BREAKING! COVID-19 News: Study Warns That Frequent Boosters May Cause Humoral Immune Tolerance And Inhibit The Activation Of CD8+ T Cells!
: A new study led by researchers from Department of Immunology, College of Basic Medicine, Chongqing Medical University-China involving mice models have found that extended course of recombinant receptor binding domain (RBD) vaccine boosters actually leads to humoral immune tolerance instead of functional humoral immunity and also impairs serum neuralization activity along with inhibiting the activation of CD8+T cells and also suppressing the formation of germinal center.
The repetitive applications of vaccine boosters have been brought up in face of continuous emergence of various SARS-CoV-2 variants and sub-lineages with neutralization escape mutations, but their protective efficacy and potential adverse effects remain largely unknown.
Already a number of COVID-19 News
coverages concerning studies about the boosters are beginning to raise a lot of questions.
The study team compared the humoral and cellular immune responses of an extended course of recombinant receptor binding domain (RBD) vaccine boosters with those from conventional immunization strategy in a Balb/c mice model.
The study findings showed that multiple vaccine boosters after the conventional vaccination course significantly decreased RBD-specific antibody titers and serum neutralizing efficacy against the Delta and Omicron variants, and profoundly impaired CD4+ and CD8+T cell activation and increased PD-1 and LAG-3 expressions in these T cells.
The study findings mechanistically confirmed that extended vaccination with RBD boosters overturned the protective immune memories by promoting adaptive immune tolerance.
The study findings demonstrate potential risks with the continuous use of SARS-CoV-2 vaccine boosters, providing immediate implications for the global COVID-19 vaccination enhancement strategies.
A few observed limitations of the studies were that rodent animal models instead of primate were used and that the duration between dos
es was shorter while the time interval between doses was fixed irrespective of waning and the effects were observed after 4th doses & with homologous boosters.
The study findings were published in the peer reviewed journal: iScience.
The study findings showed that the protective effects from the humoral immunity and cellular immunity established by the conventional immunization were both profoundly impaired during the extended vaccination course. Specifically, extended vaccination not only fully impaired the amount and the neutralizing efficacy of serum RBD-specific antibodies, but also shortened the long-term humoral memory. This is associated with immune tolerance in germinal center response, along with decreased numbers of spleen germinal center B and Tfh cells.
The study findings also showed that extended immunization reduced the functional responses of CD4+ and CD8+T cells, restrained the population of memory T cells, and up-regulated the expression of PD-1 and LAG-3 in Te sub-type cells. An increased percentile of Treg cells was also observed, accompanied by significant elevation of IL-10 production.
The study findings provided crucial evidence that repetitive administration of RBD booster vaccines may negatively impact the immune response established by a conventional vaccination course and promote adaptive immune tolerance.
The evidenced immune tolerance from repetitive dosing with homologous boosters in the study suggests that caution should be exercised when optimizing the extended plan for SARS-CoV-2 booster vaccination.
Instead of merely continuous dosing with homologous prime vaccines, a mid-way switch to heterologous booster choices may offer a chance of improvement to the observed energy against Omicron mutants.
It was proposed that such a vaccination strategy may take advantage of the otherwise unsatisfying immune response consequential to the serum phenomenon termed antibody imprinting or original antigenic sin (OAS), which has been an emerging subject in SARS-CoV-2 vaccination, especially for children. https://pubmed.ncbi.nlm.nih.gov/34937927/
It is believed that encountering heterologous boosters, the OAS-dominated immune memory response might generate a faster and stronger neutralizing protection from a preferential activation of existing B cell clones with antibodies recognizing epitopes of the wild-type strain.
This might provide a window of opportunity for sufficient time and accumulation of heterologous antigens that could induce proper recruitment of new naive B cells to generate another primary or secondary response to new epitopes presented. It is reasonable to speculate that such variant-specific immune adaptation may enhance the durability and/or efficacy for the evolving protective need. Within such framework, tailored mRNA vaccines may be a good choice to circumvent the loss of effective humoral and cellular immunity from conventional vaccines developed with the wild-type virus.
Considering the differences between human and mice in mechanism of OAS, further studies are definitely needed to strategically optimize the application of vaccine boosters for durable protection against SARS-CoV-2.
It was found that with prolonged booster vaccination to mice, significantly reduced number of elementary factors and assistant T cells that would be required for B cell maturation and activation were found, relative to the conventional course of immunization. Insufficient availability of Tfh cells might hinder the conventional process of B cell functional differentiation, and the decreased amount of serum IL-4 might impede B cell activation. These assumptions were supported by the fact that a significantly lower number of active B cells was detected within the germinal center from mice of the extended immunization group as comparing to the animals received conventional course of vaccination.
Importantly, the study findings showed that the proportion of memory B cell was markedly reduced in the extended immunization group, together with signs of B cell immune tolerance, indicating the repetitive vaccination of booster shots shared similar mechanisms as seen from humoral immune tolerance of repeated antigen exposure, as during chronic viral infections.
Besides humoral immune responses, cellular immune tolerance was observed during the extended course of RBD booster vaccination. Limited levels of antigen-specific memory T cell activation and profoundly decreased IL-2 and IFN-γ secretion were found in the sera of the extended group, contrast to sustained cellular immune responses after 4 dosings of RBD vaccines.
It was previously reported that the chronic infection with HBV virus could result in antigen-specific cellular immune tolerance, which was manifested as a partial or complete inability to induce active immune response from antigen-specific CD8+T cells and significant increase in the surface expressions of inhibitory receptors, including PD-1, Tim-3 and CTLA-4. Similarly, the study findings showed that prolonged administration of RBD booster vaccines overtly increased the levels of PD-1 and LAG-3, accompanied by significant reduction of the memory CD8+T cells.
Significantly, this is of particular importance, because memory CD8+T cell response is shown to play a predominant role for effective response against newly emerged SARS-CoV-2 variants, which greatly challenged humoral immunity with collective neutralization escape mutations.
Hence, over-stimulation with the same booster vaccine or reinfection after vaccination may severely hamper the cellular immune response established by conventional vaccine course, which, together with challenged humoral immune responses, may lead to prolonged disease duration and/or aggravation of symptoms in recipients.
Also, it has been found that over-vaccination may generate an immunosuppression micro-environment that is also an important facilitator of immune tolerance.
The study findings showed that both the percentage of CD25+Foxp3+CD4+ Treg cells and the levels of immunosuppression cytokines IL-10 were up-regulated after extended RBD vaccine booster vaccination. This may result in reduced activation and differentiation of B cells on antigen stimulation, as well as functional inhibition of antigen-presenting cells (APCs) and consequential decrease in CD8+T cell activation.
It was also observed that both humoral and cellular immune tolerance with the doses of extended booster administrations, which made it safe to speculate that over-vaccination might severely impact the immune protective efficacy established by conventional SARS-CoV-2 immunization, and probably enhance disease severity for new COVID-19 patients or re-infectants.
It was also noted that RBD subunit vaccines cannot entirely represent inactivated or mRNA vaccines, especially in antigen delivery way.
A recent study demonstrated that a fourth mRNA vaccination of healthy young health care workers only shows marginal benefits. Whether extended vaccination with other COVID-19 vaccines based on wild-type SARS-CoV-2 sequence will induce immune tolerance, further investigations are required.
The study team concluded that the study findings characterized the comprehensive effects of extended immunization with RBD booster vaccines in a balb/c mouse model. The study findings revealed that repeated dosing after the establishment of vaccine response might not further improve the antigen-specific reactivity; instead, it could cause systematic tolerance and inability to generate effective humoral and cellular immune responses to current SARS-CoV-2 variants.
The study findings provide timely information for the prevention of COVID-19. It puts an extended immunization course with two or more RBD-based vaccine boosters at debate, and warns for the future applications of vaccine enhancers without proper evaluation of serum antibody titers and T cell functions.
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