From genes to environment: A life-course approach to prevent pediatric autoimmune diseases

Table 5 Licensed and candidate vaccines: Direction of effect on autoimmune disease risk, rare signals, and evidence type

Vaccine	Target infection(s)	Direction of effect on autoimmune risk (population level)	Notable autoimmune-type adverse events (rare)	Evidence type/key findings
Rotavirus	Rotavirus gastroenteritis	Possible decrease in T1DM incidence in some large cohorts, while others report a neutral effect	No consistent autoimmune signal has been demonstrated	Large administrative and time-series cohort studies have yielded mixed results; some show a modest (approximately 33%) reduction in T1DM risk following a complete vaccine series in specific cohorts
MMR	Measles, mumps, rubella	Neutral. No proven increase in the risk of chronic autoimmune diseases	Immune thrombocytopenic purpura has a very rare association (approximately 1 per 40000 doses), which is typically self-limited. The risk of neurological complications from measles infection is far higher	Decades of evidence from large case-control studies, active surveillance systems, and analyses by advisory committees (e.g., ACIP)
Hepatitis B	Hepatitis B virus	Neutral. No increase in the incidence of multiple sclerosis or other autoimmune diseases	No consistently demonstrated autoimmune-type adverse events	Large nested case-control studies and cohort studies, including a landmark study published in the New England Journal of Medicine, have shown no association with MS
Meningococcal conjugate	Neisseria meningitidis	Neutral. No increased risk of autoimmune diseases	No causal link to GBS has been found in large cohort studies, despite initial post-licensure signals	Extensive pharmacoepidemiology and record-validated cohort studies have provided a reassuring safety profile
Pneumococcal (PCV13, PPSV23)	Streptococcus pneumoniae	Neutral. No increased risk of autoimmune diseases	None consistently demonstrated	Large-scale safety studies and post-licensure surveillance have found no association with autoimmune conditions
Varicella (chickenpox)	Varicella-zoster virus	Neutral. No increased risk of autoimmune diseases	Very rare cases of vasculitis or arthritis have been reported, but a causal link has not been established. The risk of these conditions from natural infection is higher	Extensive safety data from clinical trials and post-licensure surveillance systems
HPV	Human papillomavirus	Neutral. No increase in autoimmune diseases, including MS, IBD, and SLE, has been found	Very rare cases of GBS have been observed in some post-licensure analyses, but overall rates are not elevated compared to the background population	Extensive multinational cohort studies, case-control studies, and national surveillance registries have consistently shown a reassuring safety profile with no causal link
Influenza (seasonal)	Influenza A and B viruses	Neutral. Prevention of influenza infection significantly reduces the risk of post-infectious autoimmune complications	GBS is a very rare adverse event, with an estimated risk of approximately 1-2 cases per million doses, which is lower than the risk of GBS from influenza infection itself	Evidence from meta-analyses of randomized trials, large-scale surveillance data (e.g., from the CDC), and national cohorts
COVID-19 mRNA	SARS-CoV-2	Neutral. No signal for chronic autoimmune disease; preventing infection reduces post-infectious autoimmunity	Myocarditis/pericarditis is a rare, typically mild adverse event, with the highest risk observed in adolescent and young adult males, particularly after the second dose. The risk of these conditions from COVID-19 infection itself is significantly higher	National surveillance (CDC’s V-safe and VAERS), international cohorts, and analyses published in reputable journals like JAMA have characterized these rare events
(Future) EBV vaccine	EBV	Potential decrease (hypothesized). Strong potential to reduce the incidence of MS and other EBV-linked autoimmune diseases	N/A; no licensed product available yet	Evidence is based on strong epidemiological and mechanistic links between EBV infection and autoimmune diseases; multiple vaccine platforms are currently in development
(Future) T1DM vaccine	N/A (Immunomodulatory)	Potential decrease (hypothesized). Aims to induce immune tolerance to prevent the autoimmune attack on the pancreas	N/A; no licensed product available yet	Multiple clinical trials are underway for both oral and parenteral immunomodulatory vaccines; early results for oral insulin and other agents have shown promise in delaying disease progression

The table summarizes currently licensed vaccines and selected candidate vaccines, outlining their population-level impact on autoimmune disease risk, the risk of rare autoimmune-type adverse events, and the strength and type of supporting evidence. Across extensive epidemiologic, clinical trial, and post-licensure surveillance data, the overwhelming evidence demonstrates that routine childhood vaccines have a neutral or protective effect on autoimmune risk. In contrast, natural infections - many of which these vaccines prevent - carry substantially higher autoimmune complications, including Guillain-Barre syndrome, myocarditis, thrombocytopenia, vasculitis, and post-infectious autoimmunity. Rare autoimmune-type events following vaccination are typically mild, self-limited, and far less frequent than those triggered by infection. Candidate vaccines targeting Epstein-Barr virus and type 1 diabetes mellitus have the potential to reduce autoimmune disease incidence by interrupting key causal pathways. Evidence is synthesized from multinational cohort studies, ecological analyses, randomized trials, national vaccine safety systems, and expert advisory committee reviews.

T1DM: Type 1 diabetes mellitus; MMR: Measles-mumps-rubella; ACIP: Advisory committee on immunization practices; MS: Multiple sclerosis; GBS: Guillain-Barre syndrome; PCV13: 13-valent pneumococcal conjugate vaccine; PPSV23: 23-Valent pneumococcal polysaccharide vaccine; IBD: Inflammatory bowel disease; SLE: Systemic lupus erythematosus; CDC: Centers for disease control and prevention; VAERS: Vaccine adverse event reporting system; HPV: Human papillomavirus; COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; EBV: Epstein-Barr virus; N/A: Not applicable.