Vaccines are among the most effective public health tools for combating certain infectious diseases such as influenza. The role of the humoral immune system in vaccine-induced protection is widely appreciated; however, our understanding of how antibody specificities relate to B cell function remains limited due to the complexity of polyclonal antibody responses. To address this, we developed the Spec-seq framework, which allows for simultaneous monoclonal antibody (mAb) characterization and transcriptional profiling from the same single cell. Here, we present the first application of the Spec-seq framework, which we applied to human plasmablasts after influenza vaccination in order to characterize transcriptional differences governed by B cell receptor (BCR) isotype and vaccine reactivity. Our analysis did not find evidence of long-term transcriptional specialization between plasmablasts of different isotypes. However, we did find enhanced transcriptional similarity between clonally related B cells, as well as distinct transcriptional signatures ascribed by BCR vaccine recognition. These data suggest IgG and IgA vaccine–positive plasmablasts are largely similar, whereas IgA vaccine–negative cells appear to be transcriptionally distinct from conventional, terminally differentiated, antigen-induced peripheral blood plasmablasts.
Karlynn E. Neu, Jenna J. Guthmiller, Min Huang, Jennifer La, Marcos C. Vieira, Kangchon Kim, Nai-Ying Zheng, Mario Cortese, Micah E. Tepora, Natalie J. Hamel, Karla Thatcher Rojas, Carole Henry, Dustin Shaw, Charles L. Dulberger, Bali Pulendran, Sarah Cobey, Aly A. Khan, Patrick C. Wilson
Despite showing success in treating melanoma and haematological malignancies, adoptive cell therapy (ACT) has generated only limited effects in solid tumors. This is, in part, due to a lack of specific antigen targets, poor trafficking/infiltration and immunosuppression in the tumor microenvironment. In this study, we combined ACT with oncolytic virus vaccines (OVV) to drive expansion and tumor infiltration of transferred antigen-specific T cells, and demonstrated that the combination is highly potent for the eradication of established solid tumors. Consistent with other successful immunotherapies, this approach elicited severe autoimmune consequence when the antigen targeted was a self-protein. However, modulation of IFNα/β signaling, either by functional blockade or rational choice of an OVV backbone, ameliorated autoimmune side effects without compromising antitumor efficacy. Our study uncovers a pathogenic role for IFNα/β in facilitating autoimmune toxicity during cancer immunotherapy and offers a safe and powerful combinatorial regimen with immediate translational applications.
Scott R. Walsh, Donald Bastin, Lan Chen, Andrew Nguyen, Christopher J. Storbeck, Charles Lefebvre, David Stojdl, Jonathan L. Bramson, John C. Bell, Yonghong Wan
Activation of HIV-1 reservoirs and induction of anti–HIV-1 T cells are critical to control HIV-1 rebound after combined antiretroviral therapy (cART). Here we evaluated in humanized mice (hu-mice) with persistent HIV-1 infection the therapeutic effect of TLR3 agonist and a CD40-targeting HIV-1 vaccine, which consists of a string of 5 highly conserved CD4+ and CD8+ T cell epitope-rich regions of HIV-1 Gag, Nef, and Pol fused to the C-terminus of a recombinant anti-human CD40 antibody (αCD40.HIV5pep). We show that αCD40.HIV5pep vaccination coadministered with poly(I:C) adjuvant induced HIV-1–specific human CD8+ and CD4+ T cell responses in hu-mice. Interestingly, poly(I:C) treatment also reactivated HIV-1 reservoirs. When administrated in therapeutic settings in HIV-1–infected hu-mice under effective cART, αCD40.HIV5pep with poly(I:C) vaccination induced HIV-1–specific CD8+ T cells and reduced the level of cell-associated HIV-1 DNA (or HIV-1 reservoirs) in lymphoid tissues. Most strikingly, the vaccination significantly delayed HIV-1 rebound after cART cessation. In summary, the αCD40.HIV5pep with poly(I:C) vaccination approach both activates replication of HIV-1 reservoirs and enhances the anti–HIV-1 T cell response, leading to a reduced level of cell-associated HIV-1 DNA or reservoirs. Our proof-of-concept study has significant implication for the development of CD40-targeting HIV-1 vaccine to enhance anti–HIV-1 immunity and reduce HIV-1 reservoirs in patients with suppressive cART.
Liang Cheng, Qi Wang, Guangming Li, Riddhima Banga, Jianping Ma, Haisheng Yu, Fumihiko Yasui, Zheng Zhang, Giuseppe Pantaleo, Matthieu Perreau, Sandra Zurawski, Gerard Zurawski, Yves Levy, Lishan Su
The adjuvanted varicella-zoster virus glycoprotein E (VZV gE) subunit herpes zoster vaccine (HZ/su) confers higher protection against HZ than the live attenuated zoster vaccine (ZV). To understand the immunologic basis for the different efficacies of the vaccines, we compared immune responses to the vaccines in adults 50- to 85-year-old. gE-specific T cells were very low/undetectable before vaccination when analyzed by FluoroSpot and flow cytometry. Both ZV and HZ/su increased gE-specific responses, but at peak memory response (PMR) after vaccination (30 days after ZV or after the second dose of HZ/su) gE-specific CD4+ and CD8+ T-cell responses were ≥ 10-fold higher in HZ/su compared with ZV recipients. Comparing the vaccines, T cell memory responses, including gE- and VZV-IL2+ spot-forming cells (SFC), were higher in HZ/su recipients and cytotoxic and effector responses were lower. At 1 year after vaccination, all gE-Th1 and VZV-IL2+ SFC remained higher in HZ/su compared to ZV recipients. Mediation analyses showed that IL2+ PMR were necessary for the persistence of Th1 responses to either vaccine and VZV-IL2+ PMR explained 73% of the total effect of HZ/su on persistence. This emphasizes the biological importance of the memory responses, which were clearly superior in HZ/su compared with ZV participants.
Myron J. Levin, Miranda E. Kroehl, Michael J. Johnson, Andrew Hammes, Dominik Reinhold, Nancy Lang, Adriana Weinberg
Germinal centers (GCs) are major sites of clonal B cell expansion and generation of long-lived, high-affinity antibody responses to pathogens. Signaling through toll-like receptors(TLRs) on B cells promotes many aspects of GC B cell responses, including affinity-maturation, class-switching and differentiation into long-lived memory and plasma cells. A major challenge for effective vaccination is identifying strategies to specifically promote GC B cell responses. Here we have identified a mechanism of regulation of GC B cell TLR signaling, mediated by αv integrins and non-canonical autophagy. Using B cell-specific αv-knockout mice, we show that loss of αv-mediated TLR regulation increased GC B cell expansion, somatic-hypermutation, class-switching, and generation of long-lived plasma cells after immunization with virus-like particles(VLPs) or antigens associated with TLR ligand adjuvants. Furthermore, targeting αv-mediated regulation increased the magnitude and breadth of antibody responses to influenza virus vaccination. These data therefore identify a mechanism of regulation of GC B cells, which can be targeted to enhance antibody responses to vaccination.
Fiona Raso, Sara Sagadiev, Samuel Du, Emily Gage, Tanvi Arkatkar, Genita Metzler, Lynda M. Stuart, Mark T. Orr, David Rawlings, Shaun Jackson, Adam Lacy-Hulbert, Mridu Acharya
In the mid-1990s, whole-cell (wP) pertussis vaccines were associated with local and systemic adverse events, which prompted their replacement with acellular (aP) vaccines in many high-income countries. In the past decade rates of pertussis disease have increased in children receiving only acellular pertussis vaccines. We compared the immune responses to acellular pertussis boosters in children who received their initial doses with either wP or aP vaccines using activation-induced marker (AIM) assays. Specifically, we examined pertussis-specific memory CD4+ T cell responses ex vivo, highlighting a Type 2/Th2 versus Type 1/Th1 and Th17 differential polarization as a function of childhood vaccination. Remarkably, after a contemporary aP booster, cells from donors originally primed with aP were 1) associated with increased IL-4, IL-5, IL-13, IL-9 and TGF-β and decreased IFNγ and IL-17 production; 2) defective in their ex vivo capacity to expand memory cells; and 3) less capable to proliferate in vitro. These differences appeared to be T cell-specific, since equivalent increases of antibody titers and plasmablasts after aP boost were seen in both groups. In conclusion, our data suggest that long lasting effects and differential polarization and proliferation exists between adults originally vaccinated with aP versus wP despite repeated acellular boosters.
Ricardo da Silva Antunes, Mariana Babor, Chelsea Carpenter, Natalie Khalil, Mario Cortese, Alexander J Mentzer, Grégory Seumois, Christopher D. Petro, Lisa A. Purcell, Pandurangan Vijayanand, Shane Crotty, Bali Pulendran, Bjorn Peters, Alessandro Sette
Vaccine responses vary by geographic location. We have previously described how HIV-associated inflammation leads to fibrosis of secondary lymph nodes (LNs) and T cell depletion. We hypothesized that other infections may cause LN inflammation and fibrosis, in a process similar to that seen in HIV infection, which may lead to T cell depletion and affect vaccine responses. We studied LNs of individuals from Kampala, Uganda, before and after yellow fever vaccination (YFV) and found fibrosis in LNs that was similar to that seen in HIV infection. We found blunted antibody responses to YFV that correlated to the amount of LN fibrosis and loss of T cells, including T follicular helper cells. These data suggest that LN fibrosis is not limited to HIV infection and may be associated with impaired immunologic responses to vaccines. This may have an impact on vaccine development, especially for infectious diseases prevalent in the developing world.
Cissy Kityo, Krystelle Nganou Makamdop, Meghan Rothenberger, Jeffrey G. Chipman, Torfi Hoskuldsson, Gregory J. Beilman, Bartosz Grzywacz, Peter Mugyenyi, Francis Ssali, Rama S. Akondy, Jodi Anderson, Thomas E. Schmidt, Thomas Reimann, Samuel P. Callisto, Jordan Schoephoerster, Jared Schuster, Proscovia Muloma, Patrick Ssengendo, Eirini Moysi, Constantinos Petrovas, Ray Lanciotti, Lin Zhang, Maria T. Arévalo, Benigno Rodriguez, Ted M. Ross, Lydie Trautmann, Rafick-Pierre Sekaly, Michael M. Lederman, Richard A. Koup, Rafi Ahmed, Cavan Reilly, Daniel C. Douek, Timothy W. Schacker
Enterotoxigenic Escherichia coli (ETEC) infections are highly prevalent in developing countries where clinical presentations range from asymptomatic colonization to severe cholera-like illness. The molecular basis for these varied presentations, that may involve strain-specific virulence features as well as host factors, have not been elucidated. We demonstrate that when challenged with ETEC strain H10407, originally isolated from a case of cholera-like illness, blood group A human volunteers developed severe diarrhea more frequently than individuals from other blood groups. Interestingly, a diverse population of ETEC strains, including H10407, secrete a novel adhesin molecule, EtpA. As many bacterial adhesins also agglutinate red blood cells, we combined the use of glycan arrays, biolayer inferometry, and non-canonical amino acid labeling with hemagglutination studies to demonstrate that EtpA is a dominant ETEC blood group A specific lectin/hemagglutinin. Importantly, we also show that EtpA interacts specifically with glycans expressed on intestinal epithelial cells from blood group A individuals, and that EtpA-mediated bacterial-host interactions accelerate bacterial adhesion and the effective delivery both heat-labile and heat-stable toxins of ETEC. Collectively, these data provide additional insight into the complex molecular basis of severe ETEC diarrheal illness that may inform rational design of vaccines to protect those at highest risk.
Pardeep Kumar, F. Matthew Kuhlmann, Subhra Chakroborty, A. Louis Bourgeois, Jennifer Foulke-Abel, Brunda Tumala, Tim J. Vickers, David A. Sack, Barbara DeNearing, Clayton D. Harro, W. Shea Wright, Jeffrey C. Gildersleeve, Matthew A. Ciorba, Srikanth Santhanam, Chad K. Porter, Ramiro L. Gutierrez, Michael G. Prouty, Mark S. Riddle, Alexander Polino, Alaullah Sheikh, Mark Donowitz, James M. Fleckenstein
Vaccines targeting glycan structures at the surface of pathogenic microbes must overcome the inherent T cell–independent nature of immune responses against glycans. Carbohydrate conjugate vaccines achieve this by coupling bacterial polysaccharides to a carrier protein that recruits heterologous CD4 T cells to help B cell maturation. Yet they most often produce low- to medium-affinity immune responses of limited duration in immunologically fit individuals and disappointing results in the elderly and immunocompromised patients. Here, we hypothesized that these limitations result from suboptimal T cell help. To produce the next generation of more efficacious conjugate vaccines, we have explored a synthetic design aimed at focusing both B cell and T cell recognition to a single short glycan displayed at the surface of a virus-like particle. We tested and established the proof of concept of this approach for 2 serotypes of
Zinaida Polonskaya, Shenglou Deng, Anita Sarkar, Lisa Kain, Marta Comellas-Aragones, Craig S. McKay, Katarzyna Kaczanowska, Marie Holt, Ryan McBride, Valle Palomo, Kevin M. Self, Seth Taylor, Adriana Irimia, Sanjay R. Mehta, Jennifer M. Dan, Matthew Brigger, Shane Crotty, Stephen P. Schoenberger, James C. Paulson, Ian A. Wilson, Paul B. Savage, M.G. Finn, Luc Teyton
Direct delivery of aerosolized vaccines to the respiratory mucosa elicits both systemic and mucosal responses. This vaccine strategy has not been tested for Ebola virus (EBOV) or other hemorrhagic fever viruses. Here, we examined the immunogenicity and protective efficacy of an aerosolized human parainfluenza virus type 3–vectored vaccine that expresses the glycoprotein (GP) of EBOV (HPIV3/EboGP) delivered to the respiratory tract. Rhesus macaques were vaccinated with aerosolized HPIV3/EboGP, liquid HPIV3/EboGP, or an unrelated, intramuscular, Venezuelan equine encephalitis replicon vaccine expressing EBOV GP. Serum and mucosal samples from aerosolized HPIV3/EboGP recipients exhibited high EBOV-specific IgG, IgA, and neutralizing antibody titers, which exceeded or equaled titers observed in liquid recipients. The HPIV3/EboGP vaccine induced an EBOV-specific cellular response that was greatest in the lungs and yielded polyfunctional CD8+ T cells, including a subset that expressed CD103 (αE integrin), and CD4+ T helper cells that were predominately type 1. The magnitude of the CD4+ T cell response was greater in aerosol vaccinees. The HPIV3/EboGP vaccine produced a more robust cell-mediated and humoral immune response than the systemic replicon vaccine. Moreover, 1 aerosol HPIV3/EboGP dose conferred 100% protection to macaques exposed to EBOV. Aerosol vaccination represents a useful and feasible vaccination mode that can be implemented with ease in a filovirus disease outbreak situation.
Michelle Meyer, Tania Garron, Ndongala M. Lubaki, Chad E. Mire, Karla A. Fenton, Curtis Klages, Gene G. Olinger, Thomas W. Geisbert, Peter L. Collins, Alexander Bukreyev
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