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Vaccine
SYNOPSIS
Studies suggest the BioNTech mRNA COVID-19 vaccine impairs glucose control and aggravates insulin resistance in human subjects with type 2 diabetes.
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Metformin mitigates insulin signaling variations induced by COVID-19 vaccine boosters in type 2 diabetes
L. Zhai, M. Zhuang, H. Ki Wong, C. Lin, J. Zhang, G. Bao, Y. Zhang, S. Xu, J. Luo, S. Yuan, H. Leong, X. Wong, Z. Bian
The long-term effects of COVID-19 vaccines have not been well characterized. Zhai et al. conducted a longitudinal clinical trial to determine the effects of the COVID-19 vaccine in healthy controls, pre-diabetic subjects, and diabetic subjects. The corresponding author of this study Zhaoxiang Bian, is a Professor at the Hong Kong Baptist University and a leading expert in the execution of clinical trials with Chinese medicines.
A total of 180 participants receiving BioNTech mRNA COVID-19 (BNT) vaccination (60 in each of the following groups: pre-diabetes mellitus, diabetes mellitus, and healthy controls) were recruited and observed over two weeks for their changes in insulin sensitivity before and after two doses of BNT. Biomarkers were taken for immune response, glucose intolerance, and insulin resistance. Diabetic patients exhibited similar immune responses (i.e., production of IgG antibodies) as healthy controls after receiving the BNT booster. In contrast to immune responses, authors report exacerbated risks of glucose intolerance and insulin resistance after the booster shot in pre-diabetic and diabetic patients. 61.1% and 66.7% of diabetic subjects had impairment of insulin sensitivity and increased risks of cardiovascular complications, respectively. These results suggest the vaccine impairs glucose control and aggravates insulin resistance in human subjects with type 2 diabetes. Following on, animal studies were conducted to determine the mechanisms of the inhibitory action of BNT vaccination on glucose control. Compared to mice treated with saline, mice treated with the BNT vaccine (intramuscular injection at an equivalent human dosage of 4.5 μg/kg) exhibited immune responses similar as shown by the elevation of SARS-CoV-2 spike protein in serum. After the fourth dose of BNT vaccine mice exhibited impaired glucose tolerance. Based on investigated biomarkers of diabetes the authors speculate that glucose intolerance was mediated by impairment of insulin sensitivity rather than impaired insulin secretion. Researchers further showed that metformin, a common anti-diabetic medication, improved the impaired insulin signaling induced by COVID-19 vaccination in mice.
Approximately 12% (38.4 million) and 38% (97.6 million) of the US population have diabetes and prediabetes, respectively (https://www.cdc.gov/diabetes/data/statistics-report/index.html). Clinical and animal studies by Zhai et al. provide clear evidence of safety issues of the COVID-19 vaccines in diabetics or populations with metabolic conditions.
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Concerns have arisen about the potential neurodevelopmental implications of mRNA vaccines, especially in susceptible groups such as pregnant women and their offspring.
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Prenatal Exposure to COVID-19 mRNA Vaccine BNT162b2 Induces Autism-Like Behaviors in Male Neonatal Rats: Insights into WNT and BDNF Signaling Perturbations
M. Erdogan, O. Gurbuz, M. Bozkurt, O. Erbas
Erdogan and co-workers investigated neurodevelopmental pathologies in the offspring of pregnant rodents vaccinated with the COVID-19 mRNA BNT162b2 vaccine. A significant error in the methodology was identified with the dosing of rodents. Researchers administered a human dose (30 ug) of BNT162b2, which would amount to 300 times the effective dose to rodents. Experiments with pregnant rodents injected with BNT162b2 were compared with a control group injected with 1 mL/kg saline. Offspring from the BNT162b2 (13 male – 8 female) and control (10 male – 10 female) were allowed to reach early adulthood (50 days postnatal) before behavioral and motor tests. Subsequently, all animals from each group were sacrificed for histological, biochemical, and transcriptome analysis of the brain. A reduction in social behavior and physiological (motor) effects was significant only in males from the vaccine group. The histological analysis indicated pathology of the hippocampus (involved in learning and memory) and cerebrum (involved in motor control) for the vaccine group. Notable dysmorphological changes were evident with cells of the hippocampus elongated, while for the cerebellum, some alterations in the cellular architecture Purkinje cell layer were evident. Bioassays indicated lower counts of neuronal count and a reduction in neurotransmitter brain-derived neurotrophic factor (BDNF) in the vaccine group. Histological and bioassays indicate clear biomarkers of neurotoxicity in the brain with cell atrophy and a reduction of neuroplasticity (the ability of neural networks in the brain to change through growth and reorganization). Targeted transcription analysis indicated upregulation of mTOR (reported for abnormal synaptic transduction and neurotransmitter overstimulation) for males and a decrease in Wnt signalling pathway (involved in embryonic neurodevelopment to adulthood). A previous article in 2023 by Erdogan et al. (https://doi.org/10.1007/s11481-023-10089-4) indicated the long-term neurotoxicity of artificial spike protein (SP) to the developing unborn fetus. This study further corroborates this earlier study of the potential harm of maternal bodily synthesis of SP to the developing fetus, post-maternal COVID-19 vaccination.
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Recent research on placental, embryo, and brain organoids suggests that the COVID-19 virus may potentially affect embryonic organs, including the brain.
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Prenatal SARS-CoV-2 Spike Protein Exposure Induces Autism-Like Neurobehavioral Changes in Male Neonatal Rats.
M. Erdogan, M. Turk, G. Doganay, I. Sever, B. Ozkul, I. Sogut, E. Eroglu, Y. Uyanikgil, O. Erbas
Erdogan et al. conducted preclinical studies in pregnant rodents injected with SARS-COVID-19 spike protein (SP) (40 ug/kg) combined with adjuvant aluminum hydroxide (AAH) (150 ug/kg). Experiments with SP+AAH were compared with a control and a benchmark group, injected with 1 mL/kg saline or AAH respectively. Offspring (10 males-females) from each group were allowed to reach early adulthood (50 days postnatal) before behavioral and motor tests. Subsequently, all animals from each group were sacrificed for biochemical and histological analysis of the brain. Findings indicated that male rats exposed to the SP+AAH displayed a higher rate of impaired performance in behavioral studies with signatures of neurodevelopmental disorders, such as reduced sociability, learning and memory, and motor skills. Histological analysis of the hippocampus (involved in learning and memory) and cerebrum (involved in motor control) of the brains of male rodents indicated biomarkers for neurotoxicity, with neuroinflammation and neuronal cell death in male rats exposed to the SP+AAH when compared to control and benchmark groups. Biomarkers for neuroinflammation included higher levels of tumor necrosis factor-alpha (TNF-α), interleukin-17 (IL-17), nuclear factor kappa B (NF-κB), and lactate and lower levels of brain-derived neurotrophic factor (BDNF). A growing body of research has implicated maternal immune activation (miA) comprised of the placental-fetal barrier by vaccines and environmental toxins, as a leading cause of neurodevelopmental disorders. Results here clearly indicate the potential association between prenatal exposure to SP and neurodevelopmental disorders with a bias towards males. A cross-sectional study in 2022 by Garcia-Flores published in Nature Communications (https://doi.org/10.1038/s41467-021-27745-z) stated that – “…SARS-CoV-2 is not detected in the placental tissues, nor is the sterility of the placenta compromised by maternal viral infection”. Results here indicate miA and breach of the placental-fetal barrier by SP, leading to lifelong neuropathology and altered behaviors in offspring. Current guidelines from the CDC (https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/pregnancy.html) state that “…COVID-19 vaccination before and during pregnancy is safe, effective, and beneficial to both the pregnant person and the baby.” Although work by Erdogan et al. is preclinical, proof of principle, and speculative, it provides clear warning signals to the of the potential harm to the developing unborn fetus by maternal bodily synthesis of SP, post-maternal COVID-19 vaccination.
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Global use of inactivated SARS-CoV-2 vaccines with Alum adjuvants have been used in COVID-19 pandemic response, but risk of breakthrough with novel variants and zoonotic reservoirs may lead to adverse outcomes, including VAERD.
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Adjuvant-dependent effects on the safety and efficacy of inactivated SARS-CoV-2 vaccines during heterologous infection by a SARS-related coronavirus
M. Heise, J. Dillard, S. Taft-Benz, A. Knight, E. Anderson, K. Pressey, B. Parotti, S. Martinez, J. Diaz, S. Sarkar, E. Madden, G. De la Cruz, L. Adams, K. Dinnon, III, S. Leist, D. Martinez, A. Schaefer, J. Powers, B. Yount, I. Castillo, N. Morales, J. Burdick, M. Katrina Evangelista, L. Ralph, N. Pankow, C. Linnertz, P. Lakshmanane, S. Montgomery, M. Ferris, R. Baric, V. Baxter
Inactivated whole virus SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide (Alum) are among the most widely used COVID-19 vaccines globally and have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous virus infection in healthy recipients, the emergence of novel SARS-CoV-2 variants and the presence of large zoonotic reservoirs provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes including vaccine-associated enhanced respiratory disease (VAERD). To evaluate this possibility, we tested the performance of an inactivated SARS-CoV-2 vaccine (iCoV2) in combination with Alum against either homologous or heterologous coronavirus challenge in a mouse model of coronavirus-induced pulmonary disease. Consistent with human results, iCoV2 + Alum protected against homologous challenge. However, challenge with a heterologous SARS-related coronavirus, Rs-SHC014-CoV (SHC014), up to at least 10 months post-vaccination, resulted in VAERD in iCoV2 + Alum-vaccinated animals, characterized by pulmonary eosinophilic infiltrates, enhanced pulmonary pathology, delayed viral clearance, and decreased pulmonary function. In contrast, vaccination with iCoV2 in combination with an alternative adjuvant (RIBI) did not induce VAERD and promoted enhanced SHC014 clearance. Further characterization of iCoV2 + Alum-induced immunity suggested that CD4+ T cells were a major driver of VAERD, and these responses were partially reversed by re-boosting with recombinant Spike protein + RIBI adjuvant. These results highlight potential risks associated with vaccine breakthrough in recipients of Alum-adjuvanted inactivated vaccines and provide important insights into factors affecting both the safety and efficacy of coronavirus vaccines in the face of heterologous virus infections.
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Vaccines can have beneficial off-target (heterologous) effects that alter immune responses to, and protect against, unrelated infections. The heterologous effects of COVID-19 vaccines have not been investigated in children.
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BNT162b2 COVID-19 vaccination in children alters cytokine responses to heterologous pathogens and Toll-like receptor agonists
A. Noé, T. D. Dang, C. Axelrad, E. Burrell, S. Germano, S. Elia, D. Burgner, K. P. Perrett, N. Curtis, N. L. Messina
In addition to antigen-specific adaptive immunity to the target pathogen and cross-protective immunity to related microbes (e.g., protection against Mycobacterium tuberculosis and Mycobacterium leprae induced by Mycobacterium bovis-derived bacille Calmette–Guérin (BCG)) (1), vaccines have off-target (heterologous) effects that protect against unrelated pathogens (2–4).
In high-mortality settings, live-attenuated vaccines are associated with reductions in all-cause infant mortality greater than can be attributed to vaccine-specific protection alone (5–7). The reduction in all-cause mortality in high-mortality settings is proposed to be due, at least in part, to protection against infections unrelated to the vaccine target (2–4). Trained immunity, the process by which innate immune cells such as monocytes develop immunological memory through metabolic and epigenetic changes, is one proposed mechanism by which vaccines exert heterologous effects (8, 9). Understanding heterologous effects and trained immunity, and harnessing positive heterologous effects has the potential to extend vaccine-induced protection to a diverse array of pathogens.
The COVID-19 pandemic has prompted a resurgence of interest in the heterologous effects of BCG and other vaccines and compounds (10–14). Heterologous immunological effects following vaccination have been explored in several studies by assessing in vitro cytokine responses to heterologous antigens (9, 15–19). Two small studies have reported on heterologous effects of COVID-19 vaccines. One study in adults reported that following adenoviral COVID-19 (ChAdOx1) vaccination, monocyte proinflammatory cytokine and chemokine production and glycolysis is enhanced in resting states as well as in response to unrelated stimulants (20). COVID-19 mRNA-based vaccines have been reported to modulate transcriptional profiles in monocytes from adults (21). To date, the heterologous effects of COVID-19 vaccines have not been investigated in children.
In the COVID-19-Specific vaccine and heterologous Immunity in MIS BAIR (COSI BAIR) study (22), we investigated the heterologous and specific immunological effects of BNT162b2 COVID-19 vaccination in children.
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Students at North American universities risk disenrollment due to third-dose COVID-19 vaccine mandates. We present a risk-benefit assessment of boosters in this age group and provide five ethical arguments against mandates.
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COVID-19 Vaccine Boosters for Young Adults: A Risk-Benefit Assessment and Five Ethical Arguments Against Mandates at Universities
K. Bardosh, A. Krug, E. Jamrozik, T. Lemmens, S. Keshavjee, V. Prasad, M.A. Makary, S. Baral, H. Stefan, B. Tracy, “COVID-19 Vaccine Boosters for Young Adults: A Risk-Benefit Assessment and Five Ethical Arguments against Mandates at Universities” (August 31, 2022). Available at SSRN: https://ssrn.com/abstract=4206070 or http://dx.doi.org/10.2139/ssrn.4206070
Students at North American universities risk disenrollment due to third-dose COVID-19 vaccine mandates. We present a risk-benefit assessment of boosters in this age group and provide five ethical arguments against mandates. We estimate that 22,000 – 30,000 previously uninfected adults aged 18-29 must be boosted with an mRNA vaccine to prevent one COVID-19 hospitalization. Using CDC and sponsor-reported adverse event data, we find that booster mandates may cause a net expected harm: per COVID-19 hospitalization prevented in previously uninfected young adults, we anticipate 18 to 98 serious adverse events, including 1.7 to 3.0 booster-associated myocarditis cases in males, and 1,373 to 3,234 cases of grade ≥3 reactogenicity which interferes with daily activities. Given the high prevalence of post-infection immunity, this risk-benefit profile is even less favorable. University booster mandates are unethical because: 1) no formal risk-benefit assessment exists for this age group; 2) vaccine mandates may result in a net expected harm to individual young people; 3) mandates are not proportionate: expected harms are not outweighed by public health benefits given the modest and transient effectiveness of vaccines against transmission; 4) US mandates violate the reciprocity principle because rare serious vaccine-related harms will not be reliably compensated due to gaps in current vaccine injury schemes; and 5) mandates create wider social harms. We consider counter-arguments such as a desire for socialization and safety and show that such arguments lack scientific and/or ethical support. Finally, we discuss the relevance of our analysis for current 2-dose Covid-19 vaccine mandates in North America.