Publications by authors named "Jens Wrammert"

86 Publications

Evaluation of Cellular and Serological Responses to Acute SARS-CoV-2 Infection Demonstrates the Functional Importance of the Receptor-Binding Domain.

J Immunol 2021 May 5. Epub 2021 May 5.

Centers for Childhood Infections and Vaccines, Children's Healthcare of Atlanta and Emory University, Department of Pediatrics, Atlanta, GA;

The factors that control the development of an effective immune response to the recently emerged SARS-CoV-2 virus are poorly understood. In this study, we provide a cross-sectional analysis of the dynamics of B cell responses to SARS-CoV-2 infection in hospitalized COVID-19 patients. We observe changes in B cell subsets consistent with a robust humoral immune response, including significant expansion of plasmablasts and activated receptor-binding domain (RBD)-specific memory B cell populations. We observe elevated titers of Abs to SARS-CoV-2 RBD, full-length Spike, and nucleoprotein over the course of infection, with higher levels of RBD-specific IgG correlating with increased serum neutralization. Depletion of RBD-specific Abs from serum removed a major portion of neutralizing activity in most individuals. Some donors did retain significant residual neutralization activity, suggesting a potential Ab subset targeting non-RBD epitopes. Taken together, these findings are instructive for future vaccine design and mAb strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.2001420DOI Listing
May 2021

Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells.

medRxiv 2021 Apr 27. Epub 2021 Apr 27.

Ending the COVID-19 pandemic will require long-lived immunity to SARS-CoV-2. We evaluated 254 COVID-19 patients longitudinally from early infection and for eight months thereafter and found a predominant broad-based immune memory response. SARS-CoV-2 spike binding and neutralizing antibodies exhibited a bi-phasic decay with an extended half-life of >200 days suggesting the generation of longer-lived plasma cells. In addition, there was a sustained IgG+ memory B cell response, which bodes well for a rapid antibody response upon virus re-exposure. Polyfunctional virus-specific CD4+ and CD8+ T cells were also generated and maintained with an estimated half-life of 200 days. Interestingly, the CD4+ T cell response equally targeted several SARS-CoV-2 proteins, whereas the CD8+ T cell response preferentially targeted the nucleoprotein, highlighting the importance of including the nucleoprotein as a potential vaccine antigen. Taken together, these results suggest that broad and effective immunity may persist long-term in recovered COVID-19 patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.04.19.21255739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095229PMC
April 2021

Impact of Immunoglobulin Isotype and Epitope on the Functional Properties of O-Specific Polysaccharide-Specific Monoclonal Antibodies.

mBio 2021 04 20;12(2). Epub 2021 Apr 20.

Division of Infectious Disease, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA

causes the severe diarrheal disease cholera. Clinical disease and current oral cholera vaccines generate antibody responses associated with protection. Immunity is thought to be largely mediated by lipopolysaccharide (LPS)-specific antibodies, primarily targeting the O-antigen. However, the properties and protective mechanism of functionally relevant antibodies have not been well defined. We previously reported on the early B cell response to cholera in a cohort of Bangladeshi patients, from which we characterized a panel of human monoclonal antibodies (MAbs) isolated from acutely induced plasmablasts. All antibodies in that previous study were expressed in an IgG1 backbone irrespective of their original isotype. To clearly determine the impact of affinity, immunoglobulin isotype and subclass on the functional properties of these MAbs, we re-engineered a subset of low- and high-affinity antibodies in different isotype and subclass immunoglobulin backbones and characterized the impact of these changes on binding, vibriocidal, agglutination, and motility inhibition activity. While the high-affinity antibodies bound similarly to O-antigen, irrespective of isotype, the low-affinity antibodies displayed significant avidity differences. Interestingly, despite exhibiting lower binding properties, variants derived from the low-affinity MAbs had comparable agglutination and motility inhibition properties to the potently binding antibodies, suggesting that how the MAb binds to the O-antigen may be critical to function. In addition, not only pentameric IgM and dimeric IgA, but also monomeric IgA, was remarkably more potent than their IgG counterparts at inhibiting motility. Finally, analyzing highly purified F(ab) versions of these antibodies, we show that LPS cross-linking is essential for motility inhibition. Immunity to the severe diarrheal disease cholera is largely mediated by lipopolysaccharide (LPS)-specific antibodies. However, the properties and protective mechanisms of functionally relevant antibodies have not been well defined. Here, we have engineered low and high-affinity LPS-specific antibodies in different immunoglobulin backbones in order to assess the impact of affinity, immunoglobulin isotype, and subclass on binding, vibriocidal, agglutination, and motility inhibition functional properties. Importantly, we found that affinity did not directly dictate functional potency since variants derived from the low-affinity MAbs had comparable agglutination and motility inhibition properties to the potently binding antibodies. This suggests that how the antibody binds sterically may be critical to function. In addition, not only pentameric IgM and dimeric IgA, but also monomeric IgA, was remarkably more potent than their IgG counterparts at inhibiting motility. Finally, analyzing highly purified F(ab) versions of these antibodies, we show that LPS cross-linking is essential for motility inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.03679-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092325PMC
April 2021

Infection- and vaccine-induced antibody binding and neutralization of the B.1.351 SARS-CoV-2 variant.

Cell Host Microbe 2021 04 20;29(4):516-521.e3. Epub 2021 Mar 20.

Department of Medicine, Emory University School of Medicine, Atlanta, GA 30329, USA; Hope Clinic of Emory Vaccine Center, Emory University, Decatur, GA 30030, USA.

The emergence of SARS-CoV-2 variants with mutations in the spike protein is raising concerns about the efficacy of infection- or vaccine-induced antibodies. We compared antibody binding and live virus neutralization of sera from naturally infected and Moderna-vaccinated individuals against two SARS-CoV-2 variants: B.1 containing the spike mutation D614G and the emerging B.1.351 variant containing additional spike mutations and deletions. Sera from acutely infected and convalescent COVID-19 patients exhibited a 3-fold reduction in binding antibody titers to the B.1.351 variant receptor-binding domain of the spike protein and a 3.5-fold reduction in neutralizing antibody titers against SARS-CoV-2 B.1.351 variant compared to the B.1 variant. Similar results were seen with sera from Moderna-vaccinated individuals. Despite reduced antibody titers against the B.1.351 variant, sera from infected and vaccinated individuals containing polyclonal antibodies to the spike protein could still neutralize SARS-CoV-2 B.1.351, suggesting that protective humoral immunity may be retained against this variant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chom.2021.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980225PMC
April 2021

Prevalence of SARS-CoV-2 antibodies in pediatric healthcare workers.

Int J Infect Dis 2021 Apr 12;105:474-481. Epub 2021 Mar 12.

Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States; Children's Healthcare of Atlanta, Atlanta, GA, United States; Center for Clinical and Translational Research, of Children's Healthcare of Atlanta and Emory University, Atlanta, GA, United States.

Objectives: To determine SARS-CoV-2-antibody prevalence in pediatric healthcare workers (pHCWs).

Design: Baseline prevalence of anti-SARS-CoV-2-IgG was assessed in a prospective cohort study from a large pediatric healthcare facility. Prior SARS-CoV-2 testing history, potential risk factors and anxiety level about COVID-19 were determined. Prevalence difference between emergency department (ED)-based and non-ED-pHCWs was modeled controlling for those covariates. Chi-square test-for-trend was used to examine prevalence by month of enrollment.

Results: Most of 642 pHCWs enrolled were 31-40years, female and had no comorbidities. Half had children in their home, 49% had traveled, 42% reported an illness since January, 31% had a known COVID-19 exposure, and 8% had SARS-CoV-2 PCR testing. High COVID-19 pandemic anxiety was reported by 71%. Anti-SARS-CoV-2-IgG prevalence was 4.1%; 8.4% among ED versus 2.0% among non-ED pHCWs (p < 0.001). ED-work location and known COVID-19 exposure were independent risk factors. 31% of antibody-positive pHCWs reported no symptoms. Prevalence significantly (p < 0.001) increased from 3.0% in April-June to 12.7% in July-August.

Conclusions: Anti-SARS-CoV-2-IgG prevalence was low in pHCWs but increased rapidly over time. Both working in the ED and exposure to a COVID-19-positive contact were associated with antibody-seropositivity. Ongoing universal PPE utilization is essential. These data may guide vaccination policies to protect front-line workers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijid.2021.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952267PMC
April 2021

Characterization of neutralizing versus binding antibodies and memory B cells in COVID-19 recovered individuals from India.

Virology 2021 06 5;558:13-21. Epub 2021 Mar 5.

ICGEB-Emory Vaccine Center, International Center for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India. Electronic address:

India is one of the most affected countries by COVID-19 pandemic; but little is understood regarding immune responses to SARS-CoV-2 in this region. Herein we examined SARS-CoV-2 neutralizing antibodies, IgG, IgM, IgA and memory B cells in COVID-19 recovered individual from India. While a vast majority of COVID-19 recovered individuals showed SARS-CoV-2 RBD-specific IgG, IgA and IgM antibodies (38/42, 90.47%; 21/42, 50%; 33/42, 78.57% respectively), only half of them had appreciable neutralizing antibody titers. RBD-specific IgG, but not IgA or IgM titers, correlated with neutralizing antibody titers and RBD-specific memory B cell frequencies. These findings have timely significance for identifying potential donors for plasma therapy using RBD-specific IgG assays as surrogate measurement for neutralizing antibodies in India. Further, this study provides useful information needed for designing large-scale studies towards understanding of inter-individual variation in immune memory to SARS CoV-2 natural infection for future vaccine evaluation and implementation efforts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.virol.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934698PMC
June 2021

Reduced binding and neutralization of infection- and vaccine-induced antibodies to the B.1.351 (South African) SARS-CoV-2 variant.

bioRxiv 2021 Feb 22. Epub 2021 Feb 22.

The emergence of SARS-CoV-2 variants with mutations in the spike protein is raising concerns about the efficacy of infection- or vaccine-induced antibodies to neutralize these variants. We compared antibody binding and live virus neutralization of sera from naturally infected and spike mRNA vaccinated individuals against a circulating SARS-CoV-2 B.1 variant and the emerging B.1.351 variant. In acutely-infected (5-19 days post-symptom onset), convalescent COVID-19 individuals (through 8 months post-symptom onset) and mRNA-1273 vaccinated individuals (day 14 post-second dose), we observed an average 4.3-fold reduction in antibody titers to the B.1.351-derived receptor binding domain of the spike protein and an average 3.5-fold reduction in neutralizing antibody titers to the SARS-CoV-2 B.1.351 variant as compared to the B.1 variant (spike D614G). However, most acute and convalescent sera from infected and all vaccinated individuals neutralize the SARS-CoV-2 B.1.351 variant, suggesting that protective immunity is retained against COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.02.20.432046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924283PMC
February 2021

Comparison of Antibody Class-Specific SARS-CoV-2 Serologies for the Diagnosis of Acute COVID-19.

J Clin Microbiol 2021 03 19;59(4). Epub 2021 Mar 19.

Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.

Accurate diagnosis of acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is critical for appropriate management of patients with this disease. We examined the possible complementary role of laboratory-developed class-specific clinical serology in assessing SARS-CoV-2 infection in hospitalized patients. Serological tests for immunoglobulin G (IgG), IgA, and IgM antibodies against the receptor binding domain (RBD) of SARS-CoV-2 were evaluated using samples from real-time reverse transcription-quantitative PCR (qRT-PCR)-confirmed inpatient coronavirus disease 2019 (COVID-19) cases. We analyzed the influence of timing and clinical severity on the diagnostic value of class-specific COVID-19 serology testing. Cross-sectional analysis revealed higher sensitivity and specificity at lower optical density cutoffs for IgA in hospitalized patients than for IgG and IgM serology (IgG area under the curve [AUC] of 0.91 [95% confidence interval {CI}, 0.89 to 0.93] versus IgA AUC of 0.97 [95% CI, 0.96 to 0.98] versus IgM AUC of 0.95 [95% CI, 0.92 to 0.97]). The enhanced performance of IgA serology was apparent in the first 2 weeks after symptom onset and the first week after PCR testing. In patients requiring intubation, all three tests exhibit enhanced sensitivity. Among PCR-negative patients under investigation for SARS-CoV-2 infection, 2 out of 61 showed clear evidence of seroconversion IgG, IgA, and IgM. Suspected false-positive results in the latter population were most frequently observed in IgG and IgM serology tests. Our findings suggest the potential utility of IgA serology in the acute setting and explore the benefits and limitations of class-specific serology as a complementary diagnostic tool to PCR for COVID-19 in the acute setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JCM.02026-20DOI Listing
March 2021

The amphibian peptide Yodha is virucidal for Zika and dengue viruses.

Sci Rep 2021 Jan 12;11(1):602. Epub 2021 Jan 12.

Emory Vaccine Center, Yerkes National Primate Center, Emory University, 954 Gatewood Road, Atlanta, GA, 30329, USA.

Zika virus (ZIKV) has emerged as a serious health threat in the Americas and the Caribbean. ZIKV is transmitted by the bite of an infected mosquito, sexual contact, and blood transfusion. ZIKV can also be transmitted to the developing fetus in utero, in some cases resulting in spontaneous abortion, fetal brain abnormalities, and microcephaly. In adults, ZIKV infection has been correlated with Guillain-Barre syndrome. Despite the public health threat posed by ZIKV, neither a vaccine nor antiviral drugs for use in humans are currently available. We have identified an amphibian host defense peptide, Yodha, which has potent virucidal activity against ZIKV. It acts directly on the virus and destroys Zika virus particles within 5 min of exposure. The Yodha peptide was effective against the Asian, African, and South American Zika virus strains and has the potential to be developed as an antiviral therapeutic in the fight against Zika virus. The peptide was also effective against all four dengue virus serotypes. Thus, Yodha peptide could potentially be developed as a pan-therapeutic for Zika and dengue viruses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-80596-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804942PMC
January 2021

Development of a Rapid Focus Reduction Neutralization Test Assay for Measuring SARS-CoV-2 Neutralizing Antibodies.

Curr Protoc Immunol 2020 12;131(1):e116

Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia.

SARS-CoV-2 is a recently emerged human coronavirus that has escalated to a pandemic. There are currently no approved vaccines for SARS-CoV-2, which causes severe respiratory illness or death. Defining the antibody response to SARS-CoV-2 will be essential for understanding disease progression, long-term immunity, and vaccine efficacy. Here we describe two methods for evaluating the neutralization capacity of SARS-CoV-2 antibodies. The basic protocol is a focus reduction neutralization test (FRNT), which involves immunostaining infected cells with a chromogen deposit readout. The alternate protocol is a modification of the FRNT that uses an infectious clone-derived SARS-CoV-2 virus expressing a fluorescent reporter. These protocols are adapted for use in a high-throughput setting, and are compatible with large-scale vaccine studies or clinical testing. © 2020 Wiley Periodicals LLC Basic Protocol: Focus reduction neutralization test Alternate Protocol: mNeonGreen-based focus reduction neutralization test (FRNT-mNG).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpim.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864545PMC
December 2020

Humans Surviving Cholera Develop Antibodies against Vibrio cholerae O-Specific Polysaccharide That Inhibit Pathogen Motility.

mBio 2020 11 17;11(6). Epub 2020 Nov 17.

Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.

The mechanism of protection against cholera afforded by previous illness or vaccination is currently unknown. We have recently shown that antibodies targeting O-specific polysaccharide (OSP) of correlate highly with protection against cholera. is highly motile and possesses a flagellum sheathed in OSP, and motility of correlates with virulence. Using high-speed video microscopy and building upon previous animal-related work, we demonstrate that sera, polyclonal antibody fractions, and OSP-specific monoclonal antibodies recovered from humans surviving cholera block motility at both subagglutinating and agglutinating concentrations. This antimotility effect is reversed by preadsorbing sera and polyclonal antibody fractions with purified OSP and is associated with OSP-specific but not flagellin-specific monoclonal antibodies. Fab fragments of OSP-specific polyclonal antibodies do not inhibit motility, suggesting a requirement for antibody-mediated cross-linking in motility inhibition. We show that OSP-specific antibodies do not directly affect viability, but that OSP-specific monoclonal antibody highly protects against death in the murine cholera model. We used competitive index studies to demonstrate that OSP-specific antibodies impede colonization and survival of in intestinal tissues and that this impact is motility dependent. Our findings suggest that the impedance of motility by antibodies targeting OSP contributes to protection against cholera. Cholera is a severe dehydrating illness of humans caused by is a highly motile bacterium that has a single flagellum covered in lipopolysaccharide (LPS) displaying O-specific polysaccharide (OSP), and motility correlates with its ability to cause disease. The mechanisms of protection against cholera are not well understood; however, since is a noninvasive intestinal pathogen, it is likely that antibodies that bind the pathogen or its products in the intestinal lumen contribute to protection from infection. Here, we demonstrate that OSP-specific antibodies isolated from humans surviving cholera in Bangladesh inhibit motility and are associated with protection against challenge in a motility-dependent manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.02847-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683404PMC
November 2020

Editorial: Advances in Plasma Cells in Health and Disease.

Front Immunol 2020 21;11:606737. Epub 2020 Oct 21.

Unit of Age Related Diseases, Division of Genetics and Cell Biology, Ospedale San Raffaele, Milano, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.606737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609968PMC
October 2020

Quantitative SARS-CoV-2 Serology in Children With Multisystem Inflammatory Syndrome (MIS-C).

Pediatrics 2020 12 2;146(6). Epub 2020 Sep 2.

Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia;

Objectives: We aimed to measure severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological responses in children hospitalized with multisystem inflammatory syndrome in children (MIS-C) compared with those with coronavirus disease 2019 (COVID-19), those with Kawasaki disease (KD), and hospitalized pediatric controls.

Methods: From March 17, 2020, to May 26, 2020, we prospectively identified hospitalized children with MIS-C ( = 10), symptomatic COVID-19 ( = 10), and KD ( = 5) and hospitalized controls ( = 4) at Children's Healthcare of Atlanta. With institutional review board approval, we obtained prospective and residual blood samples from these children and measured SARS-CoV-2 spike receptor-binding domain (RBD) immunoglobulin M and immunoglobulin G (IgG), full-length spike IgG, and nucleocapsid protein antibodies using quantitative enzyme-linked immunosorbent assays and SARS-CoV-2 neutralizing antibodies using live-virus focus-reduction neutralization assays. We statistically compared the log-transformed antibody titers among groups and performed linear regression analyses.

Results: All children with MIS-C had high titers of SARS-CoV-2 RBD IgG antibodies, which correlated with full-length spike IgG antibodies ( = 0.956; < .001), nucleocapsid protein antibodies ( = 0.846; < .001), and neutralizing antibodies ( = 0.667; < .001). Children with MIS-C had significantly higher SARS-CoV-2 RBD IgG antibody titers (geometric mean titer 6800; 95% confidence interval 3495-13 231) than children with COVID-19 (geometric mean titer 626; 95% confidence interval 251-1563; < .001), children with KD (geometric mean titer 124; 95% confidence interval 91-170; < .001), and hospitalized controls (geometric mean titer 85; < .001). All children with MIS-C also had detectable RBD immunoglobulin M antibodies, indicating recent SARS-CoV-2 infection. RBD IgG titers correlated with the erythrocyte sedimentation rate ( = 0.512; < .046) and with hospital ( = 0.548; = .014) and ICU lengths of stay ( = 0.590; = .010).

Conclusions: Quantitative SARS-CoV-2 serology may have a role in establishing the diagnosis of MIS-C, distinguishing it from similar clinical entities, and stratifying risk for adverse outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2020-018242DOI Listing
December 2020

Rapid Generation of Neutralizing Antibody Responses in COVID-19 Patients.

Cell Rep Med 2020 Jun 8;1(3):100040. Epub 2020 Jun 8.

Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.

SARS-CoV-2, the virus responsible for COVID-19, is causing a devastating worldwide pandemic, and there is a pressing need to understand the development, specificity, and neutralizing potency of humoral immune responses during acute infection. We report a cross-sectional study of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in a cohort of 44 hospitalized COVID-19 patients. RBD-specific IgG responses are detectable in all patients 6 days after PCR confirmation. Isotype switching to IgG occurs rapidly, primarily to IgG1 and IgG3. Using a clinical SARS-CoV-2 isolate, neutralizing antibody titers are detectable in all patients by 6 days after PCR confirmation and correlate with RBD-specific binding IgG titers. The RBD-specific binding data were further validated in a clinical setting with 231 PCR-confirmed COVID-19 patient samples. These findings have implications for understanding protective immunity against SARS-CoV-2, therapeutic use of immune plasma, and development of much-needed vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xcrm.2020.100040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276302PMC
June 2020

Influenza vaccine-induced human bone marrow plasma cells decline within a year after vaccination.

Science 2020 10 13;370(6513):237-241. Epub 2020 Aug 13.

Emory Vaccine Center and Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA.

A universal vaccine against influenza would ideally generate protective immune responses that are not only broadly reactive against multiple influenza strains but also long-lasting. Because long-term serum antibody levels are maintained by bone marrow plasma cells (BMPCs), we investigated the production and maintenance of these cells after influenza vaccination. We found increased numbers of influenza-specific BMPCs 4 weeks after immunization with the seasonal inactivated influenza vaccine, but numbers returned to near their prevaccination levels after 1 year. This decline was driven by the loss of BMPCs induced by the vaccine, whereas preexisting BMPCs were maintained. Our results suggest that most BMPCs generated by influenza vaccination in adults are short-lived. Designing strategies to enhance their persistence will be a key challenge for the next generation of influenza vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aaz8432DOI Listing
October 2020

3M-052, a synthetic TLR-7/8 agonist, induces durable HIV-1 envelope-specific plasma cells and humoral immunity in nonhuman primates.

Sci Immunol 2020 06;5(48)

Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, 954, Gatewood Road, Atlanta, GA, USA.

A fundamental challenge in vaccinology is learning how to induce durable antibody responses. Live viral vaccines induce antibody responses that last a lifetime, but those induced with subunit vaccines wane rapidly. Studies in mice and humans have established that long-lived plasma cells (LLPCs) in the bone marrow (BM) are critical mediators of durable antibody responses. Here, we present data that adjuvanting an HIV-1 clade C 1086.C-derived gp140 immunogen (Env) with a novel synthetic Toll-like receptor (TLR)-7/8 agonist named 3M-052 formulated in poly(lactic--glycolic)acid or PLGA nanoparticles (NPs) or with alum, either alone or in combination with a TLR-4 agonist GLA, induces notably high and persistent (up to ~1 year) frequencies of Env-specific LLPCs in the BM and serum antibody responses in rhesus macaques. Up to 36 and 18% of Env-specific cells among total IgG-secreting BM-resident plasma cells were detected at peak and termination, respectively. In contrast, adjuvanting Env with alum or GLA in NP induced significantly lower (~<100-fold) LLPC and antibody responses. Immune responses induced by 3M-052 were also significantly higher than those induced by a combination of TLR-7/8 (R848) and TLR-4 (MPL) agonists. Adjuvanting Env with 3M-052 also induced robust activation of blood monocytes, strong plasmablast responses in blood, germinal center B cells, T follicular helper (T) cells, and persistent Env-specific plasma cells in draining lymph nodes. Overall, these results demonstrate efficacy of 3M-052 in promoting high magnitude and durability of antibody responses via robust stimulation of innate immunity and BM-resident LLPCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciimmunol.abb1025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109745PMC
June 2020

Rapid generation of neutralizing antibody responses in COVID-19 patients.

medRxiv 2020 May 8. Epub 2020 May 8.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.05.03.20084442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274246PMC
May 2020

Induction of Transient Virus Replication Facilitates Antigen-Independent Isolation of SIV-Specific Monoclonal Antibodies.

Mol Ther Methods Clin Dev 2020 Mar 13;16:225-237. Epub 2020 Feb 13.

Department of Pathology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.

Structural characterization of the HIV-1 Envelope (Env) glycoprotein has facilitated the development of Env probes to isolate HIV-specific monoclonal antibodies (mAbs). However, preclinical studies have largely evaluated these virus-specific mAbs against chimeric viruses, which do not naturally infect non-human primates, in contrast to the unconstrained simian immunodeficiency virus (SIV)mac239 clone. Given the paucity of native-like reagents for the isolation of SIV-specific B cells, we examined a method to isolate SIVmac239-specific mAbs without using Env probes. We first activated virus-specific B cells by inducing viral replication after the infusion of a CD8β-depleting mAb or withdrawal of antiretroviral therapy in SIVmac239-infected rhesus macaques. Following the rise in viremia, we observed 2- to 4-fold increases in the number of SIVmac239 Env-reactive plasmablasts in circulation. We then sorted these activated B cells and obtained 206 paired Ab sequences. After expressing 122 mAbs, we identified 14 Env-specific mAbs. While these Env-specific mAbs bound to both the SIVmac239 SOSIP.664 trimer and to infected primary rhesus CD4 T cells, five also neutralized SIVmac316. Unfortunately, none of these mAbs neutralized SIVmac239. Our data show that this method can be used to isolate virus-specific mAbs without antigenic probes by inducing bursts of contemporary replicating viruses .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.omtm.2020.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021589PMC
March 2020

Plasmablast, Memory B Cell, CD4+ T Cell, and Circulating Follicular Helper T Cell Responses to a Non-Replicating Modified Vaccinia Ankara Vaccine.

Vaccines (Basel) 2020 Feb 6;8(1). Epub 2020 Feb 6.

.Hope Clinic, Department of Medicine, Emory University School of Medicine, Decatur, GA 30030, USA.

Background Vaccinia is known to induce antibody and cellular responses. Plasmablast, circulating follicular helper T (cT) cells, cytokine-expressing CD4 T cells, and memory B cells were compared between subcutaneous (SC) and needle-free jet injection (JI) recipients of non-replicating modified vaccinia Ankara (MVA) vaccine. Methods Vaccinia-naïve adults received MVA SC or by JI on Days 1 and 29. Vaccinia-specific antibodies were quantified by plaque reduction neutralization test (PRNT) and enzyme-linked immunosorbent assay. Plasmablast, cT, and cytokine-expressing CD4 T cells were assessed on Days 1, 8, 15, 29, 36, 43 (cT and CD4+ only) and 57. Memory B cells were measured on Days 1 and 57. Results Of the 36 enrolled subjects, only 22 received both vaccinations and had evaluable specimens after the second vaccine. Plasmablasts peaked one week after each vaccine. Day 15 plasmablasts correlated with peak PRNT titers. cT peaked on Days 8 and 36 and correlated with Day 36 plasmablasts. CD4+ peaked at Day 29 and one-third produced ≥2 cytokines. Day 57 memory B cells ranged from 0.1% to 0.17% of IgG-secreting B cells. Conclusions This study provides insights into the cellular responses to non-replicating MVA, currently used as a vector for a variety of novel vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/vaccines8010069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158692PMC
February 2020

Cross-Reactive Antibodies during Zika Virus Infection: Protection, Pathogenesis, and Placental Seeding.

Cell Host Microbe 2020 01;27(1):14-24

Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, GA 30322, USA; Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, GA 30329, USA. Electronic address:

Humoral immunity is an essential component of the protective immune response to flavivirus infection. Typically, primary infection generates a robust neutralizing antibody response that mediates viral control and protection. It is becoming increasingly apparent that secondary infection with a closely related flavivirus strain can result in immunological cross-reactivity; however, the consequences to infection outcome remain controversial. Since its introduction to Brazil in 2015, Zika virus (ZIKV) has caused an epidemic of fetal congenital malformations within the Americas. Because ZIKV is a mosquito-borne flavivirus with a high degree of sequence and structural homology to Dengue virus (DENV), the role of immunological cross-reactivity in ZIKV and DENV infections has become a great concern. In this review, we highlight contemporary findings that implicate a role for flavivirus antibodies in mediating protection, contributing to pathogenesis, and seeding the human placenta.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chom.2019.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802743PMC
January 2020

Decreased humoral immunity to mumps in young adults immunized with MMR vaccine in childhood.

Proc Natl Acad Sci U S A 2019 09 3;116(38):19071-19076. Epub 2019 Sep 3.

Hope Clinic of the Emory Vaccine Center, Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA 30030;

In the past decade, multiple mumps outbreaks have occurred in the United States, primarily in close-contact, high-density settings such as colleges, with a high attack rate among young adults, many of whom had the recommended 2 doses of mumps-measles-rubella (MMR) vaccine. Waning humoral immunity and the circulation of divergent wild-type mumps strains have been proposed as contributing factors to mumps resurgence. Blood samples from 71 healthy 18- to 23-year-old college students living in a non-outbreak area were assayed for antibodies and memory B cells (MBCs) to mumps, measles, and rubella. Seroprevalence rates of mumps, measles, and rubella determined by IgG enzyme-linked immunosorbent assay (ELISA) were 93, 93, and 100%, respectively. The index standard ratio indicated that the concentration of IgG was significantly lower for mumps than rubella. High IgG avidity to mumps Enders strain was detected in sera of 59/71 participants who had sufficient IgG levels. The frequency of circulating mumps-specific MBCs was 5 to 10 times lower than measles and rubella, and 10% of the participants had no detectable MBCs to mumps. Geometric mean neutralizing antibody titers (GMTs) by plaque reduction neutralization to the predominant circulating wild-type mumps strain (genotype G) were 6-fold lower than the GMTs against the Jeryl Lynn vaccine strain (genotype A). The majority of the participants (80%) received their second MMR vaccine ≥10 years prior to study participation. Additional efforts are needed to fully characterize B and T cell immune responses to mumps vaccine and to develop strategies to improve the quality and durability of vaccine-induced immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1905570116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754597PMC
September 2019

Single-Cell Analysis Suggests that Ongoing Affinity Maturation Drives the Emergence of Pemphigus Vulgaris Autoimmune Disease.

Cell Rep 2019 07;28(4):909-922.e6

Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, GA, USA; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Electronic address:

Pemphigus vulgaris (PV) is an autoimmune disease characterized by blistering sores on skin and mucosal membranes, caused by autoantibodies primarily targeting the cellular adhesion protein, desmoglein-3 (Dsg3). To better understand how Dsg3-specific autoantibodies develop and cause disease in humans, we performed a cross-sectional study of PV patients before and after treatment to track relevant cellular responses underlying disease pathogenesis, and we provide an in-depth analysis of two patients by generating a panel of mAbs from single Dsg3-specific memory B cells (MBCs). Additionally, we analyzed a paired sample from one patient collected 15-months prior to disease diagnosis. We find that Dsg3-specific MBCs have an activated phenotype and show signs of ongoing affinity maturation and clonal selection. Monoclonal antibodies (mAbs) with pathogenic activity primarily target epitopes in the extracellular domains EC1 and EC2 of Dsg3, though they can also bind to the EC4 domain. Combining antibodies targeting different epitopes synergistically enhances in vitro pathogenicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2019.06.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684256PMC
July 2019

Antigenic Drift of the Influenza A(H1N1)pdm09 Virus Neuraminidase Results in Reduced Effectiveness of A/California/7/2009 (H1N1pdm09)-Specific Antibodies.

mBio 2019 04 9;10(2). Epub 2019 Apr 9.

Division of Viral Products, Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland, USA

The effectiveness of influenza vaccines against circulating A(H1N1)pdm09 viruses was modest for several seasons despite the absence of antigenic drift of hemagglutinin (HA), the primary vaccine component. Since antibodies against HA and neuraminidase (NA) contribute independently to protection against disease, antigenic changes in NA may allow A(H1N1)pdm09 viruses to escape from vaccine-induced immunity. In this study, analysis of the specificities of human NA-specific monoclonal antibodies identified antigenic sites that have changed over time. The impact of these differences on inhibition of enzyme activity was not evident for polyclonal antisera until viruses emerged in 2013 without a predicted glycosylation site at amino acid 386 in NA. Phylogenetic and antigenic cartography demonstrated significant antigenic changes that in most cases aligned with genetic differences. Typical of NA drift, the antigenic difference is observed in one direction, with antibodies against conserved antigenic domains in A/California/7/2009 (CA/09) continuing to inhibit NA of recent A(H1N1)pdm09 viruses reasonably well. However, ferret CA/09-specific antiserum that inhibited the NA of A/Michigan/45/2015 (MI/15) very well , protected mice against lethal MI/15 infection poorly. These data show that antiserum against the homologous antigen is most effective and suggest the antigenic properties of NA should not be overlooked when selecting viruses for vaccine production. The effectiveness of seasonal influenza vaccines against circulating A(H1N1)pdm09 viruses has been modest in recent years, despite the absence of antigenic drift of HA, the primary vaccine component. Human monoclonal antibodies identified antigenic sites in NA that changed early after the new pandemic virus emerged. The reactivity of ferret antisera demonstrated antigenic drift of A(H1N1)pdm09 NA from 2013 onward. Passive transfer of serum raised against A/California/7/2009 was less effective than ferret serum against the homologous virus in protecting mice against a virus with the NA of more recent virus, A/Michigan/45/2015. Given the long-standing observation that NA-inhibiting antibodies are associated with resistance against disease in humans, these data demonstrate the importance of evaluating NA drift and suggest that vaccine effectiveness might be improved by selecting viruses for vaccine production that have NAs antigenically similar to those of circulating influenza viruses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.00307-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456748PMC
April 2019

Vaccine induction of antibodies and tissue-resident CD8+ T cells enhances protection against mucosal SHIV-infection in young macaques.

JCI Insight 2019 02 21;4(4). Epub 2019 Feb 21.

Departments of Pathology, and Microbiology & Immunology, Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, California, USA.

Antibodies and cytotoxic T cells represent 2 arms of host defense against pathogens. We hypothesized that vaccines that induce both high-magnitude CD8+ T cell responses and antibody responses might confer enhanced protection against HIV. To test this hypothesis, we immunized 3 groups of nonhuman primates: (a) Group 1, which includes sequential immunization regimen involving heterologous viral vectors (HVVs) comprising vesicular stomatitis virus, vaccinia virus, and adenovirus serotype 5-expressing SIVmac239 Gag; (b) Group 2, which includes immunization with a clade C HIV-1 envelope (Env) gp140 protein adjuvanted with nanoparticles containing a TLR7/8 agonist (3M-052); and (c) Group 3, which includes a combination of both regimens. Immunization with HVVs induced very high-magnitude Gag-specific CD8+ T cell responses in blood and tissue-resident CD8+ memory T cells in vaginal mucosa. Immunization with 3M-052 adjuvanted Env protein induced robust and persistent antibody responses and long-lasting innate responses. Despite similar antibody titers in Groups 2 and 3, there was enhanced protection in the younger animals in Group 3, against intravaginal infection with a heterologous SHIV strain. This protection correlated with the magnitude of the serum and vaginal Env-specific antibody titers on the day of challenge. Thus, vaccination strategies that induce both CD8+ T cell and antibody responses can confer enhanced protection against infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.126047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478416PMC
February 2019

Influenza Virus Vaccination Elicits Poorly Adapted B Cell Responses in Elderly Individuals.

Cell Host Microbe 2019 03 19;25(3):357-366.e6. Epub 2019 Feb 19.

Department of Medicine, Section of Rheumatology, The University of Chicago, Chicago, IL 60637, USA. Electronic address:

Influenza is a leading cause of death in the elderly, and the vaccine protects only a fraction of this population. A key aspect of antibody-mediated anti-influenza virus immunity is adaptation to antigenically distinct epitopes on emerging strains. We examined factors contributing to reduced influenza vaccine efficacy in the elderly and uncovered a dramatic reduction in the accumulation of de novo immunoglobulin gene somatic mutations upon vaccination. This reduction is associated with a significant decrease in the capacity of antibodies to target the viral glycoprotein, hemagglutinin (HA), and critical protective epitopes surrounding the HA receptor-binding domain. Immune escape by antigenic drift, in which viruses generate mutations in key antigenic epitopes, becomes highly exaggerated. Because of this reduced adaptability, most B cells activated in the elderly cohort target highly conserved but less potent epitopes. Given these findings, vaccines driving immunoglobulin gene somatic hypermutation should be a priority to protect elderly individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chom.2019.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452894PMC
March 2019

Kinetics of antibody response to influenza vaccination in renal transplant recipients.

Transpl Immunol 2019 04 18;53:51-60. Epub 2019 Jan 18.

Emory Transplant Center, Emory University School of Medicine, Atlanta, GA 30322, United States.

Annual vaccination is routinely used in organ transplant recipients for immunization against seasonal influenza. However, detailed analysis of the kinetics of vaccine-induced immune responses in this population is lacking. In this study, we investigated the kinetics of vaccine strains-specific antibody responses to trivalent influenza vaccine in a group of renal transplant recipients and a control group. First, we found that the geometric mean hemagglutination inhibition titer against all 3 vaccine strains in the transplant cohort was significantly low when compared to control subjects. Next, whereas the control group sera showed significantly higher HA-specific IgG and isotype IgG1 antibodies at all four time points, a similar increase in the transplant group was delayed until day 28. Interestingly, within the transplant group, subjects receiving belatacept/MMF/prednisone-based regimen had significantly lower levels of total IgG and HA-specific IgG when compared to tacrolimus/MMF/prednisone-based regimen. Even though IgG-ASC response in both cohorts peaked at day 7 post-vaccination, the frequency of IgG-ASC was significantly low in the transplant group. Taken together, our studies show delayed kinetics and lower levels of influenza vaccine-specific antibody responses in renal transplant recipients and, more importantly, indicate the need to probe and improve current vaccination strategies in renal transplant recipients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trim.2019.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471676PMC
April 2019

Pre-Existing Dengue Immunity Drives a DENV-Biased Plasmablast Response in ZIKV-Infected Patient.

Viruses 2018 12 29;11(1). Epub 2018 Dec 29.

Division of Infectious Disease, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.

The re-emergence of Zika virus (ZIKV) in the western hemisphere has most significantly affected dengue virus (DENV) endemic regions. Due to the geographical overlap between these two closely related flaviviruses, numerous individuals who suffered ZIKV infection during recent outbreaks may have also previously been exposed to DENV. As such, the impact of pre-existing dengue immunity on immune responses to ZIKV has been an area of focused research and interest. To understand how B cell responses to a ZIKV infection may be modulated by prior dengue exposures, we compared and contrasted plasmablast repertoire and specificity between two ZIKV-infected individuals, one dengue-naïve (ZK018) and the other dengue-experienced (ZK016). In addition to examining serological responses, we generated 59 patient plasmablast-derived monoclonal antibodies (mAbs) to define the heterogeneity of the early B cell response to ZIKV. Both donors experienced robust ZIKV-induced plasmablast expansions early after infection, with comparable mutational frequencies in their antibody variable genes. However, notable differences were observed in plasmablast clonality and functional reactivity. Plasmablasts from the dengue-experienced donor ZK016 included cells with shared clonal origin, while ZK018 mAbs were entirely clonally unrelated. Both at the mAb and plasma level, ZK016 antibodies displayed extensive cross-reactivity to DENV1-4, and preferentially neutralized DENV compared to ZIKV. In contrast, the neutralization activity of ZK018 mAbs was primarily directed towards ZIKV, and fewer mAbs from this donor were cross-reactive, with the cross-reactive phenotype largely limited to fusion loop-specific mAbs. ZK016 antibodies caused greater enhancement of DENV2 infection of FcRγ-expressing cells overall compared to ZK018, with a striking difference at the plasma level. Taken together, these data strongly suggest that the breadth and protective capacity of the initial antibody responses after ZIKV infection may depend on the dengue immune status of the individual. These findings have implications for vaccine design, given the likelihood that future epidemics will involve both dengue-experienced and naïve populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/v11010019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356269PMC
December 2018

Cross-Reactive Dengue Virus Antibodies Augment Zika Virus Infection of Human Placental Macrophages.

Cell Host Microbe 2018 11;24(5):731-742.e6

Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, GA 30322, USA; Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, GA 30329, USA. Electronic address:

Zika virus (ZIKV), which emerged in regions endemic to dengue virus (DENV), is vertically transmitted and results in adverse pregnancy outcomes. Antibodies to DENV can cross-react with ZIKV, but whether these antibodies influence ZIKV vertical transmission remains unclear. Here, we find that DENV antibodies increase ZIKV infection of placental macrophages (Hofbauer cells [HCs]) from 10% to over 80% and enhance infection of human placental explants. ZIKV-anti-DENV antibody complexes increase viral binding and entry into HCs but also result in blunted type I interferon, pro-inflammatory cytokine, and antiviral responses. Additionally, ZIKV infection of HCs and human placental explants is enhanced in an immunoglobulin G subclass-dependent manner, and targeting FcRn reduces ZIKV replication in human placental explants. Collectively, these findings support a role for pre-existing DENV antibodies in enhancement of ZIKV infection of select placental cell types and indicate that pre-existing immunity to DENV should be considered when addressing ZIKV vertical transmission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chom.2018.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394860PMC
November 2018

Broadly Reactive Human Monoclonal Antibodies Elicited following Pandemic H1N1 Influenza Virus Exposure Protect Mice against Highly Pathogenic H5N1 Challenge.

J Virol 2018 08 31;92(16). Epub 2018 Jul 31.

Emory Vaccine Center, School of Medicine, Emory University, Atlanta, Georgia, USA

Broadly cross-reactive antibodies (Abs) that recognize conserved epitopes within the influenza virus hemagglutinin (HA) stalk domain are of particular interest for their potential use as therapeutic and prophylactic agents against multiple influenza virus subtypes, including zoonotic virus strains. Here, we characterized four human HA stalk-reactive monoclonal antibodies (MAbs) for their binding breadth and affinity, neutralization capacity, and protective potential against an highly pathogenic avian influenza virus. The monoclonal antibodies were isolated from individuals shortly following infection with (70-1F02 and 1009-3B05) or vaccination against (05-2G02 and 09-3A01) A(H1N1)pdm09. Three of the MAbs bound HAs from multiple strains of group 1 viruses, and one MAb, 05-2G02, bound to both group 1 and group 2 influenza A virus HAs. All four antibodies prophylactically protected mice against a lethal challenge with the highly pathogenic A/Vietnam/1203/04 (H5N1) strain. Two MAbs, 70-1F02 and 09-3A01, were further tested for their therapeutic efficacy against the same strain and showed good efficacy in this setting as well. One MAb, 70-1F02, cocrystallized with H5 HA and showed heavy-chain-only interactions similar to those seen with the previously described CR6261 anti-stalk antibody. Finally, we show that antibodies that compete with these MAbs are prevalent in serum from an individual recently infected with the A(H1N1)pdm09 virus. The antibodies described here can be developed into broad-spectrum antiviral therapeutics that could be used to combat infections by zoonotic or emerging pandemic influenza viruses. The rise in zoonotic infections of humans by emerging influenza viruses is a worldwide public health concern. The majority of recent zoonotic human influenza cases were caused by H7N9 and H5Nx viruses and were associated with high morbidity and mortality. In addition, seasonal influenza viruses are estimated to cause up to 650,000 deaths annually worldwide. Currently available antiviral treatment options include only neuraminidase inhibitors, but some influenza viruses are naturally resistant to these drugs, and others quickly develop resistance-conferring mutations. Alternative therapeutics are urgently needed. Broadly protective antibodies that target the conserved "stalk" domain of the hemagglutinin represent potential potent antiviral prophylactic and therapeutic agents that can assist pandemic preparedness. Here, we describe four human monoclonal antibodies that target conserved regions of influenza HA and characterize their binding spectrum as well as their protective capacity in prophylactic and therapeutic settings against a lethal challenge with a zoonotic influenza virus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.00949-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069173PMC
August 2018