Comparative antibody responses to the live-attenuated and recombinant herpes zoster vaccines

Two herpes zoster (HZ) vaccines licensed in the United States are recommended by the Advisory Committee on Immunization Practices (ACIP): 1) live-attenuated vaccine (ZVL) using vOka strain varicella-zoster virus (VZV), and 2) recombinant adjuvanted vaccine (RZV) containing recombinant VZV glycoprotein E (gE). Two phase 3 clinical trials of RZV led the Advisory Committee on Immunization Practices (ACIP) to recommend it with preferred status. VZV T cell-mediated immunity (CMI), but not humoral immunity, are considered essential for protection against HZ. Published studies of humoral immunity focused on VZV-specific IgG concentration. To complement reports comparing the CMI responses to these vaccines, we compared humoral responses in ZVL and RZV recipients, emphasizing functional qualities (avidity and neutralization). Baseline avidities to a VZV glycoprotein mixture (gp) were near the upper limit of detection, but avidity to gE was much lower. Small increases in gp avidity were observed for both RZV and ZVL vaccination [19 and 12 avidity index units (AIU), respectively]. RZV boosted both gE avidity and VZV neutralizing antibody significantly more than ZVL (mean gE avidity boost: 47 AIU versus 22 AIU; mean neutralizing antibody boost: 22-fold versus 8-fold). Increases in neutralizing antibodies strongly correlated with gE avidity increases (r=0.5) and moderately with gp avidity increases (r=0.23). After 1 year, 81% of RZV recipients and only 18% of ZVL recipients retained >50% of their peak avidity boosts. These results are consistent with the CMI responses to these vaccines: RZV responses are skewed to long-term memory, whereas ZVL preferentially induces transient effector responses. IMPORTANCE These observations further distinguish the immunogenicity and duration of the immune response of the two vaccines. In addition, measurements of functional humoral immunity (IgG avidity, neutralizing antibody) in response to zoster immunization, alone or combined with other immune markers, might contribute to practical in vitro correlates of protection. Finally, combined with previous observations of the cell-mediated response to these vaccines, this study suggests that vaccine development could benefit from more expansive and granular assessments of acquired immunity during early phase 1 immunogenicity trials.

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Durable SARS-CoV-2 B cell immunity after mild or severe disease

10.1101/2020.10.28.20220996 ◽

2020 ◽

Author(s):

Clinton O. Ogega ◽

Nicole E. Skinner ◽

Paul W. Blair ◽

Han-Sol Park ◽

Kirsten Littlefield ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Humoral Immunity ◽

Neutralizing Antibodies ◽

Severe Disease ◽

Flow Cytometric Analysis ◽

Neutralizing Antibody ◽

Cell Mediated Immunity ◽

Specific Class ◽

Cell Immunity

AbstractMultiple studies have shown loss of SARS-CoV-2 specific antibodies over time after infection, raising concern that humoral immunity against the virus is not durable. If immunity wanes quickly, millions of people may be at risk for reinfection after recovery from COVID-19. However, memory B cells (MBC) could provide durable humoral immunity even if serum neutralizing antibody titers decline. We performed multi-dimensional flow cytometric analysis of S protein receptor binding domain (S-RBD)-specific MBC in cohorts of ambulatory COVID-19 patients with mild disease, and hospitalized patients with moderate to severe disease, at a median of 54 (39-104) days after onset of symptoms. We detected S-RBD-specific class-switched MBC in 13 out of 14 participants, including 4 of the 5 participants with lowest plasma levels of anti-S-RBD IgG and neutralizing antibodies. Resting MBC (rMBC) made up the largest proportion of S-RBD-specific class-switched MBC in both cohorts. FCRL5, a marker of functional memory when expressed on rMBC, was dramatically upregulated on S-RBD-specific rMBC. These data indicate that most SARS-CoV-2-infected individuals develop S-RBD-specific, class-switched MBC that phenotypically resemble germinal center-derived B cells induced by effective vaccination against other pathogens, providing evidence for durable B cell-mediated immunity against SARS-CoV-2 after recovery from mild or severe COVID-19 disease.Graphical Abstract

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A longitudinal study of SARS-CoV-2-infected patients reveals a high correlation between neutralizing antibodies and COVID-19 severity

Cellular and Molecular Immunology ◽

10.1038/s41423-020-00588-2 ◽

2021 ◽

Author(s):

Vincent Legros ◽

Solène Denolly ◽

Manon Vogrig ◽

Bertrand Boson ◽

Eglantine Siret ◽

...

Keyword(s):

Intensive Care ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Surface Protein ◽

Humoral Response ◽

Neutralizing Antibody ◽

Rapid Decline ◽

Serum Samples ◽

Immune Correlates ◽

Human Coronaviruses

AbstractUnderstanding the immune responses elicited by SARS-CoV-2 infection is critical in terms of protection against reinfection and, thus, for public health policy and vaccine development for COVID-19. In this study, using either live SARS-CoV-2 particles or retroviruses pseudotyped with the SARS-CoV-2 S viral surface protein (Spike), we studied the neutralizing antibody (nAb) response in serum samples from a cohort of 140 SARS-CoV-2 qPCR-confirmed infections, including patients with mild symptoms and also more severe forms, including those that required intensive care. We show that nAb titers correlated strongly with disease severity and with anti-spike IgG levels. Indeed, patients from intensive care units exhibited high nAb titers; conversely, patients with milder disease symptoms had heterogeneous nAb titers, and asymptomatic or exclusive outpatient-care patients had no or low nAbs. We found that nAb activity in SARS-CoV-2-infected patients displayed a relatively rapid decline after recovery compared to individuals infected with other coronaviruses. Moreover, we found an absence of cross-neutralization between endemic coronaviruses and SARS-CoV-2, indicating that previous infection by human coronaviruses may not generate protective nAbs against SARS-CoV-2. Finally, we found that the D614G mutation in the spike protein, which has recently been identified as the current major variant in Europe, does not allow neutralization escape. Altogether, our results contribute to our understanding of the immune correlates of SARS-CoV-2-induced disease, and rapid evaluation of the role of the humoral response in the pathogenesis of SARS-CoV-2 is warranted.

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Antibody titers measured by commercial assays are correlated with neutralizing antibody titers calibrated by international standards

10.1101/2021.07.16.21260618 ◽

2021 ◽

Author(s):

Yu-An Kung ◽

Chung-Guei Huang ◽

Sheng-Yu Huang ◽

Kuan-Ting Liu ◽

Peng-Nien Huang ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Geometric Mean ◽

Neutralizing Antibody ◽

Diagnostic Techniques ◽

International Standards ◽

World Health ◽

Serum Samples ◽

Antibody Titers ◽

Health Organization

The World Health Organization (WHO) has highlighted the importance of an international standard (IS) for SARS-CoV-2 neutralizing antibody titer detection, with the aim of calibrating different diagnostic techniques. In this study, IS was applied to calibrate neutralizing antibody titers (IU/mL) and binding antibody titers (BAU/mL) in response to SARS-CoV-2 vaccines. Serum samples were collected from participants receiving the Moderna (n = 20) and Pfizer (n = 20) vaccines at three time points: pre-vaccination, after one dose, and after two doses. We obtained geometric mean titers of 1404.16 and 928.75 IU/mL for neutralizing antibodies after two doses of the Moderna and Pfizer vaccines, respectively. These values provide an important baseline for vaccine development and the implementation of non-inferiority trials. We also compared three commercially available kits from Roche, Abbott, and MeDiPro for the detection of COVID-19 antibodies based on binding affinity to S1 and/or RBD. Our results demonstrated that antibody titers measured by commercial assays are highly correlated with neutralizing antibody titers calibrated by IS.

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Safety and Immunogenicity Evaluation of Inactivated whole-virus-SARS-COV-2 As Emerging Vaccine Development In Egypt

10.1101/2021.03.01.433130 ◽

2021 ◽

Author(s):

Amani A. Saleh ◽

Mohamed A. Saad ◽

Islam Ryan ◽

Magdy Amin ◽

Mohamed I. Shindy ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Clinical Symptoms ◽

Neutralizing Antibody ◽

Positive Development ◽

Virus Challenge ◽

Cell Monolayers ◽

Transmission Electron ◽

Dose Concentration ◽

Antibody Titers

AbstractThe current worldwide pandemic COVID-19 is causing severe human health problems, with high numbers of mortality rates and huge economic burdens that require an urgent demand for safe, and effective and vaccine development. Our study was the first trail to development and evaluation of safety and immune response to inactivated whole SARS-COV-2 virus vaccine adjuvanted with aluminium hydroxide. We used characterized SARS-COV-2 strain, severe acute respiratory syndrome coronavirus 2 isolates (SARS-CoV-2/human/EGY/Egy-SERVAC/2020) with accession numbers; MT981440; MT981439; MT981441; MT974071; MT974069 and MW250352 at GenBank that isolated from Egyptian patients SARS-CoV-2-positive. Development of the vaccine was carried out in a BSL - 3 facilities and the immunogenicity was determined in mice at two doses (55µg and 100µg per dose). All vaccinated mice were received a booster dose 14 days post first immunization. Our results demonstrated distinct cytopathic effect on the vero cell monolayers induced through SARS-COV-2 propagation and the viral particles were identified as Coronaviridae by transmission electron microscopy. SARS-CoV-2 was identified by RT-PCR performed on the cell culture. Immunogenicity of the developed vaccine indicated the high antigen-binding and neutralizing antibody titers, regardless the dose concentration, with excellent safety profiles.However, no deaths or clinical symptoms in mice groups. The efficacy of the inactivated vaccine formulation was tested by wild virus challenge the vaccinated mice and detection of viral replication in lung tissues. Vaccinated mice recorded complete protection from challenge infection three weeks post second dose. SARS-COV-2 replication was not observed in the lungs of mice following SARS-CoV-2 challenge, regardless of the level of serum neutralizing antibodies. This finding will support the future trials for evaluation an applicable SARS-CoV-2 vaccine candidate.

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Prevalence and Persistence of Maternal Dengue Neutralizing Antibodies in Infants From Central and Southern Thailand: A Retrospective Cohort Study

Asia Pacific Journal of Public Health ◽

10.1177/1010539519853396 ◽

2019 ◽

Vol 31 (4) ◽

pp. 288-295 ◽

Cited By ~ 1

Author(s):

Adrienne Guignard ◽

François Haguinet ◽

Stéphanie Wéry ◽

Phirangkul Kerdpanich

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Geometric Mean ◽

Neutralizing Antibody ◽

Maternal Antibodies ◽

Childhood Immunization ◽

Serum Samples ◽

Denv Serotypes ◽

Antibody Titers ◽

Antibody Kinetics

Understanding maternal dengue virus (DENV) neutralizing antibody kinetics in infants remains timely to develop a safe and effective childhood immunization. This retrospective study evaluated the prevalence and persistence of maternal antibody titers against DENV serotypes 1 to 4 in 139 Thai infants at 2, 6, and 7 months of age, using serum samples collected in a vaccination trial ( http://clinicaltrials.gov ; NCT00197275). Neutralizing antibodies against all 4 DENV serotypes were detected in 87.8% and 22.9% of infants at 2 and 7 months, respectively. At 2 months, DENV-4 neutralizing antibody geometric mean titers were notably lower (80) compared with DENV-1 to DENV-3 (277-471). Our results corroborate previous findings that DENV-1 to DENV-4 maternal antibodies persist at 7 months despite titers decrease from 2 months onwards. As persisting maternal antibodies may inhibit immune responses in DENV-vaccinated infants, a comprehensive understanding of DENV antibody kinetics is required in the perspective of vaccine development for infants.

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Controlled Human Hookworm Infection: Accelerating Human Hookworm Vaccine Development

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy083 ◽

2018 ◽

Vol 5 (5) ◽

Cited By ~ 15

Author(s):

David Diemert ◽

Doreen Campbell ◽

Jill Brelsford ◽

Caitlyn Leasure ◽

Guangzhao Li ◽

...

Keyword(s):

Vaccine Development ◽

Phase 1 ◽

Gastrointestinal Symptoms ◽

The United States ◽

Good Manufacturing Practice ◽

Application Site ◽

Central Component ◽

Hookworm Infection ◽

Patent Infection

Abstract Background Controlled human hookworm infection (CHHI) is a central component of a proposed hookworm vaccination-challenge model (HVCM) to test the efficacy of candidate vaccines. Critical to CHHI is the manufacture of Necator americanus infective larvae (NaL3) according to current Good Manufacturing Practice (cGMP) and the determination of an inoculum of NaL3 that is safe and reliably induces patent infection. Methods cGMP-grade NaL3 were produced for a phase 1 trial in 20 healthy, hookworm-naïve adults in the United States, who received either 25 or 50 NaL3. Participants were monitored for 12–18 weeks postinfection for safety, tolerability, and patency of N. americanus infection. Results Both NaL3 doses were well tolerated. Early manifestations of infection included pruritus, pain, and papulovesicular rash at the application site. Gastrointestinal symptoms and eosinophilia appeared after week 4 postinfection. The 50 NaL3 inoculum induced patent N. americanus infection in 90% of this dose group. Conclusions The inoculum of 50 NaL3 was well tolerated and consistently induced patent N. americanus infection suitable for future HVCM trials. Clinical Trials Registration NCT01940757.

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Neutralizing Antibody Responses in COVID-19 Convalescent Sera

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa673 ◽

2020 ◽

Vol 223 (1) ◽

pp. 47-55 ◽

Cited By ~ 1

Author(s):

William T Lee ◽

Roxanne C Girardin ◽

Alan P Dupuis ◽

Karen E Kulas ◽

Anne F Payne ◽

...

Keyword(s):

Neutralizing Antibodies ◽

High Titer ◽

Experimental Treatment ◽

Neutralizing Antibody ◽

Maximal Activity ◽

The United States ◽

Enzyme Linked Immunosorbent Assay ◽

United States Food ◽

Antibody Titers ◽

Antibody Levels

Abstract Passive transfer of antibodies from COVID-19 convalescent patients is being used as an experimental treatment for eligible patients with SARS-CoV-2 infections. The United States Food and Drug Administration’s (FDA) guidelines for convalescent plasma initially recommended target antibody titers of 160. We evaluated SARS-CoV-2 neutralizing antibodies in sera from recovered COVID-19 patients using plaque reduction neutralization tests (PRNT) at moderate (PRNT50) and high (PRNT90) stringency thresholds. We found that neutralizing activity significantly increased with time post symptom onset (PSO), reaching a peak at 31–35 days PSO. At this point, the number of sera having neutralizing titers of at least 160 was approximately 93% (PRNT50) and approximately 54% (PRNT90). Sera with high SARS-CoV-2 antibody levels (>960 enzyme-linked immunosorbent assay titers) showed maximal activity, but not all high-titer sera contained neutralizing antibody at FDA recommended levels, particularly at high stringency. These results underscore the value of serum characterization for neutralization activity.

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2764. Generation of a Balanced, Tetravalent Dengue Vaccine Based on Contemporary Strains Using a Computational, Synthetic Biology-Based Platform

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.2441 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S975-S975

Author(s):

Ying Wang ◽

Charles B Stauft ◽

Kanakatte Raviprakash ◽

J Robert Coleman ◽

Steffen Mueller

Keyword(s):

Human Cell ◽

Neutralizing Antibodies ◽

Vaccine Dose ◽

Neutralizing Antibody ◽

Denv Infection ◽

The United States ◽

Wild Type ◽

Lethal Challenge ◽

Denv Serotypes ◽

Tetravalent Vaccine

Abstract Background The WHO estimates that there may be 50 million cases of dengue virus (DENV) infection worldwide every year. There is no safe vaccine against DENV licensed in the United States. The development of a balanced and effective anti-DENV vaccine is vital to preventing morbidity and mortality. Codagenix used its proprietary SAVE (Synthetic Attenuated Virus Engineering) platform to generate and test a live attenuated, tetravalent vaccine against DENV. Methods Codagenix used SAVE to substitute under-represented human codons and codon-pairs into the E protein sequences of contemporary strains of DENV1-4, producing either a fully human-cell-deoptimized prM-E (E-Min), or a partially deoptimized prM-E (E-W/Min) to allow for balancing of the vaccine’s immunogenicity. Full genomes containing deoptimized E-Min and E-W/Min in the DENV2 backbone were transfected into cells to recover live-attenuated, human-cell-deoptimized vaccine strains. Mice were vaccinated with 106 FFU of each DENV vaccine (alone or together), boosted on day 21 and assessed for neutralizing antibodies by PRNT50 and survival after lethal challenge with mouse-adapted wild-type (WT) DENV. Cynomolgus macaques were immunized with a mixture of 106 FFU of each DENV vaccine strain. Two doses were administered on study day 1 and 57 and serum neutralizing antibodies were determined on day 57 and 85 by a microneutralization assay. Results SAVE deoptimized DENV viruses grew to wild-type (between 107 and 108 FFU/ml) levels at permissive temperatures (<37C). All vaccine strains generated neutralizing antibody levels comparable to WT. A tetravalent formulation containing all four E-Min strains protected mice from lethal challenge with DENV3. A tetravalent formulation of Codagenix DENV-E-W/Min vaccine elicited a robust and balanced neutralizing antibody response in non-human primates (NHPs) against all four DENV serotypes after a single dose. A second vaccine dose did not boost antibody titers significantly. Conclusion The ability to rationally balance the attenuation of multiple vaccine strains, thereby avoiding antibody-dependent enhancement, is a unique advantage of the Codagenix SAVE platform. Codagenix DENV vaccine viruses generated balanced, sterilizing immunity in NHPs after one dose. Disclosures All authors: No reported disclosures.

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Replicating Rather than Nonreplicating Adenovirus-Human Immunodeficiency Virus Recombinant Vaccines Are Better at Eliciting Potent Cellular Immunity and Priming High-Titer Antibodies

Journal of Virology ◽

10.1128/jvi.79.16.10200-10209.2005 ◽

2005 ◽

Vol 79 (16) ◽

pp. 10200-10209 ◽

Cited By ~ 75

Author(s):

Bo Peng ◽

Liqun Rejean Wang ◽

Victor Raúl Gómez-Román ◽

Alberta Davis-Warren ◽

David C. Montefiori ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Humoral Immunity ◽

Cellular Immunity ◽

Neutralizing Antibodies ◽

High Titer ◽

Neutralizing Antibody ◽

Preclinical Trial ◽

Immunodeficiency Virus ◽

Hiv Envelope ◽

Hiv 1

ABSTRACT A major challenge in combating the human immunodeficiency virus (HIV) epidemic is the development of vaccines capable of inducing potent, persistent cellular immunity and broadly reactive neutralizing antibody responses to HIV type 1 (HIV-1). We report here the results of a preclinical trial using the chimpanzee model to investigate a combination vaccine strategy involving sequential priming immunizations with different serotypes of adenovirus (Ad)/HIV-1MN env/rev recombinants and boosting with an HIV envelope subunit protein, oligomeric HIVSF162 gp140ΔV2. The immunogenicities of replicating and nonreplicating Ad/HIV-1MN env/rev recombinants were compared. Replicating Ad/HIV recombinants were better at eliciting HIV-specific cellular immune responses and better at priming humoral immunity against HIV than nonreplicating Ad-HIV recombinants carrying the same gene insert. Enhanced cellular immunity was manifested by a greater frequency of HIV envelope-specific gamma interferon-secreting peripheral blood lymphocytes and better priming of T-cell proliferative responses. Enhanced humoral immunity was seen in higher anti-envelope binding and neutralizing antibody titers and better induction of antibody-dependent cellular cytotoxicity. More animals primed with replicating Ad recombinants mounted neutralizing antibodies against heterologous R5 viruses after one or two booster immunizations with the mismatched oligomeric HIV-1SF162 gp140ΔV2 protein. These results support continued development of the replicating Ad-HIV recombinant vaccine approach and suggest that the use of replicating vectors for other vaccines may prove fruitful.

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Comparative Immunogenicity of Subtype A Human Immunodeficiency Virus Type 1 Envelope Exhibiting Differential Exposure of Conserved Neutralization Epitopes

Journal of Virology ◽

10.1128/jvi.01687-09 ◽

2009 ◽

Vol 84 (5) ◽

pp. 2573-2584 ◽

Cited By ~ 18

Author(s):

Catherine A. Blish ◽

D. Noah Sather ◽

George Sellhorn ◽

Leonidas Stamatatos ◽

Yide Sun ◽

...

Keyword(s):

Antibody Response ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Neutralizing Antibody ◽

Immunodeficiency Virus ◽

Cd4 Binding Site ◽

Variable Loops ◽

Linear Epitopes ◽

Subtype A ◽

Hiv 1

ABSTRACT Development of broadly cross-reactive neutralizing antibodies (NAbs) remains a major goal of HIV-1 vaccine development, but most candidate envelope immunogens have had limited ability to cross-neutralize heterologous strains. To evaluate the immunogenicity of subtype A variants of HIV-1, rabbits were immunized with pairs of closely related subtype A envelopes from the same individual. In each immunogen pair, one variant was readily neutralized by a variety of monoclonal antibodies and plasma antibodies, while the other was neutralization resistant, suggesting differences in the exposures of key epitopes. The breadth of the antibody response was evaluated against subtype A, B, C, and D variants of HIV-1. The specificity of the immunogen-derived neutralizing antibody response was also compared to that of the infected individuals from whom these variants were cloned. None of the immunogens produced broad neutralizing antibodies in immunized animals, and most of the neutralizing antibodies were directed to the variable loops, particularly the V3 loop. No detectable antibodies to either of the potentially exposed conserved epitopes, the membrane proximal external region, or the CD4 binding site were found with immunized rabbits. In contrast, relatively little of the neutralizing activity within the plasma samples of the infected individuals was directed to linear epitopes within the variable loops. These data indicate that immunogens designed to expose conserved regions did not enhance generation of broadly neutralizing antibodies in comparison with the immunogens that failed to expose those regions using this immunization approach.

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