Uversky, V.N.; Redwan, E.M.; Makis, W.; Rubio-Casillas, A. IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SARS-CoV-2 Spike Protein. Vaccines2023, 11, 991.
Uversky, V.N.; Redwan, E.M.; Makis, W.; Rubio-Casillas, A. IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SARS-CoV-2 Spike Protein. Vaccines 2023, 11, 991.
Cite as:
Uversky, V.N.; Redwan, E.M.; Makis, W.; Rubio-Casillas, A. IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SARS-CoV-2 Spike Protein. Vaccines2023, 11, 991.
Uversky, V.N.; Redwan, E.M.; Makis, W.; Rubio-Casillas, A. IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SARS-CoV-2 Spike Protein. Vaccines 2023, 11, 991.
Abstract
Due to the health crisis caused by SARS-CoV-2, the creation of a new vaccine platform based on mRNA was implemented. Globally, around 13.32 billion COVID-19 vaccine doses of diverse platforms have been given, and up to this date, 69.7% of the total population received at least one injection of a COVID-19 vaccine. Although these vaccines prevent hospitalization and severe forms of the disease, increasing evidence has shown they do not produce sterilizing immunity, allowing people to suffer frequent re-infections. Recent research has also raised concerns that mRNA vaccines could induce immune tolerance, which, added to that caused by the virus itself, could complicate the clinical course of a COVID-19 infection. Furthermore, recent investigations have found high IgG4 levels in people who were administered two or more injections of mRNA vaccines. It has been suggested that an increase in IgG4 levels could have a protecting role by preventing immune over-activation, similar to that occurring during successful allergen-specific immunotherapy by inhibiting IgE-induced effects. Altogether, evidence suggests that the reported increase in the IgG4 levels detected after repeated vaccination with the mRNA vaccines is not a protective mechanism; rather, it may be a part of the immune tolerance mechanism to the spike protein that could promote unopposed SARS-CoV2 infection and replication by suppressing natural antiviral responses. IgG4-induced suppression of the immune system due to repeated vaccination can also cause autoimmune diseases, promotes cancer growth, and autoimmune myocarditis in susceptible individuals.
Medicine and Pharmacology, Pulmonary and Respiratory Medicine
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received:
28 March 2023
Commenter:
John Collis
The commenter has declared there is no conflict of interests.
Comment:
Although IgG4 is anti inflammatory and reduces the response of IgE to allergens, does this really mean that it is more tolerant of the spike protein? Pillai(2023) argues that because IgG4 can bind with IgG1 that it may be more specific. However it may be of concern if the quantity of IgG4 increases significantly. Should this be a reason not to be vaccinated?
Pillai S. Is it bad, is it good, or is IgG4 just misunderstood? Sci Immunol. 2023 Mar 31;8(81):eadg7327. doi: 10.1126/sciimmunol.adg7327. Epub 2023 Mar 24. PMID: 36749191.
The commenter has declared there is no conflict of interests.
Comment:
Dear John Collins: Thank you very much for your important comments.
As you may have noticed, our work is a hypothesis. We are proposing a scientific explanation based, for example, on the results of clinical trials with vaccines for HIV and malaria. In these trials, repeated vaccination resulted in the production of the IgG4 antibody. In both trials, an increase in IgG4 levels was associated with a higher risk of contracting HIV or malaria.
In the malaria trial, researchers noticed a distinct pattern for IgG subclasses to the EBA-175 antigen: higher concentrations of particular antibodies known as neutralizing IgG1 and IgG3 were linked to a reduced likelihood of contracting malaria in the second year. As the levels of IgG1 doubled, the risk of malaria reduced by about 50%, and when the levels of IgG3 doubled, the risk of malaria decreased by about 60% [105]
On the other side, the probability of contracting malaria increased by around three times when non-neutralizing IgG4 levels doubled. Up to the age of 24 months, IgG1 and IgG3 demonstrated 51% and 56% protective effects respectively, however, IgG4 was linked to a higher risk of malaria infection throughout this age range [105]. It's interesting to note that a separate study also found a link between high IgG4 levels and a higher risk of infection and malaria exacerbations [111].
So, if our hypothesis is correct, then, an increase in IgG4 levels could explain SARS-CoV-2´s breakthrough infections. In addition, we also hypothesized that IgG4 antibodies could impair antiviral responses, for example, IgG4 could block recognition and attack by cytotoxic T cells, thus the infected cell is not destroyed (see figure in page 12), and facilitating viral persistence in the host, leading to chronic infection.
Our work must be read and interpreted for what it is: a hypothesis, which must be experimentally evaluated.
Here are some methods to demonstrate the effect of IgG4 antibodies on antiviral responses against SARS-CoV-2:
In vitro studies: In vitro studies can be used to demonstrate the effect of IgG4 antibodies on antiviral responses against SARS-CoV-2. For example, researchers can isolate immune cells from individuals infected with SARS-CoV-2 and incubate them with IgG4 antibodies. The researchers can then measure the cells' ability to produce antiviral cytokines and kill infected cells. If the presence of IgG4 antibodies impairs the cells' ability to produce antiviral responses, it would suggest that these antibodies could contribute to the progression of SARS-CoV-2 infection.
Animal models: Animal models can also be used to investigate the effect of IgG4 antibodies on antiviral responses against SARS-CoV-2. Researchers can use genetically modified mice that lack the ability to produce IgG4 antibodies and compare their immune responses to SARS-CoV-2 infection to normal mice. If the absence of IgG4 antibodies leads to a more robust antiviral response and better disease outcomes, it would suggest that IgG4 antibodies impair antiviral responses against SARS-CoV-2.
Clinical studies: Clinical studies can be used to examine the relationship between IgG4 antibodies and disease outcomes in individuals infected with SARS-CoV-2. Researchers can measure the levels of IgG4 antibodies in patients' blood samples and correlate them with disease severity and antiviral responses. If high levels of IgG4 antibodies are associated with worse disease outcomes and impaired antiviral responses, it would suggest that these antibodies play a role in the progression of SARS-CoV-2 infection.
Cross-sectional studies: Cross-sectional studies can be used to compare the levels of IgG4 antibodies and antiviral responses among individuals with different disease outcomes. For example, researchers can compare the levels of IgG4 antibodies and antiviral responses in patients with mild disease versus severe disease. If high levels of IgG4 antibodies are associated with impaired antiviral responses and worse disease outcomes, it would suggest that these antibodies play a role in the progression of SARS-CoV-2 infection.
Longitudinal studies: Longitudinal studies can be used to track changes in IgG4 antibody levels and antiviral responses over time in individuals infected with SARS-CoV-2. For example, researchers can measure the levels of IgG4 antibodies and antiviral responses in patients at different time points during the course of their infection. If increases in IgG4 antibody levels are associated with declines in antiviral responses, it would suggest that these antibodies contribute to the progression of SARS-CoV-2 infection.
Inhibition studies: Inhibition studies can be used to directly test the ability of IgG4 antibodies to impair antiviral responses against SARS-CoV-2. For example, researchers can incubate immune cells with both IgG4 antibodies and neutralizing antibodies that block the effects of IgG4 antibodies. The researchers can then measure the cells' ability to produce antiviral cytokines and kill infected cells. If blocking the effects of IgG4 antibodies leads to a more robust antiviral response, it would provide direct evidence that these antibodies impair antiviral responses against SARS-CoV-2.
Overall, a combination of in vitro and in vivo studies, as well as clinical and epidemiological studies, can help establish the relationship between IgG4 antibodies and antiviral responses against SARS-CoV-2.
Regarding your question: Should this be a reason not to be vaccinated? After a carefull review of the literature we have cited in our work, I personally do not recommend to receive more boosters.
Our hypothesis must be demonstrated or refuted experimentally before we can reach a definitive conclusion, but
there is evidence from animal studies, which we cited in page 13: " In this regard, it was recently demonstrated that following the traditional vaccination scheme, the serum-neutralizing effectiveness 'in mice' against the Delta and Omicron variants of the COVID-19 Pfizer vaccine was dramatically diminished after numerous booster doses [12]. Repeated antigen stimulation reportedly caused CD8+ T cells to become exhausted. These boosters also significantly diminished CD4+ and CD8+ T cell responses and enhanced programmed cell death protein 1 (PD-1) and lymphocyte activation gene-
3 (LAG-3) production in these T cells [124]. The prolonged vaccination decreased the normal development of the germinal center and hindered the generation of memory B cells specific for RBD. This research additionally revealed that prolonged RBD vaccine booster immunization increased the concentration of the immunosuppressive cytokine IL-10 as
well as the proportion of CD25+Foxp3+CD4+ Treg cells. The conventional SARS-CoV-2 vaccine's ability to provide immunological protection may be significantly impacted by over-vaccination. If this happens, either newly diagnosed COVID-19 cases or people who have already contracted the virus again may have a more severe case of the illness. This
concept was proposed after seeing tolerance of both the humoral and cellular immune responses to prolonged booster immunization doses [124].
Comment 2
Received:
28 March 2023
Commenter:
John Collis
The commenter has declared there is no conflict of interests.
Comment:
"increasing evidence has shown they do not produce sterilizing immunity", is it not true that no vaccine is sterilising? Certainly the tetanus vaccine does not prevent infection with the tetanus bacteria as it is a vaccine against the toxin produced by the bacteria. No injected vaccine against a respiratory tract or gastrointestinal infection can prevent infection as the immune system responses are different, with IgA being predominant in mucosa and IgG as the humoral response.
The commenter has declared there is no conflict of interests.
Comment:
Dear John Collins: Thank you for this important observation. We have changed that sentence for this one: increasing evidence has shown that, as many other vaccines, they do not produce sterilizing immunity, allowing people to suffer frequent re-infections.
Certainly, the majority of vaccines do not produce sterilizing immunity.
Response 2 to
Comment 2
Received:
4 April 2023
Commenter:
Gustavo Sandri Heidner
The commenter has declared there is no conflict of interests.
Comment:
Would the authors elaborate more on this claim: increasing evidence has shown that, as many other vaccines, they do not produce sterilizing immunity, allowing people to suffer frequent re-infections.
Specifically, there are no other instances in which reinfections are cited, or discussed throughout the manuscript, except in the title of Gazit et al. (2022)'s publication (in References). Similarly, the use of frequent in relation to re-infections without defining frequent/infrequent and without further discussing it in the manuscript is sufficiently unspecific to confuse the lay reader and may be misconstrued as fact even though it lacks scientific referencing.
Comment 3
Received:
3 April 2023
Commenter:
Rémy Honoré
The commenter has declared there is no conflict of interests.
Comment:
Bonjour,
La notion de tolérance fait référence à l’absence de réactivité immunologique spécifique envers un antigène, faisant suite à une première rencontre avec ce même antigène. Bien que la tolérance la plus importante soit la non-réactivité vis-à-vis d’antigènes du soi, il est aussi possible d’induire une tolérance à des antigènes du non soi. Lorsqu’un antigène induit de la tolérance on dit qu’il est tolérogène.
En immunologie, la tolérance est l'absence ou le faible niveau de réaction inflammatoire face à un antigène. Son contraire est l'anaphylaxie.
On distingue :
- la tolérance centrale, relative à la maturation des lymphocytes B et T, ainsi qu'à la reconnaissance et tolérance du soi ;
- la tolérance périphérique, relative aux lymphocytes B et T matures dans le système lymphatique périphérique ainsi qu'à leur faible activation en cas d'absence de promoteur de la réaction inflammatoire, ou en présence de facteurs de régulation (diminution) de la réaction inflammatoire.
Le processus induisant une tolérance à un antigène donné s'appelle la tolérogenèse. Elle n'est possible que dans un organisme immunocompétent sous certaines conditions. On identifie entre autres certaines cellules immunitaires relativement en amont du processus : les tTreg, les pTreg, les iTreg3.
Parmi les pathologies liées à un manque de tolérance immunitaire :
- Allergies
- Fausses couches
- Maladies auto-immunes
Les patients atteints de COVID long montrent des signes de maladie auto-immune ou de maladies inflammatoires chroniques.
La vaccination ARNm répétée représente ainsi, potentiellement, un moyen d'induire une certaine tolérance au virus en présentant l'antigène, la spike protéine, de manière controlée par l'organisme lui même.
Une étape vers la restauration de la tolérance immunitaire au soi dans les maladies auto-immunes humaines : https://www.medecinesciences.org/en/articles/medsci/full_html/2007/02/medsci2007232p167/medsci2007232p167.html
Received:
3 April 2023
Commenter:
Rémy Honoré
The commenter has declared there is no conflict of interests.
Comment:
Hello,
The concept of tolerance refers to the absence of specific immunological reactivity to an antigen, following a first encounter with that same antigen. Although the most important tolerance is non-reactivity to self antigens, it is also possible to induce tolerance to non-self antigens. When an antigen induces tolerance it is said to be tolerogenic.
In immunology, tolerance is the absence or low level of inflammatory reaction to an antigen. Its opposite is anaphylaxis.
We distinguish :
- central tolerance, related to the maturation of B and T lymphocytes, as well as to the recognition and tolerance of the self;
- peripheral tolerance, related to mature B and T lymphocytes in the peripheral lymphatic system and to their weak activation in the absence of promoters of the inflammatory reaction, or in the presence of factors regulating (reducing) the inflammatory reaction.
The process of inducing tolerance to a given antigen is called tolerogenesis. It is only possible in an immunocompetent organism under certain conditions. Among others, certain immune cells are identified relatively early in the process: tTreg, pTreg, iTreg3.
Among the pathologies related to a lack of immune tolerance:
- Allergies
- Miscarriages
- Autoimmune diseases
INDUCTION OF TOLERANCE TO NON-SELF
Tolerance can also be induced against non-self antigens: this can occur by modifying the antigen, by injecting it by specific routes such as orally, or when the antigen is administered while the immune system is developing for example. Some bacteria and viruses have devised clever ways to induce tolerance so that the host does not kill them. Ex: Lepromatous leprosy patients do not mount an immune response against Mycobacterium leprae.
Whether autoimmune in the strict sense or autoinflammatory, all of these diseases result from a dysfunction of the immune system and evolve into chronic inflammatory diseases.
Patients with long COVID show evidence of autoimmune disease or chronic inflammatory disease.
Repeated mRNA vaccination thus represents a potential means of inducing tolerance to the virus by presenting the antigen, the spike protein, in a manner controlled by the body itself.
The commenter has declared there is no conflict of interests.
Comment:
Dear Rémy Honoré: Thank you very much for your interesting information about the mechanisms of immune tolerance.
You mentioned a very important data in your comment: " Some bacteria and viruses have devised clever ways to induce tolerance so that the host does not kill them. Ex: Lepromatous leprosy patients do not mount an immune response against Mycobacterium leprae".
Respecfuly, we do keep our hypothesis that " A tolerant immune system can allow SARS-CoV-2 persistence in the host and promote the establishment of a chronic infection, similarly to that generated by the hepatitis B virus (HBV), the human immune deficiency virus (HIV), and the hepatitis C virus (HCV) [128].
We also wrote: " It has been suggested that an increase in IgG4 levels could have a protective role similar to that occurring during successful allergen-specific immunotherapy by inhibiting IgE-induced effects [11]. Allergen tolerance is an immune system adaptation characterized by a particular non-inflammatory response to an allergen that, under other conditions, would probably result in cell-mediated or humoral immunity, which would cause tissue inflammation and/or IgE synthesis [113]. In other words, the immune system “learns” to tolerate a foreign although innocuous antigen. However, a very different situation occurs when a virus invades our body. In this scenario, vaccine-induced tolerance can potentially have several negative, unintended consequences because tolerance to the spike protein could inhibit the immune system to detect and attack the pathogen (Figure 4), thus potentially exacerbating SARS-CoV2 pathology in individuals who suffer re-infection of COVID-19 in the setting of vaccine-induced immune suppression.
This leads us to conclude that it is incorrect to compare the increase in IgG4 levels between allergy treatments and the reported increase in IgG4 antibodies after repeated vaccination or infection with SARS-CoV-2. The induced tolerance against the spike protein could produce an impaired immune response against the virus when these patients suffer a re-infection. Although SARS-CoV2 has a high rate of transmissibility, the severity of infections has fortunately been reduced as a result of a change in affinity towards the upper respiratory tract [118-121]. These findings may explain why Omicron infections caused fewer severe effects [122,123]. However, without an adequate protection level, even the new Omicron sub-variants (considered as mild) could cause severe multi-organ damage and death in immuno-compromised individuals. .
In the HIV and malaria trials, an increase in IgG4 levels was directly linked to increased probability of contracting both diseases. Furthermore, our hypothesis is based on a recent animal study. https://www.sciencedirect.com/science/article/pii/S2589004222017515
Extended SARS-CoV-2 RBD booster vaccination induces humoral and cellular immune tolerance in mice
The authors demonstrated that :
- Extended immunization did not enhance RBD specific antibody production in mice
- Extended immunization reduced serum neutralizing antibody responses
- Extended immunization inhibited the production of RBD-specific memory B cells
- Extended immunization suppressed the formation of the germinal center
- Extended immunization inhibited the activation of CD4+T cell immune responses
- Extended immunization inhibited CD8+ T cell-mediated immune response
Discussion:
Therefore, 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.
Moreover, over-vaccination may generate an immunosuppression micro-environment that is also an important facilitator of immune tolerance. We demonstrated 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 (Damo and Joshi, 2019; Field et al., 2020; Turner et al., 2020). Indeed, we observed 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.
IMPORTANTLY: The authors suggested this: " The evidenced immune tolerance from repetitive dosing with homologous boosters in our study suggests that caution should be exercised when optimizing the extended plan for SARS-CoV-2 booster vaccination. Instead of 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 (Reynolds et al., 2022). Such 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 (Lavinder and Ippolito, 2022).
We also encourage you to read the works from Chung et al., (2014) and Dobaño et al., (2012)
- Chung, A.W.; Ghebremichael, M.; Robinson, H.; Brown, E.; Choi, I.; Lane, S.; Dugast, A.-S.; Schoen, M.K.; Rolland, M.; Suscovich, T.J. Polyfunctional Fc-effector profiles mediated by IgG subclass selection distinguish RV144 and VAX003 vaccines. Science translational medicine 2014, 6, 228ra238-228ra238.
- Dobaño, C.; Quelhas, D.; Quintó, L.; Puyol, L.; Serra-Casas, E.; Mayor, A.; Nhampossa, T.; Macete, E.; Aide, P.; Mandomando, I. Age-dependent IgG subclass responses to Plasmodium falciparum EBA-175 are differentially associated with incidence of malaria in Mozambican children. Clinical and Vaccine Immunology 2012, 19, 157-166.
The commenter has declared there is no conflict of interests.
Comment:
Dear Gustavo Sandri Heidner: Thank you very much for your comments. They will improve the quality of our work.
Indeed, breakthrough infections are not rare. There are several works describing that compared with alpha and delta, Omicron breaktrhough infections are more frequent (up to 19 % in one study (Sanghavi et al., 2022):
- Sanghavi DK, Bhakta S, Wadei HM, Bosch W, Cowart JB, Carter RE, Shah SZ, Pollock BD, Neville MR, Oman SP, Speicher L, Siegel J, Scindia AD, Libertin CR, Kunze KL, Johnson PW, Matson MW, Franco PM. Low antispike antibody levels correlate with poor outcomes in COVID-19 breakthrough hospitalizations. J Intern Med. 2022 Jul;292(1):127-135. doi: 10.1111/joim.13471. Epub 2022 Mar 24. PMID: 35194861; PMCID: PMC9115098.
- Pulliam, J. R. C. et al. Increased risk of SARS-CoV-2 reinfection associated with emergence of Omicron in South Africa. Science 376, eabn4947 (2022).
- Altarawneh, H. N. et al. Protection against the Omicron variant from previous SARS-CoV-2 infection. N. Engl. J. Med. 386, 1288–1290 (2022).
- Accorsi, E. K. et al. Association between 3 doses of mRNA COVID-19 vaccine and symptomatic infection caused by the SARS-CoV-2 Omicron and Delta variants. JAMA 327, 639–651 (2022).
- Christensen PA, Olsen RJ, Long SW, Snehal R, Davis JJ, Saavedra MO, Reppond K, Shyer MN, Cambric J, Gadd R, Thakur RM, Batajoo A, Mangham R, Pena S, Trinh T, Kinskey JC, Williams G, Olson R, Gollihar J, Musser JM. Signals of significantly increased vaccine breakthrough, decreased hospitalization rates, and less severe disease in patients with coronavirus disease 2019 caused by the omicron variant of severe acute respiratory syndrome coronavirus 2 in Houston, Texas. Am J Pathol 192: 642–652, 2022. doi:10.1016/j.ajpath.2022.01.007.
- Khoury, J., Najjar-Debbiny, R., Hanna, A., Jabbour, A., Ahmad, Y. A., Saffuri, A., ... & Hakim, F. (2021). COVID-19 vaccine–Long term immune decline and breakthrough infections. Vaccine, 39(48), 6984-6989.
All these studies have showed that breakthrough infections (although frequent), are mild in young and healthy people but not in older people with comorbidities. For example, Juthani et al., (2022), identified 969 patients who were admitted to a Yale New Haven Health System hospital with a confirmed positive PCR test for SARS-CoV-2. Severity of COVID-19 infection was determined on the basis of established guidelines. Patients deemed to have a breakthrough SARS-CoV-2 infection—ie, the 54 patients who were fully vaccinated—were evaluated for illness severity. Among this cohort, we found that 25 (46%) patients were asymptomatic (admitted to hospital for a non-COVID-19-related diagnosis but with an incidental positive PCR test for SARS-CoV-2), four (7%) had mild disease, 11 (20%) had moderate disease, and 14 (26%) had severe or critical illness. Among those with severe or critical illness, the median age was 80·5 years (IQR 76·5–85·0); four of 14 patients required intensive care, one required mechanical ventilation, and three died. Pre-existing comorbidities in the 14 patients with severe or critical illness included overweight (body–mass index >25 kg/m2; n=9), cardiovascular disease (n=12), lung disease (n=7), malignancy (n=4), type 2 diabetes (n=7), and use of an immunosuppressive agents .
- Juthani, Prerak V., et al. "Hospitalisation among vaccine breakthrough COVID-19 infections." The Lancet Infectious Diseases 21.11 (2021): 1485-1486.
The global vaccination policy is based more on monetary issues than on evidence-based clinical criteria. That is why in the discussion section we invite to reflection: " Finally, these negative outcomes are not expected to affect all people who have received these mRNA vaccines. Individuals with genetic susceptibility, immune deficiencies, and co-morbidities probably would be the most likely to be affected. However, this gives rise to a disturbing paradox: if people who are the most affected by the COVID-19 disease (the elderly, diabetics, hypertensive, and immunocompromised people like those
with HIV) are also more susceptible to suffering the negative effects of mRNA vaccines,
is it then justified to booster them? As Omicron subvariants have been demonstrated to be less pathogenic [133-138], and mRNA vaccines do not protect against re-infection [14,116], clinicians should be aware of the possible
detrimental effects on the immune system by administering boosters.
Thank you again. We will add references above mentioned.
Commenter: John Collis
The commenter has declared there is no conflict of interests.
Pillai S. Is it bad, is it good, or is IgG4 just misunderstood? Sci Immunol. 2023 Mar 31;8(81):eadg7327. doi: 10.1126/sciimmunol.adg7327. Epub 2023 Mar 24. PMID: 36749191.
Commenter:
The commenter has declared there is no conflict of interests.
As you may have noticed, our work is a hypothesis. We are proposing a scientific explanation based, for example, on the results of clinical trials with vaccines for HIV and malaria. In these trials, repeated vaccination resulted in the production of the IgG4 antibody. In both trials, an increase in IgG4 levels was associated with a higher risk of contracting HIV or malaria.
In the malaria trial, researchers noticed a distinct pattern for IgG subclasses to the EBA-175 antigen: higher concentrations of particular antibodies known as neutralizing IgG1 and IgG3 were linked to a reduced likelihood of contracting malaria in the second year. As the levels of IgG1 doubled, the risk of malaria reduced by about 50%, and when the levels of IgG3 doubled, the risk of malaria decreased by about 60% [105]
On the other side, the probability of contracting malaria increased by around three times when non-neutralizing IgG4 levels doubled. Up to the age of 24 months, IgG1 and IgG3 demonstrated 51% and 56% protective effects respectively, however, IgG4 was linked to a higher risk of malaria infection throughout this age range [105]. It's interesting to note that a separate study also found a link between high IgG4 levels and a higher risk of infection and malaria exacerbations [111].
So, if our hypothesis is correct, then, an increase in IgG4 levels could explain SARS-CoV-2´s breakthrough infections. In addition, we also hypothesized that IgG4 antibodies could impair antiviral responses, for example, IgG4 could block recognition and attack by cytotoxic T cells, thus the infected cell is not destroyed (see figure in page 12), and facilitating viral persistence in the host, leading to chronic infection.
Our work must be read and interpreted for what it is: a hypothesis, which must be experimentally evaluated.
Here are some methods to demonstrate the effect of IgG4 antibodies on antiviral responses against SARS-CoV-2:
In vitro studies: In vitro studies can be used to demonstrate the effect of IgG4 antibodies on antiviral responses against SARS-CoV-2. For example, researchers can isolate immune cells from individuals infected with SARS-CoV-2 and incubate them with IgG4 antibodies. The researchers can then measure the cells' ability to produce antiviral cytokines and kill infected cells. If the presence of IgG4 antibodies impairs the cells' ability to produce antiviral responses, it would suggest that these antibodies could contribute to the progression of SARS-CoV-2 infection.
Animal models: Animal models can also be used to investigate the effect of IgG4 antibodies on antiviral responses against SARS-CoV-2. Researchers can use genetically modified mice that lack the ability to produce IgG4 antibodies and compare their immune responses to SARS-CoV-2 infection to normal mice. If the absence of IgG4 antibodies leads to a more robust antiviral response and better disease outcomes, it would suggest that IgG4 antibodies impair antiviral responses against SARS-CoV-2.
Clinical studies: Clinical studies can be used to examine the relationship between IgG4 antibodies and disease outcomes in individuals infected with SARS-CoV-2. Researchers can measure the levels of IgG4 antibodies in patients' blood samples and correlate them with disease severity and antiviral responses. If high levels of IgG4 antibodies are associated with worse disease outcomes and impaired antiviral responses, it would suggest that these antibodies play a role in the progression of SARS-CoV-2 infection.
Cross-sectional studies: Cross-sectional studies can be used to compare the levels of IgG4 antibodies and antiviral responses among individuals with different disease outcomes. For example, researchers can compare the levels of IgG4 antibodies and antiviral responses in patients with mild disease versus severe disease. If high levels of IgG4 antibodies are associated with impaired antiviral responses and worse disease outcomes, it would suggest that these antibodies play a role in the progression of SARS-CoV-2 infection.
Longitudinal studies: Longitudinal studies can be used to track changes in IgG4 antibody levels and antiviral responses over time in individuals infected with SARS-CoV-2. For example, researchers can measure the levels of IgG4 antibodies and antiviral responses in patients at different time points during the course of their infection. If increases in IgG4 antibody levels are associated with declines in antiviral responses, it would suggest that these antibodies contribute to the progression of SARS-CoV-2 infection.
Inhibition studies: Inhibition studies can be used to directly test the ability of IgG4 antibodies to impair antiviral responses against SARS-CoV-2. For example, researchers can incubate immune cells with both IgG4 antibodies and neutralizing antibodies that block the effects of IgG4 antibodies. The researchers can then measure the cells' ability to produce antiviral cytokines and kill infected cells. If blocking the effects of IgG4 antibodies leads to a more robust antiviral response, it would provide direct evidence that these antibodies impair antiviral responses against SARS-CoV-2.
Overall, a combination of in vitro and in vivo studies, as well as clinical and epidemiological studies, can help establish the relationship between IgG4 antibodies and antiviral responses against SARS-CoV-2.
Regarding your question: Should this be a reason not to be vaccinated? After a carefull review of the literature we have cited in our work, I personally do not recommend to receive more boosters.
Our hypothesis must be demonstrated or refuted experimentally before we can reach a definitive conclusion, but
there is evidence from animal studies, which we cited in page 13: " In this regard, it was recently demonstrated that following the traditional vaccination scheme, the serum-neutralizing effectiveness 'in mice' against the Delta and Omicron variants of the COVID-19 Pfizer vaccine was dramatically diminished after numerous booster doses [12]. Repeated antigen stimulation reportedly caused CD8+ T cells to become exhausted. These boosters also significantly diminished CD4+ and CD8+ T cell responses and enhanced programmed cell death protein 1 (PD-1) and lymphocyte activation gene-
3 (LAG-3) production in these T cells [124]. The prolonged vaccination decreased the normal development of the germinal center and hindered the generation of memory B cells specific for RBD. This research additionally revealed that prolonged RBD vaccine booster immunization increased the concentration of the immunosuppressive cytokine IL-10 as
well as the proportion of CD25+Foxp3+CD4+ Treg cells. The conventional SARS-CoV-2 vaccine's ability to provide immunological protection may be significantly impacted by over-vaccination. If this happens, either newly diagnosed COVID-19 cases or people who have already contracted the virus again may have a more severe case of the illness. This
concept was proposed after seeing tolerance of both the humoral and cellular immune responses to prolonged booster immunization doses [124].
Commenter: John Collis
The commenter has declared there is no conflict of interests.
Commenter:
The commenter has declared there is no conflict of interests.
Certainly, the majority of vaccines do not produce sterilizing immunity.
Commenter: Gustavo Sandri Heidner
The commenter has declared there is no conflict of interests.
Specifically, there are no other instances in which reinfections are cited, or discussed throughout the manuscript, except in the title of Gazit et al. (2022)'s publication (in References). Similarly, the use of frequent in relation to re-infections without defining frequent/infrequent and without further discussing it in the manuscript is sufficiently unspecific to confuse the lay reader and may be misconstrued as fact even though it lacks scientific referencing.
Commenter: Rémy Honoré
The commenter has declared there is no conflict of interests.
La notion de tolérance fait référence à l’absence de réactivité immunologique spécifique envers un antigène, faisant suite à une première rencontre avec ce même antigène. Bien que la tolérance la plus importante soit la non-réactivité vis-à-vis d’antigènes du soi, il est aussi possible d’induire une tolérance à des antigènes du non soi. Lorsqu’un antigène induit de la tolérance on dit qu’il est tolérogène.
En immunologie, la tolérance est l'absence ou le faible niveau de réaction inflammatoire face à un antigène. Son contraire est l'anaphylaxie.
On distingue :
- la tolérance centrale, relative à la maturation des lymphocytes B et T, ainsi qu'à la reconnaissance et tolérance du soi ;
- la tolérance périphérique, relative aux lymphocytes B et T matures dans le système lymphatique périphérique ainsi qu'à leur faible activation en cas d'absence de promoteur de la réaction inflammatoire, ou en présence de facteurs de régulation (diminution) de la réaction inflammatoire.
Le processus induisant une tolérance à un antigène donné s'appelle la tolérogenèse. Elle n'est possible que dans un organisme immunocompétent sous certaines conditions. On identifie entre autres certaines cellules immunitaires relativement en amont du processus : les tTreg, les pTreg, les iTreg3.
Parmi les pathologies liées à un manque de tolérance immunitaire :
- Allergies
- Fausses couches
- Maladies auto-immunes
Les patients atteints de COVID long montrent des signes de maladie auto-immune ou de maladies inflammatoires chroniques.
La vaccination ARNm répétée représente ainsi, potentiellement, un moyen d'induire une certaine tolérance au virus en présentant l'antigène, la spike protéine, de manière controlée par l'organisme lui même.
Une étape vers la restauration de la tolérance immunitaire au soi dans les maladies auto-immunes humaines :
https://www.medecinesciences.org/en/articles/medsci/full_html/2007/02/medsci2007232p167/medsci2007232p167.html
Commenter: Rémy Honoré
The commenter has declared there is no conflict of interests.
The concept of tolerance refers to the absence of specific immunological reactivity to an antigen, following a first encounter with that same antigen. Although the most important tolerance is non-reactivity to self antigens, it is also possible to induce tolerance to non-self antigens. When an antigen induces tolerance it is said to be tolerogenic.
In immunology, tolerance is the absence or low level of inflammatory reaction to an antigen. Its opposite is anaphylaxis.
We distinguish :
- central tolerance, related to the maturation of B and T lymphocytes, as well as to the recognition and tolerance of the self;
- peripheral tolerance, related to mature B and T lymphocytes in the peripheral lymphatic system and to their weak activation in the absence of promoters of the inflammatory reaction, or in the presence of factors regulating (reducing) the inflammatory reaction.
The process of inducing tolerance to a given antigen is called tolerogenesis. It is only possible in an immunocompetent organism under certain conditions. Among others, certain immune cells are identified relatively early in the process: tTreg, pTreg, iTreg3.
Among the pathologies related to a lack of immune tolerance:
- Allergies
- Miscarriages
- Autoimmune diseases
INDUCTION OF TOLERANCE TO NON-SELF
Tolerance can also be induced against non-self antigens: this can occur by modifying the antigen, by injecting it by specific routes such as orally, or when the antigen is administered while the immune system is developing for example. Some bacteria and viruses have devised clever ways to induce tolerance so that the host does not kill them. Ex: Lepromatous leprosy patients do not mount an immune response against Mycobacterium leprae.
Whether autoimmune in the strict sense or autoinflammatory, all of these diseases result from a dysfunction of the immune system and evolve into chronic inflammatory diseases.
Patients with long COVID show evidence of autoimmune disease or chronic inflammatory disease.
Repeated mRNA vaccination thus represents a potential means of inducing tolerance to the virus by presenting the antigen, the spike protein, in a manner controlled by the body itself.
A step toward restoring immune tolerance to self in human autoimmune diseases
https://www.medecinesciences.org/en/articles/medsci/full_html/2007/02/medsci2007232p167/medsci2007232p167.html
Commenter:
The commenter has declared there is no conflict of interests.
You mentioned a very important data in your comment: " Some bacteria and viruses have devised clever ways to induce tolerance so that the host does not kill them. Ex: Lepromatous leprosy patients do not mount an immune response against Mycobacterium leprae".
Respecfuly, we do keep our hypothesis that " A tolerant immune system can allow SARS-CoV-2 persistence in the host and promote the establishment of a chronic infection, similarly to that generated by the hepatitis B virus (HBV), the human immune deficiency virus (HIV), and the hepatitis C virus (HCV) [128].
We also wrote: " It has been suggested that an increase in IgG4 levels could have a protective role similar to that occurring during successful allergen-specific immunotherapy by inhibiting IgE-induced effects [11]. Allergen tolerance is an immune system adaptation characterized by a particular non-inflammatory response to an allergen that, under other conditions, would probably result in cell-mediated or humoral immunity, which would cause tissue inflammation and/or IgE synthesis [113]. In other words, the immune system “learns” to tolerate a foreign although innocuous antigen. However, a very different situation occurs when a virus invades our body. In this scenario, vaccine-induced tolerance can potentially have several negative, unintended consequences because tolerance to the spike protein could inhibit the immune system to detect and attack the pathogen (Figure 4), thus potentially exacerbating SARS-CoV2 pathology in individuals who suffer re-infection of COVID-19 in the setting of vaccine-induced immune suppression.
This leads us to conclude that it is incorrect to compare the increase in IgG4 levels between allergy treatments and the reported increase in IgG4 antibodies after repeated vaccination or infection with SARS-CoV-2. The induced tolerance against the spike protein could produce an impaired immune response against the virus when these patients suffer a re-infection. Although SARS-CoV2 has a high rate of transmissibility, the severity of infections has fortunately been reduced as a result of a change in affinity towards the upper respiratory tract [118-121]. These findings may explain why Omicron infections caused fewer severe effects [122,123]. However, without an adequate protection level, even the new Omicron sub-variants (considered as mild) could cause severe multi-organ damage and death in immuno-compromised individuals. .
In the HIV and malaria trials, an increase in IgG4 levels was directly linked to increased probability of contracting both diseases. Furthermore, our hypothesis is based on a recent animal study.
https://www.sciencedirect.com/science/article/pii/S2589004222017515 Extended SARS-CoV-2 RBD booster vaccination induces humoral and cellular immune tolerance in mice
The authors demonstrated that :
- Extended immunization did not enhance RBD specific antibody production in mice
- Extended immunization reduced serum neutralizing antibody responses
- Extended immunization inhibited the production of RBD-specific memory B cells
- Extended immunization suppressed the formation of the germinal center
- Extended immunization inhibited the activation of CD4+T cell immune responses
- Extended immunization inhibited CD8+ T cell-mediated immune response
Discussion:
Therefore, 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.
Moreover, over-vaccination may generate an immunosuppression micro-environment that is also an important facilitator of immune tolerance. We demonstrated 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 (Damo and Joshi, 2019; Field et al., 2020; Turner et al., 2020). Indeed, we observed 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.
IMPORTANTLY: The authors suggested this: " The evidenced immune tolerance from repetitive dosing with homologous boosters in our study suggests that caution should be exercised when optimizing the extended plan for SARS-CoV-2 booster vaccination. Instead of 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 (Reynolds et al., 2022). Such 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 (Lavinder and Ippolito, 2022).
We also encourage you to read the works from Chung et al., (2014) and Dobaño et al., (2012)
- Chung, A.W.; Ghebremichael, M.; Robinson, H.; Brown, E.; Choi, I.; Lane, S.; Dugast, A.-S.; Schoen, M.K.; Rolland, M.; Suscovich, T.J. Polyfunctional Fc-effector profiles mediated by IgG subclass selection distinguish RV144 and VAX003 vaccines. Science translational medicine 2014, 6, 228ra238-228ra238.
- Dobaño, C.; Quelhas, D.; Quintó, L.; Puyol, L.; Serra-Casas, E.; Mayor, A.; Nhampossa, T.; Macete, E.; Aide, P.; Mandomando, I. Age-dependent IgG subclass responses to Plasmodium falciparum EBA-175 are differentially associated with incidence of malaria in Mozambican children. Clinical and Vaccine Immunology 2012, 19, 157-166.
We thank you again for your interest in our work.
Commenter:
The commenter has declared there is no conflict of interests.
Indeed, breakthrough infections are not rare. There are several works describing that compared with alpha and delta, Omicron breaktrhough infections are more frequent (up to 19 % in one study (Sanghavi et al., 2022):
- Sanghavi DK, Bhakta S, Wadei HM, Bosch W, Cowart JB, Carter RE, Shah SZ, Pollock BD, Neville MR, Oman SP, Speicher L, Siegel J, Scindia AD, Libertin CR, Kunze KL, Johnson PW, Matson MW, Franco PM. Low antispike antibody levels correlate with poor outcomes in COVID-19 breakthrough hospitalizations. J Intern Med. 2022 Jul;292(1):127-135. doi: 10.1111/joim.13471. Epub 2022 Mar 24. PMID: 35194861; PMCID: PMC9115098.
- Pulliam, J. R. C. et al. Increased risk of SARS-CoV-2 reinfection associated with emergence of Omicron in South Africa. Science 376, eabn4947 (2022).
- Altarawneh, H. N. et al. Protection against the Omicron variant from previous SARS-CoV-2 infection. N. Engl. J. Med. 386, 1288–1290 (2022).
- Accorsi, E. K. et al. Association between 3 doses of mRNA COVID-19 vaccine and symptomatic infection caused by the SARS-CoV-2 Omicron and Delta variants. JAMA 327, 639–651 (2022).
- Christensen PA, Olsen RJ, Long SW, Snehal R, Davis JJ, Saavedra MO, Reppond K, Shyer MN, Cambric J, Gadd R, Thakur RM, Batajoo A, Mangham R, Pena S, Trinh T, Kinskey JC, Williams G, Olson R, Gollihar J, Musser JM. Signals of significantly increased vaccine breakthrough, decreased hospitalization rates, and less severe disease in patients with coronavirus disease 2019 caused by the omicron variant of severe acute respiratory syndrome coronavirus 2 in Houston, Texas. Am J Pathol 192: 642–652, 2022. doi:10.1016/j.ajpath.2022.01.007.
- Khoury, J., Najjar-Debbiny, R., Hanna, A., Jabbour, A., Ahmad, Y. A., Saffuri, A., ... & Hakim, F. (2021). COVID-19 vaccine–Long term immune decline and breakthrough infections. Vaccine, 39(48), 6984-6989.
All these studies have showed that breakthrough infections (although frequent), are mild in young and healthy people but not in older people with comorbidities. For example, Juthani et al., (2022), identified 969 patients who were admitted to a Yale New Haven Health System hospital with a confirmed positive PCR test for SARS-CoV-2. Severity of COVID-19 infection was determined on the basis of established guidelines. Patients deemed to have a breakthrough SARS-CoV-2 infection—ie, the 54 patients who were fully vaccinated—were evaluated for illness severity. Among this cohort, we found that 25 (46%) patients were asymptomatic (admitted to hospital for a non-COVID-19-related diagnosis but with an incidental positive PCR test for SARS-CoV-2), four (7%) had mild disease, 11 (20%) had moderate disease, and 14 (26%) had severe or critical illness. Among those with severe or critical illness, the median age was 80·5 years (IQR 76·5–85·0); four of 14 patients required intensive care, one required mechanical ventilation, and three died. Pre-existing comorbidities in the 14 patients with severe or critical illness included overweight (body–mass index >25 kg/m2; n=9), cardiovascular disease (n=12), lung disease (n=7), malignancy (n=4), type 2 diabetes (n=7), and use of an immunosuppressive agents .
- Juthani, Prerak V., et al. "Hospitalisation among vaccine breakthrough COVID-19 infections." The Lancet Infectious Diseases 21.11 (2021): 1485-1486.
The global vaccination policy is based more on monetary issues than on evidence-based clinical criteria. That is why in the discussion section we invite to reflection: " Finally, these negative outcomes are not expected to affect all people who have received these mRNA vaccines. Individuals with genetic susceptibility, immune deficiencies, and co-morbidities probably would be the most likely to be affected. However, this gives rise to a disturbing paradox: if people who are the most affected by the COVID-19 disease (the elderly, diabetics, hypertensive, and immunocompromised people like those
with HIV) are also more susceptible to suffering the negative effects of mRNA vaccines,
is it then justified to booster them? As Omicron subvariants have been demonstrated to be less pathogenic [133-138], and mRNA vaccines do not protect against re-infection [14,116], clinicians should be aware of the possible
detrimental effects on the immune system by administering boosters.
Thank you again. We will add references above mentioned.