My critique to the CDC study discussed below complements a unique overview of the safety and efficacy shortcomings associated with the Covid-19 (C-19) vaccines, particularly the mRNA-based ones (https://pubmed.ncbi.nlm.nih.gov/38274635/). It addresses the prevailing mainstream narrative asserting that, even during the Omicron era, C-19 vaccines continue to offer protection against (severe) C-19 disease.
To grasp my critique fully, it's crucial for people to recognize that while C-19 vaccine recipients were/ are still largely shielded from (severe) C-19 illness when exposed to vaccine breakthrough infections (VBTIs) caused by early/ late Omicron descendants, this protection comes at the cost of immune refocusing and subsequent immune evasion.
Here is why the emergence of Omicron and its steadily evolving descendants poses a significant threat to highly C-19 vaccinated populations, despite all the rhetoric on improved/ updated C-19 vaccine boosters: Since the emergence of Omicron, the ability of most C-19 vaccinees to mitigate infection is no longer primarily dependent on highly antigen-specific virus-neutralizing antibodies. On the other hand, their ability to eliminate virus-infected target host cells, thereby mitigating C-19 disease, is not due to antigen-specific memory CD8+ T cells, as no cross-reactive cytolytic activity has ever been reported to be induced upon C-19 vaccination or natural SARS-CoV-2 (SC-2) infection. Instead, it is reasonable to assume that their ability to prevent (severe) C-19 disease largely relies on short-lived variant-nonspecific PNNAbs (polyreactive, non-neutralizing antibodies) elicited during vaccine breakthrough infections (VBTIs) and variant-nonspecific cytotoxic T lymphocytes (CTLs) generated as a result of VBTI-induced immune refocusing. Consequently, there is no guarantee that updated C-19 vaccines will continue to elicit such short-lived surrogate adaptive immune responses, ensuring sustained protection against new Omicron variants. Currently circulating Omicron descendants (including the JN.1 clan) are now increasingly threatening protection against severe C-19 disease in vaccinees due to their high level of intrinsic infectiousness (see figure above).
Fig.: Newly emerged, highly infectious Omicron descendants do not rely on PNNAbs to infect target host cells (1). Replication of highly infectious variants generates an immunological environment that promotes their adsorption onto tissue-resident DCs. PNNAbs bind in high quantities to progeny virus tethered to these DCs, which subsequently migrate to the lungs and other distal organs (2). Diminished production of these virulence-inhibiting PNNAbs, combined with their enhanced binding to DC-tethered virions, leads to increasing immune selection pressure on viral virulence in highly C-19 vaccinated populations. As previously SIR-primed Abs bind with low-affinity to the highly infectious, antigenically more distant immune escape variant, large Ab-virus complexes are taken up into patrolling APCs (3). Enhanced uptake of large Ab-virus complexes into APCs facilitates strong activation of CTLs, thereby enabling the elimination of virus-infected host while impeding T help to assist in boosting previously SIR-primed Abs. Diminished boosting of previously primed anti-S Abs results in diminished production of PNNAbs. As explained in the text, enhanced viral uptake by APCs will slow down the adsorption of highly infectious progeny virions on migratory DCs and thereby mitigate the decrease in PNNAb concentration resulting from diminished production. Hence, PNNAb levels may not decline rapidly enough in a sufficiently large portion of the population to widely release the brakes on PNNAb-mediated inhibition of viral trans infection. However, with more infectious BA.2.86 descendants (i.e., the JN.1 clan) emerging and rapidly growing in prevalence, highly C-19 vaccinated populations are exerting a steadily increasing immune selection pressure on viral virulence. This is thought to eventually trigger the selection of a new variant that has the capacity to cause highly virulent VBTIs in highly C-19-vaccinated populations due to PNNAb-dependent enhancement of severe C-19 disease.
By Geert Vanden Bossche (https://www.voiceforscienceandsolidarity.org/; Independent Research) and Kris Denhaerynck (Epidemiology and Biostatistics, Independent Research, Basel, CHE)
We read the following publication: Early Estimates of Updated 2023–2024 (Monovalent XBB.1.5) COVID-19 Vaccine Effectiveness Against Symptomatic SARS-CoV-2 Infection Attributable to Co-Circulating Omicron Variants Among Immunocompetent Adults — Increasing Community Access to Testing Program, United States, September 2023–January 2024 (https://www.cdc.gov/mmwr/volumes/73/wr/pdfs/mm7304a2-H.pdf). This publication is yet another attempt by health authorities to promote vaccines based on its alleged effective protection, while disregarding any safety concerns.
However, based on statistical and immunological considerations alone, the conclusions and recommendations from the CDC should be deemed invalid.
There are several reasons why this type of study design does not provide enough strong evidence to guide policy recommendations.
The choice for a retrospective case-control study may be efficient in terms of subject recruitment; however, it comes at a cost because it introduces bias that cannot be convincingly remediated by controlling for a number of confounders.
Another drawback of the use of a case-control study design is the inability to assess effectiveness in terms of relative risks. Odds ratios can be considered approximations of relative risks if prevalences are small. With high prevalences, as in this study, odds ratios tend to show higher values than their relative risk counterparts would. A crude odds ratio of 1.78 derivable from table 2, in favor of those who received an updated vaccine booster dose, cannot be considered a convincingly strong association, given the bias-prone study setup.
Furthermore, although vaccine effectiveness percentages of 49% and 60% may sound impressive, these are mere algebraic transformations of odds ratios, leaving the question of what such percentages truly represent. Adding to the impressive nature of these estimates are their relatively narrow confidence intervals, which fail to account for the clustered nature of their various source locations. Robust inference should have be used, incorporating the extra variability data collection points may generate.
In addition, recruitment of only symptomatic patients makes it difficult to assess ‘vaccine effectiveness against symptomatic disease’. By only selecting those with symptoms, stratification bias may be induced, whereby significant relationships can be found in a particular stratum that are absent in the population at large.
An even more fundamental critique concerns the fact that biological life functions as a complex adaptive system. Introducing system-wide interventions may disturb its dynamic equilibrium in unforeseeable ways. The risk of long-term consequences worse than the short-term gain is not reflected in the confidence intervals around the effectiveness estimates because these assume that underlying processes generating the variability in responses to the intervention are independent of each other. However, if everything is connected to everything, as is the case in complex systems, affecting everything with a universal intervention could lead to system perturbations not captured by the current statistical uncertainty estimates. The possibility of VBTIs is an example of such an event, in which a system transforms from one dynamic equilibrium into another.
As previously reported (https://www.trialsitenews.com/a/the-conclusions-drawn-from-scientists-molecular-stamp-collection-exercises-create-false-expectations-for-addressing-the-continuous-emergence-of-sars-97944a34), updated mRNA-based monovalent XBB.1.5 C-19 vaccines are likely to activate previously induced broadly cross-reactive B cells through VBTI-induced steric immune refocusing (SIR). Due to their diminished antigen-specificity and affinity, these new antibodies (Abs) only exhibit subneutralizing capacity. Consequently, their neutralizing effect is short-lived, resulting in suboptimal immune pressure on viral infectiousness and facilitating viral immune escape.
Suboptimal virus neutralization may explain why some individuals with VBTI may initially test negative in PCR (polymerase chain reaction) tests or home test kits, only to test positive a few days later (https://www.msn.com/en-us/health/other/is-the-new-covid-variant-jn1-too-smart-for-home-tests-here-s-what-science-has-to-say/ar-BB1hjvBf). Furthermore, repeated VBTIs or updated vaccine boosters following previous vaccine doses is believed to enhance the formation of Ab-virus complexes, promoting uptake by antigen-presenting cells and activating variant-nonspecific cytotoxic T lymphocyte (CTL) responses (https://www.trialsitenews.com/a/the-conclusions-drawn-from-scientists-molecular-stamp-collection-exercises-create-false-expectations-for-addressing-the-continuous-emergence-of-sars-97944a34). Since CTL responses rapidly clear virus-infected cells, PCR testing conducted several days after symptom onset may again turn negative. Consequently, it is quite possible that individuals with COVID-19, when tested for the first time several days after the symptoms started, may simply test negative, even though SC-2 caused their illness.
The above-described immunological dynamics already explain why calculation of vaccine efficacy (VE) against symptomatic SC-2 infection should not be based on comparing odds of receipt versus nonreceipt of the updated C-19 vaccine among case and control patients, as defined by the authors from the CDC. It also elucidates why the alleged VE tended to diminish as the median interval since the last dose increased or as VE was calculated based on results from S(pike)-gene target failure (SGTF) analysis1, which is indicative of BA2.86/ JN.1 lineages2. In addition, the authors pretend that the results of their analysis ‘can be interpreted as the incremental benefit of receipt of updated COVID-19 vaccine beyond existing vaccination-induced, infection-induced, or hybrid immunity.’ However, knowing that frequently occurring VBTIs can offer provisional protection against symptomatic infection on their own, and assuming that symptomatic re-exposure may have motivated a significant number of vaccine recipients to receive an updated vaccine booster, the incremental clinical benefit of an updated C-19 vaccine booster cannot be proven.
These observations underscore the importance of performing PCR testing both at the early onset of symptoms and several days thereafter in C-19 vaccinees who are repeatedly exposed to highly infectious SC-2 immune escape varia0nts (i.e., in highly C-19 vaccinated populations), including those who have received updated C-19 vaccine boosters. Failure to consider the role of SIR in directing the immune response towards broadly cross-reactive Abs with reduced affinity can result in the misinterpretation of negative PCR data, potentially leading to an overestimation of the efficacy of updated vaccine boosters against symptomatic SC-2 infection. Furthermore, SIR is not solely induced by updated mRNA-based vaccination but also by VBTI (https://www.trialsitenews.com/a/the-conclusions-drawn-from-scientists-molecular-stamp-collection-exercises-create-false-expectations-for-addressing-the-continuous-emergence-of-sars-97944a34), contributing to the overestimation of the impact of updated vaccine boosters on the calculated figure for VE as reported in the current study.
The current report suggests that symptoms prompting individuals to undergo testing were less likely attributable to SC-2 infection and more likely caused by other illnesses among those who recently received an updated vaccine booster dose one week to four months before testing, but that SC-2 infection was more likely responsible for symptoms in individuals who did not receive an updated C-19 vaccine dose!
Firstly, this study has not been conducted in a manner that could potentially demonstrate a causal link between the receipt of updated C-19 vaccine and protection from symptomatic SC-2 infection. Secondly, the authors did not investigate the impact of virus-binding properties of SIR-recalled Abs on virus neutralization or cytolytic capacity towards virus-infected cells (i.e., resulting from Ab-virus complex formation and internalization). Their conclusions, therefore, lack scientific basis to suggest that updated monovalent C-19 vaccines will continue to protect against symptomatic infections as BA.2.86/ JN.1 and
other immune evasive lineages continue to circulate and evolve (Updated COVID Vaccine Highly Effective Against JN.1 Variant (everydayhealth.com). If the VE were real, or at least reliable, the authors should be able to offer a mechanistic explanation regarding how and why updated vaccine booster shots sterilize infections caused by SC-2 variants with unprecedented immune escape capacity. As previously discussed, the Abs responsible for this sterilizing effect result from VBTI-mediated immune refocusing and exhibit high avidity to non-ACE2-competitive binding sites. Consequently, they do not provide a consistent or prolonged neutralizing effect, or merely facilitate short-lived CTL-mediated viral clearance following the production of viral progeny (https://www.voiceforscienceandsolidarity.org/scientific-blog/unfortunately-its-not-over).
Considering the lack of convincing statistical evidence of a causal relationship between a negative PCR test result and receipt of the updated booster vaccine in C-19 vaccinees who reported C-19-like illness symptoms combined with the significant side effects associated with C-19 vaccines (https://pubmed.ncbi.nlm.nih.gov/38274635/) and their inability to offer long-lasting and antigen-specific immune protection, thus promoting the dominant spread of highly infectious immune escape variants and hindering the activation of cell-based innate immunity, the CDC's recommendation for all individuals aged ≥6 months to stay up to date with C-19 vaccination, including receiving a dose of updated C-19 vaccine is not only an insult to science but also ethically irresponsible advice (https://www.voiceforscienceandsolidarity.org/scientific-blog/what-happens-if-a-pandemic-involving-a-virus-naturally-causing-acute-self-limiting-infection-fails-to-generate-herd-immunity).
The CDC recently published a similarly misleading study on the purported effectiveness of bivalent mRNA-based C-19 vaccines in children and adolescents (https://jamanetwork.com/journals/jama/fullarticle/2814536).
The authors calculated estimated hazard ratios for the first occurrence of SC-2 infection in study participants to compare the effectiveness of a bivalent C-19 vaccine dose in preventing infection. Based on the very same statistical considerations as outlined above, the calculation models they used (i.e., Cox proportional hazards models) do not allow to reliably assess the effectiveness of bivalent mRNA C-19 vaccines in preventing SC-2 infection.
Regardless of the unsuitability of their calculation models, the authors’ assessment represents at best ‘a sloppy snapshot’ into the pandemic's evolutionary trajectory. During the part of the pandemic captured by this study, both BA.2/ 5 VBTIs and bivalent vaccine boosters have been responsible for refocusing humoral immune responses towards broadly neutralizing Abs. As previously reported, it has been found that the virus-neutralizing activity of these Abs is short-lived (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9793397/). Consequently, the calculated figure for the 'snapshot' effectiveness of the bivalent vaccines against laboratory-confirmed infection may have significantly decreased if the mean observation time after vaccination for those who received the bivalent C-19 vaccine dose had been extended beyond 2 months (and if the sample size had been meaningfully increased!).
As immune refocusing in C-19 vaccinees may have also been triggered by VBTIs occurring before or after they received a bivalent C-19 vaccine, prior to enrollment or study period start, it cannot be ruled out that these previous exposures were the primary contributors to the VE purportedly attributed to the bivalent C-19 vaccines. As VBTIs frequently occurred during the Omicron BA.4/5 period, their (short-lived) effect on virus neutralization (via elicitation of new Abs) could have led to a significant overestimation of the calculated figure for effectiveness of the bivalent C-19 vaccines reported in this study. This may especially pertain to ‘vaccine-updated’ study participants as self- or parent-reporting of these infections may not have been very popular. This is important as the study findings indeed appear to suggest (within the limitations of the study cited by the authors) a favorable effect of prior SC-2 infection on the apparent effectiveness of bivalent C-19 vaccines against new SC-2 infections.
But, even more importantly, the authors of this publication do not seem to realize that a prolonged decrease in neutralizing capacity of SIR-elicited Abs allows highly C-19 vaccinated populations to exert strong immune selection pressure on viral infectiousness, thereby promoting the spread of new emerging, more infectious immune-evasive variants and posing a threat to all C-19 vaccinees whose cell-based innate immune system had not been sufficiently trained due to PNNAb-dependent enhancement of viral infectiousness. This, of course, also applies to C-19 vaccinees who received an additional bivalent C-19 vaccine. It puts them at high risk of severe C-19 disease in case a SC-2 variant is selected that overcomes the inhibitory effect of PNNAbs on viral virulence.
Because of all of the above and given the significant side effects associated with C-19 vaccines (https://pubmed.ncbi.nlm.nih.gov/38274635/), the conclusions drawn from this study by the CDC cannot be scientifically justified. Their recommendation (‘All eligible children and adolescents should remain up to date with recommended C-19 vaccines’) is therefore absolutely unacceptable.
 The study was not sufficiently powered though to prove statisticalsignificance between VE assessed at 7–59 days after receipt of updated vaccinecompared to assessment of VE at 60–119 days after receipt of updated vaccine.
 Reduction or failure of spike gene (S-gene) amplification in real-timereverse transcription–polymerase chain reaction testing is a time-dependent,proxy indicator of JN.1 infection.
Geert Vanden Bossche received his DVM from the University of Ghent, Belgium, and his PhD degree in Virology from the University of Hohenheim, Germany. He held adjunct faculty appointments at universities in Belgium and Germany. After his career in Academia, Geert joined several vaccine companies (GSK Biologicals, Novartis Vaccines, Solvay Biologicals) to serve various roles in vaccine R&D as well as in late vaccine development.
Geert then moved on to join the Bill & Melinda Gates Foundation’s Global Health Discovery team in Seattle (USA) as Senior Program Officer; he then worked with the Global Alliance for Vaccines and Immunization (GAVI) in Geneva as Senior Ebola Program Manager. At GAVI he tracked efforts to develop an Ebola vaccine. He also represented GAVI in fora with other partners, including WHO, to review progress on the fight against Ebola and to build plans for global pandemic preparedness.
Back in 2015, Geert scrutinized and questioned the safety of the Ebola vaccine that was used in ring vaccination trials conducted by WHO in Guinea. His critical scientific analysis and report on the data published by WHO in the Lancet in 2015 was sent to all international health and regulatory authorities involved in the Ebola vaccination program. After working for GAVI, Geert joined the German Center for Infection Research in Cologne as Head of the Vaccine Development Office. He is at present primarily serving as a Biotech / Vaccine consultant while also conducting his own research on Natural Killer cell-based vaccines.