What’s Known

The World Health Organization (WHO) recommends universal administration of birth dose vaccines, including hepatitis B (HBV), oral polio vaccine (OPV), and bacillus Calmette-Guérin (BCG), to prevent early-life infectious diseases. These vaccines are generally considered safe, with reported side effects being predominantly mild and transient, such as low-grade fever, local swelling, or irritability.

What’s New

This review critically examined unexplored dimensions of neonatal vaccination, including immune immaturity, the potential epigenetic implications of early immune activation, and possible autoimmune and neurological consequences. It also addressed challenges of limited immunogenicity and the effectiveness of targeted vaccination strategies. The authors proposed an “As Low and Late As Reasonably Achievable” (ALLARA) based strategy to optimize safety, efficacy, and long-term outcomes of early-life immunization.

Introduction

At birth, both the immune system and the brain of a newborn are functionally immature, possessing only basic capabilities that evolve rapidly during the first 2 years of life. ¹ This period is characterized by extensive neurodevelopment, including structural growth, myelination, and connectivity, alongside cognitive, motor, and sensory maturation, all of which influence lifelong behavior. ^{2 - 5} Simultaneously, the neonatal immune system is underdeveloped, with reduced functionality in key components, such as monocytes, neutrophils, dendritic cells, natural killer (NK) cells, and T-cells. ⁶ Early immunity primarily relies on maternal antibodies transferred via the placenta and breast milk. ⁷ Accordingly, studies suggested that immune hyperactivity during fetal and early infancy stages could shape lifelong brain and immune function, potentially increasing disease susceptibility. ^{8 - 12} This concept—that early immune events can have permanent developmental consequences—raises the concern that neonatal exposure to multiple vaccine antigens could alter neuroimmune developmental programs and induce long-term changes in gene expression through epigenetic mechanisms such as DNA methylation or histone modification.

Vaccination represents one of the most effective public health interventions, preventing the spread of infectious diseases and significantly reducing associated morbidity and mortality. Its goal is to elicit a long-lasting, pathogen-specific immune response, while minimizing adverse reactions. It is therefore imperative that vaccine-mediated protection during early life is both safe and efficient. To this end, the World Health Organization (WHO) recommends the administration of specific vaccines, namely the hepatitis B virus (HBV), bacillus Calmette-Guérin (BCG), and oral polio (OPV) vaccine, within the first 24 hours of life. These are referred to as birth-dose vaccines. ^{13 - 15}

In this review, we examined neonatal vaccination from a neuroimmune perspective, focusing on its potential epigenetic impacts, safety challenges, efficacy, and current strategies. Special attention was paid to how early immune activation might influence the developing nervous system and long-term health outcomes. This study aimed to provide healthcare professionals and policymakers with evidence-based insights to help guide neonatal vaccination strategies that carefully balance robust immunological protection with neurodevelopmental safety.

Early Life Experience and Lifelong Health

The immune and nervous systems undergo critical, coordinated development during early life, and their interplay significantly affects lifelong health. A growing body of evidence indicate that early life adversity (ELA) could induce long-lasting changes in the immune function, increasing susceptibility to chronic diseases later in life. ^{16 - 18} The immune system is integral to normal brain development, behavior, and neural function, ¹⁸ and immune dysregulation during sensitive developmental windows may contribute to neurological and psychiatric disorders. ¹⁹ Postnatal immune activity has been directly linked to neurological impairments and an increased risk of autoimmune diseases. ^{19 , 20}

ELA refers to a wide range of adverse exposures—including trauma, stress, infections, and environmental toxins—that can shape immune system development through epigenetic reprogramming. ²¹ Such early-life programming may increase the risk of chronic diseases, including cardiovascular, pulmonary, autoimmune, and neurological disorders. ^{22 - 27} Given that neonatal vaccines are administered during these sensitive developmental periods, it is crucial to investigate their potential epigenetic impacts on the neuroimmune axis (figure 1).

Figure 1. The figure illustrates how early-life exposures, such as stress, trauma, infection, and toxins, can dysregulate the neonatal immune system, contributing to disease in adulthood. It also raises the question of whether neonatal vaccination, as another form of immune-activating factor, could exert similar long-term neuroimmune effects.

Studies suggested that ELA could lead to heightened innate immune responsiveness and chronic low-grade inflammation, characterized by elevated pro-inflammatory cytokines, such as interleukin-6 (IL-6) and C-reactive protein (CRP). ^{28 - 30} A prominent example is fetal inflammatory response syndrome (FIRS), marked by elevated fetal plasma IL-6 levels in utero, which is associated with an increased risk of neurodevelopmental, psychiatric, autoimmune, cardiovascular, and pulmonary diseases. ^{31 - 33} Similarly, the BCG vaccine—administered at birth in many countries—induces the production of IL-6, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α), a process known as trained immunity that involves epigenetic reprogramming of innate immunity and monocytes’ function. ^{34 - 37} IL-6 levels have been reported to remain elevated for up to a year following BCG vaccination, ³⁷ raising concerns about whether this sustained immune activation could represent a form of maladaptive epigenetic reprogramming.

IL-6 is a key cytokine that regulates immune activation, acute phase responses, and tissue repair. However, its chronic elevation is implicated in the pathogenesis of autoimmune disorders, chronic inflammatory diseases, and certain cancers. Consequently, IL-6 blockade has shown therapeutic benefits in experimental models of inflammatory bowel disease, diabetes, multiple sclerosis, asthma, rheumatoid arthritis, and inflammation-related cancers. ³⁸ Elevated IL-6 also facilitates infiltration of dendritic cells and macrophages into the brain, disrupting neuronal excitability and neurotransmission, which can result in long-term impairments in synaptogenesis and neurogenesis. ^{39 , 40}

In parallel, the colonization of infant gut microbiota has been widely recognized for its role in brain development and establishing an early life imprint on the immune system. ⁴¹ However, alterations to the commensal gut microbiota during this period might increase the risk of inflammatory or allergic diseases later in life. Enterovirus colonization in early infancy, for instance, could restructure the gut microbiome and potentially trigger autoimmunity. ⁴² Given this established pathway of virus-induced dysbiosis, an important question arises: could the administration of live attenuated poliovirus via neonatal vaccination contribute to microbiome dysbiosis and an increased risk of autoimmunity?

Newborns possess a uniquely tolerant immunological state, characterized by abundant T regulatory (Treg) cells. These cells are essential for maintaining a balanced and controlled immune system and for preventing inappropriate immune activation. Tregs are key players in controlling inflammation, preventing autoimmunity, and ensuring immune responses are appropriately scaled. ⁴³ However, because Tregs can dampen vaccine-induced immunity, adjuvants are often used to suppress Treg activity and enhance immunogenicity. ^{44 , 45} While this approach supports vaccine efficacy, it may also transiently reduce Treg function in infants. This raises a challenging question: could this early-life reduction in Treg-mediated suppression impact the establishment of lifelong self-tolerance, thereby increasing susceptibility to autoimmunity and future dysregulated immune responses?

Autoimmune and Neurological Adverse Events Following Immunization

A significant body of evidence, including case reports, original articles, reviews, and comparative studies, documented the association between HBV, BCG, and polio vaccines—as well as HBV vaccine adjuvants—and the subsequent development of autoimmune and neurological disorders. However, establishing a causal relationship is challenging. Some of these challenges are discussed in this section.

Vaccine safety surveillance data suggested that most vaccine side effects are usually mild and transient, lasting 1-2 days. However, concerns have been raised regarding the potential for later adverse events. ^{46 , 47} Furthermore, the durations of pre- and post-license clinical trials are often insufficient for evaluation of long-term side effects. While many studies indicated that harmful exposures during early life could heighten vulnerability to chronic diseases later in life, ^{16 - 18 , 48 , 49} scientific literature described several pathways by which vaccines, similar to viruses and other microorganisms, could trigger autoimmune reactions. These include molecular mimicry, cross-reactivity, bystander activation, epitope spreading, and antigen persistence. ^{50 - 56} For instance, HBV vaccine epitopes were reported in the context of synergistic autoimmune competence. ⁵⁷ Additionally, components of the HBV vaccine demonstrated sequence homology and molecular mimicry with human proteins: with the hair follicle protein solute carrier family 45 member 2 (SLC45A2), and with myelin basic protein and myelin oligodendrocyte glycoprotein. These are proposed as plausible biological mechanisms for alopecia areata and multiple sclerosis, respectively. ^{58 , 59}

We have reviewed studies reporting adverse effects to highlight the potential of these vaccines to contribute to autoimmune and neurological diseases. The cited studies often support a causal link based on a short temporal relationship—typically less than 2 months—between vaccine administration and the appearance of autoimmunity. These adverse effects are not confined to childhood, underscoring the potential for these vaccines to contribute to such conditions across different age groups.

HBV Vaccine Adverse Events

Multiple case reports and case series highlighted a connection between the HBV vaccine and various autoimmune and neurological diseases, including arthritis/polyarthralgia, lupus erythematosus, multiple sclerosis, optic neuritis, vasculitis, alopecia areata, erythema nodosum, polyarteritis nodosa (PAN), thrombocytopenic purpura, evans syndrome, Guillain-Barré Syndrome (GBS), glomerulonephritis, uveitis, polymyositis, dermatomyositis, Takayasu’s arteritis, Hashimoto’s thyroiditis, Graves’ disease, childhood bullous pemphigoid, chronic fatigue syndrome, cutaneous pseudo lymphoma, vitiligo, lichen planus. A comprehensive list is presented in table 1.

In addition to the side effects associated with HBV vaccine epitopes, HBV vaccines contain aluminum adjuvants as boosters of immune response. The adjuvants are substances added to vaccines to enhance the immunogenicity of the vaccine antigens. ^{97 - 99} Studies indicated that aluminum-based adjuvants in the HBV vaccine are associated with neuro-psychiatric symptoms, fatigue, mucocutaneous, musculoskeletal, and gastrointestinal complaints. They have also been linked to autoimmune/inflammatory syndrome induced by adjuvants (ASIA) syndrome, autism spectrum disorder, sarcoidosis, Sjogren’s syndrome, elevated titers of autoantibodies, and undifferentiated connective tissue diseases, as summarized in table 2. Aluminum compounds can persist in the human body for many years post-vaccination. ¹⁰⁰

Moreover, aluminum has demonstrated a detrimental impact on the blood-brain barrier (BBB) and is connected to microglia-triggered pro-inflammatory cytokine release. Due to its high reactivity, the aluminum ion (Al³⁺) can interfere with several biological functions in the developing brain, including enzymatic activities of key metabolic pathways. In the context of infancy, a significant correlation has been reported between pediatric vaccines containing aluminum adjuvants and the incidence of autism spectrum disorders. Infants receiving these vaccines have a notably higher incidence of autism spectrum disorder (ASD), suggesting a potential association between these vaccine components and developmental sequelae. ¹⁰¹

BCG Vaccine Adverse Events

Previous studies reported autoimmune and neurological disorders following BCG vaccination. A portion of the evidence regarding BCG adverse events is derived from studies utilizing intravesical BCG (iBCG) for cancer immunotherapy. Reported side effects include juvenile idiopathic arthritis (JIA), juvenile dermatomyositis, Takayasu arteritis, autoimmune pancreatitis, GBS, optic neuritis, meningitis, vasculitis, psoriasis, endophthalmitis, uveitis, autoimmune retinopathies, Hodgkin’s lymphoma, lymphadenitis, osteomyelitis, osteitis, and disseminated disease (BCGosis), as illustrated in table 3.

Besides, BCG vaccination has presented a significantly high rate of complications in patients with severe combined immunodeficiency (SCID), leading to substantial morbidity and mortality. An analysis of BCG-vaccinated patients with SCID from 28 centers across 17 countries revealed that early vaccination (≤1 month) was associated with a higher prevalence of BCG-related complications and death. ¹⁰⁸

OPV Vaccine Adverse Events

Although adverse events related to the oral polio vaccine (OPV) are generally considered rare, cases of autoimmune effects following colonization of the gut by the attenuated polioviruses, a serotype of enterovirus C within the picornaviridae family, have been reported. Autoimmune events associated with OPV include multiple sclerosis, childhood acute disseminated encephalomyelitis, vaccine-associated paralytic poliomyelitis (VAPP), acute flaccid paralysis, immune thrombocytopenia (ITP), Gianotti-Crosti syndrome (GCS), transverse myelitis, ulcerative colitis (UC), and Crohn’s disease (CD), as detailed in table 4.

Challenges of Discovering Adverse Events Post-Vaccination

The WHO provides a comprehensive guideline for assessing causality in adverse events following immunization (AEFI), emphasizing well-defined clinical documentation, a temporal association with vaccination, biological plausibility, and the exclusion of alternative causes. ¹⁴⁴ This framework prioritizes identifying strong alternative explanations—such as genetic or pre-existing conditions—before attributing events to vaccines. While this method ensures scientific rigor, it may overlook the complex, multifactorial nature of autoimmune and neurologic diseases, particularly when vaccines act as contributing factors rather than single causes. Moreover, although biological plausibility and timing are central to the WHO’s approach, vaccines can affect the developing immune and nervous systems—especially in early life—with clinical manifestations potentially appearing years later. This underscores the critical need for long-term monitoring. Finally, emerging research is essential to reveal pathophysiological mechanisms that are not yet fully understood.

The WHO guideline also depends heavily on existing literature to assess and often exclude causal links. However, the current literature is often derived from passively gathered data, such as that in the vaccine adverse event reporting system (VAERS), which has inherent methodological limitations. These include a lack of systematic follow-up, significant underreporting, and a failure to capture delayed onset conditions, particularly autoimmune or chronic diseases that manifest long after vaccination. Furthermore, there is no clear guidance on appropriate time windows for monitoring such delayed-onset diseases. It is therefore inappropriate to assume that autoimmune side effects are rare in the absence of robust and comprehensive documentation. Overlapping symptoms and intensive infant vaccination schedules further complicate the identification of specific causal relationships.

To enhance causality assessment, a robust, multidisciplinary approach involving epidemiologists, clinicians, immunologists, and basic scientists is essential. Such collaboration can help elucidate the nuanced relationships between vaccination and long-term immunological or neurological outcomes, thereby informing evidence-based public health strategies.

Another avenue for exploring causal relationships and potential side effects is to compare health outcomes between vaccinated versus unvaccinated populations. Although such studies are often not feasible due to high vaccination coverage in many countries, a limited number of observational surveys exist (table 5). These studies reported higher prevalence of developmental delays, severe allergies, attention-deficit hyperactivity disorder (ADHD), autism spectrum disorders, and even infections (e.g., pneumonia and otitis media) in vaccinated cohorts. Future studies with a two-group design are required to provide further insights.

Efficacy of Neonatal Vaccines

The neonatal immune system is characterized by a state of immune tolerance. At this stage of life, all circulating antibodies are of maternal origin, providing passive immunity until the newborn’s own antibody production becomes robust around 3 months after birth. ^{7 , 148 - 150} These maternal antibodies are highly effective against most infections. ⁷ Due to the inherent immaturity of the immune system, neonatal innate immunity relies on distinctive mechanisms. In response to pathogens, the innate immune system serves as the first line of defense. However, neonatal monocytes and dendritic cells (DCs) produce less TNF, IL-12, and IFN-γ, while increasing the production of IL-6, IL-10, and IL-23. ^{151 , 152} Neutrophils exhibit quantitative and qualitative differences compared to those in older children. ¹⁵³ NK cells display diminished cytotoxic capability and impaired release of destructive substances against infected cells. ¹⁵⁴ Furthermore, neonatal NK cells release less IFN-γ, and their adhesion is compromised due to decreased expression of specific adhesion molecules. ¹⁵⁵ This immunological bias renders newborns prone to low inflammatory responses and impairs their responses to many vaccines. ¹⁵⁶ In this section, we examine the efficacy of BCG, HBV, and OPV vaccines during the neonatal period. The results are summarized in table 6.

HBV Vaccine Efficacy

Hepatitis B surface antibodies (anti-HBs) are produced by the immune system in response to the hepatitis B surface antigen and serve as a marker for immunity. ^{168 - 170} Vaccine efficacy, an anti-HBs level >10 IU/L after vaccination, provides complete protection against acute and chronic hepatitis B. ^{15 , 171} The HBV vaccine is highly effective in infants, with over 95% of healthy recipients developing seroprotective anti-HBs levels within 1 month after the final dose. ^{172 , 173} However, few studies have evaluated the seroprotective rate of the HBV vaccine specifically in the neonatal period. These studies reported seroconversion rates of only 18% to 50%, 1 month after receiving the birth dose, without accounting for the potential interference of maternal antibodies (table 6). ^{157 , 174} Moreover, several studies indicated that individuals with a low antibody response exhibited reduced T-cell proliferation and cytokine production. ^{158 , 175 - 177} Research also showed that the immune response was enhanced when the first vaccination dose was administered at 2 months of age. ^{174 , 178 - 180} This improvement could be attributed to the maturation of the infant’s immune system. ^{181 - 183} A large review in Africa demonstrated that children born to HBsAg-negative mothers, the risk of infection remained minimal even when vaccination began at 2 months, suggesting no clear additional benefits from the HBV birth dose. ¹⁸⁴

BCG Vaccine Efficacy

The BCG vaccine has stood as the exclusive vaccine against tuberculosis (TB) for decades. ¹⁴⁶ We did not identify any studies specifically reporting the efficacy of BCG vaccination in the early neonatal period. However, a study reported 42% efficacy in children under 5 years of age, ¹⁶⁰ while another showed 32% efficacy in children under 3 against all forms of tuberculosis. ¹⁵⁹

A limited number of studies explored the immune responses following neonatal BCG vaccination. These investigations have identified CD4-positive (CD4+) and CD8-positive (CD8+)T lymphocytes as the predominant responding cell populations. ^{36 , 185} The CD4+ T-cells notably upregulate IFN-γ, TNF-α, IL-2, and IL-6, whereas CD8+ T-cells demonstrate minimal to undetectable production of IFN-γ, TNF-α, and IL-2. ^{35 , 36 , 186} However, the reliability of BCG-specific CD4+ and CD8+ T-cell cytokine expression as a correlate of protection against childhood TB has been questioned. ^{35 , 187} The limited efficacy of vaccination confirms this theory. ¹⁸⁸

Furthermore, investigations revealed that Th1 immune responses become detectable approximately 2-3 months post-vaccination. ^{187 , 189} Studies have also indicated that immunogenicity is enhanced when BCG administration is postponed until 10 weeks of age. ¹⁸⁶

OPV Vaccine Efficacy

Multiple studies have evaluated the effectiveness of the birth dose of the live attenuated oral poliovirus vaccine (OPV). The observed seroconversion rates revealed a range of responses across the different poliovirus serotypes. For type 1, seroconversion rates spanned from 6% to 42% (mean=28%), for type 2, the rates ranged from 2% to 63% (mean=36%), and for type 3, the seroconversion rates varied between 2% and 35% (mean=16%). ^{161 - 167} This considerable variability underscored the limited and unpredictable immune response triggered by the OPV birth dose in the neonatal period. A more robust immune response is observed with increasing age, highlighting the critical importance of timing and subsequent booster doses for achieving reliable protection against poliovirus infection.

Current Neonatal Vaccination Strategies

The Expanded Program on Immunization (EPI) was established by the WHO in 1974 with the initial goal of protecting children against six major diseases: tuberculosis, polio, diphtheria, tetanus, pertussis, and measles. The program has since expanded its scope to include additional vaccines and immunization coverage goals. A key component of the EPI is the “birth dose”— the administration of a vaccine shortly after birth to provide early protection against diseases that pose an immediate risk to newborns. This strategy is critical for preventing mother-to-child or early environmental transmission of specific infections.

According to WHO guidelines, the birth dose includes specific vaccines to be given within the first 24 hours of life: the BCG vaccine, the zero dose of OPV, and the HBV vaccine. ^{13 - 15} However, the specific vaccines included and their exact timing can vary based on national health policies and local disease prevalence.

Globally, two primary vaccination strategies are typically implemented for newborns: the ‘general recommendation’ strategy and the ‘recommendation to at-risk groups’ strategy. A general recommendation strategy for neonates involves compulsory administration of essential vaccines to all newborns to establish early protection against preventable diseases. In contrast, the ‘recommendation for at-risk groups’, also known as the selective or targeted strategy, focuses on identifying and prioritizing neonates who face a higher likelihood of exposure to specific infectious diseases or an increased risk of complications due to underlying health conditions or environmental factors.

Nations worldwide implement distinct childhood immunization strategies to protect infants from infectious diseases. While some countries adopt a universal approach, vaccinating all newborns irrespective of their risk factors, others employ a targeted strategy, focusing on specific at-risk groups. Several countries, including Austria, Belgium, the Czech Republic, Denmark, Germany, Iceland, Italy, the Netherlands, Slovakia, and Spain, have discontinued universal BCG vaccination, removing it from their routine schedules. Others, such as Cyprus, Finland, France, Norway, Slovenia, Sweden, and the United Kingdom, currently recommend it exclusively for specific at-risk categories of children. This approach notably includes those with parents from high-TB-prevalence countries or with a family history of TB. The rationale for this targeted approach in low-endemic countries is based on the low infection risk, a high number needed to vaccinate (NNV), i.e., the number of healthy individuals who must be vaccinated to prevent one case of TB, and a high rate of adverse events per prevented TB case.

A similar pattern is seen with the HBV birth dose. Some countries, including Austria, Cameroon, Finland, Germany, Greece, Hungary, Iceland, and Ireland, have not included it in their routine immunization schedules. In contrast, several countries, such as Canada, Belgium, Czechia, Denmark, Estonia, France, Italy, Japan, Latvia, Luxembourg, the Netherlands, New Zealand, Norway, San Marino, Slovakia, Spain, Sweden, Switzerland, and the United Kingdom, recommend HBV birth dose for at-risk groups. This selective recommendation reflects a targeted public health approach, likely considering factors, such as regional prevalence, disease severity, and available resources. Furthermore, OPV is administered in many countries from 2 months of age. Such diverse approaches highlight the adaptability of immunization strategies to individual country requirements and health priorities.

Neonate Vaccination: Future Directions

Neonatal vaccination plays a critical role in preventing early-life infectious diseases, yet it presents unique challenges due to the immaturity of the infant’s immune system. The limited immunogenic responses in neonates can reduce vaccine efficacy and raise concerns regarding the long-term impact of early immune activation. As the immune system matures with age, a more robust and balanced response can be achieved, supporting the consideration of delayed or staged immunization schedules.

Recent concerns have focused on the potential neuroimmune effects of immune stimulation during sensitive developmental windows. Emerging evidence suggested that early-life immune activation might influence epigenetic programming and increase the risk of autoimmune and neurodevelopmental disorders later in life. In response, several countries have begun adopting selective neonatal vaccination strategies, prioritizing high-risk infants and integrating early screening programs. This shift offers valuable opportunities to evaluate long-term outcomes between vaccinated and unvaccinated populations and to tailor immunization strategies more precisely. Figure 2 conceptually outlines these four key considerations—epigenetic impacts, safety challenges, efficacy, and current strategies—guiding a more cautious and evidence-based reevaluation of neonatal vaccination policy.

Figure 2. This roadmap illustrates how critical assessment of four key factors—epigenetic impacts, safety challenges, efficacy, and current strategies—highlights the potential influence of early-life immune activation on long-term health. This integrated analysis supports a shift toward more cautious and evidence-based vaccination approaches.

Conclusion

Vaccination remains a cornerstone of pediatric health. However, its application in the neonatal period requires careful consideration. The balance between providing early protection against infectious diseases and the potential risks of overstimulating the developing immune system must be guided by rigorous scientific evidence. A growing body of research highlight that neonatal immune responses differ significantly from those in older children, necessitating an individualized, developmentally informed approach to vaccine scheduling and administration.

As technologies such as artificial intelligence and precision medicine advance, they offer unprecedented opportunities to design personalized vaccine schedules based on an infant’s genetic predispositions and environmental risk factors. Adopting a flexible, risk-based framework—aligned with the ALLARA principle—can help optimize both safety and efficacy of early-life immunization. Ultimately, neonatal vaccination policies must prioritize long-term neurological and immunological well-being, ensuring that each administered vaccine is both necessary and appropriate for the individual infant.

Acknowledgment

We would like to express our gratitude to all those who have encouraged a critical and balanced perspective on vaccination, reminding us to view vaccines—resembling any medical intervention—as procedures that require careful consideration of both risks and benefits, rather than assuming them to be inherently risk-free.

Authors’ Contribution

Z.P: Contributed to study conception and design, data analysis, manuscript revision; M.N: Responsible for data acquisition, data interpretation, drafting major sections of the manuscript; K.M: Supervised the project, contributed to data interpretation, critically revised the manuscript; R.S: Assisted in study design, coordinated clinical data collection, contributed to drafting; M.E: Performed data analysis, ensured data quality, participated in manuscript revision; F.H: Conducted the literature review, contributed to data interpretation, assisted in manuscript preparation. All authors have read and approved the final manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Declaration of AI

We declare that AI tools (Chat gpt-4) were used solely to assist with language editing, grammar correction, and improvement of clarity in the manuscript. AI tools were not used to generate original scientific content, analyze data, interpret results, or draw conclusions. All study design, data analysis, interpretation of results, and scientific judgments were performed by the authors. The authors take full responsibility for the accuracy, originality, and integrity of the work and confirm that the manuscript complies with the journal’s ethical and authorship guidelines.

Conflict of Interest

None declared.

References

1. Bateson P, Barker D, Clutton-Brock T, Deb D, D’Udine B, Foley RA, et al. Developmental plasticity and human health. Nature. 2004; 430:419-21. DOI | PubMed
2. Dekaban AS. Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights. Ann Neurol. 1978; 4:345-56. DOI | PubMed
3. Richards JE, Conte S. The Cambridge Handbook of Infant Development: Brain, Behavior, and Cultural Context. Cambridge Handbooks in Psychology. Cambridge: Cambridge University Press; 2020.
4. Gilmore JH, Knickmeyer RC, Gao W. Imaging structural and functional brain development in early childhood. Nat Rev Neurosci. 2018; 19:123-37. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
5. Tierney AL, Nelson CA. Brain Development and the Role of Experience in the Early Years. Zero Three. 2009; 30:9-13. Publisher Full Text | PubMed [ PMC Free Article ]
6. Georgountzou A, Papadopoulos NG. Postnatal Innate Immune Development: From Birth to Adulthood. Front Immunol. 2017; 8:957. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
7. Cinicola B, Conti MG, Terrin G, Sgrulletti M, Elfeky R, Carsetti R, et al. The Protective Role of Maternal Immunization in Early Life. Front Pediatr. 2021; 9:638871. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
8. Danese A, S JL. Psychoneuroimmunology of Early-Life Stress: The Hidden Wounds of Childhood Trauma? Neuropsychopharmacology. 2017; 42:99-114. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
9. Eriksson M, Raikkonen K, Eriksson JG. Early life stress and later health outcomes--findings from the Helsinki Birth Cohort Study. Am J Hum Biol. 2014; 26:111-6. DOI | PubMed
10. Spitzer C, Bouchain M, Winkler LY, Wingenfeld K, Gold SM, Grabe HJ, et al. Childhood trauma in multiple sclerosis: a case-control study. Psychosom Med. 2012; 74:312-8. DOI | PubMed
11. Laforest-Lapointe I, Arrieta MC. Patterns of Early-Life Gut Microbial Colonization during Human Immune Development: An Ecological Perspective. Front Immunol. 2017; 8:788. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
12. Hata M, Hata M, Andriessen EM, Juneau R, Pilon F, Crespo-Garcia S, et al. Early-life peripheral infections reprogram retinal microglia and aggravate neovascular age-related macular degeneration in later life. J Clin Invest. 2023; 133Publisher Full Text | DOI | PubMed [ PMC Free Article ]
13. BCG vaccines: WHO position paper - February 2018. Wkly Epidemiol Rec. 2018; 93:73-96. PubMed
14. Polio vaccines: WHO position paper - March, 2016. Wkly Epidemiol Rec. 2016; 91:145-68. PubMed
15. Hepatitis B vaccines: WHO position paper - July 2017. Wkly Epidemiol Rec. 2017; 92:369-92. PubMed
16. Nobile S, Di Sipio Morgia C, Vento G. Perinatal Origins of Adult Disease and Opportunities for Health Promotion: A Narrative Review. J Pers Med. 2022; 12Publisher Full Text | DOI | PubMed [ PMC Free Article ]
17. Bilbo SD, Schwarz JM. Early-life programming of later-life brain and behavior: a critical role for the immune system. Front Behav Neurosci. 2009; 3:14. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
18. Brydges NM, Reddaway J. Neuroimmunological effects of early life experiences. Brain Neurosci Adv. 2020; 4:2398212820953706. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
19. Kim J, Erice C, Rohlwink UK, Tucker EW. Infections in the Developing Brain: The Role of the Neuro-Immune Axis. Front Neurol. 2022; 13:805786. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
20. Robaina Castellanos GR, Riesgo Rodriguez Sde L. Neonatal sepsis and neurodevelopment in very low birth weight infants in Matanzas, Cuba 2006-2010: a prospective cohort study. Medwave. 2016; 16:e6422. DOI | PubMed
21. Grova N, Schroeder H, Olivier JL, Turner JD. Epigenetic and Neurological Impairments Associated with Early Life Exposure to Persistent Organic Pollutants. Int J Genomics. 2019; 2019:2085496. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
22. Rocca WA, Gazzuola Rocca L, Smith CY, Esterov D, Kapoor E, St Sauver JL, et al. Adverse childhood experiences increase the long-term accumulation of morbidity in women. Commun Med (Lond). 2025; 5:287. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
23. Wu Y, Xu R, Gasevic D, Yang Z, Yu P, Wen B, et al. UK Biobank data demonstrate long-term exposure to floods is a risk factor for incident dementia. Commun Med (Lond). 2025; 5:71. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
24. Alley J, Gassen J, Slavich GM. The effects of childhood adversity on twenty-five disease biomarkers and twenty health conditions in adulthood: Differences by sex and stressor type. Brain Behav Immun. 2025; 123:164-76. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
25. Sonu S, Post S, Feinglass J. Adverse childhood experiences and the onset of chronic disease in young adulthood. Prev Med. 2019; 123:163-70. DOI | PubMed
26. Tan H, Zhou H, Chen J, Ren H, Guo Y, Jiang X. Association of early life adversity with cardiovascular disease and its potential mechanisms: a narrative review. Front Public Health. 2024; 12:1341266. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
27. Friedman EM, Karlamangla AS, Gruenewald TL, Koretz B, Seeman TE. Early life adversity and adult biological risk profiles. Psychosom Med. 2015; 77:176-85. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
28. Miller GE, Chen E. Harsh family climate in early life presages the emergence of a proinflammatory phenotype in adolescence. Psychol Sci. 2010; 21:848-56. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
29. Miller GE, Chen E, Fok AK, Walker H, Lim A, Nicholls EF, et al. Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling. Proc Natl Acad Sci U S A. 2009; 106:14716-21. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
30. Ehrlich KB, Ross KM, Chen E, Miller GE. Testing the biological embedding hypothesis: Is early life adversity associated with a later proinflammatory phenotype? Dev Psychopathol. 2016; 28:1273-83. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
31. Jung E, Romero R, Yeo L, Diaz-Primera R, Marin-Concha J, Para R, et al. The fetal inflammatory response syndrome: the origins of a concept, pathophysiology, diagnosis, and obstetrical implications. Semin Fetal Neonatal Med. 2020; 25:101146. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
32. Giovannini E, Bonasoni MP, Pascali JP, Giorgetti A, Pelletti G, Gargano G, et al. Infection Induced Fetal Inflammatory Response Syndrome (FIRS): State-of- the-Art and Medico-Legal Implications-A Narrative Review. Microorganisms. 2023; 11Publisher Full Text | DOI | PubMed [ PMC Free Article ]
33. Gibson B, Goodfriend E, Zhong Y, Melhem NM. Fetal inflammatory response and risk for psychiatric disorders. Transl Psychiatry. 2023; 13:224. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
34. Lalor MK, Floyd S, Gorak-Stolinska P, Ben-Smith A, Weir RE, Smith SG, et al. BCG vaccination induces different cytokine profiles following infant BCG vaccination in the UK and Malawi. J Infect Dis. 2011; 204:1075-85. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
35. Kagina BM, Abel B, Scriba TJ, Hughes EJ, Keyser A, Soares A, et al. Specific T cell frequency and cytokine expression profile do not correlate with protection against tuberculosis after bacillus Calmette-Guerin vaccination of newborns. Am J Respir Crit Care Med. 2010; 182:1073-9. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
36. Soares AP, Kwong Chung CK, Choice T, Hughes EJ, Jacobs G, van Rensburg EJ, et al. Longitudinal changes in CD4(+) T-cell memory responses induced by BCG vaccination of newborns. J Infect Dis. 2013; 207:1084-94. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
37. Pablos-Mendez A, Raviglione MC, Laszlo A, Binkin N, Rieder HL, Bustreo F, et al. Global surveillance for antituberculosis-drug resistance, 1994-1997. World Health Organization-International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. N Engl J Med. 1998; 338:1641-9. DOI | PubMed
38. Neurath MF, Finotto S. IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev. 2011; 22:83-9. DOI | PubMed
39. Wu YQ, Shen J, Zhou QL, Zhao HW, Liu LR, Liu X. Interleukin-6 and interleukin-8 in diagnosing neonatal septicemia. J Biol Regul Homeost Agents. 2016; 30:1107-13. PubMed
40. Lyra ESNM, Goncalves RA, Pascoal TA, Lima-Filho RAS, Resende EPF, Vieira ELM, et al. Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer’s disease. Transl Psychiatry. 2021; 11:251. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
41. Yao Y, Cai X, Ye Y, Wang F, Chen F, Zheng C. The Role of Microbiota in Infant Health: From Early Life to Adulthood. Front Immunol. 2021; 12:708472. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
42. Morse ZJ, Simister RL, Crowe SA, Horwitz MS, Osborne LC. Virus induced dysbiosis promotes type 1 diabetes onset. Front Immunol. 2023; 14:1096323. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
43. Yang L, Jin R, Lu D, Ge Q. T cell Tolerance in Early Life. Front Immunol. 2020; 11:576261. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
44. Ndure J, Flanagan KL. Targeting regulatory T cells to improve vaccine immunogenicity in early life. Front Microbiol. 2014; 5:477. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
45. Batista-Duharte A, Tellez-Martinez D, Fuentes DLP, Carlos IZ. Molecular adjuvants that modulate regulatory T cell function in vaccination: A critical appraisal. Pharmacol Res. 2018; 129:237-50. DOI | PubMed
46. Bernini L, Manzini CU, Ferri C. BCG and autoimmunity. Vaccines and Autoimmunity. 2015;197-206. DOI
47. Smyk DS, Sakkas LI, Shoenfeld Y, Bogdanos DP. Hepatitis B vaccination and autoimmunity. Vaccines and Autoimmunity. 2015;147-62. DOI
48. Goenka A, Kollmann TR. Development of immunity in early life. J Infect. 2015; 71:S112-20. DOI | PubMed
49. Huang H, Shu N, Mishra V, Jeon T, Chalak L, Wang ZJ, et al. Development of human brain structural networks through infancy and childhood. Cereb Cortex. 2015; 25:1389-404. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
50. Ercolini AM, Miller SD. The role of infections in autoimmune disease. Clin Exp Immunol. 2009; 155:1-15. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
51. Anaya JM, Restrepo-Jimenez P, Ramirez-Santana C. The autoimmune ecology: an update. Curr Opin Rheumatol. 2018; 30:350-60. DOI | PubMed
52. Schattner A, Rager-Zisman B. Virus-induced autoimmunity. Rev Infect Dis. 1990; 12:204-22. DOI | PubMed
53. von Herrath MG, Fujinami RS, Whitton JL. Microorganisms and autoimmunity: making the barren field fertile? Nat Rev Microbiol. 2003; 1:151-7. DOI | PubMed
54. Cohen AD, Shoenfeld Y. Vaccine-induced autoimmunity. J Autoimmun. 1996; 9:699-703. DOI | PubMed
55. Agmon-Levin N, Paz Z, Israeli E, Shoenfeld Y. Vaccines and autoimmunity. Nat Rev Rheumatol. 2009; 5:648-52. DOI | PubMed
56. Arango M-T, Shoenfeld Y, Cervera R, Anaya J-M. Infection and autoimmune diseases. Autoimmunity: from bench to bedside. Bogota: El Rosario University Press; 2013.
57. Geier DA, Geier MR. A case-control study of serious autoimmune adverse events following hepatitis B immunization. Autoimmunity. 2005; 38:295-301. DOI | PubMed
58. Bogdanos DP, Smith H, Ma Y, Baum H, Mieli-Vergani G, Vergani D. A study of molecular mimicry and immunological cross-reactivity between hepatitis B surface antigen and myelin mimics. Clin Dev Immunol. 2005; 12:217-24. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
59. Gherardi RK, Coquet M, Cherin P, Belec L, Moretto P, Dreyfus PA, et al. Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle. Brain. 2001; 124:1821-31. DOI | PubMed
60. Geier MR, Geier DA, Zahalsky AC. A review of hepatitis B vaccination. Expert Opin Drug Saf. 2003; 2:113-22. DOI | PubMed
61. Maubec E, Pinquier L, Viguier M, Caux F, Amsler E, Aractingi S, et al. Vaccination-induced cutaneous pseudolymphoma. J Am Acad Dermatol. 2005; 52:623-9. DOI | PubMed
62. Junior DST. Environmental and individual factors associated with protection and predisposition to autoimmune diseases. Int J Health Sci (Qassim). 2020; 14:13-23. Publisher Full Text | PubMed [ PMC Free Article ]
63. Ortega-Hernandez OD, Shoenfeld Y. Infection, vaccination, and autoantibodies in chronic fatigue syndrome, cause or coincidence? Ann N Y Acad Sci. 2009; 1173:600-9. DOI | PubMed
64. Mikaeloff Y, Caridade G, Suissa S, Tardieu M. Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood. Neurology. 2009; 72:873-80. DOI | PubMed
65. Herroelen L, de Keyser J, Ebinger G. Central-nervous-system demyelination after immunisation with recombinant hepatitis B vaccine. Lancet. 1991; 338:1174-5. DOI | PubMed
66. Tourbah A, Gout O, Liblau R, Lyon-Caen O, Bougniot C, Iba-Zizen MT, et al. Encephalitis after hepatitis B vaccination: recurrent disseminated encephalitis or MS? Neurology. 1999; 53:396-401. DOI | PubMed
67. Agmon-Levin N, Zafrir Y, Kivity S, Balofsky A, Amital H, Shoenfeld Y. Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the ‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’ (ASIA). Immunol Res. 2014; 60:376-83. DOI | PubMed
68. Nancy AL, Shoenfeld Y. Chronic fatigue syndrome with autoantibodies--the result of an augmented adjuvant effect of hepatitis-B vaccine and silicone implant. Autoimmun Rev. 2008; 8:52-5. DOI | PubMed
69. Richardson CT, Hayden MS, Gilmore ES, Poligone B. Evaluation of the Relationship between Alopecia Areata and Viral Antigen Exposure. Am J Clin Dermatol. 2018; 19:119-26. DOI | PubMed
70. Choffray A, Pinquier L, Bachelez H. Exacerbation of lupus panniculitis following anti-hepatitis-B vaccination. Dermatology. 2007; 215:152-4. DOI | PubMed
71. Luhadia K, Abugrin M, Kiani R, Ahmady A, Virk J, Yashi K. Hepatitis B Vaccine and Multiple Sclerosis: Cause or Coincidence. Cureus. 2022; 14:e29941. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
72. Limas C, Limas CJ. Lichen planus in children: a possible complication of hepatitis B vaccines. Pediatr Dermatol. 2002; 19:204-9. DOI | PubMed
73. de la Fuente S, Hernandez-Martin A, de Lucas R, Gonzalez-Ensenat MA, Vicente A, Colmenero I, et al. Postvaccination bullous pemphigoid in infancy: report of three new cases and literature review. Pediatr Dermatol. 2013; 30:741-4. DOI | PubMed
74. Erbagci Z. Childhood bullous pemphigoid following hepatitis B immunization. J Dermatol. 2002; 29:781-5. DOI | PubMed
75. Berkun Y, Mimouni D, Shoenfeld Y. Pemphigus following hepatitis B vaccination--coincidence or causality? Autoimmunity. 2005; 38:117-9. DOI | PubMed
76. Vital C, Vital A, Gbikpi-Benissan G, Longy-Boursier M, Climas MT, Castaing Y, et al. Postvaccinal inflammatory neuropathy: peripheral nerve biopsy in 3 cases. J Peripher Nerv Syst. 2002; 7:163-7. DOI | PubMed
77. de Carvalho JF, Pereira RM, Shoenfeld Y. Systemic polyarteritis nodosa following hepatitis B vaccination. Eur J Intern Med. 2008; 19:575-8. DOI | PubMed
78. Maillefert JF, Farge P, Gazet-Maillefert MP, Tavernier C. Mental nerve neuropathy as a result of hepatitis B vaccination. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997; 83:663-4. DOI | PubMed
79. Zaas A, Scheel P, Venbrux A, Hellmann DB. Large artery vasculitis following recombinant hepatitis B vaccination: 2 cases. J Rheumatol. 2001; 28:1116-20. PubMed
80. Agmon-Levin N, Zafrir Y, Paz Z, Shilton T, Zandman-Goddard G, Shoenfeld Y. Ten cases of systemic lupus erythematosus related to hepatitis B vaccine. Lupus. 2009; 18:1192-7. DOI | PubMed
81. Altman A, Szyper-Kravitz M, Shoenfeld Y. HBV vaccine and dermatomyositis: is there an association? Rheumatol Int. 2008; 28:609-12. DOI | PubMed
82. Geier MR, Geier DA. A case-series of adverse events, positive re-challenge of symptoms, and events in identical twins following hepatitis B vaccination: analysis of the Vaccine Adverse Event Reporting System (VAERS) database and literature review. Clin Exp Rheumatol. 2004; 22:749-55. PubMed
83. Geier MR, Geier DA. Hepatitis B vaccination safety. Ann Pharmacother. 2002; 36:370-4. DOI | PubMed
84. Pennesi M, Torre G, Del Santo M, Sonzogni A. Glomerulonephritis after recombinant hepatitis B vaccine. Pediatr Infect Dis J. 2002; 21:172-3. DOI | PubMed
85. Poirriez J. A preliminary experiment of absorption of antinuclear antibodies by the hepatitis B vaccine components, in a case of neurolupus. Vaccine. 2004; 22:3166-8. DOI | PubMed
86. Schattner A. Consequence or coincidence? The occurrence, pathogenesis and significance of autoimmune manifestations after viral vaccines. Vaccine. 2005; 23:3876-86. DOI | PubMed
87. Ramirez-Rivera J, Vega-Cruz AM, Jaume-Anselmi F. Polymyositis: rare complication of hepatitis B vaccination. An unusual cause of toxic shock syndrome. Bol Asoc Med P R. 2003; 95:13-6. PubMed
88. Agmon-Levin N, Kivity S, Szyper-Kravitz M, Shoenfeld Y. Transverse myelitis and vaccines: a multi-analysis. Lupus. 2009; 18:1198-204. DOI | PubMed
89. Maillefert JF, Sibilia J, Toussirot E, Vignon E, Eschard JP, Lorcerie B, et al. Rheumatic disorders developed after hepatitis B vaccination. Rheumatology (Oxford). 1999; 38:978-83. DOI | PubMed
90. Ronchi F, Cecchi P, Falcioni F, Marsciani A, Minak G, Muratori G, et al. Thrombocytopenic purpura as adverse reaction to recombinant hepatitis B vaccine. Arch Dis Child. 1998; 78:273-4. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
91. Neau D, Bonnet F, Michaud M, Perel Y, Longy-Boursier M, Ragnaud JM, et al. Immune thrombocytopenic purpura after recombinant hepatitis B vaccine: retrospective study of seven cases. Scand J Infect Dis. 1998; 30:115-8. DOI | PubMed
92. Chave T, Neal C, Camp R. Henoch-Schonlein purpura following hepatitis B vaccination. J Dermatolog Treat. 2003; 14:179-81. DOI | PubMed
93. Khamaisi M, Shoenfeld Y, Orbach H. Guillain-Barre syndrome following hepatitis B vaccination. Clin Exp Rheumatol. 2004; 22:767-70. PubMed
94. Girard M. Autoimmune hazards of hepatitis B vaccine. Autoimmun Rev. 2005; 4:96-100. DOI | PubMed
95. Wise RP, Kiminyo KP, Salive ME. Hair loss after routine immunizations. JAMA. 1997; 278:1176-8. PubMed
96. Avci Z, Bayram C, Malbora B. Hepatitis B vaccine-associated atypical hemolytic uremic syndrome. Turk J Haematol. 2013; 30:418-9. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
97. Edelman R. The development and use of vaccine adjuvants. Mol Biotechnol. 2002; 21:129-48. DOI | PubMed
98. Pulendran B, Ahmed R. Immunological mechanisms of vaccination. Nat Immunol. 2011; 12:509-17. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
99. Kuroda E, Coban C, Ishii KJ. Particulate adjuvant and innate immunity: past achievements, present findings, and future prospects. Int Rev Immunol. 2013; 32:209-20. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
100. Guimaraes LE, Baker B, Perricone C, Shoenfeld Y. Vaccines, adjuvants and autoimmunity. Pharmacol Res. 2015; 100:190-209. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
101. Boretti A. Reviewing the association between aluminum adjuvants in the vaccines and autism spectrum disorder. J Trace Elem Med Biol. 2021; 66:126764. DOI | PubMed
102. Shoenfeld Y, Agmon-Levin N. ‘ASIA’ - autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. 2011; 36:4-8. DOI | PubMed
103. Zafrir Y, Agmon-Levin N, Paz Z, Shilton T, Shoenfeld Y. Autoimmunity following hepatitis B vaccine as part of the spectrum of ‘Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants’ (ASIA): analysis of 93 cases. Lupus. 2012; 21:146-52. DOI | PubMed
104. Shaw CA, Tomljenovic L. Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity. Immunol Res. 2013; 56:304-16. DOI | PubMed
105. Ewing GE. What is regressive autism and why does it occur? Is it the consequence of multi-systemic dysfunction affecting the elimination of heavy metals and the ability to regulate neural temperature? N Am J Med Sci. 2009; 1:28-47. Publisher Full Text | PubMed [ PMC Free Article ]
106. Tomljenovic L, Shaw CA. Aluminum vaccine adjuvants: are they safe? Curr Med Chem. 2011; 18:2630-7. DOI | PubMed
107. Borba V, Malkova A, Basantsova N, Halpert G, Andreoli L, Tincani A, et al. Classical Examples of the Concept of the ASIA Syndrome. Biomolecules. 2020; 10Publisher Full Text | DOI | PubMed [ PMC Free Article ]
108. Marciano BE, Huang CY, Joshi G, Rezaei N, Carvalho BC, Allwood Z, et al. BCG vaccination in patients with severe combined immunodeficiency: complications, risks, and vaccination policies. J Allergy Clin Immunol. 2014; 133:1134-41. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
109. Jain M, Vadboncoeur J, Garg SJ, Biswas J. Bacille Calmette-Guerin: An ophthalmic perspective. Surv Ophthalmol. 2022; 67:307-20. DOI
110. Khalili N, Mohammadzadeh I, Khalili N, Heredia RJ, Zoghi S, Boztug K, et al. BCGitis as the primary manifestation of chronic granulomatous disease. IDCases. 2021; 23:e01038. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
111. Dahl J, Holvik K, Heldal E, Grimnes G, Hoff M, Finnes TE, et al. Individual Variation in Adaptive Immune Responses and Risk of Hip Fracture-A NOREPOS Population-Based Cohort Study. J Bone Miner Res. 2020; 35:2327-34. DOI | PubMed
112. Tsujioka Y, Nozaki T, Nishimura G, Miyazaki O, Jinzaki M, Kono T. BCG osteomyelitis: tips for diagnosis. Skeletal Radiol. 2022; 51:1571-84. DOI | PubMed
113. Wang J, Zhou F, Jiang MB, Xu ZH, Ni YH, Wu QS. Epidemiological characteristics and trends of Bacillus Calmette-Guerin lymphadenitis in Shanghai, China from 2010 to 2019. Hum Vaccin Immunother. 2022; 18:1938922. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
114. Sellami K, Amouri M, Kmiha S, Bahloul E, Aloulou H, Sfaihi L, et al. Adverse Reactions Due to the Bacillus Calmette-Guerin Vaccine: Twenty Tunisian Cases. Indian J Dermatol. 2018; 63:62-5. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
115. Modrzejewska M, Karczewicz D, Kordek A, Rudnicki J, Czajka R. [The detachment of retina as possible complication after BCG vaccination during HOP--description of case]. Klin Oczna. 2006; 108:446-9. PubMed
116. Salmon C, Conus F, Parent ME, Benedetti A, Rousseau MC. Association between Bacillus Calmette-Guerin vaccination and lymphoma: a population-based birth cohort study. J Intern Med. 2019; 286:583-95. DOI | PubMed
117. Shoenfeld Y, Aron-Maor A, Tanai A, Ehrenfeld M. Bcg and autoimmunity: another two-edged sword. J Autoimmun. 2001; 16:235-40. DOI | PubMed
118. Schuchmann L, Pernice W, Hufschmidt C, Adler CP. Tuberculous arthritis--a rare, but important differential diagnosis in juvenile chronic arthritis. Monatsschr Kinderheilkd. 1991; 139:244-7. PubMed
119. Anis O, Yogev D, Dotan A, Tsur AM, David P, Vishnevskia Dai V, et al. Autoimmune disorders caused by intravesical bacillus Calmette-Guerine treatment: A systematic review. Autoimmun Rev. 2023; 22:103329. DOI | PubMed
120. Sharan S, Thirkill CE, Grigg JR. Autoimmune retinopathy associated with intravesical BCG therapy. Br J Ophthalmol. 2005; 89:927-8. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
121. Nakagawa T, Shigehara K, Naito R, Yaegashi H, Nakashima K, Iijima M, et al. Reiter’s syndrome following intravesical Bacillus Calmette-Guerin therapy for bladder carcinoma: a report of five cases. Int Cancer Conf J. 2018; 7:148-51. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
122. Genereau T, Koeger AC, Chaibi P, Bourgeois P. Polymyalgia rheumatica with temporal arteritis following intravesical Calmette-Guerin bacillus immunotherapy for bladder cancer. Clin Exp Rheumatol. 1996; 14:110. PubMed
123. Thepot C, Martigny J, Simon L, Bellin J, Larget-Piet B, Chevalier X. Acute polyarthritis after BCG-therapy for bladder carcinoma in a patient with ankylosing spondylitis. Rev Rhum Engl Ed. 1995; 62:459-61. PubMed
124. Granel B, Serratrice J, Morange PE, Disdier P, Weiller PJ. Cryoglobulinemia vasculitis following intravesical instillations of bacillus Calmette-Guerin. Clin Exp Rheumatol. 2004; 22:481-2. PubMed
125. Tsuchiya H, Hanata N, Harada H, Shoda H, Fujio K. Intestinal ulcers induced by intravesical bacillus Calmette-Guerin therapy. Mod Rheumatol Case Rep. 2021; 5:421-4. DOI | PubMed
126. Parent ME, Richer M, Liang P. The first case of bacillus Calmette-Guerin-induced small-vessel central nervous system vasculitis. Clin Rheumatol. 2018; 37:2297-302. DOI | PubMed
127. Beisland C, Holsen DS. Vitiligo--an autoimmune side-effect of intravesical bacillus Calmette-Guerin instillation? Scand J Urol Nephrol. 2004; 38:182-3. DOI | PubMed
128. Vittori F, Groslafeige C. [Tuberculosis lupus after BCG vaccination. A rare complication of the vaccination]. Arch Pediatr. 1996; 3:457-9. DOI | PubMed
129. Izumi AK, Matsunaga J. BCG vaccine-induced lupus vulgaris. Arch Dermatol. 1982; 118:171-2. PubMed
130. Noishiki C, Hayasaka Y, Yoshida R, Ogawa R. Over 90% of Childhood BCG Vaccine-Induced Keloids in Japan Occur in Women. Dermatol Ther (Heidelb). 2023; 13:1137-47. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
131. Abid H, Figuigui M, Adil Ibrahimi S, El Abkari M, Mzyiene M, Ennaciri S, et al. Acute Hepatitis Induced by Intravesical BCG Therapy: A Rare but Serious Complication. Case Reports Hepatol. 2021; 2021:4574879. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
132. Yamazaki-Nakashimada MA, Unzueta A, Berenise Gamez-Gonzalez L, Gonzalez-Saldana N, Sorensen RU. BCG: a vaccine with multiple faces. Hum Vaccin Immunother. 2020; 16:1841-50. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
133. Sumida Y, Kanemasa K, Tachibana S, Maekawa K, Nakano T. A case of autoimmune pancreatitis occurring during intravesical bacillus Calmette Guerin immunotherapy for ureteral cancer. Nihon Shokakibyo Gakkai Zasshi. 2003; 100:1328-32. PubMed
134. Foucard T, Hjelmstedt A. BCG-osteomyelitis and -osteoarthritis as a complication following BCG-vaccination. Acta Orthop Scand. 1971; 42:142-51. DOI | PubMed
135. Zawar V, Chuh A. A case-control study on the association of pulse oral poliomyelitis vaccination and Gianotti-Crosti syndrome. Int J Dermatol. 2017; 56:75-9. DOI | PubMed
136. Gao J, Kang G, Hu R, Zhang L, Yu J, Wang Z, et al. Adverse events following immunization with bivalent oral poliovirus vaccine in Jiangsu, China. Br J Clin Pharmacol. 2021; 87:4831-8. DOI | PubMed
137. Akbayram S, Karaman K, Ece I, Hatice Akbayram T. Acute immune thrombocytopenic purpura following oral polio vaccination. Platelets. 2015; 26:705. DOI | PubMed
138. Elkhayat HA, El-Rashidy OF, Elagouza IA, Zaitoun R, Abbas YAA. Childhood acute disseminated encephalomyelitis: an Egyptian pilot study. Acta Neurol Belg. 2020; 120:549-55. DOI | PubMed
139. Kelly H. Evidence for a causal association between oral polio vaccine and transverse myelitis: A case history and review of the Literature. J Paediatr Child Health. 2006; 42:155-9. DOI | PubMed
140. Hughes AM, Ponsonby AL, Dear K, Dwyer T, Taylor BV, van der Mei I, et al. Childhood infections, vaccinations, and tonsillectomy and risk of first clinical diagnosis of CNS demyelination in the Ausimmune Study. Mult Scler Relat Disord. 2020; 42:102062. DOI | PubMed
141. Pineton de Chambrun G, Dauchet L, Gower-Rousseau C, Cortot A, Colombel JF, Peyrin-Biroulet L. Vaccination and Risk for Developing Inflammatory Bowel Disease: A Meta-Analysis of Case-Control and Cohort Studies. Clin Gastroenterol Hepatol. 2015; 13:1405-15. DOI | PubMed
142. Platt LR, Estivariz CF, Sutter RW. Vaccine-associated paralytic poliomyelitis: a review of the epidemiology and estimation of the global burden. J Infect Dis. 2014; 210:S380-9. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
143. Dhiman R, Prakash SC, Sreenivas V, Puliyel J. Correlation between Non-Polio Acute Flaccid Paralysis Rates with Pulse Polio Frequency in India. Int J Environ Res Public Health. 2018; 15Publisher Full Text | DOI | PubMed [ PMC Free Article ]
144. Puliyel J, Naik P. Revised World Health Organization (WHO)’s causality assessment of adverse events following immunization-a critique. F1000Res. 2018; 7:243. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
145. Hooker BS, Miller NZ. Analysis of health outcomes in vaccinated and unvaccinated children: Developmental delays, asthma, ear infections and gastrointestinal disorders. SAGE Open Med. 2020; 8:2050312120925344. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
146. Hooker BS, Miller NZ. Health effects in vaccinated versus unvaccinated children, with covariates for breastfeeding status and type of birth. Journal of Translational Science. 2021; 7:1-11. DOI
147. Mawson AR, Ray BD, Bhuiyan AR, Jacob B. Pilot comparative study on the health of vaccinated and unvaccinated 6-to 12-year-old US children. J Transl Sci. 2017; 3:1-12. DOI
148. Basha S, Surendran N, Pichichero M. Immune responses in neonates. Expert Rev Clin Immunol. 2014; 10:1171-84. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
149. Marchant A, Kollmann TR. Understanding the ontogeny of the immune system to promote immune-mediated health for life. Front Immunol. 2015; 6:77. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
150. Adkins B, Leclerc C, Marshall-Clarke S. Neonatal adaptive immunity comes of age. Nat Rev Immunol. 2004; 4:553-64. DOI | PubMed
151. Willems F, Vollstedt S, Suter M. Phenotype and function of neonatal DC. Eur J Immunol. 2009; 39:26-35. DOI | PubMed
152. Leiber A, Graf B, Spring B, Rudner J, Kostlin N, Orlikowsky TW, et al. Neonatal monocytes express antiapoptotic pattern of Bcl-2 proteins and show diminished apoptosis upon infection with Escherichia coli. Pediatr Res. 2014; 76:142-9. DOI | PubMed
153. Abughali N, Berger M, Tosi MF. Deficient total cell content of CR3 (CD11b) in neonatal neutrophils. Blood. 1994; 83:1086-92. PubMed
154. Guilmot A, Hermann E, Braud VM, Carlier Y, Truyens C. Natural killer cell responses to infections in early life. J Innate Immun. 2011; 3:280-8. DOI | PubMed
155. Le Garff-Tavernier M, Beziat V, Decocq J, Siguret V, Gandjbakhch F, Pautas E, et al. Human NK cells display major phenotypic and functional changes over the life span. Aging Cell. 2010; 9:527-35. DOI | PubMed
156. Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol. 2007; 7:379-90. DOI | PubMed
157. Soulie JC, Devillier P, Santarelli J, Goudeau A, Vermeulen P, Guellier M, et al. Immunogenicity and safety in newborns of a new recombinant hepatitis B vaccine containing the S and pre-S2 antigens. Vaccine. 1991; 9:545-8. DOI | PubMed
158. Strandmark J, Darboe A, Diray-Arce J, Ben-Othman R, Vignolo SM, Rao S, et al. A single birth dose of Hepatitis B vaccine induces polyfunctional CD4(+) T helper cells. Front Immunol. 2022; 13:1043375. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
159. Martinez L, Cords O, Liu Q, Acuna-Villaorduna C, Bonnet M, Fox GJ, et al. Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis. Lancet Glob Health. 2022; 10:e1307-e16. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
160. Roy A, Eisenhut M, Harris RJ, Rodrigues LC, Sridhar S, Habermann S, et al. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ. 2014; 349:g4643. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
161. Waggie Z, Geldenhuys H, Sutter RW, Jacks M, Mulenga H, Mahomed H, et al. Randomized trial of type 1 and type 3 oral monovalent poliovirus vaccines in newborns in Africa. J Infect Dis. 2012; 205:228-36. DOI | PubMed
162. Sutter RW, John TJ, Jain H, Agarkhedkar S, Ramanan PV, Verma H, et al. Immunogenicity of bivalent types 1 and 3 oral poliovirus vaccine: a randomised, double-blind, controlled trial. Lancet. 2010; 376:1682-8. DOI | PubMed
163. el-Sayed N, el-Gamal Y, Abbassy AA, Seoud I, Salama M, Kandeel A, et al. Monovalent type 1 oral poliovirus vaccine in newborns. N Engl J Med. 2008; 359:1655-65. DOI | PubMed
164. Bhaskaram P, Nair KM, Hemalatha P, Murthy N, Nair P. Systemic and mucosal immune response to polio vaccination with additional dose in newborn period. J Trop Pediatr. 1997; 43:232-4. DOI | PubMed
165. Jain PK, Dutta AK, Nangia S, Khare S, Saili A. Seroconversion following killed polio vaccine in neonates. Indian J Pediatr. 1997; 64:511-5. DOI | PubMed
166. Khare S, Kumari S, Nagpal IS, Sharma D, Verghese T. Oral polio vaccination in infants: beneficial effect of additional dose at birth. Indian J Pediatr. 1993; 60:275-81. DOI | PubMed
167. Dong DX, Hu XM, Liu WJ, Li JS, Jin YC, Tan SG, et al. Immunization of neonates with trivalent oral poliomyelitis vaccine (Sabin). Bull World Health Organ. 1986; 64:853-60. Publisher Full Text | PubMed [ PMC Free Article ]
168. Szmuness W, Stevens CE, Harley EJ, Zang EA, Oleszko WR, William DC, et al. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engl J Med. 1980; 303:833-41. DOI | PubMed
169. Szmuness W, Stevens CE, Zang EA, Harley EJ, Kellner A. A controlled clinical trial of the efficacy of the hepatitis B vaccine (Heptavax B): a final report. Hepatology. 1981; 1:377-85. DOI | PubMed
170. Francis DP, Hadler SC, Thompson SE, Maynard JE, Ostrow DG, Altman N, et al. The prevention of hepatitis B with vaccine. Report of the centers for disease control multi-center efficacy trial among homosexual men. Ann Intern Med. 1982; 97:362-6. DOI | PubMed
171. Immunisation against hepatitis B. Lancet. 1988; 1:875-6. PubMed
172. Venters C, Graham W, Cassidy W. Recombivax-HB: perspectives past, present and future. Expert Rev Vaccines. 2004; 3:119-29. DOI | PubMed
173. Assad S, Francis A. Over a decade of experience with a yeast recombinant hepatitis B vaccine. Vaccine. 1999; 18:57-67. DOI | PubMed
174. Stevens CE, Toy PT, Taylor PE, Lee T, Yip HY. Prospects for control of hepatitis B virus infection: implications of childhood vaccination and long-term protection. Pediatrics. 1992; 90:170-3. PubMed
175. Gelinas L, Abu-Raya B, Ruck C, Cai B, Kollmann TR. Hepatitis B virus vaccine–induced cell-mediated immunity correlates with humoral immune response following primary vaccination during infancy. ImmunoHorizons. 2017; 1:42-52. DOI
176. Larsen CE, Xu J, Lee S, Dubey DP, Uko G, Yunis EJ, et al. Complex cytokine responses to hepatitis B surface antigen and tetanus toxoid in responders, nonresponders and subjects naive to hepatitis B surface antigen. Vaccine. 2000; 18:3021-30. DOI | PubMed
177. Jarrosson L, Kolopp-Sarda MN, Aguilar P, Bene MC, Lepori ML, Vignaud MC, et al. Most humoral non-responders to hepatitis B vaccines develop HBV-specific cellular immune responses. Vaccine. 2004; 22:3789-96. DOI | PubMed
178. del Canho R, Grosheide PM, Voogd M, Huisman WM, Heijtink RA, Schalm SW. Immunogenicity of 20 micrograms of recombinant DNA hepatitis B vaccine in healthy neonates: a comparison of three different vaccination schemes. J Med Virol. 1993; 41:30-4. DOI | PubMed
179. Mazel JA, Schalm SW, de Gast BC, Nuijten AS, Heijtink RA, Botman MJ, et al. Passive-active immunisation of neonates of HBsAg positive carrier mothers: preliminary observations. Br Med J (Clin Res Ed). 1984; 288:513-5. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
180. Schalm SW, Mazel JA, de Gast GC, Heijtink RA, Botman MJ, Banffer JR, et al. Prevention of hepatitis B infection in newborns through mass screening and delayed vaccination of all infants of mothers with hepatitis B surface antigen. Pediatrics. 1989; 83:1041-8. PubMed
181. Marchant A, Newport M. Prevention of infectious diseases by neonatal and early infantile immunization: prospects for the new millennium. Curr Opin Infect Dis. 2000; 13:241-6. DOI | PubMed
182. Siegrist CA. Neonatal and early life vaccinology. Vaccine. 2001; 19:3331-46. DOI | PubMed
183. Marchant A, Pihlgren M, Goetghebuer T, Weiss HA, Ota MO, Schlegel-Hauter SE, et al. Predominant influence of environmental determinants on the persistence and avidity maturation of antibody responses to vaccines in infants. J Infect Dis. 2006; 193:1598-605. DOI | PubMed
184. Ansari A, Vincent JP, Moorhouse L, Shimakawa Y, Nayagam S. Risk of early horizontal transmission of hepatitis B virus in children of uninfected mothers in sub-Saharan Africa: a systematic review and meta-analysis. Lancet Glob Health. 2023; 11:e715-e28. DOI | PubMed
185. Tena-Coki NG, Scriba TJ, Peteni N, Eley B, Wilkinson RJ, Andersen P, et al. CD4 and CD8 T-cell responses to mycobacterial antigens in African children. Am J Respir Crit Care Med. 2010; 182:120-9. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
186. Kagina BM, Abel B, Bowmaker M, Scriba TJ, Gelderbloem S, Smit E, et al. Delaying BCG vaccination from birth to 10 weeks of age may result in an enhanced memory CD4 T cell response. Vaccine. 2009; 27:5488-95. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
187. Libraty DH, Zhang L, Woda M, Acosta LP, Obcena A, Brion JD, et al. Neonatal BCG vaccination is associated with enhanced T-helper 1 immune responses to heterologous infant vaccines. Trials Vaccinol. 2014; 3:1-5. Publisher Full Text | DOI | PubMed [ PMC Free Article ]
188. Hatherill M, Cobelens F. Infant BCG vaccination is beneficial, but not sufficient. Lancet Glob Health. 2022; 10:e1220-e1. DOI | PubMed
189. Hussey GD, Watkins ML, Goddard EA, Gottschalk S, Hughes EJ, Iloni K, et al. Neonatal mycobacterial specific cytotoxic T-lymphocyte and cytokine profiles in response to distinct BCG vaccination strategies. Immunology. 2002; 105:314-24. Publisher Full Text | DOI | PubMed [ PMC Free Article ]