scholarly journals Humoral Immune Correlates for Prevention of Postnatal Cytomegalovirus Acquisition

2019 ◽  
Vol 220 (5) ◽  
pp. 772-780 ◽  
Author(s):  
Frances M Saccoccio ◽  
Jennifer A Jenks ◽  
Hannah L Itell ◽  
Shuk Hang Li ◽  
Madison Berry ◽  
...  
Keyword(s):  
Maternal Antibodies ◽  
Glycoprotein B ◽  
Cmv Infection ◽  
Humoral Immune ◽  
Immune Correlates ◽  
Perinatal Hiv ◽  
Igg Binding ◽  
Specific Igg ◽  
Hiv Exposure ◽  
Cmv Status

Abstract Background Development of a cytomegalovirus (CMV) vaccine is a high priority. However, the ability of antibodies to protect against CMV infection is not well characterized. Studies of maternal antibodies in infants offer the potential to identify humoral correlates of protection against postnatal acquisition. Methods This hypothesis-generating study analyzed 29 Ugandan mother-infant pairs that were followed weekly for CMV acquisition. Seventeen mothers and no infants were infected with human immunodeficiency virus (HIV). We evaluated the association between CMV-specific immunoglobulin G (IgG) responses in mothers at the time of delivery and their infants’ CMV status at 6 months of age. We also assessed levels of CMV-specific IgG in infants at 6 weeks of age. CMV-specific IgG responses in the mother-infant pairs were then analyzed on the basis of perinatal HIV exposure. Results We found similar levels of multiple CMV glycoprotein–specific IgG binding specificities and functions in mothers and infants, irrespective of perinatal HIV exposure or infant CMV status at 6 months of age. However, the glycoprotein B–specific IgG titer, measured by 2 distinct assays, was higher in infants without CMV infection and was moderately associated with delayed CMV acquisition. Conclusions These data suggest that high levels of glycoprotein B–specific IgG may contribute to the partial protection against postnatal CMV infection afforded by maternal antibodies, and they support the continued inclusion of glycoprotein B antigens in CMV vaccine candidates.

scholarly journals 116. Role of Maternal Antibodies in Protection Against Postnatal Cytomegalovirus Acquisition

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S4-S4
Author(s):  
Frances Saccoccio ◽  
Hannah Itell ◽  
Skukhang Li ◽  
Jennifer Jenks ◽  
Guan Xie ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Natural Infection ◽  
The United States ◽  
Immune Correlates ◽  
Perinatal Hiv ◽  
Igg Binding ◽  
Maternal Hiv ◽  
Specific Igg ◽  
Humoral Responses

Abstract Background Congenital cytomegalovirus (CMV) is the leading infectious cause of birth defects in the United States. Development of an effective CMV vaccine is a public health priority. However, CMV vaccine development is limited by a poor understanding of the immune correlates of protection, including the role of CMV-specific IgG. Defining the role of passively acquired maternal IgG in the protection of half of the CMV-exposed, breastfeeding infants against postnatal CMV acquisition may inform CMV vaccine design Methods We analyzed CMV-specific humoral responses in 29 CMV-seropositive Ugandan mother–infant pairs. Seventeen mothers were HIV co-infected. Infants were followed weekly for postnatal CMV acquisition using saliva PCR. Twelve infants acquired CMV and 17 infants did not acquire CMV in the first 6 months of life. We compared CMV-specific IgG responses at delivery of mothers whose infants acquired CMV to mothers whose infants did not acquire CMV by 6 months of life and in the infants at 6 weeks of life. We also compared CMV-specific responses in mothers at delivery and infants at 6 weeks of life based on maternal HIV status. Results We found similar CMV-specific total IgG and IgG3 binding, avidity index, neutralization, antibody-dependent cellular phagocytosis, and antibody-dependent cellular cytotoxicity responses in mothers whose infants did or did not acquire CMV by 6 months of life. Moreover, similar CMV-specific IgG binding and neutralization responses were also found between infants who did or did not acquire CMV by 6 months of life. Finally, CMV-specific IgG responses were similar in HIV-infected and uninfected mothers at delivery and in infants at 6 weeks of life regardless of perinatal HIV exposure. Conclusion CMV-binding and functional IgG responses do not appear to impact infant susceptibility to postnatal CMV acquisition in the first 6 months of life, and therefore other viral or immunologic factors contribute to the inefficiency of this mode of CMV transmission. Thus, to provide sterilizing protection against mucosal CMV acquisition, an antibody-based CMV vaccine would likely have to induce higher magnitude or qualitatively different responses than that of natural infection. Disclosures All authors: No reported disclosures.

scholarly journals Antibody binding to native cytomegalovirus glycoprotein B predicts vaccine efficacy

2020 ◽  
Author(s):  
Jennifer A. Jenks ◽  
Cody S. Nelson ◽  
Hunter K. Roark ◽  
Matt Goodwin ◽  
Robert F. Pass ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Antibody Binding ◽  
Vaccine Antigen ◽  
Glycoprotein B ◽  
Two Phase ◽  
Humoral Immune ◽  
Immune Correlates ◽  
Igg Binding ◽  
Native Cell ◽  
A Cell

AbstractHuman cytomegalovirus (HCMV) is the most common infectious cause of congenital disease and post-transplant complications worldwide, yet vaccine development remains hampered by a limited understanding of protective immune responses. We investigated humoral immune correlates of protection against HCMV acquisition elicited by the most efficacious HCMV vaccine tested to-date, soluble glycoprotein B (gB) with MF59 adjuvant (gB/MF59), which achieved ∼50% efficacy in two phase II clinical trials. Protection against primary infection correlated with high magnitude antibody binding to gB expressed on a cell surface, but not to the vaccine antigen. Further, we identified monoclonal antibodies that differentially recognized soluble and cell-associated gB, highlighting structural differences essential for protective immunity. These results indicate the importance of the native, cell-associated gB conformation in future HCMV vaccine design.One Sentence SummaryPartially-effective HCMV gB/MF59 vaccine-elicited IgG binding to cell-associated gB correlates with protection against HCMV

scholarly journals Antibody binding to native cytomegalovirus glycoprotein B predicts efficacy of the gB/MF59 vaccine in humans

2020 ◽  
Vol 12 (568) ◽  
pp. eabb3611
Author(s):  
Jennifer A. Jenks ◽  
Cody S. Nelson ◽  
Hunter K. Roark ◽  
Matthew L. Goodwin ◽  
Robert F. Pass ◽  
...  
Keyword(s):  
Protective Immunity ◽  
Vaccine Development ◽  
Multiple Logistic Regression Analysis ◽  
Vaccine Antigen ◽  
Glycoprotein B ◽  
Functional Responses ◽  
Humoral Immune ◽  
Immune Correlates ◽  
Igg Binding ◽  
Native Cell

Human cytomegalovirus (CMV) is the most common infectious cause of infant brain damage and posttransplant complications worldwide. Despite the high global burden of disease, vaccine development to prevent infection remains hampered by challenges in generating protective immunity. The most efficacious CMV vaccine candidate tested to date is a soluble glycoprotein B (gB) subunit vaccine with MF59 adjuvant (gB/MF59), which achieved 50% protection in multiple historical phase 2 clinical trials. The vaccine-elicited immune responses that conferred this protection have remained unclear. We investigated the humoral immune correlates of protection from CMV acquisition in populations of CMV-seronegative adolescent and postpartum women who received the gB/MF59 vaccine. We found that gB/MF59 immunization elicited distinct CMV-specific immunoglobulin G (IgG)–binding profiles and IgG-mediated functional responses in adolescent and postpartum vaccinees, with heterologous CMV strain neutralization observed primarily in adolescent vaccinees. Using penalized multiple logistic regression analysis, we determined that protection against primary CMV infection in both cohorts was associated with serum IgG binding to gB present on a cell surface but not binding to the soluble vaccine antigen, suggesting that IgG binding to cell-associated gB is an immune correlate of vaccine efficacy. Supporting this, we identified gB-specific monoclonal antibodies that differentially recognized soluble or cell-associated gB, revealing that there are structural differences in cell-associated and soluble gB are relevant to the generation of protective immunity. Our results highlight the importance of the native, cell-associated gB conformation in future CMV vaccine design.

scholarly journals Rapid generation of neutralizing antibody responses in COVID-19 patients

2020 ◽  
Author(s):  
Mehul S Suthar ◽  
Matthew Zimmerman ◽  
Robert Kauffman ◽  
Grace Mantus ◽  
Susanne Linderman ◽  
...  
Keyword(s):  
Acute Infection ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Neutralization Activity ◽  
Viral Neutralization ◽  
Humoral Immune ◽  
Igg Binding ◽  
Antibody Titers ◽  
Specific Igg ◽  
Rapid Generation

SARS-CoV-2 is currently causing a devastating pandemic and there is a pressing need to understand the dynamics, specificity, and neutralizing potency of the humoral immune response during acute infection. Herein, we report the dynamics of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in 44 COVID-19 patients. RBD-specific IgG responses were detectable in all patients 6 days after PCR confirmation. Using a clinical isolate of SARS-CoV-2, neutralizing antibody titers were also detectable in all patients 6 days after PCR confirmation. The magnitude of RBD-specific IgG binding titers correlated strongly with viral neutralization. In a clinical setting, the initial analysis of the dynamics of RBD-specific IgG titers was corroborated in a larger cohort of PCR-confirmed patients (n=231). These findings have important implications for our understanding of protective immunity against SARS-CoV-2, the use of immune plasma as a therapy, and the development of much-needed vaccines.

scholarly journals 2651. Protection Against Human Cytomegalovirus Acquisition Is Associated with IgG Binding to Cell-Associated CMV glycoprotein B in Two Historical gB/MF59 Vaccine Cohorts

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S928-S928 ◽  
Author(s):  
Jennifer A Jenks ◽  
Cody S Nelson ◽  
Robert F Pass ◽  
David I Bernstein ◽  
Hunter K Roark ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Congenital Infection ◽  
Glycoprotein B ◽  
Transfected Cells ◽  
Humoral Immune ◽  
Adolescent Women ◽  
Phase Ii Clinical Trials ◽  
Group Data ◽  
Igg Binding ◽  
Native Cell

Abstract Background Human cytomegalovirus (CMV) is the most common congenital infection worldwide. A CMV glycoprotein B (gB) subunit vaccine with MF59 adjuvant achieved ~50% protection in phase II clinical trials in postpartum and adolescent women. Interestingly, postpartum vaccinees showed poor virus neutralization but robust antibody-dependent cellular phagocytosis (ADCP). In this study, we performed a combined humoral immune correlate of risk analysis in vaccinees to define vaccine-elicited immune responses associated with protection and targets for vaccine candidate immunogenicity. Methods gB/MF59 vaccinees who became infected and those who remained uninfected were 2:1 matched on race and number of vaccine doses. This study included 42 women from the adolescent (14 infected, 28 uninfected) and 33 from the postpartum cohorts (11 infected, 22 uninfected). IgG binding to whole gB, gB-neutralizing epitopes, FCRs, and whole virions were assessed by standard or multiplex ELISA. IgG binding to gB mRNA-transfected HEK293Ts was measured by flow cytometry. Neutralization of Towne, TB40/E, and AD169-repaired-GFP strains were measured in MRC-5, BJ5Ta, and/or ARPE-19 cells. Phagocytosis was assessed by THP-1 uptake of fluorescently conjugated TB40/E and AD169-repaired-GFP virions. Multiple linear regression controlling for cohort was performed for the combined log-transformed group data (apriori significance cut-off of P < 0.05, Benjamin–Hochberg FDR < 0.2). Results Vaccine-elicited antibodies in adolescent and postpartum cohorts exhibited similar magnitude IgG binding to soluble HCMV gB protein, gB-neutralizing domains, and gB-transfected cells. Autologous Towne strain neutralization was observed in both cohorts, but heterologous strain neutralization was observed only in adolescent vaccinees (P = 0.001). Both cohorts exhibited robust phagocytosis of HCMV virions. Regression analyses revealed that risk of HCMV acquisition in vaccinees was associated with magnitude IgG binding to gB-transfected cells (P = 0.006, FDR = 0.15), not neutralization or phagocytosis responses. Conclusion Protection against primary HCMV infection was significantly associated with vaccine-elicited IgG binding to gB-transfected cells, suggesting the importance of a native, cell-associated gB conformation in future vaccine candidates. Disclosures All authors: No reported disclosures.

scholarly journals SARS-CoV-2 specific antibody and neutralization assays reveal the wide range of the humoral immune response to virus

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Mikail Dogan ◽  
Lina Kozhaya ◽  
Lindsey Placek ◽  
Courtney Gunter ◽  
Mesut Yigit ◽  
...  
Keyword(s):  
Specific Antibody ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
High Specificity ◽  
Spike Protein ◽  
Humoral Immune ◽  
Specificity And Sensitivity ◽  
Wide Range ◽  
Specific Igg ◽  
Negative Controls

AbstractDevelopment of antibody protection during SARS-CoV-2 infection is a pressing question for public health and for vaccine development. We developed highly sensitive SARS-CoV-2-specific antibody and neutralization assays. SARS-CoV-2 Spike protein or Nucleocapsid protein specific IgG antibodies at titers more than 1:100,000 were detectable in all PCR+ subjects (n = 115) and were absent in the negative controls. Other isotype antibodies (IgA, IgG1-4) were also detected. SARS-CoV-2 neutralization was determined in COVID-19 and convalescent plasma at up to 10,000-fold dilution, using Spike protein pseudotyped lentiviruses, which were also blocked by neutralizing antibodies (NAbs). Hospitalized patients had up to 3000-fold higher antibody and neutralization titers compared to outpatients or convalescent plasma donors. Interestingly, some COVID-19 patients also possessed NAbs against SARS-CoV Spike protein pseudovirus. Together these results demonstrate the high specificity and sensitivity of our assays, which may impact understanding the quality or duration of the antibody response during COVID-19 and in determining the effectiveness of potential vaccines.

scholarly journals Correlates of Immune Protection following Cutaneous Immunization with an Attenuated Burkholderia pseudomallei Vaccine

2013 ◽  
Vol 81 (12) ◽  
pp. 4626-4634 ◽  
Author(s):  
Ediane B. Silva ◽  
Andrew Goodyear ◽  
Marjorie D. Sutherland ◽  
Nicole L. Podnecky ◽  
Mercedes Gonzalez-Juarrero ◽  
...  
Keyword(s):  
Immune Responses ◽  
Vaccine Strain ◽  
Protective Immunity ◽  
Burkholderia Pseudomallei ◽  
Partial Protection ◽  
Content Type ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Immune Correlates ◽  
Draining Lymph Nodes

ABSTRACTInfections with the Gram-negative bacteriumBurkholderia pseudomallei(melioidosis) are associated with high mortality, and there is currently no approved vaccine to prevent the development of melioidosis in humans. Infected patients also do not develop protective immunity to reinfection, and some individuals will develop chronic, subclinical infections withB. pseudomallei. At present, our understanding of what constitutes effective protective immunity againstB. pseudomalleiinfection remains incomplete. Therefore, we conducted a study to elucidate immune correlates of vaccine-induced protective immunity against acuteB. pseudomalleiinfection. BALB/c and C57BL/6 mice were immunized subcutaneously with a highly attenuated, Select Agent-excludedpurMdeletion mutant ofB. pseudomallei(strain Bp82) and then subjected to intranasal challenge with virulentB. pseudomalleistrain 1026b. Immunization with Bp82 generated significant protection from challenge withB. pseudomallei, and protection was associated with a significant reduction in bacterial burden in lungs, liver, and spleen of immunized mice. Humoral immunity was critically important for vaccine-induced protection, as mice lacking B cells were not protected by immunization and serum from Bp82-vaccinated mice could transfer partial protection to nonvaccinated animals. In contrast, vaccine-induced protective immunity was found to be independent of both CD4 and CD8 T cells. Tracking studies demonstrated uptake of the Bp82 vaccine strain predominately by neutrophils in vaccine-draining lymph nodes and by smaller numbers of dendritic cells (DC) and monocytes. We concluded that protection following cutaneous immunization with a live attenuatedBurkholderiavaccine strain was dependent primarily on generation of effective humoral immune responses.

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

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

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

scholarly journals Effect of Parenteral Vaccination of Newborn Holstein Calves against Viral Agents Involved in Bovine Respiratory Disease (BRD)

2020 ◽  
Vol 48 ◽  
Author(s):  
Viviani Gomes ◽  
Diego Daniel Gonzalez ◽  
Karina Medici Madureira ◽  
Marina Valeria Mozgovoj ◽  
Camila Costa Baccili ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Respiratory Disease ◽  
Management Practices ◽  
Immune Defense ◽  
Maternal Antibodies ◽  
Control Group ◽  
Humoral Immune ◽  
Unvaccinated Control ◽  
Holstein Calves ◽  
Newborn Calves

Background: Newborn calves are born immunosuppressed, hypogammaglobulinemic, immunologically immature, and therefore more vulnerable to many infectious diseases. During pregnancy, the fetal-placental environment is regulated by Th2-type cytokines that neutralize Th1 responses, an important factor for immune defense against viral agents. The ingestion and absorption of colostral immunoglobulins enhance the immunity of the neonate. However, the presence of maternal antibodies might negatively affect the success of parental vaccination in the first two months of life. This study aimed to evaluate the effecacy of parenteral vaccination in newborn calves with high titers of maternal antibodies against respiratory viruses.Materials, Methods & Results: Twenty-eight Holstein calves were allocated to the vaccinated group (VAC, n = 18) or an unvaccinated control group (NVAC, n = 10). The initial vaccination with 5 mL of a commercial vaccine occurred around the 14th day of life (D14) and the booster at D35. Respiratory and diarrhea symptoms were evaluated at D12, D14, D16, D20, D31, D36, D45, D53, and D60. Blood samples were taken for leukogram, haptoglobin, and seroneutralization of BVDV, BoHV-1, BRSV, and BPI3V, at the time of vaccination at D14 (T1), at booster (D35, T2), and 21 days after the booster (D56, T3). Despite the increased prevalence of BRD during the period of the study, no calves from either group exhibited respiratory disease at D12 or D14. In subsequent assessments, the frequency of BRD increased over time in the VAC group until it reached a maximum prevalence of 38.9% (7/18) at D31. In the NVAC group, the maximum prevalence observed was 40% at D45 and D60. A comparison of the frequencies for BRD cases showed a statistical trend at D36 (P = 0.07), with a higher prevalence for the NVAC group (30%) in relation to the VAC group (5.6%). For the NVAC group, a greater number of total leukocytes was observed at T3 (P = 0.038) and granulocytes (trend) at T2 (P = 0.066). Time analysis demonstrated a decrease in haptoglobin concentration in both groups (NVAC, P = 0.005 and VAC, P = 0.006), with a reduction in the values at T1 and T3 (NVAC = 0.005 and VAC = 0.024). Antibody titers were similar between groups for BVDV, BoHV-1, and BRSV. Higher titers for BPI3V were observed for the VAC group at D56 (P = 0.045).Discussion: The early-onset BRD was present in both groups between 30 and 60 days of age, based on the higher prevalence observed. These data reinforce the importance of early immunization programmes before infection. Factors such as management practices and facilities may have also contributed to the higher prevalence of BRD. The increased number of leukocytes and neutrophils at T2 (D35) and T3 (D56) in the NVAC group points to a stronger inflammatory response to various types of potential challenges. The inflammatory leukocyte profile explains the higher haptoglobin values observed in the NVAC group at T2 (D35). The similarity of titers of antibodies against BVDV, BoHV-1, and BRSV between groups may indicate that vaccinating the calves at 14 days of age did not induce a humoral immune response to these viruses, likely due to interference from the maternal antibodies. Early vaccination prevented a drop in specific viral antibodies and promoted partial protection for vaccinated calves around 14 days of age, with a decrease in the intensity of the inflammatory response at the peak of the disease and a higher concentration of antibodies against BPI3V after the booster.

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