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Vaccine, Epigenetics, Autoimmune diseases, Nervous system diseases, Birth dose vaccine, What&,rsquo 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-Gu&,eacute rin (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&,rsquo 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 &,ldquo As Low and Late As Reasonably Achievable&,rdquo (ALLARA) based strategy to optimize safety, efficacy, and long-term outcomes of early-life immunization. IntroductionAt 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&,mdash that early immune events can have permanent developmental consequences&,mdash 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-Gu&,eacute rin (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&,mdash including trauma, stress, infections, and environmental toxins&,mdash 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&,mdash administered at birth in many countries&,mdash induces the production of IL-6, interferon gamma (IFN-&,gamma ), and tumor necrosis factor alpha (TNF-&,alpha ), a process known as trained immunity that involves epigenetic reprogramming of innate immunity and monocytes&,rsquo 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&,mdash as well as HBV vaccine adjuvants&,mdash 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&,mdash typically less than 2 months&,mdash 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-Barr&,eacute Syndrome (GBS), glomerulonephritis, uveitis, polymyositis, dermatomyositis, Takayasu&,rsquo s arteritis, Hashimoto&,rsquo s thyroiditis, Graves&,rsquo disease, childhood bullous pemphigoid, chronic fatigue syndrome, cutaneous pseudo lymphoma, vitiligo, lichen planus. A comprehensive list is presented in table 1,.Author, year, referenceEventsType of studyGeier et al., 2005 57, Multiple sclerosis, optic neuritis, vasculitis, arthritis, alopecia, lupus erythematosus, rheumatoid arthritisCase controlGeier M et al., 2003 60, Erythema nodusum, lichen planus, polyarteritis nodosa, Reiter syndrome, thrombocytopenic purpura, Evans syndrome, acute posterior multifocal placoid pigment epitheliopathy, optic neuritis, transverse myelitis, central nervous system demyelination, cerebellar ataxia, multiple sclerosis, chronic fatigue syndromeReviewMaubec et al., 2005 61, Cutaneous pseudolymphoma, vitiligo, chronic fatigue syndromeCase seriesJ&,uacute nior et al., 2020 62, Graves&,rsquo Disease, rheumatoid arthritis (RA), psoriasis, lupus, Hashimoto&,rsquo s thyroiditis (HT), vitiligoCase controlOscar-Danilo et al., 2009 63, Chronic fatigue syndromeReviewMikaeloff et al., 2009 64, Multiple sclerosisCase controlHerroelen et al., 1991 65, Multiple sclerosisCase reportsTourbah et al., 1999 66, Central nervous system demyelinationCase seriesAgmon-Levin et al., 2014 67, Chronic fatigue syndrome, fibromyalgiaCase controlNancy et al., 2008 68, Chronic fatigue syndromeCase reportsRichardson et al., 2018 69, Alopecia areataCase reportsChoffray et al., 2007 70, Lupus panniculitisCase reportsLuhadia et al., 2022 71, Multiple sclerosisCase reportsCase Series et al., 2002 72, Lichen planusCase seriesde la Fuente et al., 2013 73, Childhood bullous pemphigoidCase seriesErbagci et al., 2002 74, Childhood bullous pemphigoidCase reportsBerkun et al., 2005 75, PemphigusCase reportsVital et al., 2002 76, Inflammatory neuropathyCase reportsDe Carvalho et al., 2008 77, Systemic polyarteritis nodosaReviewMaillefert et al., 1997 78, PolyarthralgiaCase reportsZaas et al, 2001 79, Takayasu&,rsquo s arteritisCase reportsAgmon-Levin et al., 2009 80, Systemic lupus erythematosusCase seriesBogdanos et al., 2009 58, Multiple sclerosisCase controlAltman et al., 2008 81, DermatomyositisCase reportsGeier et al., 2004 82, Arthritis, rheumatoid arthritis, myelitis, optic neuritis, multiple sclerosis, Guillain-Barr&,eacute syndrome, glomerulonephritis, thrombocytopenia, systemic lupus erythematosusCase seriesGeier et al., 2002 83, Arthralgia, arthrosis, arthritis, thrombocytopenia, hepatitis, erythema, Guillain-Barr&,eacute Syndrome, myelitis, vasculitisVAERSPennesi et al., 2002 84, GlomerulonephritisCase reportsPoierriez J et al., 2004 85, Transverse myelitis, neurolupusCase reportsSchattner et al., 2005 86, Rheumatoid arthritis, reactive arthritis, vasculitis, encephalitis, neuropathy, thrombocytopeniaReviewCohen et al., 1996 54, Erythema nodosum, immune thrombocytopenia, myasthenia gravis, uveitis, Reiter&,rsquo s syndrome, arthritis, systemic lupus erythematosus, central nervous system demyelination, anti-DNA antibodies emergence, Evans&,rsquo syndromeReviewRamirez Rivera et al., 2003 87, PolymyositisCase reportAgmon-Levin, 2009 88, Transverse myelitis with a short interval &,lt 2 monthsMultianalysisMaillefert et al., 1999 89, Rheumatoid arthritis, systemic lupus erythematosus, polyarthralgia, myalgia, vasculitis, miscellaneous with mixed presentationsOriginal articleRonch etal., 1998 90, Immune thrombocytopenic in infants within 1 monthCase seriesNeau et al., 1998 91, Immune thrombocytopenic in childrenCase seriesBerkun et al., 2005 75, PemphigusCase reportsChave et al., 2003 92, Henoch shonlein purpuraCase reportKhamaisi et al., 2004 93, Guillain-Barr&,eacute syndromeCase reportsGirard et al., 2004 94, Multiple sclerosis, chronic fatigue syndromeReviewWise et al., 1997 95, AlopeciaCase SeriesAvci et al., 2013 96, Hemolytic uremic syndromeCase reportVAERS, vaccine adverse event reporting system |