Susan Johnson

All Publications

• Adenovirus type 5 SARS-CoV-2 vaccines delivered orally or intranasally reduced disease severity and transmission in a hamster model. Science translational medicine Langel, S. N., Johnson, S., Martinez, C. I., Tedjakusuma, S. N., Peinovich, N., Dora, E. G., Kuehl, P. J., Irshad, H., Barrett, E. G., Werts, A. D., Tucker, S. N. 2022; 14 (658): eabn6868

  Abstract

  Transmission-blocking strategies that slow the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and protect against coronavirus disease 2019 (COVID-19) are needed. We have developed an orally delivered adenovirus type 5-vectored SARS-CoV-2 vaccine candidate that expresses the spike protein. Here, we demonstrated that hamsters vaccinated by the oral or intranasal route had robust and cross-reactive antibody responses. We then induced a postvaccination infection by inoculating vaccinated hamsters with SARS-CoV-2. Orally or intranasally vaccinated hamsters had decreased viral RNA and infectious virus in the nose and lungs and experienced less lung pathology compared to mock-vaccinated hamsters after SARS-CoV-2 challenge. Naïve hamsters exposed in a unidirectional air flow chamber to mucosally vaccinated, SARS-CoV-2-infected hamsters also had lower nasal swab viral RNA and exhibited fewer clinical symptoms than control animals, suggesting that the mucosal route reduced viral transmission. The same platform encoding the SARS-CoV-2 spike and nucleocapsid proteins elicited mucosal cross-reactive SARS-CoV-2-specific IgA responses in a phase 1 clinical trial (NCT04563702). Our data demonstrate that mucosal immunization is a viable strategy to decrease SARS-CoV-2 disease and airborne transmission.

  View details for DOI 10.1126/scitranslmed.abn6868

  View details for PubMedID 35511920

  View details for PubMedCentralID PMC9097881

• Oral Vaccination Protects Against Severe Acute Respiratory Syndrome Coronavirus 2 in a Syrian Hamster Challenge Model. The Journal of infectious diseases Johnson, S., Martinez, C. I., Tedjakusuma, S. N., Peinovich, N., Dora, E. G., Birch, S. M., Kajon, A. E., Werts, A. D., Tucker, S. N. 2022; 225 (1): 34-41

  Abstract

  Vaccines that are shelf stable and easy to administer are crucial to improve vaccine access and reduce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission around the world.In this study, we demonstrate that an oral, adenovirus-based vaccine candidate protects against SARS-CoV-2 in a Syrian hamster challenge model.Hamsters administered 2 doses of VXA-CoV2-1 showed a reduction in weight loss and lung pathology and had completely eliminated infectious virus 5 days postchallenge. Oral immunization induced antispike immunoglobulin G, and neutralizing antibodies were induced upon oral immunization with the sera, demonstrating neutralizing activity.Overall, these data demonstrate the ability of oral vaccine candidate VXA-CoV2-1 to provide protection against SARS-CoV-2 disease.

  View details for DOI 10.1093/infdis/jiab561

  View details for PubMedID 34758086

  View details for PubMedCentralID PMC8689930

• Expansion of Inefficient HIV-Specific CD8 T Cells during Acute Infection JOURNAL OF VIROLOGY Eller, M. A., Goonetilleke, N., Tassaneetrithep, B., Eller, L. A., Costanzo, M. C., Johnson, S., Betts, M. R., Krebs, S. J., Slike, B. M., Nitayaphan, S., Rono, K., Tovanabutra, S., Maganga, L., Kibuuka, H., Jagodzinski, L., Peel, S., Rolland, M., Marovich, M. A., Kim, J. H., Michael, N. L., Robb, M. L., Streeck, H. 2016; 90 (8): 4005-4016

  Abstract

  Attrition within the CD4(+)T cell compartment, high viremia, and a cytokine storm characterize the early days after HIV infection. When the first emerging HIV-specific CD8(+)T cell responses gain control over viral replication it is incomplete, and clearance of HIV infection is not achieved even in the rare cases of individuals who spontaneously control viral replication to nearly immeasurably low levels. Thus, despite their partial ability to control viremia, HIV-specific CD8(+)T cell responses are insufficient to clear HIV infection. Studying individuals in the first few days of acute HIV infection, we detected the emergence of a unique population of CD38(+)CD27(-)CD8(+)T cells characterized by the low expression of the CD8 receptor (CD8(dim)). Interestingly, while high frequencies of HIV-specific CD8(+)T cell responses occur within the CD38(+)CD27(-)CD8(dim)T cell population, the minority populations of CD8(bright)T cells are significantly more effective in inhibiting HIV replication. Furthermore, the frequency of CD8(dim)T cells directly correlates with viral load and clinical predictors of more rapid disease progression. We found that a canonical burst of proliferative cytokines coincides with the emergence of CD8(dim)T cells, and the size of this population inversely correlates with the acute loss of CD4(+)T cells. These data indicate, for the first time, that early CD4(+)T cell loss coincides with the expansion of a functionally impaired HIV-specific CD8(dim)T cell population less efficient in controlling HIV viremia.A distinct population of activated CD8(+)T cells appears during acute HIV infection with diminished capacity to inhibit HIV replication and is predictive of viral set point, offering the first immunologic evidence of CD8(+)T cell dysfunction during acute infection.

  View details for DOI 10.1128/JVI.02785-15

  View details for Web of Science ID 000375123800019

  View details for PubMedID 26842474

  View details for PubMedCentralID PMC4810544

• The Nucleoprotein Is Required for Lymphocytic Choriomeningitis Virus-Based Vaccine Vector Immunogenicity JOURNAL OF VIROLOGY Darbre, S., Johnson, S., Kallert, S., Lambert, P., Siegrist, C., Pinschewer, D. D. 2015; 89 (22): 11734-11738

  Abstract

  Recombinant glycoprotein-deficient lymphocytic choriomeningitis virus-based vaccine vectors (rLCMV/ΔGP) are potent CD8(+) T cell inducers. To investigate the underlying molecular requirements, we generated a nucleoprotein-deficient vector counterpart (rLCMV/ΔNP). NP but not GP is a minimal trans-acting factor for viral transcription and genome replication. We found that, unlike rLCMV/ΔGP, rLCMV/ΔNP failed to elicit detectable CD8(+) T cell responses unless NP was trans complemented in a transgenic host. Hence, NP-dependent intracellular gene expression is essential for LCMV vector immunogenicity.

  View details for DOI 10.1128/JVI.01613-15

  View details for Web of Science ID 000363467200049

  View details for PubMedID 26355095

  View details for PubMedCentralID PMC4645649

• Cooperativity of HIV-Specific Cytolytic CD4 T Cells and CD8 T Cells in Control of HIV Viremia JOURNAL OF VIROLOGY Johnson, S., Eller, M., Teigler, J. E., Maloveste, S. M., Schultz, B. T., Soghoian, D. Z., Lu, R., Oster, A. F., Chenine, A., Alter, G., Dittmer, U., Marovich, M., Robb, M. L., Michael, N. L., Bolton, D., Streeck, H. 2015; 89 (15): 7494-7505

  Abstract

  CD4+ T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4+ T cell functions beyond helper effects have been described, and a role for cytolytic CD4+ T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4+ T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4+ T cells revealed a distinct transcriptional signature compared to Th1 CD4+ cells but shared similar features with HIV-specific cytolytic CD8+ T cells. Furthermore, HIV-specific cytolytic CD4+ T cells showed comparable killing activity relative to HIV-specific CD8+ T cells and worked cooperatively in the elimination of virally infected cells. Interestingly, we found that cytolytic CD4+ T cells emerge early during acute HIV infection and tightly follow acute viral load trajectory. This emergence was associated to the early viral set point, suggesting an involvement in early control, in spite of CD4 T cell susceptibility to HIV infection. Our data suggest cytolytic CD4+ T cells as an independent subset distinct from Th1 cells that show combined activity with CD8+ T cells in the long-term control of HIV infection.The ability of the immune system to control chronic HIV infection is of critical interest to both vaccine design and therapeutic approaches. Much research has focused on the effect of the ability of CD8+ T cells to control the virus, while CD4+ T cells have been overlooked as effectors in HIV control due to the fact that they are preferentially infected. We show here that a subset of HIV-specific CD4+ T cells cooperate in the cytolytic control of HIV replication. Moreover, these cells represent a distinct subset of CD4+ T cells showing significant transcriptional and phenotypic differences compared to HIV-specific Th1 cells but with similarities to CD8+ T cells. These findings are important for our understanding of HIV immunopathology.

  View details for DOI 10.1128/JVI.00438-15

  View details for Web of Science ID 000358277800006

  View details for PubMedID 25972560

  View details for PubMedCentralID PMC4505667

• Protective Efficacy of Individual CD8(+) T Cell Specificities in Chronic Viral Infection JOURNAL OF IMMUNOLOGY Johnson, S., Bergthaler, A., Graw, F., Flatz, L., Bonilla, W. V., Siegrist, C., Lambert, P., Regoes, R. R., Pinschewer, D. D. 2015; 194 (4): 1755-1762

  Abstract

  Specific CD8(+) T cells (CTLs) play an important role in resolving protracted infection with hepatitis B and C virus in humans and lymphocytic choriomeningitis virus (LCMV) in mice. The contribution of individual CTL specificities to chronic virus control, as well as epitope-specific patterns in timing and persistence of antiviral selection pressure, remain, however, incompletely defined. To monitor and characterize the antiviral efficacy of individual CTL specificities throughout the course of chronic infection, we coinoculated mice with a mixture of wild-type LCMV and genetically engineered CTL epitope-deficient mutant virus. A quantitative longitudinal assessment of viral competition revealed that mice continuously exerted CTL selection pressure on the persisting virus population. The timing of selection pressure characterized individual epitope specificities, and its magnitude varied considerably between individual mice. This longitudinal assessment of "antiviral efficacy" provides a novel parameter to characterize CTL responses in chronic viral infection. It demonstrates remarkable perseverance of all antiviral CTL specificities studied, thus raising hope for therapeutic vaccination in the treatment of persistent viral diseases.

  View details for DOI 10.4049/jimmunol.1401771

  View details for Web of Science ID 000349462000039

  View details for PubMedID 25567678

  View details for PubMedCentralID PMC4323683

• The alarmin interleukin-33 drives protective antiviral CD8? T cell responses. Science Bonilla, W. V., Fröhlich, A., Senn, K., Kallert, S., Fernandez, M., Johnson, S., Kreutzfeldt, M., Hegazy, A. N., Schrick, C., Fallon, P. G., Klemenz, R., Nakae, S., Adler, H., Merkler, D., Löhning, M., Pinschewer, D. D. 2012; 335 (6071): 984-989

  Abstract

  Pathogen-associated molecular patterns decisively influence antiviral immune responses, whereas the contribution of endogenous signals of tissue damage, also known as damage-associated molecular patterns or alarmins, remains ill defined. We show that interleukin-33 (IL-33), an alarmin released from necrotic cells, is necessary for potent CD8(+) T cell (CTL) responses to replicating, prototypic RNA and DNA viruses in mice. IL-33 signaled through its receptor on activated CTLs, enhanced clonal expansion in a CTL-intrinsic fashion, determined plurifunctional effector cell differentiation, and was necessary for virus control. Moreover, recombinant IL-33 augmented vaccine-induced CTL responses. Radio-resistant cells of the splenic T cell zone produced IL-33, and efficient CTL responses required IL-33 from radio-resistant cells but not from hematopoietic cells. Thus, alarmin release by radio-resistant cells orchestrates protective antiviral CTL responses.

  View details for DOI 10.1126/science.1215418

  View details for PubMedID 22323740

• Viral replicative capacity is the primary determinant of lymphocytic choriomeningitis virus persistence and immunosuppression PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Bergthaler, A., Flatz, L., Hegazy, A. N., Johnson, S., Horvath, E., Loehning, M., Pinschewer, D. D. 2010; 107 (50): 21641-21646

  Abstract

  The Clone 13 (Cl13) strain of lymphocytic choriomeningitis virus is widely studied as a model of chronic systemic viral infection. Here, we used reverse genetic techniques to identify the molecular basis of Cl13 persistence and immunosuppression, the characteristics differentiating it from the closely related Armstrong strain. We found that a single-point mutation in the Cl13 polymerase was necessary and partially sufficient for viral persistence and immunosuppression. A glycoprotein mutation known to enhance dendritic cell targeting accentuated both characteristics but when introduced alone, failed to alter the phenotype of the Armstrong strain. The decisive polymerase mutation increased intracellular viral RNA load in plasmacytoid dendritic cells, which we identified as a main initial target cell type in vivo, and increased viremia in the early phase of infection. These findings establish the enhanced replicative capacity as the primary determinant of the Cl13 phenotype. Viral persistence and immunosuppression can, thus, represent a direct consequence of excessive viral replication overwhelming the host's antiviral defense.

  View details for DOI 10.1073/pnas.1011998107

  View details for Web of Science ID 000285521500076

  View details for PubMedID 21098292

  View details for PubMedCentralID PMC3003068

• Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8(+) T cell immunity NATURE MEDICINE Flatz, L., Hegazy, A. N., Bergthaler, A., Verschoor, A., Claus, C., Fernandez, M., Gattinoni, L., Johnson, S., Kreppel, F., Kochanek, S., van den Broek, M., Radbruch, A., Levy, F., Lambert, P., Siegrist, C., Restifo, N. P., Loehning, M., Ochsenbein, A. F., Nabel, G. J., Pinschewer, D. D. 2010; 16 (3): 339-U142

  Abstract

  Lymphocytic choriomeningitis virus (LCMV) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective CD8(+) T cell (cytotoxic T lymphocyte (CTL)) immunity. Here we have harnessed the immunobiology of this arenavirus for vaccine delivery. By using producer cells constitutively synthesizing the viral glycoprotein (GP), it was possible to replace the gene encoding LCMV GP with vaccine antigens to create replication-defective vaccine vectors. These rLCMV vaccines elicited CTL responses that were equivalent to or greater than those elicited by recombinant adenovirus 5 or recombinant vaccinia virus in their magnitude and cytokine profiles, and they exhibited more effective protection in several models. In contrast to recombinant adenovirus 5, rLCMV failed to elicit vector-specific antibody immunity, which facilitated re-administration of the same vector for booster vaccination. In addition, rLCMV elicited T helper type 1 CD4+ T cell responses and protective neutralizing antibodies to vaccine antigens. These features, together with low seroprevalence in humans, suggest that rLCMV may show utility as a vaccine platform against infectious diseases and cancer.

  View details for DOI 10.1038/nm.2104

  View details for Web of Science ID 000275289500042

  View details for PubMedID 20139992

  View details for PubMedCentralID PMC3247638

• Selected Toll-like Receptor Ligands and Viruses Promote Helper-Independent Cytotoxic T Cell Priming by Upregulating CD40L on Dendritic Cells IMMUNITY Johnson, S., Zhan, Y., Sutherland, R. M., Mount, A. M., Bedoui, S., Brady, J. L., Carrington, E. M., Brown, L. E., Belz, G. T., Heath, W. R., Lew, A. M. 2009; 30 (2): 218-227

  Abstract

  CD40L (CD154) on CD4(+) T cells has been shown to license dendritic cells (DCs) via CD40 to prime cytotoxic T lymphocyte (CTL) responses. We found that the converse (CD40L on DCs) was also important. Anti-CD40L treatment decreased endogenous CTL responses to both ovalbumin and influenza infection even in the absence of CD4(+) T cells. DCs expressed CD40L upon stimulation with agonists to Toll-like receptor 3 (TLR3) and TLR9. Moreover, influenza infection, which stimulates CTLs without help, upregulated CD40L on DCs, but herpes simplex infection, which elicits CTLs through help, did not. CD40L-deficient (Cd40lg(-/-)) DCs are suboptimal both in vivo in bone marrow chimera experiments and in vitro in mixed lymphocyte reactions. In contrast, Cd40lg(-/-) CD8(+) T cells killed as effectively as wild-type cells. Thus, CD40L upregulation on DCs promoted optimal priming of CD8(+) T cells without CD4(+) T cells, providing a mechanism by which pathogens may elicit helper-independent CTL immunity.

  View details for DOI 10.1016/j.immuni.2008.11.015

  View details for Web of Science ID 000263710500009

  View details for PubMedID 19200758

  View details for PubMedCentralID PMC2694753

• Milk IgA responses are augmented by antigen delivery to the mucosal addressin cellular adhesion molecule 1 VACCINE Johnson, S., Bourges, D., Wijburg, O., Strugnell, R. A., Lew, A. M. 2006; 24 (27-28): 5552-5558

  Abstract

  The mucosal addressin cellular adhesion molecule 1 (MAdCAM) is expressed on the venules of the gut associated lymphoid tissue (GALT); it is also expressed on the venules of the lobules of the mammary gland. We have previously found that MAdCAM-targeting using a rat anti-MAdCAM monoclonal Ab as both antigen and targeting moiety resulted in an enhanced local IgA gut response. We therefore surmised that such targeting may also enhance IgA responses in the mammary gland. We show that our model antigen localizes to the lobules of the mammary glands as well as the GALT, but not to the draining lymph nodes and that targeting MAdCAM results in secretory IgA responses in the milk. We provide evidence that this milk IgA Ab is of a secretory nature and is consistent with derivation from gut plasmablasts that have migrated to the mammary gland. Targeting MAdCAM may be a way for a novel vaccine strategy that affords protection to the mammary gland and the suckling neonate.

  View details for DOI 10.1016/j.vaccine.2006.04.029

  View details for Web of Science ID 000238859700003

  View details for PubMedID 16723174

• Bypassing luminal barriers, delivery to a gut addressin by parenteral targeting elicits local IgA responses INTERNATIONAL IMMUNOLOGY McKenzie, B. S., Corbett, A. J., JOHNSON, S., Brady, J. L., Pleasance, J., Kramer, D. R., Boyle, J. S., Jackson, D. C., Strugnell, R. A., Lew, A. M. 2004; 16 (11): 1613-1622

  Abstract

  Induction of mucosal immunity, particularly to subunit vaccines, has been problematic. The primary hurdle to successful mucosal vaccination is the effective delivery of vaccine antigen to the mucosal associated lymphoid tissue. Physical and chemical barriers restrict antigen access and, moreover, immune responses induced in the mucosa can be biased towards tolerance or non-reactivity. We proposed that these difficulties could be circumvented by targeting antigen to the gastrointestinal associated lymphoid tissue via systemic (parenteral) rather than alimentary routes, using antibodies specific for the mucosal addressin cellular adhesion molecule-1 (MAdCAM). After intravenous or intramuscular injection of such rat antibodies in mice, we found a greatly enhanced (up to 3 logs) anti-rat antibody response. MAdCAM targeting induces a rapid IgA antibody response in the gut and vastly improves the systemic antibody response. Targeting also enhanced T cell proliferation and cytokine responses. Parenteral targeting of mucosal addressins may represent a generic technique for bypassing mucosal barriers and eliminating the need for adjuvants in the induction of proximal and systemic immunity.

  View details for DOI 10.1093/intimm/dxh163

  View details for Web of Science ID 000224482300007

  View details for PubMedID 15466913