It looks like you're using an Ad Blocker.
Please white-list or disable AboveTopSecret.com in your ad-blocking tool.
Some features of ATS will be disabled while you continue to use an ad-blocker.
Interestingly, the nature of clonal B and T cell responses differed dramatically between infected and vaccinated individuals, suggesting that inflammatory responses associated with infection influence the trajectory of the adaptive immune response – differences that may have important implications for our understanding of durability of protective immune responses.
However, our analysis revealed striking differences in the frequency of key immune populations between COVID-19 patients and healthy volunteers prior to and following vaccination
originally posted by: TheAMEDDDoc
a reply to: Extremistcontent
I’m not sure what you are saying? Antibodies are supposed to wane with time, same goes with effector cells. These memory and effector cells are self sustaining and undergo clonal expansion against their targets. You cannot wipe them unless you destroy the progenitor cell populations. You need chemo or radiation or removal of tissue for that.
Although the presence of antibodies is commonly used as an indicator of protective immunity following vaccination or infection, it may not be the only, nor the key, correlate of immune protection. Indeed, CMI responses are necessary for mounting proper antibody responses in addition to other immune functions. CMI responses to viral infection generally involve different classes of T cells including CD8+ cytotoxic T lymphocytes (CTLs), which kill infected cells, and CD4+ T-helper (Th) cells, which vary by subset in their ability to enhance CTL and antibody responses (Th1 and TFH), modulate immunity at mucosal surfaces (Th17) and regulate these responses and limit tissue damage (Tregs) 4
Antibodies to SARS-CoV-2 evolve rapidly after infection and coincide with disease progression. Emerging data suggest that early SARS-CoV-2-specific antibody titres are elevated in those with severe disease1, calling into question the role of the antibody response in immunopathology.
previous vaccine studies for SARS-CoV suggest that vaccine-induced antibodies may directly promote enhanced disease upon exposure to the virus
However, we also found that vaccinees generate more non-neutralizing antibodies than COVID-19 survivors resulting in a lower ratio of neutralizing to binding antibodies.
These data were already apparent in the early phase clinical trials but remained unrecognized at the time
Interestingly, low-titer convalescent serum had the highest relative amount of neutralizing antibodies, whereas the proportion of binding antibodies was increased in sera with higher measured antibody titers.
The majority of plasmablasts sampled after vaccination do, in fact, produce non-neutralizing antibodies.
For non-macrophage tropic respiratory viruses such as RSV and measles, non-neutralizing antibodies have been shown to induce ADE and ERD by forming immune complexes that deposit into airway tissues and activate cytokine and complement pathways, resulting in inflammation, airway obstruction and, in severe cases, leading to acute respiratory distress syndrome10,11,22,23
Both ADE pathways can occur when non-neutralizing antibodies or antibodies at sub-neutralizing levels bind to viral antigens without blocking or clearing infection.
ADE via FcγRIIa-mediated endocytosis into phagocytic cells can be observed in vitro and has been extensively studied for macrophage-tropic viruses, including dengue virus in humans16 and FIPV in cats15.
In this mechanism, non-neutralizing antibodies bind to the viral surface and traffic virions directly to macrophages, which then internalize the virions and become productively infected.
Populations will be central or peripheral, in tissue or circulating. NK and CD8 cell responses will be generated against a viral infection, followed later by antibody generation as support. NK first unless there is a delayed IFN response or the pathogen can produce virokines/viroceptors that trick the NK cell into thinking MHC I and presentation of self is ok in the nucleated cell.
we observed a significant reduction in the production if IFN-α secreted after stimulation with poly I:C and R848 after the administration of the second dose of the vaccine (Figure 1H, 1I). This may hamper the initial innate immune response against the virus, as defects in TLR7 have been shown to result in and increased susceptibility to COVID-19 in young males (Van Der Made et al., 2020).
originally posted by: Extremistcontent
I've given you many clips from research backing exactly what I've said. Nothing you have said negates any of it.
how about this, it kills the production of CTL"s and NK's. There. Exact same thing.
It must be nice to live in the bliss of ignorance
Find a little piece of minutae and harp on and on about it.
originally posted by: TheAMEDDDoc
a reply to: Extremistcontent
I honestly don’t know where the antibody saves all and prevents infection argument came up. No vaccine prevents pathogen entry and replication but that’s what the media and Fauci say to get people to vaccinate. I don’t get the focus, they don’t just sit around and hang out waiting for the pathogen.
We are always taught, with these types of respiratory viruses, that NK and CD8 T cell function were key with interferon type 1, then type 3 to have the best hope for ISG activation in the host. Then licensing and crosstalk between MHC I and II in dendritic cells and T cells to fill in the gaps. If interferon alpha and beta are delayed, you could die, NK cells won’t keep it in check until cytotoxic T cells respond
Ineffective IFN innate immunity has been strongly associated with failure to control a primary SARS-CoV-2 infection and a high risk of fatal COVID-19, accompanied by innate cell immunopathology and a plasma cytokine signature of elevated CXCL10, interleukin (IL)-6, and IL-8 in many studies
These data suggest that a candidate COVID-19 vaccine consisting only of SARS-CoV-2 spike would be capable of eliciting SARS-CoV-2-specific CD4+ T cell responses of similar representation to that of natural COVID-19 disease, but the data also indicate that there are many potential CD4+ T cell targets in SARS-CoV-2, and inclusion of additional SARS-CoV-2 structural antigens such as M and N would better mimic the natural SARS-CoV-2-specific CD4+ T cell response observed in mild to moderate COVID-19 disease.
CD4+ T cell responses were detected in 40%–60% of unexposed individuals.
Regarding the value of cross-reactive T cells, influenza (flu) immunology in relationship to pandemics may be instructive. In the context of the 2009 H1N1 influenza pandemic, preexisting T cell immunity existed in the adult population, which focused on the more conserved internal influenza viral proteins (Greenbaum et al., 2009). The presence of cross-reactive T cells was found to correlate with less severe disease (Sridhar et al., 2013, Wilkinson et al., 2012). The frequent availability of cross-reactive memory T cell responses might have been one factor contributing to the lesser severity of the H1N1 flu pandemic (Hancock et al., 2009). Cross-reactive immunity to influenza strains has been modeled to be a critical influencer of susceptibility to newly emerging, potentially pandemic, influenza strains (Gostic et al., 2016).
A failure to develop protective immunity could occur due to a T cell and/or antibody response of insufficient magnitude or durability, with the neutralizing antibody response being dependent on the CD4+ T cell response (Crotty, 2019, Zhao et al., 2016). Thus, there is urgent need to understand the magnitude and composition of the human CD4+ and CD8+ T cell responses to SARS-CoV-2.
SARS-CoV-1 responses, spike was reported as essentially the only target of CD8+ T cell responses (Li et al., 2008),
Our data indicate a somewhat different pattern of immunodominance for SARS-CoV-2 CD8+ T cell reactivity (Figures 6D and 6E), with spike protein accounting for ∼26% of the reactivity, and N accounting for ∼12%. Significant reactivity in COVID-19 recovered subjects was derived from other antigens, such as M (22%), nsp6 (15%), ORF8 (10%), and ORF3a (7%) (Figures 6D and 6E). In unexposed donors, SARS-CoV-2-reactive CD8+ T cells were detected in at least four different donors (Figure S7 ), with less clear targeting of specific SARS-CoV-2 proteins than was observed for CD4+ T cells, suggesting that coronavirus CD8+ T cell cross-reactivity exists but is less widespread than CD4+ T cell cross-reactivity.
The spike protein was a target of human SARS-CoV-2 CD8+ T cell responses, but it is not dominant. SARS-CoV-2 M was just as strongly recognized, and significant reactivity was noted for other antigens, mostly nsp6, ORF3a, and N, which comprised nearly 50% of the total CD8+ T cell response, on average. Thus, these data indicate that candidate COVID-19 vaccines endeavoring to elicit CD8+ T cell responses against the spike protein will be eliciting a relatively narrow CD8+ T cell response compared to the natural CD8+ T cell response observed in mild to moderate COVID-19 disease.
An optimal vaccine CD8+ T cell response to SARS-CoV-2 might benefit from additional class I epitopes, such as the ones derived from the M, nsp6, ORF3a, and/or N.
This is very similar to influenza virus infection, where viral surface hemagglutinin elicited mostly CD4+ T cell responses, whereas the majority of CD8+ T cell responses were specific to viral internal proteins.
A higher proportion of CD8+ T cell responses was observed in mild disease, suggesting a potential protective role of CD8+ T cell responses in mild disease or a pathogenic role of CD4+ T cell responses in severe disease, which merits further investigation.
The identification of non-spike dominant CD8+ T cell epitopes suggests the potential importance of including non-spike proteins such as NP, M and ORFs in future vaccine designs.
"in individuals with a pre-existing immunity against SARS-CoV-2, the second vaccine dose not only fail to boost humoral immunity but determines a contraction of the spike-specific T cell response.”
"the second vaccination dose appears to exert a detrimental effect in the overall magnitude of the spike-specific humoral response in COVID-19 recovered individuals."
On the other hand, individuals with pre-existing immunity against SARS-CoV-2 should be spared the second dose of the vaccine, at least temporarily, to prevent a possible contraction of their spike-specific memory T cell immunity.
the mechanisms of the contraction of the spike-induced production of IFN-gamma in COVID-19 recovered subjects observed after the second vaccination dose were not investigated. We can only hypothesize that the effector memory CD4+ T cells expanded by first vaccine dose in COVID-19 recovered individuals may be prone to activation-induced cell death (AICD) after the second vaccination dose.
We cannot however exclude that the second dose of the vaccine may only functionally exhaust the spike-specific T cells without really reducing the quantity of the long-term pool of effector memory T cells. Therefore, more detailed analysis of the phenotype of the spike-specific T cells induced by COVID-19 vaccines both in naïve and recovered individuals are needed to answer these questions.
Despite RT-PCR confirmed COVID-19, specific antibodies to SARS-CoV-2 spike are undetectable in serum in approximately 10% of convalescent patients after mild disease course. This raises the question of induction and persistence of SARS-CoV-2-reactive T cells in these convalescent individuals.
Stimulation with SARS-CoV-2 spike and nucleocapsid (NCAP) as well as HCoV spike peptide pools elicited a similar T cell response in seropositive and seronegative post COVID-19 patients.
Significantly higher frequencies of polyfunctional cytokine nucleocapsid reactive CD4+ T cells (triple positive for IFNγ, TNFα, and IL-2) were observed in both, seropositive (p = 0.008) and seronegative (p = 0.04), COVID-19 convalescent compared to healthy controls and were detectable up to day 162 post RT-PCR positivity in seronegative convalescents. Our data indicate an important role of NCAP-specific T cells for viral control.
Natural infection induced expansion of larger CD8 T cell clones, including distinct clusters likely due to the recognition of a broader set of epitopes presented by the virus not seen in the mRNA vaccine.
Spike specific polyfunctional IFNγ+IL-2+ and IFNγ+TNFα+ CD4, but not CD8, T cells were evident 2 weeks post prime-boost vaccination
CD4 T cells secreted elevated levels of cytokines (IL-6, IL-10), cytotoxic molecules (Granzyme A and Granzyme B), and costimulatory factor (sCD137; soluble 4-1BB) (Figure 3I). Additionally, modest induction of IL-2 and IL-4 by CD4 T cells was measured
Next, we compared the changes in T cell clonal dynamics with infection or vaccination. Vaccination was associated with a shift towards increased CDR3 lengths (Figure 4A). Infection was associated with expansion of large clones (>100 cells), while vaccination induced expansion of primarily small sized clones (2-3 cells)
More importantly, SARS-CoV-2–reactive T cells in our moderate and severe patients were predominantly of the Th1 phenotype. Although the observed Th1-mediated response is regarded as protective immunity (9, 65), it also can contribute to immunopathogenesis (66). In this context, our finding of a dominant Th2 response of SARS-CoV-2–reactive T cells in mild disease patients raises the question about the beneficial effect of Th1 immunity. One could speculate that even though the Th1 response is generally protective against viral infections, a more balanced combination of Th1/Th2 responses could lead to a milder form of illness among COVID-19 patients. This was illustrated in SARS-CoV-2–responding T cells in patients with mild disease exhibiting a dominant Th2 phenotype (e.g., IL-10, IL-4, and IL-13). It has been shown that COVID-19 infection is more severe in elderly patients with different comorbidities that are generally associated with an inflammatory state and Th1 response (67), whereas children have a tendency to develop an anti-inflammatory Th2 predominant response, which may in part explain a milder course of illness seen after SARS-CoV-2 infection (68, 69). The abundance of IL-4–secreting CD8+ T cells in a group of older adults may not only counterbalance the overproduction of Th1 cytokines but has also been associated with an intact humoral immunity in old age (70). In our study, there was no indication of Th2 response in severe patients but instead a Th17 phenotype was observed. The presence of IL-17+CD8+ T cells in COVID-19 patients with severe disease suggests that these cells may be present in inflamed tissues as reported in the lungs of COPD patients (71).
Bone marrow plasma cells (BMPCs) are an essential source of medium-term protective antibodies both after vaccination and infection(Halliley et al., 2015; Nutt et al., 2015), but longer-term protection likely requires memory B cells(Iwasaki, 2016; Turner et al., 2021a). Individuals who have recovered from COVID-19 have a significantly lower risk of SARS-CoV-2 reinfection(Hall et al., 2021). A recent 12-month longitudinal study was published with 1,782 plasma samples from 869 convalescent plasma donors in Wuhan, China. This study has shown that among COVID-19 plasma donors the positive rate of IgG antibody against the SARS-CoV-2 receptor binding domain (RBD) in the spike protein exceeded 70% for 12 months post-diagnosis(C. Li et al., 2021). In our study, we show that following vaccination, the levels of anti-SARS-CoV-2 antibodies decrease rapidly, indicating that BMPCs may not be created adequately and therefore anti-SARS-CoV-2 humoral immunity might be transient(Ibarrondo et al., 2020; Seow et al., 2020). After infection, SARS-CoV-2 proteins and nucleic acids could remain in the gut for at least two months, boosting the continued antibody evolution in germinal centers, preferring epitopes overlapping with the ACE2-binding site on the RBD(Gaebler et al., 2021).