Our meta-analysis indicated that receiving any type of vaccine in the first year of life may be protective against childhood leukemia. When specific types of vaccine were separately analyzed, however, only the analysis of BCG revealed at least some evidence of a reduced risk. Because BCG is given early, it was not possible in this study to separate any potential protective effect of early vaccination from BCG vaccination itself. However, a protective association with BCG cannot be ruled out, given that no other individual vaccine was associated with a reduced risk of leukemia in this meta-analysis.

The protective association we observed between early vaccination (and/or BCG) and risk of childhood leukemia overall may involve similar biological pathways to those underlying the apparent reduction in leukemia risk associated with day-care attendance12. Similar to the potential for common infections during day-care attendance, exposure of children to microbial pathogen in vaccines early in life may mimic the role of infections in triggering the response of the naïve immune system. Schmiegelow et at proposed the hypothalamus-pituitary-adrenal axis hypothesis in which infections at early stage of life may alter plasma cortisol levels46. This can result in elimination of leukemic cells and reduce the risk of ALL46,47. Moreover, there is evidence that vaccines, both viral and bacterial, also have the ability to raise the plasma cortisol48,49,50,51. Thus, the adrenal hypothesis may explain in immunological terms the association between early vaccination and risk of leukemia. Such a mechanism would also be consistent with Greaves’ delayed-infection hypothesis52. However, this does not explain why BCG – but none of the other specific (mostly viral) vaccines – appeared to be associated (albeit weakly) with a reduction in leukemia risk.

Heterologous (or “off-target”) effects of BCG vaccination in children have been consistently observed53,54; outcomes for which there is some evidence of a protective include all-cause infant mortality32,53 and childhood cancer32. The biological pathways involved are unclear, but are thought to involve lymphocyte activation and/or innate immune memory that could promote protection beyond the intended target pathogen. Potential mechanisms are discussed in detail by Goodridge et al.53. In addition, many animal studies have reported beneficial effects of BCG in enhancing the immune response to unrelated pathogens55 and tumours. Theorically and practically, BCG vaccine has been utilized as an immunotherapy for a certain cancer56,57,58. The mechanism in which BCG vaccine ameliorates effectively cancer was not well-explored. Several studies investigated the alteration of different types of cytokines by BCG vaccine59,60,61,62, such as Th1’s cytokines (IFN-γ, TNF-α, IL-12) and Th2’s cytokines (IL-10, IL-4). These substances play roles in regulation of natural killer cells, macrophages or cytotoxic T lymphocytes cells61, which have antitumor effects. In addition, the antitumor activity of BCG vaccine through activating human dendritic cells, an antigen-present cells, has been studied63,64,65,66,67. This process was mediated by modulation of several cytokines such as IL2, IL10 and IFN gamma67. Taking specific antileukemia effect into consideration, studies were performed and their findings were promising. Jang et al.65 investigated the activity of dendritic cells of pediatric leukemia patients exposed by BCG, the result revealed an enhanced proliferation and maturation status. Recently, a BCG-derived heat shock protein, named HSP70, was investigated. Findings from animal and in vitro studies demonstrated an elevated immunogenicity effects against leukemia cells68,69.

Strengths

To the best of our knowledge, this is the first comprehensive systematic review and meta-analysis investigating the association between vaccination and childhood leukemia. All steps of this systematic review and meta-analysis were conducted in strict accordance with the Cochrane handbook of systematic reviews70 and reported according to the recommendations of the PRISMA statement24. Moreover, stratification according to time of vaccination (for BCG vaccination) and type of vaccination (with early vaccination, Measles vaccine and Rubella vaccines) was further examined.

Limitations

Although our systematic literature search was conducted on nine electronic libraries, the number of studies included in the final analysis was limited and it was not possible to conduct our meta-analysis by leukemia subtype. Furthermore, most of the included studies were observational. We were unable to evaluate the effects of several confounders such as prenatal and postnatal care, the nutrient supplies, and the microorganism exposure on the pooled results due to the lack of such information in the included studies. Further, some of the observational studies provided raw data only, from which we estimated crude study-specific ORs. Observational studies are subject to biases such as selection and recall bias. Except for Salonen 197622 which was at moderate risk of bias, the six remaining studies were at high risk of bias. However, these biases (if present) would most likely have similarly affected the results for all types of vaccinations, not just early vaccination and/or BCG itself. We acknowledge that the association seen with BCG vaccination was not statistically significant; however, this was likely due to a lack of statistical power and a relevant protective association remains a possibility. While seven studies reported early vaccination, four studies were before 1990 and only two were in 21st century; this led to some heterogeneity. Most studies reporting BCG vaccines were conducted before the 1980s. The design of those studies was not appropriate for evaluating the effect of BCG vaccination in risk of leukemia, because clinical trials were predominantly designed for protecting against tuberculosis. Additionally, three of them, which contained a large number of participants, reported leukemia deaths rather than leukemia cases14,26,27.

The change in vaccine schedule is worthy of note. According to Center for Disease Control and Prevention (CDC), many vaccines have currently been used for children at birth, such as HBV, or within the first year, such as DTA, Rotavirus, or Haemophilus influenza type b. These changes may alter the potential effect of early vaccine on childhood leukemia risk. Further studies should investigate the impact of these shifts in vaccine policy.