Immunology 21, no. 3 (January 8, 2014): 391–98. http://dx.doi.org/10.1128/cvi.00748-13.
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ABSTRACTVaccine-induced seropositivity (VISP) or seroreactivity (VISR), defined as the reaction of antibodies elicited by HIV vaccines with antigens used in HIV diagnostic immunoassays, can result in reactive assay results for vaccinated but uninfected individuals, with subsequent misclassification of their infection status. The eventual licensure of a vaccine will magnify this issue and calls for the development of mitigating solutions in advance. An immunoassay that discriminates between antibodies elicited by vaccine antigens and those elicited by infection has been developed to address this laboratory testing need. The HIV Selectest is based on consensus and clade-specific HIV peptides that are omitted in many HIV vaccine constructs. The assay was redesigned to enhance performance across worldwide clades and to simplify routine use via a standard kit format. The redesigned assay was evaluated with sera from vaccine trial participants, HIV-infected and uninfected individuals, and healthy controls. The HIV Selectest exhibited specificities of 99.5% with sera from uninfected recipients of 6 different HIV vaccines and 100% with sera from normal donors, while detecting HIV-1 infections, including intercurrent infections, with 95 to 100% sensitivity depending on the clade, with the highest sensitivities for clades A and C. HIV Selectest sensitivity decreased in very early seroconversion specimens, which possibly explains the slightly lower sensitivity observed for asymptomatic blood donors than for clinical HIV cases. Thus, the HIV Selectest provides a new laboratory tool for use in vaccine settings to distinguish the immune response to HIV vaccine antigens from that due to true infection.
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Riddle, Mark S., Robert W. Kaminski, Claudio Di Paolo, Chad K. Porter, Ramiro L. Gutierrez, Kristen A. Clarkson, Hailey E. Weerts, et al. "Safety and Immunogenicity of a Candidate Bioconjugate Vaccine against Shigella flexneri 2a Administered to Healthy Adults: a Single-Blind, Randomized Phase I Study." Clinical and Vaccine Immunology 23, no. 12 (August 31, 2016): 908–17. http://dx.doi.org/10.1128/cvi.00224-16.
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ABSTRACTSeveral candidate vaccines againstShigellaspp. are in development, but the lack of a clear correlate of protection from challenge with the induction of adequate immune responses among the youngest age groups in the developing world has hamperedShigellavaccine development over the past several decades. Bioconjugation technology, exploited here for anShigella flexneri2a candidate vaccine, offers a novel and potentially cost-effective way to develop and produce vaccines against a major pathogen of global health importance. Flexyn2a, a novelS. flexneri2a bioconjugate vaccine made of the polysaccharide component of theS. flexneri2a O-antigen, conjugated to the exotoxin protein A ofPseudomonas aeruginosa(EPA), was evaluated for safety and immunogenicity among healthy adults in a single-blind, phase I study with a staggered randomization approach. Thirty subjects (12 receiving 10 μg Flexyn2a, 12 receiving Flexyn2a with aluminum adjuvant, and 6 receiving placebo) were administered two injections 4 weeks apart and were followed for 168 days. Flexyn2a was well-tolerated, independently of the adjuvant and number of injections. The Flexyn2a vaccine elicited statistically significantS. flexneri2a lipopolysaccharide (LPS)-specific humoral responses at all time points postimmunization in all groups that received the vaccine. Elicited serum antibodies were functional, as evidenced by bactericidal activity againstS. flexneri2a. The bioconjugate candidate vaccine Flexyn2a has a satisfactory safety profile and elicited a robust humoral response toS. flexneri2a LPS with or without inclusion of an adjuvant. Moreover, the bioconjugate also induced functional antibodies, showing the technology's features in producing a promising candidate vaccine. (This study has been registered at ClinicalTrials.gov under registration no. NCT02388009.)
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Chou, Ai-Hsiang, Chia-Chyi Liu, Jui-Yuan Chang, Shu-Pei Lien, Meng-Shin Guo, Hau-Pong Tasi, Kuang-Nan Hsiao, et al. "Immunological Evaluation and Comparison of Different EV71 Vaccine Candidates." Clinical and Developmental Immunology 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/831282.
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Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are major causative agents of hand, foot, and mouth diseases (HFMDs), and EV71 is now recognized as an emerging neurotropic virus in Asia. Effective medications and/or prophylactic vaccines against HFMD are not available. The current results from mouse immunogenicity studies using in-house standardized RD cell virus neutralization assays indicate that (1) VP1 peptide (residues 211–225) formulated with Freund’s adjuvant (CFA/IFA) elicited low virus neutralizing antibody response (1/32 titer); (2) recombinant virus-like particles produced from baculovirus formulated with CFA/IFA could elicit good virus neutralization titer (1/160); (3) individual recombinant EV71 antigens (VP1, VP2, and VP3) formulated with CFA/IFA, only VP1 elicited antibody response with 1/128 virus neutralization titer; and (4) the formalin-inactivated EV71 formulated in alum elicited antibodies that cross-neutralized different EV71 genotypes (1/640), but failed to neutralize CVA16. In contrast, rabbits antisera could cross-neutralize strongly against different genotypes of EV71 but weakly against CVA16, with average titers 1/6400 and 1/32, respectively. The VP1 amino acid sequence dissimilarity between CVA16 and EV71 could partially explain why mouse antibodies failed to cross-neutralize CVA16. Therefore, the best formulation for producing cost-effective HFMD vaccine is a combination of formalin-inactivated EV71 and CAV16 virions.
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Mancini, Francesca, Francesca Micoli, and Omar Rossi. "Setup and Characterization of a High-Throughput Luminescence-Based Serum Bactericidal Assay (L-SBA) to Determine Functionality of Human Sera against Shigella flexneri." BioTech 11, no. 3 (July 27, 2022): 29. http://dx.doi.org/10.3390/biotech11030029.
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Shigellosis represents a major public health problem worldwide. The morbidity of the disease, especially in children in developing countries, together with the increase of antimicrobial resistance make a vaccine against Shigella an urgent medical need. Several vaccines under development are targeting Shigella lipopolysaccharide (LPS), whose extreme diversity renders necessary the development of multivalent vaccines. Immunity against Shigella LPS can elicit antibodies capable of killing bacteria in a serotype-specific manner. Therefore, although a correlation of protection against shigellosis has not been established, demonstration of vaccine-elicited antibody bactericidal activity may provide one means of vaccine protection against Shigella. To facilitate Shigella vaccine development, we have set up a high-throughput serum bactericidal assay based on luminescence readout (L-SBA), which has been already used to determine the functionality of antibodies against S. sonnei in multiple clinical trials. Here we present the setup and intra-laboratory characterization of L-SBA against three epidemiologically relevant Shigella flexneri serotypes using human sera. We assessed the linearity, repeatability and reproducibility of the method, demonstrating high assay specificity to detect the activity of antibodies against each homologous strain without any heterologous aspecificity against species-related and non-species-related strains; this assay is ready to be used to determine bactericidal activity of clinical sera raised by multivalent vaccines and in sero-epidemiological studies.
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Verma, Anita, Miriam M. Ngundi, and Drusilla L. Burns. "Mechanistic Analysis of the Effect of Deamidation on the Immunogenicity of Anthrax Protective Antigen." Clinical and Vaccine Immunology 23, no. 5 (February 24, 2016): 396–402. http://dx.doi.org/10.1128/cvi.00701-15.
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ABSTRACTThe spontaneous modification of proteins, such as deamidation of asparagine residues, can significantly affect the immunogenicity of protein-based vaccines. Using a “genetically deamidated” form of recombinant protective antigen (rPA), we have previously shown that deamidation can decrease the immunogenicity of rPA, the primary component of new-generation anthrax vaccines. In this study, we investigated the biochemical and immunological mechanisms by which deamidation of rPA might decrease the immunogenicity of the protein. We found that loss of the immunogenicity of rPA vaccine was independent of the presence of adjuvant. We assessed the effect of deamidation on the immunodominant neutralizing B-cell epitopes of rPA and found that these epitopes were not significantly affected by deamidation. In order to assess the effect of deamidation on T-cell help for antibody production elicited by rPA vaccine, we examined the ability of the wild-type and genetically deamidated forms of rPA to serve as hapten carriers. We found that when wild-type and genetically deamidated rPA were modified to similar extents with 2,4-dinitrophenyl hapten (DNP) and then used to immunize mice, higher levels of anti-DNP antibodies were elicited by wild-type DNP-rPA than those elicited by the genetically deamidated DNP-rPA, indicating that wild-type rPA elicits more T-cell help than the genetically deamidated form of the protein. These results suggest that a decrease in the ability of deamidated rPA to elicit T-cell help for antibody production is a possible contributor to its lower immunogenicity.
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Sarker, Protim, Evana Akhtar, Rakib Ullah Kuddusi, Mohammed Mamun Alam, Md Ahsanul Haq, Md Biplob Hosen, Bikash Chandra Chanda, et al. "Comparison of the Immune Responses to COVID-19 Vaccines in Bangladeshi Population." Vaccines 10, no. 9 (September 8, 2022): 1498. http://dx.doi.org/10.3390/vaccines10091498.
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Background: The adaptive immune response is a crucial component of the protective immunity against SARS-CoV-2, generated after infection or vaccination. Methods: We studied antibody titers, neutralizing antibodies and cellular immune responses to four different COVID-19 vaccines, namely Pfizer-BioNTech, Moderna Spikevax, AstraZeneca and Sinopharm vaccines in the Bangladeshi population (n = 1780). Results: mRNA vaccines Moderna (14,655 ± 11.3) and Pfizer (13,772 ± 11.5) elicited significantly higher anti-Spike (S) antibody titers compared to the Adenovector vaccine AstraZeneca (2443 ± 12.8) and inactivated vaccine Sinopharm (1150 ± 11.2). SARS-CoV-2-specific neutralizing antibodies as well as IFN-γ-secreting lymphocytes were more abundant in Pfizer and Moderna vaccine recipients compared to AstraZeneca and Sinopharm vaccine recipients. Participants previously infected with SARS-CoV-2 exhibited higher post-vaccine immune responses (S-specific and neutralizing antibodies, IFN-γ-secreting cells) compared to uninfected participants. Memory B (BMEM), total CD8+T, CD4+ central memory (CD4+CM) and T-regulatory (TREG) cells were more numerous in AstraZeneca vaccine recipients compared to other vaccine recipients. Plasmablasts, B-regulatory (BREG) and CD4+ effector (CD4+EFF) cells were more numerous in mRNA vaccine recipients. Conclusions: mRNA vaccines generated a higher antibody response, while a differential cellular response was observed for different vaccine types, suggesting that both cellular and humoral responses are important in immune monitoring of different types of vaccines.
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Arevalo, Claudia P., Marcus J. Bolton, Valerie Le Sage, Naiqing Ye, Colleen Furey, Hiromi Muramatsu, Mohamad-Gabriel Alameh, et al. "A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes." Science 378, no. 6622 (November 25, 2022): 899–904. http://dx.doi.org/10.1126/science.abm0271.
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Seasonal influenza vaccines offer little protection against pandemic influenza virus strains. It is difficult to create effective prepandemic vaccines because it is uncertain which influenza virus subtype will cause the next pandemic. In this work, we developed a nucleoside-modified messenger RNA (mRNA)–lipid nanoparticle vaccine encoding hemagglutinin antigens from all 20 known influenza A virus subtypes and influenza B virus lineages. This multivalent vaccine elicited high levels of cross-reactive and subtype-specific antibodies in mice and ferrets that reacted to all 20 encoded antigens. Vaccination protected mice and ferrets challenged with matched and mismatched viral strains, and this protection was at least partially dependent on antibodies. Our studies indicate that mRNA vaccines can provide protection against antigenically variable viruses by simultaneously inducing antibodies against multiple antigens.
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Kamei, Akinobu, Yamara S. Coutinho-Sledge, Joanna B. Goldberg, Gregory P. Priebe, and Gerald B. Pier. "Mucosal Vaccination with a Multivalent, Live-Attenuated Vaccine Induces Multifactorial Immunity againstPseudomonas aeruginosaAcute Lung Infection." Infection and Immunity 79, no. 3 (December 13, 2010): 1289–99. http://dx.doi.org/10.1128/iai.01139-10.
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ABSTRACTMany animal studies investigating adaptive immune effectors important for protection againstPseudomonas aeruginosahave implicated opsonic antibody to the antigenically variable lipopolysaccharide (LPS) O antigens as a primary effector. However, active and passive vaccination of humans against these antigens has not shown clinical efficacy. We hypothesized that optimal immunity would require inducing multiple immune effectors targeting multiple bacterial antigens. Therefore, we evaluated a multivalent live-attenuated mucosal vaccination strategy in a murine model of acuteP. aeruginosapneumonia to assess the contributions to protective efficacy of various bacterial antigens and host immune effectors. Vaccines combining 3 or 4 attenuated strains having different LPS serogroups were associated with the highest protective efficacy compared to vaccines with fewer components. Levels of opsonophagocytic antibodies, which were directed not only to the LPS O antigens but also to the LPS core and surface proteins, correlated with protective immunity. The multivalent live-attenuated vaccines overcame prior problems involving immunologic interference in the development of O-antigen-specific antibody responses when closely related O antigens were combined in multivalent vaccines. Antibodies to the LPS core were associated within vitrokilling andin vivoprotection against strains with O antigens not expressed by the vaccine strains, whereas antibodies to the LPS core and surface proteins augmented the contribution of O-antigen-specific antibodies elicited by vaccine strains containing a homologous O antigen. Local CD4 T cells in the lung also contributed to vaccine-based protection when opsonophagocytic antibodies to the challenge strain were absent. Thus, multivalent live-attenuated vaccines elicit multifactorial protective immunity toP. aeruginosalung infections.
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Huang, Ying, Monique S. França, James D. Allen, Hua Shi, and Ted M. Ross. "Next Generation of Computationally Optimized Broadly Reactive HA Vaccines Elicited Cross-Reactive Immune Responses and Provided Protection against H1N1 Virus Infection." Vaccines 9, no. 7 (July 16, 2021): 793. http://dx.doi.org/10.3390/vaccines9070793.
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Vaccination is the best way to prevent influenza virus infections, but the diversity of antigenically distinct isolates is a persistent challenge for vaccine development. In order to conquer the antigenic variability and improve influenza virus vaccine efficacy, our research group has developed computationally optimized broadly reactive antigens (COBRAs) in the form of recombinant hemagglutinins (rHAs) to elicit broader immune responses. However, previous COBRA H1N1 vaccines do not elicit immune responses that neutralize H1N1 virus strains in circulation during the recent years. In order to update our COBRA vaccine, two new candidate COBRA HA vaccines, Y2 and Y4, were generated using a new seasonal-based COBRA methodology derived from H1N1 isolates that circulated during 2013–2019. In this study, the effectiveness of COBRA Y2 and Y4 vaccines were evaluated in mice, and the elicited immune responses were compared to those generated by historical H1 COBRA HA and wild-type H1N1 HA vaccines. Mice vaccinated with the next generation COBRA HA vaccines effectively protected against morbidity and mortality after infection with H1N1 influenza viruses. The antibodies elicited by the COBRA HA vaccines were highly cross-reactive with influenza A (H1N1) pdm09-like viruses isolated from 2009 to 2021, especially with the most recent circulating viruses from 2019 to 2021. Furthermore, viral loads in lungs of mice vaccinated with Y2 and Y4 were dramatically reduced to low or undetectable levels, resulting in minimal lung injury compared to wild-type HA vaccines following H1N1 influenza virus infection.
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Cheng, Cheng, Jason G. D. Gall, Martha Nason, C. Richter King, Richard A. Koup, Mario Roederer, M. Juliana McElrath, et al. "Differential Specificity and Immunogenicity of Adenovirus Type 5 Neutralizing Antibodies Elicited by Natural Infection or Immunization." Journal of Virology 84, no. 1 (October 21, 2009): 630–38. http://dx.doi.org/10.1128/jvi.00866-09.
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ABSTRACT A recent clinical trial of a T-cell-based AIDS vaccine delivered with recombinant adenovirus type 5 (rAd5) vectors showed no efficacy in lowering viral load and was associated with increased risk of human immunodeficiency virus type 1 (HIV-1) infection. Preexisting immunity to Ad5 in humans could therefore affect both immunogenicity and vaccine efficacy. We hypothesized that vaccine-induced immunity is differentially affected, depending on whether subjects were exposed to Ad5 by natural infection or by vaccination. Serum samples from vaccine trial subjects receiving a DNA/rAd5 AIDS vaccine with or without prior immunity to Ad5 were examined for the specificity of their Ad5 neutralizing antibodies and their effect on HIV-1 immune responses. Here, we report that rAd5 neutralizing antibodies were directed to different components of the virion, depending on whether they were elicited by natural infection or vaccination in HIV vaccine trial subjects. Neutralizing antibodies elicited by natural infection were directed largely to the Ad5 fiber, while exposure to rAd5 through vaccination elicited antibodies primarily to capsid proteins other than fiber. Notably, preexisting immunity to Ad5 fiber from natural infection significantly reduced the CD4 and CD8 cell responses to HIV Gag after DNA/rAd5 vaccination. The specificity of Ad5 neutralizing antibodies therefore differs depending on the route of exposure, and natural Ad5 infection compromises Ad5 vaccine-induced immunity to weak immunogens, such as HIV-1 Gag. These results have implications for future AIDS vaccine trials and the design of next-generation gene-based vaccine vectors.
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Nelson, Cody S., Tori Huffman, Jennifer A. Jenks, Eduardo Cisneros de la Rosa, Guanhua Xie, Nathan Vandergrift, Robert F. Pass, Justin Pollara, and Sallie R. Permar. "HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions." Proceedings of the National Academy of Sciences 115, no. 24 (April 30, 2018): 6267–72. http://dx.doi.org/10.1073/pnas.1800177115.
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Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, frequently causing hearing loss and brain damage in afflicted infants. A vaccine to prevent maternal acquisition of HCMV during pregnancy is necessary to reduce the incidence of infant disease. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine platform is the most successful HCMV vaccine tested to date, demonstrating ∼50% efficacy in preventing HCMV acquisition in multiple phase 2 trials. However, the mechanism of vaccine protection remains unknown. Plasma from 33 postpartum women gB/MF59 vaccinees at peak immunogenicity was tested for gB epitope specificity as well as neutralizing and nonneutralizing anti-HCMV effector functions and compared with an HCMV-seropositive cohort. gB/MF59 vaccination elicited IgG responses with gB-binding magnitude and avidity comparable to natural infection. Additionally, IgG subclass distribution was similar with predominant IgG1 and IgG3 responses induced by gB vaccination and HCMV infection. However, vaccine-elicited antibodies exhibited limited neutralization of the autologous virus, negligible neutralization of multiple heterologous strains, and limited binding responses against gB structural motifs targeted by neutralizing antibodies including AD-1, AD-2, and domain I. Vaccinees had high-magnitude IgG responses against AD-3 linear epitopes, demonstrating immunodominance against this nonneutralizing, cytosolic region. Finally, vaccine-elicited IgG robustly bound membrane-associated gB on the surface of transfected or HCMV-infected cells and mediated virion phagocytosis, although were poor mediators of NK cell activation. Altogether, these data suggest that nonneutralizing antibody functions, including virion phagocytosis, likely played a role in the observed 50% vaccine-mediated protection against HCMV acquisition.
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Hatano, Kazue, and Gerald B. Pier. "Complex Serology and Immune Response of Mice to Variant High-Molecular-Weight O Polysaccharides Isolated fromPseudomonas aeruginosa Serogroup O2 Strains." Infection and Immunity 66, no. 8 (August 1, 1998): 3719–26. http://dx.doi.org/10.1128/iai.66.8.3719-3726.1998.
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ABSTRACT The O antigen of the Pseudomonas aeruginosalipopolysaccharide is the optimal target for protective antibodies, but the unusual and complex nature of their sugar substituents has made it difficult to define the range of these structures needed in an effective vaccine. Most clinical isolates of P. aeruginosacan be classified into 10 O-antigen serogroups, but slight chemical differences among O polysaccharides within a serogroup give rise to subtype epitopes. These epitopes could impact the reactivity of O-antigen-specific antibodies, as well as the susceptibility of a target strain to protective, opsonic antibodies. To define parameters of serogroup and subtype-epitope immunogenicity, antigenicity, and surface expression on P. aeruginosa cells, we prepared high-molecular-weight O-polysaccharide vaccines from strains ofP. aeruginosa serogroup O2, for which eight structurally variant O antigens expressing six defined subtype epitopes (O2a to O2f) have been identified. A complex pattern of immune responses to these antigens was observed following vaccination of mice. The high-molecular-weight O polysaccharides were generally more immunogenic at low doses (1 and 10 μg) than at a high dose (50 μg) and usually elicited antibodies that opsonized the homologous strain for phagocytic killing. Some of the individual polysaccharides elicited cross-opsonic antibodies to a variable number of strains that express all of the defined serogroup O2 subtype epitopes. Combination into one vaccine of two antigens that individually elicited cross-reactive opsonic antibodies to most members of the O2 serogroup inhibited, instead of enhanced, the production of antibodies broadly reactive with most serogroup O2 subtype strains. Thus, immune responses to P. aeruginosa O antigens may be restricted to a limited range of epitopes on structurally complex O antigens, and combining multiple related antigens into a single vaccine formulation may inhibit the production of those antibodies best able to protect against mostP. aeruginosa strains within a given O-antigen serogroup.
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Yahalom-Ronen, Yfat, Noam Erez, Morly Fisher, Hadas Tamir, Boaz Politi, Hagit Achdout, Sharon Melamed, et al. "Neutralization of SARS-CoV-2 Variants by rVSV-ΔG-Spike-Elicited Human Sera." Vaccines 10, no. 2 (February 14, 2022): 291. http://dx.doi.org/10.3390/vaccines10020291.
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The emergence of rapidly spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a major challenge to the ability of vaccines and therapeutic antibodies to provide immunity. These variants contain mutations of specific amino acids that might impede vaccine efficacy. BriLife® (rVSV-ΔG-spike) is a newly developed SARS-CoV-2 vaccine candidate currently in phase II clinical trials. It is based on a replication-competent vesicular stomatitis virus (VSV) platform. The rVSV-ΔG-spike contains several spontaneously acquired spike mutations that correspond to SARS-CoV-2 variants’ mutations. We show that human sera from BriLife® vaccinees preserve comparable neutralization titers towards alpha, gamma, and delta variants and show less than a three-fold reduction in the neutralization capacity of beta and omicron compared to the original virus. Taken together, we show that human sera from BriLife® vaccinees overall maintain a neutralizing antibody response against all tested variants. We suggest that BriLife®-acquired mutations may prove advantageous against future SARS-CoV-2 VOCs.
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Carter, Donald M., Christopher A. Darby, Bradford C. Lefoley, Corey J. Crevar, Timothy Alefantis, Raymond Oomen, Stephen F. Anderson, et al. "Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses." Journal of Virology 90, no. 9 (February 24, 2016): 4720–34. http://dx.doi.org/10.1128/jvi.03152-15.
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ABSTRACTOne of the challenges of developing influenza A vaccines is the diversity of antigenically distinct isolates. Previously, a novel hemagglutinin (HA) for H5N1 influenza was derived from a methodology termed computationally optimized broadly reactive antigen (COBRA). This COBRA HA elicited a broad antibody response against H5N1 isolates from different clades. We now report the development and characterization of a COBRA-based vaccine for both seasonal and pandemic H1N1 influenza virus isolates. Nine prototype H1N1 COBRA HA proteins were developed and tested in mice using a virus-like particle (VLP) format for the elicitation of broadly reactive, functional antibody responses and protection against viral challenge. These candidates were designed to recognize H1N1 viruses isolated within the last 30 years. In addition, several COBRA candidates were designed based on sequences of H1N1 viruses spanning the past 100 years, including modern pandemic H1N1 isolates. Four of the 9 H1N1 COBRA HA proteins (X1, X3, X6, and P1) had the broadest hemagglutination inhibition (HAI) activity against a panel of 17 H1N1 viruses. These vaccines were used in cocktails or prime-boost combinations. The most effective regimens that both elicited the broadest HAI response and protected mice against a pandemic H1N1 challenge were vaccines that contained the P1 COBRA VLP and either the X3 or X6 COBRA VLP vaccine. These mice had little or no detectable viral replication, comparable to that observed with a matched licensed vaccine. This is the first report describing a COBRA-based HA vaccine strategy that elicits a universal, broadly reactive, protective response against seasonal and pandemic H1N1 isolates.IMPORTANCEUniversal influenza vaccine approaches have the potential to be paradigm shifting for the influenza vaccine field, with the goal of replacing the current standard of care with broadly cross-protective vaccines. We have used COBRA technology to develop an HA head-based strategy that elicits antibodies against many H1 strains that have undergone genetic drift and has potential as a “subtype universal” vaccine. Nine HA COBRA candidates were developed, and these vaccines were used alone, in cocktails or in prime-boost combinations. The most effective regimens elicited the broadest hemagglutination inhibition (HAI) response against a panel of H1N1 viruses isolated over the past 100 years. This is the first report describing a COBRA-based HA vaccine strategy that elicits a broadly reactive response against seasonal and pandemic H1N1 isolates.
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Greaney, Allison J., Rachel T. Eguia, Tyler N. Starr, Khadija Khan, Nicholas Franko, Jennifer K. Logue, Sandra M. Lord, et al. "The SARS-CoV-2 Delta variant induces an antibody response largely focused on class 1 and 2 antibody epitopes." PLOS Pathogens 18, no. 6 (June 29, 2022): e1010592. http://dx.doi.org/10.1371/journal.ppat.1010592.
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Exposure histories to SARS-CoV-2 variants and vaccinations will shape the specificity of antibody responses. To understand the specificity of Delta-elicited antibody immunity, we characterize the polyclonal antibody response elicited by primary or mRNA vaccine-breakthrough Delta infections. Both types of infection elicit a neutralizing antibody response focused heavily on the receptor-binding domain (RBD). We use deep mutational scanning to show that mutations to the RBD’s class 1 and class 2 epitopes, including sites 417, 478, and 484–486 often reduce binding of these Delta-elicited antibodies. The anti-Delta antibody response is more similar to that elicited by early 2020 viruses than the Beta variant, with mutations to the class 1 and 2, but not class 3 epitopes, having the largest effects on polyclonal antibody binding. In addition, mutations to the class 1 epitope (e.g., K417N) tend to have larger effects on antibody binding and neutralization in the Delta spike than in the D614G spike, both for vaccine- and Delta-infection-elicited antibodies. These results help elucidate how the antigenic impacts of SARS-CoV-2 mutations depend on exposure history.
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del Valle, Jorge Reyes, Patricia Devaux, Gregory Hodge, Nicholas J. Wegner, Michael B. McChesney, and Roberto Cattaneo. "A Vectored Measles Virus Induces Hepatitis B Surface Antigen Antibodies While Protecting Macaques against Measles Virus Challenge." Journal of Virology 81, no. 19 (July 18, 2007): 10597–605. http://dx.doi.org/10.1128/jvi.00923-07.
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ABSTRACT Hepatitis B virus (HBV) acute and chronic infections remain a major worldwide health problem. Towards developing an anti-HBV vaccine with single-dose scheme potential, we engineered infectious measles virus (MV) genomic cDNAs with a vaccine strain background and expression vector properties. Hepatitis B surface antigen (HBsAg) expression cassettes were inserted into this cDNA and three MVs expressing HBsAg at different levels generated. All vectored MVs, which secrete HBsAg as subviral particles, elicited humoral responses in MV-susceptible genetically modified mice. However, small differences in HBsAg expression elicited vastly different HBsAg antibody levels. The two vectors inducing the highest HBsAg antibody levels were inoculated into rhesus monkeys (Macaca mulatta). After challenge with a pathogenic MV strain (Davis87), control naive monkeys showed a classic measles rash and high viral loads. In contrast, all monkeys immunized with vaccine or a control nonvectored recombinant vaccine or HBsAg-expressing vectored MV remained healthy, with low or undetectable viral loads. After a single vaccine dose, only the vector expressing HBsAg at the highest levels elicited protective levels of HBsAg antibodies in two of four animals. These observations reveal an expression threshold for efficient induction of HBsAg humoral immune responses. This threshold is lower in mice than in macaques. Implications for the development of divalent vaccines based on live attenuated viruses are discussed.
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Galula, Jedhan U., Chung-Yu Yang, Brent S. Davis, Gwong-Jen J. Chang, and Day-Yu Chao. "Cross-reactivity reduced dengue virus 2 vaccine has no cross-protection against heterotypic dengue viruses." Future Virology 15, no. 2 (February 2020): 79–90. http://dx.doi.org/10.2217/fvl-2019-0115.
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Aim: This study assessed how prime-boost strategies influence the immunogenicity of a cross-reactivity reduced dengue virus 2 vaccine (DENV-2 RD). Materials & methods: Mice were immunized with DENV-2 RD vaccines in a heterologous DNA and virus-like particle (VLP) prime-boost. Elicited antibodies were analyzed for neutralization and protective efficacy against four DENV serotypes. Results: DENV-2 RD DNA-VLP had induced higher and broader levels of total IgG and neutralizing antibodies with statistically significant IgG titers against DENV-2 and -3. Only pups of DENV-2 RD DNA-VLP immunized female mice were fully protected against homotypic DENV challenge and partially protected (60% survival rate) against heterotypic DENV-3 lethal challenge. Conclusion: DENV-2 RD vaccine requires a multivalent format to effectively elicit a balanced and protective immunity across all four DENV serotypes.
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Michon, Pascal, Tresa Fraser, and John H. Adams. "Naturally Acquired and Vaccine-Elicited Antibodies Block Erythrocyte Cytoadherence of the Plasmodium vivaxDuffy Binding Protein." Infection and Immunity 68, no. 6 (June 1, 2000): 3164–71. http://dx.doi.org/10.1128/iai.68.6.3164-3171.2000.
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ABSTRACT Malaria merozoites require the presence of specific surface receptors on the red blood cell for invasion. Plasmodium vivax, requires the Duffy blood group antigen as an obligate receptor for invasion. The parasite Duffy binding protein (DBP) is the ligand involved in this process, making the DBP a potential vaccine candidate. A preliminary objective was to study whether people exposed to vivax malaria acquire antibodies that have the ability to block erythrocyte cytoadherence to the PvDBP. In comparison, we studied the immunogenicity of various recombinant DBP vaccines and investigated their potential to induct antifunctional antibodies. In order to do so, recombinant proteins to different regions of the putative ectodomain of the DBP and a DNA vaccine were used to immunize laboratory animals. An in vitro cytoadherence assay was used to investigate the presence of antifunctional antibodies in plasmas from people naturally exposed to vivax malaria, as well as in antisera obtained by animal vaccination. Our results showed that human plasma from populations naturally exposed to vivax malaria, as well as antisera obtained by vaccination using recombinant proteins, a DNA vaccine, and a synthetic peptide to DBP, inhibited in vitro binding of human erythrocytes to the DBP ligand domain (DBPII) in correlation to their previously measured antibody titer. Our results provide further evidence for the vaccine potential of this essential parasite adhesion molecule.
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Wang, Hongye, Zengshuai Wang, Liang Ma, Xiaoyong Zhu, Bingxiang Li, Yuhang Huang, Jingwen Li, Ming Sun, Li Shi, and Yufeng Yao. "S Trimer Derived from SARS-CoV-2 B.1.351 and B.1.618 Induced Effective Immune Response against Multiple SARS-CoV-2 Variants." Vaccines 11, no. 1 (January 16, 2023): 193. http://dx.doi.org/10.3390/vaccines11010193.
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The spread of SARS-CoV-2 and its variants leads to a heavy burden on healthcare and the global economy, highlighting the need for developing vaccines that induce broad immunity against coronavirus. Here, we explored the immunogenicity of monovalent or bivalent spike (S) trimer subunit vaccines derived from SARS-CoV-2 B.1.351 (S1-2P) or/and B.1. 618 (S2-2P) in Balb/c mice. Both S1-2P and S2-2P elicited anti-spike antibody responses, and alum adjuvant induced higher levels of antibodies than Addavax adjuvant. The dose responses of the vaccines on immunogenicity were evaluated in vivo. A low dose of 5 μg monovalent recombinant protein or 2.5 μg bivalent vaccine triggered high-titer antibodies that showed cross-activity to Beta, Delta, and Gamma RBD in mice. The third immunization dose could boost (1.1 to 40.6 times) high levels of cross-binding antibodies and elicit high titers of neutralizing antibodies (64 to 1024) prototype, Beta, Delta, and Omicron variants. Furthermore, the vaccines were able to provoke a Th1-biased cellular immune response. Significantly, at the same antigen dose, S1-2P immune sera induced stronger broadly neutralizing antibodies against prototype, Beta, Delta, and Omicron variants compared to that induced by S2-2P. At the same time, the low dose of bivalent vaccine containing S2-2P and S1-2P (2.5 μg for each antigen) significantly improved the cross-neutralizing antibody responses. In conclusion, our results showed that monovalent S1-2P subunit vaccine or bivalent vaccine (S1-2P and S2-2P) induced potent humoral and cellular responses against multiple SARS-CoV-2 variants and provided valuable information for the development of recombinant protein-based SARS-CoV-2 vaccines that protect against emerging SARS-CoV-2 variants.
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Chen, Shing C., David H. Jones, Ellen F. Fynan, Graham H. Farrar, J. Christopher S. Clegg, Harry B. Greenberg, and John E. Herrmann. "Protective Immunity Induced by Oral Immunization with a Rotavirus DNA Vaccine Encapsulated in Microparticles." Journal of Virology 72, no. 7 (1998): 5757–61. http://dx.doi.org/10.1128/jvi.72.7.5757-5761.1998.
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DNA vaccines are usually given by intramuscular injection or by gene gun delivery of DNA-coated particles into the epidermis. Induction of mucosal immunity by targeting DNA vaccines to mucosal surfaces may offer advantages, and an oral vaccine could be effective for controlling infections of the gut mucosa. In a murine model, we obtained protective immune responses after oral immunization with a rotavirus VP6 DNA vaccine encapsulated in poly(lactide-coglycolide) (PLG) microparticles. One dose of vaccine given to BALB/c mice elicited both rotavirus-specific serum antibodies and intestinal immunoglobulin A (IgA). After challenge at 12 weeks postimmunization with homologous rotavirus, fecal rotavirus antigen was significantly reduced compared with controls. Earlier and higher fecal rotavirus-specific IgA responses were noted during the peak period of viral shedding, suggesting that protection was due to specific mucosal immune responses. The results that we obtained with PLG-encapsulated rotavirus VP6 DNA are the first to demonstrate protection against an infectious agent elicited after oral administration of a DNA vaccine.
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Lijeskić, Olivera, Ivana Klun, Marija Stamenov Djaković, Nenad Gligorić, Tijana Štajner, Jelena Srbljanović, and Olgica Djurković-Djaković. "Prospective Cohort Study of the Kinetics of Specific Antibodies to SARS-CoV-2 Infection and to Four SARS-CoV-2 Vaccines Available in Serbia, and Vaccine Effectiveness: A 3-Month Interim Report." Vaccines 9, no. 9 (September 17, 2021): 1031. http://dx.doi.org/10.3390/vaccines9091031.
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Real-life data on the performance of vaccines against SARS-CoV-2 are still limited. We here present the rates of detection and levels of antibodies specific for the SARS-CoV-2 spike protein RBD (receptor binding domain) elicited by four vaccines available in Serbia, including BNT-162b2 (BioNTech/Pfizer), BBIBP-CorV (Sinopharm), Gam-COVID-Vac (Gamaleya Research Institute) and ChAdOx1-S (AstraZeneca), compared with those after documented COVID-19, at 6 weeks and 3 months post first vaccine dose or post-infection. Six weeks post first vaccine dose, specific IgG antibodies were detected in 100% of individuals fully vaccinated with BNT-162b2 (n = 100) and Gam-COVID-Vac (n = 12) and in 81.7% of BBIBP-CorV recipients (n = 148), while one dose of ChAdOx1-S (n = 24) induced specific antibodies in 75%. Antibody levels elicited by BNT-162b2 were higher, while those elicited by BBIBP-CorV were lower, than after SARS-CoV-2 infection. By 3 months post-vaccination, antibody levels decreased but remained ≥20-fold above the cut-off in BNT-162b2 but not in BBIBP-CorV recipients, when an additional 30% were seronegative. For all vaccines, antibody levels were higher in individuals with past COVID-19 than in naïve individuals. A total of twelve new infections occurred within the first 3 months post-vaccination, eight after the first dose of BNT-162b2 and ChAdOx1-S (one each) and BBIBP-CorV (six), and four after full vaccination with BBIBP-CorV, but none required hospitalization.