The opinion piece by Kakeya et. al. on the Journal of Japan Medical Association (the link to the paper is in post #1).
TL;DR: an interesting document where omissions and logical inconsistencies are used to give the impression a case has been built against mRNA vaccines.
I think that's right (and from a very useful post by
@Mauro).
Some contentious (or possibly just plain wrong) statements are made in the JMA paper without supporting citations, or with citations that don't quite support what the authors claim they do.
The authors advance some facts as possibly supporting a "vaccines cause excess deaths" hypothesis without considering much more likely, and already well-understood, explanations (e.g. in their supposition re. traces of COVID-19 in wastewater).
As per the OP,
"Significant Increase in Excess Deaths after Repeated COVID-19 Vaccination in Japan",
Hideki Kakeya, Takeshi Nitta, Yukari Kamijima, and Takayuki Miyazawa,
JMA Journal 8 (2) 2025,
https://www.jmaj.jp/detail.php?id=10.31662/jmaj.2024-0298,
let's look at this passage:
External Quote:
Although adverse reactions were more severe and autoimmune diseases reported more frequently after the second vaccination than the first, they were reported much less after boosters, which can be explained by the suppression of immunity against the SARS-CoV-2 spike protein. Indeed, recent studies have reported an increase in spike-specific immunoglobulin G4, an immunosuppressive class of antibody, and regulatory T cells after the second and subsequent vaccinations
(11), (12). This can lead to chronic infection whereby the virus remains in the intestine, for which positive test results cannot be obtained by nasal swabs. Wastewater monitoring data support this claim.
One claim at a time:
Claim (1) "...adverse reactions were more severe... ...after the second vaccination than the first..."
The authors give no evidence or references, but there is a paper paper from Japan that supports this.
We do not know if Kakeya, Nitta
et al. had this paper in mind.
"Association between Adverse Reactions to the First and Second Doses of COVID-19 Vaccine", Ken Goda, Tsuneaki Kenzaka
et al.,
Vaccines 10 (8), 2022,
https://www.sciencedirect.com/science/article/pii/S1341321X22000940,
was based on self-reporting of symptoms by 4,503 healthcare workers vaccinated with the first dose of Pfizer-BioNTech vaccine, 4,473 of whom received the second dose.
The authors document slightly more and longer-lasting adverse events for the second dose (442 respondents, 9.9%) than for the first dose (595 respondents, 13.2%).
However, all adverse events were essentially trivial (if unpleasant) and short-term.
The most common adverse event, muscular pain, was reported by 90% of respondents; the authors write
External Quote:
...it appears that a direct local reaction is associated with intramuscular injection of the vaccine.
I was going to have some fun with the author's finding that having an IM injection causes muscle pain, but thoroughness isn't bad, and it does give some insight into what might be considered an adverse reaction by the authors- in this case, the unavoidable and wholly expected discomfort from having a 25g needle jabbed into a muscle to deliver 0.3mL of liquid.
As part of their conclusion the authors write
External Quote:
Some of the adverse reactions of the Pfizer-BioNTech Comirnaty® COVID-19 vaccine have gender and age differences. However, nearly all adverse reactions disappear within a week. Therefore, these side effects are not a significant concern in recommending vaccination.
Another possible source for claim
(1): The death of a 14 year-old female post-vaccination is discussed in
"
A case of fatal multi-organ inflammation following COVID-19 vaccination", Hideyuki Nushida, Asuka Ito
et al.,
Legal Medicine 63, July 2023; the authors write
External Quote:
...the incidence of myocarditis and pericarditis is reported to be higher with second dose of the vaccine than with first dose
Both conditions are possible adverse consequences of COVID-19 vaccines, fortunately they are rare and almost always mild:
External Quote:
Thus, post-vaccination myocarditis and pericarditis had incidence rates of 0.0008–0.0047% and 0.0019–0.0050%, respectively. Although usually mild, these conditions can occur; however, severe cases resulting in death are rare.
The OP JMA authors (Kakeya, Nitta
et al.) are aware of this paper, although they do not refer to it in the context of claim
(1); they mention Japanese governmental compensation to those injured by vaccination
External Quote:
...including the fatal case of a 14-year-old girl
Incidentally, this tragic death is the only individual case that Kateya, Nitta
et al. refer to, but they do not mention a published response to the Hideyuki Nushida, Asuka Ito
et al. paper, "
Before blaming SARS-CoV-2 vaccination for unexpected death from atrial myocarditis, rule out alternative pathophysiologies", Josef Finsterer, same issue (
Legal Medicine 63, July 2023).
Claim (2) "...
autoimmune diseases reported more frequently after the second vaccination than the first..."
The authors provide no evidence or references for this important claim.
There is evidence elsewhere that COVID-19 vaccination might, rarely, trigger autoimmune conditions, or cause flair-ups of existing autoimmune disease:
"Insights into new-onset autoimmune diseases after COVID-19 vaccination", Ming Guo, Xiaoxiao Liu, Xiangmei Chen, Qinggang Li,
Autoimmunity Reviews 22 (7) 2023,
https://pmc.ncbi.nlm.nih.gov/articles/PMC10108562/:
External Quote:
In this comprehensive review, we have discussed rare autoimmune diseases that may potentially arise following COVID-19 vaccination, such as autoimmune glomerulonephritis, autoimmune rheumatic diseases, and autoimmune hepatitis, among others.
...Further exploration is necessary to establish a causal relationship between COVID-19 vaccines and the aforementioned autoimmune diseases...
...It is important to emphasize that vaccines are generally safe and necessary for disease prevention. The benefits of COVID-19 vaccination significantly outweigh the theoretical risks, and we strongly encourage worldwide vaccination to build immune protection in the population.
"Long-term risk of autoimmune diseases after mRNA-based SARS-CoV2 vaccination in a Korean, nationwide, population-based cohort study", Seung-Won Jung, Jae Joon Jeon
et al.,
Nature Communications 15 (2024)
https://www.nature.com/articles/s41467-024-50656-8:
External Quote:
We previously reported no significant difference in the risk of developing AI-CTDs between the mRNA vaccination group and the historical control group at a mean follow-up of 100 days. Our results were generally aligned with the previous study, but we found some gaps in an increased risk of some AI-CTDs, including SLE.
SLE = Systemic Lupus Erythematosus, see Wikipedia
https://en.wikipedia.org/wiki/Lupus.
There
is a reference to booster (not second) vaccinations in their discussion of possible association of COVID-19 vaccines and SLE,
External Quote:
Another study found that booster vaccinations increase circulating cell-free DNA in B cells, T cells, and monocytes (22)
but the authors do not expand on this and the referenced paper, "
B cell-derived cfDNA after primary BNT162b2 mRNA vaccination anticipates memory B cells and SARS-CoV-2 neutralizing antibodies", 2022, does not mention SLE in its abstract, listed keywords or (very) brief conclusions:
External Quote:
Conclusions: Immune cfDNA dynamics reveal the crucial role of the primary SARS-CoV-2 vaccine in shaping responses of the immune system following the booster vaccine.
Seung-Won Jung, Jae Joon Jeon
et al. (2024) continue,
External Quote:
Furthermore, our study found that booster vaccination was associated with an increased risk of developing certain AI-CTDs, such as alopecia areata, psoriasis, and rheumatoid arthritis, albeit the effect size was small. This finding could be associated with autoimmune flare-ups following repeated mRNA vaccination, which can cause subclinical diseases to become active and diagnosed... ...booster vaccinations have shown substantial safety and potential benefits of improving humoral immune response preventing COVID-19 diagnosis or reducing disease severity. Moreover, an additional dose of the vaccine could serve as a strategy to address the limitation of its waning efficacy over time. Therefore, our results are not sufficient to discourage booster vaccination...
In conclusion, our study results suggest that mRNA vaccination is generally not associated with a higher risk of most AI-CTDs. However, given that the risk of SLE and BP was increased in certain demographic conditions such as age and sex, long-term monitoring is necessary after mRNA vaccination for the development of AI-CTDs.
(AI-CTDs = autoimmune connective tissue diseases; BP = bullous pemphigoid, Wikipedia
Bullous pemphigoid).
There are other papers that indicate that autoimmune conditions might be exacerbated or caused by mRNA COVID-19 vaccines. The percentage of vaccine recipients that may be affected is very small, but clearly this is an area deserving study and the awareness of clinicians.
Interestingly, the paper "Risk of autoimmune diseases following COVID-19 and the potential protective effect from vaccination: a population-based cohort study", Kuan Peng, Xue Li
et al.,
eClinicalMedicine 63, 2023
https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00331-0/fulltext (published by
The Lancet) had different results:
External Quote:
The study included 1,028,721 COVID-19 and 3,168,467 non-COVID individuals...
... Among COVID-19 patients, completion of two doses of COVID-19 vaccine shows a decreased risk of pemphigoid, Graves' disease, anti-phospholipid antibody syndrome, immune-mediated thrombocytopenia, systemic lupus erythematosus and other autoimmune arthritis.
This is in direct contrast to the findings of Seung-Won Jung, Jae Joon Jeon
et al. (2024) re. SLE, BP and rheumatoid arthritis. They conclude
External Quote:
Interpretation
Our findings suggested that COVID-19 is associated with an increased risk of developing various ADs and the risk could be attenuated by COVID-19 vaccination. Future studies investigating pathology and mechanisms would be valuable to interpreting our findings.
(My emphasis).
Claim (3) "
...adverse reactions... ...were reported much less after boosters..."
Again, no reference in the OP paper, but there is a paper from Japan that supports this; again, we do not know if Kakeya, Nitta
et al. were thinking of this paper:
External Quote:
Compared to the incidence of overall acute adverse events after the first (n = 1,426/131,544; 1.08%) or second mRNA-1273 dose (n = 476/126,419; 0.38%), which were previously reported (Akaishi et al. 2022c), the incidence rates after the third (P < 0.0001, both against the first and second doses) and/or fourth mRNA-1273 dose (P < 0.0001, both against the first and second doses) were significantly lower.
"Acute Adverse Events at a Mass Vaccination Site after the Third and Fourth COVID-19 Vaccinations in Japan", Tetsuya Akaishi, Tamotsu Onodera
et al.,
The Tohoku Journal of Experimental Medicine 259 (4), 2023
https://www.jstage.jst.go.jp/article/tjem/259/4/259_2023.J002/_html/-char/en
Some of the adverse effects recorded in this study were more serious than those in the Goda, Kenzaka
et al. 2022 paper (above), including four people who suffered anaphylaxis, whereas the Goda, Kenzaka paper includes a high percentage of, frankly, trivial "adverse events" which Akaishi, Onodera
et al. do not document. They are not assessing the same things.
External Quote:
The most common diagnosis was vasovagal syncope/presyncope, comprising nearly half of the observed acute adverse events, followed by acute allergic reactions. The incidence of anaphylaxis was much lower, estimated to be < 0.005%
Vasovagal syncope means fainting-
Fainting (vasovagal syncope), patient information leaflet, Gloucestershire Hospitals NHS Foundation Trust 2018. Sometimes called a "simple faint". Presyncope is a feeling or fear that you're about to faint.
Not that uncommon when people receive injections, which is why injections are given while you're seated, reclining etc.
Tamotsu Onodera
et al. point out that those who had a serious adverse reaction to the first or second vaccination were less likely to receive a subsequent vaccination. This would mean that the minority of people constitutionally at risk of severe reactions are underrepresented in the cohort receiving booster vaccinations, thus there will be less adverse reactions in that cohort.
Claim (4) ".
..which can be explained by the suppression of immunity against the SARS-CoV-2 spike protein."
(See also, Claim (5) "Indeed, recent studies have reported an increase in spike-specific immunoglobulin G4, an immunosuppressive class of antibody...", below).
If booster shots of COVID-19 vaccines suppress immunity against COVID-19 -not just the the SARS-CoV-2 spike protein or any other specific viral feature acting as a target for the immune system- we would expect to see more severe illness from COVID-19 in people who have received those boosters, matched for age and other risk factors against people who have not received boosters. I'm not aware of any reputable study that claims this.
Most COVID-19 vaccines are designed to inform the immune system of the SARS-CoV-2 spike protein so that the immune system can reduce cell infection and viral replication by COVID-19. We know this works because severity of COVID-19 is less, and severe illness much less, in vaccinated people.
External Quote:
Spike (S) glycoprotein (sometimes also called spike protein, formerly known as E2) is the largest of the four major structural proteins found in coronaviruses.
...The function of the spike glycoprotein is to mediate viral entry into the host cell by first interacting with molecules on the exterior cell surface and then fusing the viral and cellular membranes.
Spike glycoprotein is highly immunogenic. Antibodies against spike glycoprotein are found in patients recovered from SARS and COVID-19. Neutralizing antibodies target epitopes on the receptor-binding domain. Most COVID-19 vaccine development efforts in response to the COVID-19 pandemic aim to activate the immune system against the spike protein.
Coronavirus spike protein, Wikipedia
https://en.wikipedia.org/wiki/Coronavirus_spike_protein.
External Quote:
Vojdani et al. found that antibodies to the SARS-CoV-2 spike protein cross-reacted with transglutaminase 3 (TTG3), transglutaminase 2(TTG2), and other proteins, suggesting that SARS-CoV-2 may trigger autoimmunity
"
Insights into new-onset autoimmune diseases after COVID-19 vaccination", full ref. above.
This suggests that antibodies to the SARS-CoV-2 spike protein as a result of COVID-19 infection (and the "Insights..." authors take it as implicit that this might also apply to vaccination) might trigger autoimmune responses in a small number of people, not immunosuppression.
Those most likely to be offered boosters (in many healthcare systems) will be those with known risk factors for poor outcomes if they contract COVID-19. COVID-19 remains widespread. If those most likely to be made severely ill by COVID-19 are having their immunity against it
reduced by booster vaccines, I suspect that fact would be recognised in the form of increased ICU admissions and deaths of people with COVID-19 infections from that cohort. But we don't see this in the real world:
External Quote:
...booster vaccinations have shown substantial safety and potential benefits of improving humoral immune response preventing COVID-19 diagnosis or reducing disease severity. Moreover, an additional dose of the vaccine could serve as a strategy to address the limitation of its waning efficacy over time. Therefore, our results are not sufficient to discourage booster vaccination...
Seung-Won Jung, Jae Joon Jeon et al. (2024)
It must be unlikely that COVID-19 boosters
suppress immunity against the SARS-CoV-2 spike protein, which is the protein that the vaccine primes the immune system against, with demonstrably effective results in diminishing severe disease, hospitalisations and deaths. The OP authors (Kakeya, Nitta
et al.) do not provide any evidence for suppression of immunity against any other pathogens (or proteins associated with pathogens).
As mentioned above, Tamotsu Onodera
et al. point out that those who had a serious adverse reaction to the first or second vaccination were less likely to receive a subsequent vaccination, so the minority of people at risk of severe reactions are underrepresented in the cohort receiving booster vaccinations- thus less adverse reactions in the cohort receiving boosters.
This might be an explanation for why there were less adverse reactions in those receiving boosters, and might be more likely than the claim that boosters reduce immunity to the SARS-CoV-2 spike protein, a claim lacking real-world validity.
Claim (5) "
Indeed, recent studies have reported an increase in spike-specific immunoglobulin G4, an immunosuppressive class of antibody..."
Well, two claims really. The "...increase in spike-specific immunoglobulin G4" is supported by Irrgang and Girling
et al. 2023, discussed below. The further claim that immunoglobulin G4 (IgG4) is an "...immunosuppressive class of antibody" is
highly questionable, does not appear to be supported by the author's references, and taken as a literal description or categorisation of IgG4 is almost certainly incorrect.
Immunoglobulin G has four classes, 1-4. Following quotes are from
Immunoglobulin G, Wikipedia:
External Quote:
IgG is the main type of antibody found in blood and extracellular fluid, allowing it to control infection of body tissues. By binding many kinds of pathogens such as viruses, bacteria, and fungi, IgG protects the body from infection.
IgG is
extremely significant in providing immunity, uniquely so at the start of life:
External Quote:
It is the only antibody isotype that has receptors to facilitate passage through the human placenta, thereby providing protection to the foetus in utero. Along with IgA secreted in the breast milk, residual IgG absorbed through the placenta provides the neonate with humoral immunity before its own immune system develops.
Interactions between different components of the immune system, antigens and other bodily systems are complex.
Some antibodies, as well as directly neutralising antigens, can modulate other antibodies/ immune responses possibly to dampen down immune responses that might be hazardous,
External Quote:
IgG are also involved in the regulation of allergic reactions... ...IgG antibodies can prevent IgE mediated anaphylaxis by intercepting a specific antigen before it binds to mast cell–associated IgE. Consequently, IgG antibodies block systemic anaphylaxis induced by small quantities of antigen but can mediate systemic anaphylaxis induced by larger quantities.
External Quote:
...if antigen persists, high affinity IgG4 is produced, which dampens down inflammation by helping to curtail FcR-mediated processes.
If the antigen remains, IgG4 mediates continued inflammatory response, which has not been successful in eradicating the antigen, and which in itself might be debilitating. The cause-and-effect here is important: As commonly understood (and understood before COVID-19 arose), IgG4 is produced as a response to a continuing antigen presence, it is not the cause of a continuing antigen presence as implied by the OP
JMA article authors.
Again, the immune system is complex. In many of us, sadly it will fail; infection remains a significant cause of death. IgG4 can in some circumstances, in some individuals, cause health problems.
External Quote:
In this Review, we discuss the unique structural characteristics of IgG4 and how these contribute to its roles in health and disease. We highlight how, depending on the setting, IgG4 responses can be beneficial (for example, in responses to allergens or parasites) or detrimental (for example, in autoimmune diseases, in antitumour responses and in anti-biologic responses).
"The unique properties of IgG4 and its roles in health and disease", T. Rispens, M.G. Huijbers,
Nature Reviews Immunology 2023
https://pmc.ncbi.nlm.nih.gov/articles/PMC10123589/
Rispens and Huijbers state IgG4 can be beneficial against allergens and parasites; this is hardly immunosuppression.
IgG4 does have a significant role in some autoimmune diseases, but that is not what the OP JMA article authors are saying, they are saying IgG4 is an immunosuppressive antibody.
The authors provide two references to support their assertion, (11) and (12).
(11), "Class switch toward noninflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination",
P. Irrgang, J. Gerling, K. Kocher
et al.,
Science Immunology 8 (79) 2023
https://www.science.org/doi/10.1126/sciimmunol.ade2798
I won't pretend to have a thorough understanding of this paper! I will try and summarise what I think is being said where it is relevant to the Kakeya, Nitta
et al.
JMA paper. -Corrections or better interpretations are welcome.
Irrgang, Gerling
et al. recruited a total of 67 healthcare workers who were receiving mRNA COVID-19 vaccines as subjects. It was found that the ratio of IgG4 to other IgGs rose significantly over time, particularly post-booster.
The authors state this has not been observed in people receiving adenovirus vector vaccines.
External Quote:
Here, we report that several months after the second vaccination, SARS-CoV-2–specific antibodies were increasingly composed of noninflammatory IgG4, which were further boosted by a third mRNA vaccination and/or SARS-CoV-2 variant breakthrough infections...
This class switch was associated with a reduced capacity of the spike-specific antibodies to mediate antibody-dependent cellular phagocytosis and complement deposition. Because Fc-mediated effector functions are critical for antiviral immunity, these findings may have consequences for the choice and timing of vaccination regimens using mRNA vaccines...
Later,
External Quote:
Repeated SARS-CoV-2 mRNA vaccinations shift the antibody response towards IgG4 subclass with decreased FcγR-dependent effector activity.
This sounds bad. In vitro, higher proportions of IgG4 result in less effects on the virus via the Fc-mediated effector function.
But...
External Quote:
While we confirmed an increased antibody avidity [avidity = strength of antibody-antigen bond, John J.] and higher neutralization capacity against the recently emerged Omicron VOC after the third vaccine dose, the switch towards distal IgG subclasses was accompanied by reduced fragment crystallizable (Fc) gamma receptor (FcγR)-mediated effector functions such as ADCP and ADCD....
-which is interesting phrasing; "While" the authors confirm apparently better viral neutralization, they are concerned about the possible reduction in Fc-mediated effector functions which they associate with raised IgG4. This seems (to me, with limited understanding) to be a legitimate area of investigation, although it was found boosters
increased antiviral
effects.
To re-quote the OP authors,
External Quote:
Because Fc-mediated effector functions are critical for antiviral immunity, these findings may have consequences for the choice and timing of vaccination regimens using mRNA vaccines...
It should be remembered
(1) it has been established, from fairly early in the use of COVID-19 vaccines, that true immunity wanes relatively quickly if it is present at all. But severity of illness is significantly reduced in the vaccinated, saving lives.
(2)
This is equally true of adenovirus vector/ other mRNA vaccines: Their effectiveness is also time-limited, and they do not confer better protection than mRNA vaccines against subsequent COVID-19 infection despite their not triggering a rise in the proportion of IgG4 as described by Irrgang, Gerling
et al.
Studies evaluating mRNA and non-mRNA coronavirus vaccines have been conducted, see "Comparison of vaccine-induced antibody neutralization against SARS-CoV-2 variants of concern following primary and booster doses of COVID-19 vaccines", Astrid K. Hvidt, Eva A. M. Baerends, Ole S. Søgaard
et al., 2022,
Frontiers in Medicine (Lausanne) vol. 9, 2022
https://pmc.ncbi.nlm.nih.gov/articles/PMC9574042/
External Quote:
All four COVID-19 vaccines evaluated in this study have been administered to reduce the incidence of COVID-19 infections and have been invaluable in reducing and preventing severe disease, hospitalization and death. Phase three trials have demonstrated that all four vaccines have high clinical efficacy against the original SARS-CoV-2 variant with mRNA-based vaccines demonstrating greater efficacy than adenoviral vector-based vaccines.
...administration of a booster dose provides great potential for improving neutralizing antibody capacity against B.1.1.529 and possible future SARS-CoV-2 VOCs.
Returning to Irrgang, Gerling
et al.,
External Quote:
IgG4 levels were significantly increased after the third vaccination...
The avidity was clearly increased after the third vaccination (Fig. 3C), which is in line with recent reports (9). Furthermore, the capacities to bind trimeric spike protein (Fig. 3D) and to prevent soluble RBD binding to ACE2 (Fig. 3E), which both serve as surrogate markers for virus neutralization, were increased after the third dose. Accordingly, this translated into superior neutralization of lentiviral (LV) particles pseudotyped with spike proteins derived from the Omicron VOC (Fig. 3F). In conclusion, repeated vaccination improved antibody effector functions mediated through the variable domain.
So while repeated mRNA vaccination might cause a significantly increased proportion of IgG4, which (in vitro) results in reduced efficiency of one defensive mechanism, the result is to increase virus neutralization- which is an aim of vaccination.
Irrgang, Gerling
et al. find increased levels of IgG4, which they correlate with a reduced effectiveness of spike-specific antibodies; however,
overall, and in spite of the author's concerns re. increased IgG4, a third vaccination resulted in
increased immune function against COVID-19. They do not present any evidence that this impairs in vivo immunity.
Irrgang, Gerling
et al., cited by the OP
JMA authors, do not claim that IgG4 is an immunosuppressive antibody:
External Quote:
High levels of antigen-specific IgG4 have been reported to correlate with successful allergen-specific immunotherapy by blocking IgE-mediated effects. In addition, increasing levels of bee venom-specific IgG4 have been detected in beekeepers over several beekeeping seasons and finally even became the dominant IgG subclass for the specific antigen, i.e. phospholipase A (PLA). Interestingly, the IgG4 response is characterized by a very slow kinetics and takes several months to appear...
Beekeepers might be a fairly niche group, but they are not known for chronic immunosuppression AFAIK.
It would seem that higher proportions of IgG4 can be initiated by environmental exposure to some natural antigens.
Immunoglobulin G, Wikipedia:
External Quote:
IgG antibodies block systemic anaphylaxis induced by small quantities of antigen... ...if antigen persists, high affinity IgG4 is produced, which dampens down inflammation by helping to curtail FcR-mediated processes.
Reduced risk of anaphylaxis and acute inflammation in beekeepers, using the mechanism (decreased FcR-mediated processes) that Irrgang, Gerling
et al. identify in conjunction with mRNA coronavirus vaccines) does not result in a host of apiary-related disease.
Taking "several months to appear" from first exposure to (some) antigens might explain a temporal correlation between raised IgG4 and booster vaccination.
Irrgang, Gerling
et al.:
External Quote:
With respect to the control of viral infections, little is known regarding virus-specific IgG4 antibody responses. As shown here for RSV-specific IgG responses, IgG4 is hardly induced by acute respiratory viral infections even after repeated exposure.
This might contradict their abstract (my emphasis),
External Quote:
Here, we report that several months after the second vaccination, SARS-CoV-2–specific antibodies were increasingly composed of noninflammatory IgG4, which were further boosted by a third mRNA vaccination and/or SARS-CoV-2 variant breakthrough infections.
If the authors are correct that the rise in IgG4 doesn't occur in those who have had non-mRNA vaccines, this is certainly scientifically interesting. However, they present no data that mRNA vaccine recipients have more frequent or severe "breakthrough" infections than those receiving non-mRNA vaccines. (If anything mRNA vaccines have a slight advantage,
Astrid K. Hvidt, Eva A. M. Baerends, Ole S. Søgaard et al., 2022 as above.)
External Quote:
Although measles-specific IgG4 antibodies can be induced by natural infection, even chronic viral infections like HCMV do not trigger significant specific IgG4 antibodies.
Irrgang, Gerling
et al.
So, IgG4 levels can be raised by a once-common infection (one of the major causes of infant death, and lifelong disability, now largely curtailed by vaccination). The majority of measles sufferers fully recover. Unlike chickenpox and its associated disease of shingles, measles is usually fully cleared by the immune system
despite the rise in IgG4 antibodies (there are rare, important exceptions, e.g. subacute sclerosing panencephalitis,
SSPE).
External Quote:
...despite abundant evidence of immunologic abnormalities associated with MeV [measles] infection, the immune response to MeV is highly effective and recovery from infection results in development of life-long immunity to reinfection.
"Measles virus persistence and its consequences", Diane E Griffin,
Current Opinion in Virology, 41, 2020.
(Vaccination does not incur a risk of SSPE, and by reducing risk of measles has vastly reduced the risk of this fatal complication.)
In contrast, Human Cytomegalovirus (HCMV, see
Wikipedia) does not generate raised IgG4 levels- and once you've got HCMV, you've got it for life. A considerable majority of humans carry it, most without knowing.
External Quote:
Congenital HCMV is the leading infectious cause of deafness, learning disabilities, and intellectual disability in children.
Wikipedia, as above; HCMV has also been implicated as a cause or contributory factor in some cancers, so it isn't trivial.
I think it's interesting that Irrgang, Gerling et al. mention MeV and HCMV and their respective effects on IgG4 levels, but don't elaborate on what we know about these infections: MeV causes raised IgG4, and is usually cleared from the body, which retains very high immunity. HCMV does not raise IgG4, but is never (as far as we know) cleared from the body, and might cause further health problems.
These real-world examples might imply that a suggestion that mRNA COVID-19 vaccines, in raising IGG4 levels, might allow chronic (and thus far undetected) infection, as per Kakeya, Nitta et al. in the OP
JMA article, is questionable.
The second reference "(12)" provided by Kakeya, Nitta et al. is not concerned with IgG4 but with regulatory T cells:
Claim (6) "
Indeed, recent studies have reported an increase in... ...regulatory T cells after the second and subsequent vaccinations..."
...The authors reference (12), "
SARS-CoV-2 spike-specific regulatory T cells (Treg) expand and develop memory in vaccine recipients suggesting a role for immune regulation in preventing severe symptoms in COVID-19", Alessandra Franco, Jaeyoon Song
et al., 2023,
Autoimmunity 56 (1).
Franco, Song
et al.
do not describe an increase in regulatory T cells (Treg) in "subsequent" (post-second) vaccinations as apparently claimed by Kakeya, Nitta
et al.:
External Quote:
Effector (TEM) and central memory (TCM) Treg were numerous as early as after two vaccine doses, with no significant differences following additional vaccine boosts... ...SARS-CoV-2 spike-specific Treg memory is fully developed as early as after the second vaccine injection with little changes over time regardless from further vaccine boosts
Author's (Franco, Song
et al.'s) own emphasis and italics.
External Quote:
Little is known about the expansion of antigen specific Treg following an anti-viral vaccination. Depending upon the physiopathology of the pathogen that the vaccine aims to prevent, the expansion of Treg could be highly beneficial and a parameter to evaluate when studying the potency of a vaccine.
Absolutely no indication whatsoever that Treg expansion post-vaccination damages immunity, as implied by Kakeya, Nitta
et al; indeed, Franco, Song
et al. suggest that Treg could be a measurable surrogate for vaccine potential: Higher Treg =
greater protection against disease.
External Quote:
The extent of SARS-CoV-2 spike-specific Treg expansion during COVID-19 [infection, not immunisation- John J.] determines the severity of the disease: a collection of reports emphasized the role of Treg in down-sizing the exuberant inflammation in acute COVID-19 subjects. Moreover, Treg isolated fromSARS-CoV-2-infected adults with severe symptomatology showed a peculiar phenotype that jeopardized their immune regulatory functions
...That is, there is an association between more severe COVID-19 infection and atypical (endogenous) Treg production.
Ergo, typical Treg production does not have that association. Franco, Song
et al. find raised Treg "...could be highly beneficial" and that vaccination increases Treg production; they did not find atypical Treg phenotypes in their vaccinated subjects.
As with othersted non-optimal response is better than innate baseline non-optimal response, maybe not. However, as we see in the Irrgang, Gi examples of human variation, there will be people in the general population who have that less advantageous- at least in the context of COVID-19 infection- Treg phenotype. They are at greater risk of severe infection from COVID-19. It is not discussed whether boosting Treg in this population via vaccination improves Treg-modulated immune response and symptom reduction- maybe boorling
et al. paper, COVID-19 vaccinations result in a variety of immune responses; in their example Fc-mediated effector function was reduced but overall antibody avidity, and importantly virus neutralization, increased with additional vaccination.
Franco and Song
et al. associate Treg expansion with better outcomes in cases of COVID-19 infection.
There is no mention of, or allusion to, immunosuppression.
Claim (7) "This can lead to chronic infection..."
Kakeya, Nitta
et al., authors of the OP
JMA article, provide no evidence for this at all. They provide no references/ citations.
The authors assert in their claim
(4) that there is evidence of immunosuppression of response to the SARS-CoV-2 spike protein, and their claims
(5) and
(6) are speculative mechanisms that might underlie
(4) if (4) is correct.
But the sources that Kakeya, Nitta
et al. cite for (5) and (6) do not state, or imply, that the phenomena they are reporting might lead to chronic infection.
Kakeya, Nitta
et al.'s evidence for (4), the Irrgang, Gerling
et al. paper, states that vaccinations increase virus neutralization.
(7) is dependant on their preceding claims, which are themselves questionable.
Despite the serious implications of (7), Kakeya, Nitta
et al. do not supply any direct evidence, or references, that suggest that chronic infection of any sort is associated with COVID-19 vaccines.
Claim (8) "Wastewater monitoring data support this claim"
That "This can lead to chronic infection whereby the virus remains in the intestine".
This in turn depends on claim
(7)- we are seeing a chain of claims, each individually questionable and each relying on Kakeya, Nitta
et al.'s selection and interpretation of evidence. Their interpretation of the evidence that they cite might itself be questionable; see
(4),
(5) and
(6) above.
Wastewater monitoring
does not support the author's claim- that COVID-19 vaccines might cause "...chronic infection whereby the virus remains in the intestine". It demonstrates that there are people with COVID-19 infections, and can give some indication of the scale of infection.
Wastewater monitoring is a long-established public health measure (maybe more attended to since the COVID-19 pandemic).
Virus and viral fragments are shed in vast numbers in faeces in many types of infection, including by asymptomatic carriers.
External Quote:
People infected with coronavirus (COVID-19) shed the virus during daily activities such as going to the toilet and blowing their nose. The virus enters the sewer system through sinks, drains and toilets. Fragments of SARS-CoV-2 (the virus that causes COVID-19) can be detected in samples of wastewater (untreated sewage).
... ...
Wastewater analysis has the benefit of detecting the virus regardless of whether people have symptoms or whether they are tested. Wastewater monitoring complements other testing programmes and public health actions to help protect against the threat of new variants.
As the threat of variants has emerged, the programme has played a key role in the detection of mutations of the virus, including those associated with known VOCs [variants of concern] and VUIs [variants under investigation]. This is achieved through genomic sequencing of wastewater samples...
"
EMHP wastewater monitoring of SARS-CoV-2 in England: 1 June to 7 February 2022", UK Health Security Agency, 24 February 2022
External Quote:
Scientists routinely monitor for:
-polio
-mpox
-COVID-19
-flu (influenza)
-respiratory syncytial virus (RSV)
... ...
In addition to COVID-19, wastewater surveillance can be used to monitor other public health threats, such as
-chemicals and pharmaceuticals, including illicit drugs
-antimicrobial resistance
-other communicable diseases, such as tuberculosis and polio
Wastewater monitoring, Public Health Agency of Canada
External Quote:
CLEVELAND, Ohio — Cleveland health officials are warning residents about a sharp increase in COVID-19 levels detected in the city's wastewater, signalling a likely uptick in community spread in the coming weeks...
...Wastewater surveillance has become a key tool for tracking community infection trends, including among people who may not seek testing or show symptoms. In addition to the COVID-19 virus surge, the same samples also revealed high levels of influenza and increasing levels of respiratory syncytial virus (RSV), though RSV remains in its baseline monitoring phase.
"Cleveland issues public health alert after spike in COVID-19 detected in wastewater", Molly Walsh, 13 June 2025,
The Plain Dealer Cleveland hosted on MSN.
We know that viruses, and virus fragments, are found in faeces and have known this for a long time. This is as true for what we usually think of as respiratory infections, e.g. influenza, as it is for other infections.
With the near-endemic status of COVID-19 since the pandemic, it is wholly expected that environmental wastewater monitoring will find COVID-19.
It is not some mystery in need of a solution, and in not reminding their readers of this, Kayeka, Nitta
et al. are arguably inviting speculation that more alarming mechanisms are involved, without having to supply any evidence.
_____________________________________________________________________________________________________________________________________
Quick summary:
Claim (1) "...adverse reactions were more severe... ...after the second vaccination than the first..."
Possibly correct, but in the overwhelming majority of cases adverse reactions were minor and brief.
No direct evidence from the JMA authors.
Claim (2) "...autoimmune diseases reported more frequently after the second vaccination than the first..."
No direct evidence from the JMA authors.
There might be a connection between COVID-19 vaccination and autoimmune disease flare-ups, possibly causation; Seung-Won Jung, Jae Joon Jeon
et al. (2024) report greater risk following boosters (not second vaccinations).
Those authors and Ming Guo, Xiaoxiao Liu
et al. (2023) state clearly that population-wide COVID-19 vaccination remains highly advisable despite their findings indicating a possible connection with autoimmune disease.
Claim (3) "...adverse reactions... ...were reported much less after boosters..."
No direct evidence from the JMA authors, but supported by Tamotsu Onodera
et al. 2023. Again, most adverse reactions were minor.
People experiencing adverse reactions to the first or second booster might be less likely to get a booster.
Claim (4) "...which can be explained by the suppression of immunity against the SARS-CoV-2 spike protein."
Kayeka, Nitta
et al. provide no clear evidence for this claim. COVID vaccines are mainly designed to target/ inform the immune system about the SARS-CoV-2 spike protein. There is no evidence that COVID booster vaccines
reduce immunity to COVID-19, plenty of evidence that they reduce symptoms, poor outcomes and deaths in the event of COVID-19 infection.
There is insufficient evidence to support this claim.
Claim (5) "Indeed, recent studies have reported an increase in spike-specific immunoglobulin G4, an immunosuppressive class of antibody..."
IgG4 is not an "immunosuppressive antibody". Irrgang, Gerling
et al. document an increase in the ratio of IgG4 to other IgGs post-vaccination. They also state that there was increased antibody : virus avidity, and greater virus neutralization "...after the third vaccine dose". That is not evidence of immunosuppression!
Again, the evidence does not support Kakeya, Nitta
et al.'s claim.
Claim (6) "Indeed, recent studies have reported an increase in... ...regulatory T cells after the second and subsequent vaccinations..."
In support of this claim Kayeka, Nitta
et al. cite Franco, Song
et al. who
(1) found an increase in regulatory T cells (Treg),
(2) wrote
External Quote:
...the expansion of Treg could be highly beneficial and a parameter to evaluate when studying the potency of a vaccine.
...with no reference to immunosuppression.
Claim (6) is not supported by the evidence cited by Kayeka, Nitta
et al., and is arguably contradicted by it.
Claim (7) "This can lead to chronic infection..."
No direct evidence for this from the
JMA authors, the claim is hypothetical: It might be a possibility if claims 4 and (5 and/ or 6) are at least substantially correct. Which they might not be.
Claim (8) "Wastewater monitoring data support this claim"
No it doesn't. Kayeka, Nitta
et al. are trying to turn untreated sewerage into evidence for their supposition.
_____________________________________________________________________________________________________________________________________
And that's for 1 paragraph of Kayeka, Nitta
et al.'s article !
I don't think "Significant Increase in Excess Deaths after Repeated COVID-19 Vaccination in Japan" stands up very well.
