Long-Term Elevated Inflammatory Protein Levels in Asymptomatic SARS-CoV-2 Infected Individuals

The clinical features of SARS-CoV-2 infection range from asymptomatic to severe disease with life-threatening complications. Understanding the persistence of immune responses in asymptomatic individuals merit special attention because of their importance in controlling the spread of the infections. We here studied the antibody and T cell responses, and a wide range of inflammation markers, in 56 SARS-CoV-2 antibody-positive individuals, identified by a population screen after the first wave of SARS-CoV-2 infection. These, mostly asymptomatic individuals, were reanalyzed 7-8 months after their infection together with 115 age-matched seronegative controls. We found that 7-8 months after the infection their antibodies to SARS-CoV-2 Nucleocapsid (N) protein declined whereas we found no decrease in the antibodies to Spike receptor-binding domain (S-RBD) when compared to the findings at seropositivity identification. In contrast to antibodies to N protein, the antibodies to S-RBD correlated with the viral neutralization capacity and with CD4+ T cell responses as measured by antigen-specific upregulation of CD137 and CD69 markers. Unexpectedly we found the asymptomatic antibody-positive individuals to have increased serum levels of S100A12, TGF-alpha, IL18, and OSM, the markers of activated macrophages-monocytes, suggesting long-term persistent inflammatory effect associated with the viral infection in asymptomatic individuals. Our results support the evidence for the long-term persistence of the inflammation process and the need for post-infection clinical monitoring of SARS-CoV-2 infected asymptomatic individuals.

Download Full-text

Soluble Spike DNA Vaccine Provides Long-Term Protective Immunity against SARS-CoV-2 in Mice and Nonhuman Primates

Vaccines ◽

10.3390/vaccines9040307 ◽

2021 ◽

Vol 9 (4) ◽

pp. 307

Author(s):

Yong Bok Seo ◽

You Suk Suh ◽

Ji In Ryu ◽

Hwanhee Jang ◽

Hanseul Oh ◽

...

Keyword(s):

T Cell ◽

Nonhuman Primates ◽

Vaccine Candidate ◽

T Cell Responses ◽

Neutralizing Antibody ◽

Dependent Manner ◽

Viral Loads ◽

Cell Responses ◽

Rapid Spread

The unprecedented and rapid spread of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) has motivated the need for a rapidly producible and scalable vaccine. Here, we developed a synthetic soluble SARS-CoV-2 spike (S) DNA-based vaccine candidate, GX-19. In mice, immunization with GX-19 elicited not only S-specific systemic and pulmonary antibody responses but also Th1-biased T cell responses in a dose-dependent manner. GX-19-vaccinated nonhuman primates seroconverted rapidly and exhibited a detectable neutralizing antibody response as well as multifunctional CD4+ and CD8+ T cell responses. Notably, when the immunized nonhuman primates were challenged at 10 weeks after the last vaccination with GX-19, they had reduced viral loads in contrast to non-vaccinated primates as a control. These findings indicate that GX-19 vaccination provides a durable protective immune response and also support further development of GX-19 as a vaccine candidate for SARS-CoV-2.

Download Full-text

Long-Term Immunity to Trypanosoma cruzi in the Absence of Immunodominanttrans-Sialidase-Specific CD8+T Cells

Infection and Immunity ◽

10.1128/iai.00241-16 ◽

2016 ◽

Vol 84 (9) ◽

pp. 2627-2638 ◽

Cited By ~ 6

Author(s):

Charles S. Rosenberg ◽

Weibo Zhang ◽

Juan M. Bustamante ◽

Rick L. Tarleton

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Trypanosoma Cruzi ◽

T Cell Responses ◽

Content Type ◽

Cell Responses ◽

Pathogen Control ◽

Immunodominant Epitopes

Trypanosoma cruziinfection drives the expansion of remarkably focused CD8+T cell responses targeting epitopes encoded by varianttrans-sialidase (TS) genes. Infection of C57BL/6 mice withT. cruziresults in up to 40% of all CD8+T cells committed to recognition of the dominant TSKB20 and subdominant TSKB18 TS epitopes. However, despite this enormous response, these mice fail to clearT. cruziinfection and subsequently develop chronic disease. One possible reason for the failure to cureT. cruziinfection is that immunodomination by these TS-specific T cells may interfere with alternative CD8+T cell responses more capable of complete parasite elimination. To address this possibility, we created transgenic mice that are centrally tolerant to these immunodominant epitopes. Mice expressing TSKB20, TSKB18, or both epitopes controlledT. cruziinfection and developed effector CD8+T cells that maintained an activated phenotype. Memory CD8+T cells from drug-cured TSKB-transgenic mice rapidly responded to secondaryT. cruziinfection. In the absence of the response to TSKB20 and TSKB18, immunodominance did not shift to other known subdominant epitopes despite the capacity of these mice to expand epitope-specific T cells specific for the model antigen ovalbumin expressed by engineered parasites. Thus, CD8+T cell responses tightly and robustly focused on a few epitopes within variant TS antigens appear to neither contribute to, nor detract from, the ability to controlT. cruziinfection. These data also indicate that the relative position of an epitope within a CD8+immunodominance hierarchy does not predict its importance in pathogen control.

Download Full-text

Optimising T cell (re)boosting strategies for adenoviral and modified vaccinia Ankara vaccine regimens in humans

npj Vaccines ◽

10.1038/s41541-020-00240-0 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Stefania Capone ◽

Anthony Brown ◽

Felicity Hartnell ◽

Mariarosaria Del Sorbo ◽

Cinzia Traboni ◽

...

Keyword(s):

T Cells ◽

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Viral Vectors ◽

Standard Dose ◽

T Cell Responses ◽

Effector Memory ◽

Cell Responses ◽

Wide Range

Abstract Simian adenoviral and modified vaccinia Ankara (MVA) viral vectors used in heterologous prime-boost strategies are potent inducers of T cells against encoded antigens and are in advanced testing as vaccine carriers for a wide range of infectious agents and cancers. It is unclear if these responses can be further enhanced or sustained with reboosting strategies. Furthermore, despite the challenges involved in MVA manufacture dose de-escalation has not been performed in humans. In this study, healthy volunteers received chimpanzee-derived adenovirus-3 and MVA vaccines encoding the non-structural region of hepatitis C virus (ChAd3-NSmut/MVA-NSmut) 8 weeks apart. Volunteers were then reboosted with a second round of ChAd3-NSmut/MVA-NSmut or MVA-NSmut vaccines 8 weeks or 1-year later. We also determined the capacity of reduced doses of MVA-NSmut to boost ChAd3-NSmut primed T cells. Reboosting was safe, with no enhanced reactogenicity. Reboosting after an 8-week interval led to minimal re-expansion of transgene-specific T cells. However, after a longer interval, T cell responses expanded efficiently and memory responses were enhanced. The 8-week interval regimen induced a higher percentage of terminally differentiated and effector memory T cells. Reboosting with MVA-NSmut alone was as effective as with ChAd3-NSmut/MVA-NSmut. A ten-fold lower dose of MVA (2 × 107pfu) induced high-magnitude, sustained, broad, and functional Hepatitis C virus (HCV)-specific T cell responses, equivalent to standard doses (2 × 108 pfu). Overall, we show that following Ad/MVA prime-boost vaccination reboosting is most effective after a prolonged interval and is productive with MVA alone. Importantly, we also show that a ten-fold lower dose of MVA is as potent in humans as the standard dose.

Download Full-text

Epitope specificity and Ia restriction of T cell responses to insulin in a system of complementing Ir genes: analysis with primed lymph node T cells and a long-term cultured T cell line

European Journal of Immunology ◽

10.1002/eji.1830130911 ◽

1983 ◽

Vol 13 (9) ◽

pp. 756-761 ◽

Cited By ~ 10

Author(s):

Eberhard Spaeth ◽

Erwin Rüde

Keyword(s):

T Cells ◽

Lymph Node ◽

T Cell ◽

Cell Line ◽

T Cell Responses ◽

Cell Responses ◽

Epitope Specificity ◽

Ir Genes

Download Full-text

Long-term CD4+ and CD8+ T-cell responses induced in HIV-uninfected volunteers following intradermal or intramuscular administration of an HIV-lipopeptide vaccine (ANRS VAC16)

Vaccine ◽

10.1016/j.vaccine.2013.06.102 ◽

2013 ◽

Vol 31 (40) ◽

pp. 4406-4415 ◽

Cited By ~ 10

Author(s):

Odile Launay ◽

Mathieu Surenaud ◽

Corinne Desaint ◽

Nadine Ben Hamouda ◽

Gilles Pialoux ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Intramuscular Administration ◽

Cell Responses

Download Full-text

Cytotoxic T cell responses to haptenated cells I. Primary, secondary and long-term cultures

European Journal of Immunology ◽

10.1002/eji.1830090905 ◽

1979 ◽

Vol 9 (9) ◽

pp. 681-690 ◽

Cited By ~ 33

Author(s):

Helmut Pohlit ◽

Werner Haas ◽

Harald von Boehmer

Keyword(s):

T Cell ◽

T Cell Responses ◽

Cytotoxic T Cell ◽

Cell Responses ◽

Cytotoxic T Cell Responses

Download Full-text

A recombinant DNA and vaccinia virus prime–boost regimen induces potent long-term T-cell responses to HCV in BALB/c mice

Vaccine ◽

10.1016/j.vaccine.2009.02.003 ◽

2009 ◽

Vol 27 (15) ◽

pp. 2085-2088 ◽

Cited By ~ 15

Author(s):

Yao Deng ◽

Ke Zhang ◽

Wenjie Tan ◽

Yue Wang ◽

Hong Chen ◽

...

Keyword(s):

T Cell ◽

Vaccinia Virus ◽

Recombinant Dna ◽

T Cell Responses ◽

Boost Regimen ◽

Cell Responses

Download Full-text

Long-Term Control of Simian Immunodeficiency Virus (SIV) in Cynomolgus Macaques Not Associated with Efficient SIV-Specific CD8+T-Cell Responses

Journal of Virology ◽

10.1128/jvi.03723-14 ◽

2015 ◽

Vol 89 (7) ◽

pp. 3542-3556 ◽

Cited By ~ 16

Author(s):

Timothée Bruel ◽

Chiraz Hamimi ◽

Nathalie Dereuddre-Bosquet ◽

Antonio Cosma ◽

So Youn Shin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

T Cell Responses ◽

Cell Depletion ◽

Viral Control ◽

Cell Responses ◽

Cynomolgus Macaques ◽

Hiv 1

ABSTRACTThe spontaneous control of human and simian immunodeficiency viruses (HIV/SIV) is typically associated with specific major histocompatibility complex (MHC) class I alleles and efficient CD8+T-cell responses, but many controllers maintain viral control despite a nonprotective MHC background and weak CD8+T-cell responses. Therefore, the contribution of this response to maintaining long-term viral control remains unclear. To address this question, we transiently depleted CD8+T cells from five SIV-infected cynomolgus macaques with long-term viral control and weak CD8+T-cell responses. Among them, only one carried the protective MHC allele H6. After depletion, four of five controllers experienced a transient rebound of viremia. The return to undetectable viremia was accompanied by only modest expansion of SIV-specific CD8+T cells that lacked efficient SIV suppression capacityex vivo. In contrast, the depletion was associated with homeostatic activation/expansion of CD4+T cells that correlated with viral rebound. In one macaque, viremia remained undetectable despite efficient CD8+cell depletion and inducible SIV replication from its CD4+T cellsin vitro. Altogether, our results suggest that CD8+T cells are not unique contributors to the long-term maintenance of low viremia in this SIV controller model and that other mechanisms, such as weak viral reservoirs or control of activation, may be important players in control.IMPORTANCESpontaneous control of HIV-1 to undetectable levels is associated with efficient anti-HIV CD8+T-cell responses. However, in some cases, this response fades over time, although viral control is maintained, and many HIV controllers (weak responders) have very low frequencies of HIV-specific CD8+T cells. In these cases, the importance of CD8 T cells in the maintenance of HIV-1 control is questionable. We developed a nonhuman primate model of durable SIV control with an immune profile resembling that of weak responders. Transient depletion of CD8+cells induced a rise in the viral load. However, viremia was correlated with CD4+T-cell activation subsequent to CD8+cell depletion. Regain of viral control to predepletion levels was not associated with restoration of the anti-SIV capacities of CD8+T cells. Our results suggest that CD8+T cells may not be involved in maintenance of viral control in weak responders and highlight the fact that additional mechanisms should not be underestimated.

Download Full-text