• In this meta-analysis of randomized controlled trials, we found that early-life bacillus Calmette-Guérin–Denmark vaccination leads to an 11% reduction in the risk of eczema in early childhood with a number needed to treat (NNT) of 33.• The intervention is more beneficial in predisposed children, including boys (NNT 20) or those born to 2 atopic parents (NNT 14).• Although the absolute reductions are modest, given the high rate of predisposed children and the well-established safety profile of this vaccine, neonatal bacillus Calmette-Guérin vaccination should be considered for predisposed children.
Increasing evidence suggests that early-life bacillus Calmette-Guérin (BCG) vaccine could prevent atopic eczema through its beneficial off-target effects. In this meta-analysis, 3 randomized control trials with similar methods were included and enabled robust estimations with low heterogeneity, involving a total of 5655 children randomized to early-life BCG Denmark (n = 2832) or no BCG (n = 2823). Meta-analyses suggest a beneficial effect of BCG to prevent eczema (risk ratio [RR], 0.89; 95% confidence interval [CI], 0.82–0.98). In subgroup analyses, BCG was more beneficial in boys (RR, 0.84; 95% CI, 0.74–0.95) and in children born to 2 atopic parents (RR, 0.81; 95% CI, 0.68–0.97). The NNT to prevent one case of eczema among children of 1 or 2 atopic parent was 20 (95% CI, 12–50). Bacillus Calmette-Guérin Denmark leads to an 11% reduction in the risk of eczema in early life. A greater effect was observed with increasing predisposition. Given its well-established safety profile, neonatal BCG vaccination should be considered for children of atopic parents.
Get full access to this article
View all access options for this article.
References
1.
AsherMI, MontefortS, BjorkstenB, et al.Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet, 2006; 368(9537):733–743.
2.
BonamonteD, FiloniA, VestitaM, et al.The role of the environmental risk factors in the pathogenesis and clinical outcome of atopic dermatitis. Biomed Res Int, 2019; 2019:2450605.
3.
FlohrC, YeoL. Atopic dermatitis and the hygiene hypothesis revisited. Curr Probl Dermatol, 2011; 41:1–34.
4.
BloomfieldSF, RookGA, ScottEA, et al.Time to abandon the hygiene hypothesis: new perspectives on allergic disease, the human microbiome, infectious disease prevention and the role of targeted hygiene. Perspect Public Health, 2016; 136(4):213–224.
5.
MarchantA, GoetghebuerT, OtaMO, et al.Newborns develop a TH1-type immune response to Mycobacterium bovis Bacillus Calmette-Guerin vaccination. J Immunol, 1999; 163(4):2249–2255.
6.
GarlyML, BaléC, MartinsCL, et al.BCG vaccination among West African infants is associated with less anergy to tuberculin and diphtheria-tetanus antigens. Vaccine, 2001; 20(3–4):468–474.
7.
HerzU, GerholdK, GruberC, et al.BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model. J Allergy Clin Immunol, 1998; 102(5):867–874.
8.
ArnoldussenDL, LinehanM, SheikhA. BCG vaccination and allergy: a systematic review and meta-analysis. J Allergy Clin Immunol, 2011; 127(1):246–253, 253 e1–21.
9.
El-ZeinM, ParentME, BenedettiA, et al.Does BCG vaccination protect against the development of childhood asthma? A systematic review and meta-analysis of epidemiological studies. Int J Epidemiol, 2010; 39(2):469–486.
10.
LinehanMF, NurmatovU, FrankTL, et al.Does BCG vaccination protect against childhood asthma? Final results from the Manchester Community Asthma Study retrospective cohort study and updated systematic review and meta-analysis. J Allergy Clin Immunol, 2014; 133(3):688–95 e14.
11.
AabyP, ShaheenSO, HeyesCB, et al.Early BCG vaccination and reduction in atopy in Guinea-Bissau. Clin Exp Allergy, 2000; 30(5):644–650.
12.
FlanaganKL, van CrevelR, CurtisN, et al.Heterologous (“nonspecific”) and sex-differential effects of vaccines: epidemiology, clinical trials, and emerging immunologic mechanisms. Clin Infect Dis, 2013; 57(2):283–289.
13.
NovakovicB, MessinaN, CurtisN. Chapter 6—The heterologous effects of bacillusCalmette-Guérin (BCG) vaccine and trained innate immunity. In: Faustman DL, ed. The Value of BCG and TNF in Autoimmunity. 2nd ed. Cambridge, Massachusetts, MA: Academic Press;, 2018:71–90.
14.
KleinnijenhuisJ, QuintinJ, PreijersF, et al.Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A, 2012; 109(43):17537–17542.
15.
KleinnijenhuisJ, QuintinJ, PreijersF, et al.BCG-induced trained immunity in NK cells: role for non-specific protection to infection. Clin Immunol, 2014; 155(2):213–219.
16.
FreyneB, DonathS, GermanoS, et al.Neonatal BCG vaccination influences cytokine responses to toll-like receptor ligands and heterologous antigens. J Infect Dis, 2018; 217(11):1798–1808.
17.
FreyneB, MessinaNL, DonathS, et al.Neonatal BCG vaccination reduces interferon-γ responsiveness to heterologous pathogens in infants from a randomized controlled trial. J Infect Dis, 2020; 221(12):1999–2009.
18.
GarlyML, MartinsCL, BaleC, et al.BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG?Vaccine, 2003; 21(21–22):2782–2790.
19.
PollardAJ, FinnA, CurtisN. Non-specific effects of vaccines: plausible and potentially important, but implications uncertain. Arch Dis Child, 2017; 102(11):1077–1081.
20.
ArtsRJW, MoorlagSJCFM, NovakovicB, et al.BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe, 2018; 23(1):89–100 e5.
21.
Giamarellos-BourboulisEJ, TsilikaM, MoorlagS, et al.Activate: randomized clinical trial of BCG vaccination against infection in the elderly. Cell, 2020; 183(2):315–323 e9.
22.
MoorlagS, ArtsRJW, van CrevelR, et al.Non-specific effects of BCG vaccine on viral infections. Clin Microbiol Infect, 2019; 25(12):1473–1478.
23.
PittetLF, CurtisN. Does bacillus Calmette-Guerin vaccine prevent herpes simplex virus recurrences? A systematic review. Rev Med Virol, 2021; 31(1):1–9.
24.
AabyP, RothA, RavnH, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period?J Infect Dis 2011;204(2):245–252.
25.
Kowalewicz-KulbatM, LochtC. BCG and protection against inflammatory and auto-immune diseases. Expert Rev Vaccines, 2017; 16(7):1–10.
26.
AngelidouA, PittetLF, FaustmanD, et al. BCG vaccine's off-target effects on allergic, inflammatory, and autoimmune diseases: worth another shot?J Allergy Clin Immunol 2022;149(1):51–54.
27.
FreyneB, CurtisN. Does neonatal BCG vaccination prevent allergic disease in later life?Arch Dis Child 2014;99(2):182–184.
28.
NavaratnaS, EstcourtMJ, BurgessJ, et al.Childhood vaccination and allergy: a systematic review and meta-analysis. Allergy, 2021; 76(7):2135–2152.
29.
PittetLF, CurtisN. Bacillus Calmette-Guérin vaccination to prevent childhood asthma: a revised meta-analysis. Allergy, 2022; 77(7):2262–2263.
30.
PageMJ, McKenzieJE, BossuytPM, et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, 2021; 372:n71.
31.
SterneJAC, SavovićJ, PageMJ, et al.RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ, 2019; 366:l4898.
SteenhuisTJ, van AalderenWMC, BloksmaN, et al.Bacille-Calmette-Guerin vaccination and the development of allergic disease in children: a randomized, prospective, single-blind study. Clin Exp Allergy, 2008; 38(1):79–85.
34.
ThostesenLM, KjaergaardJ, PihlGT, et al.Neonatal BCG vaccination and atopic dermatitis before 13 months of age: a randomized clinical trial. Allergy, 2018; 73(2):498–504.
35.
PittetLF, MessinaNL, GardinerK, et al.Prevention of infant eczema by neonatal bacillus Calmette-Guerin vaccination: the MIS BAIR randomized controlled trial. Allergy, 2022; 77(3):956–965.
36.
PittetLF, MessinaNL, GardinerK, et al.Discordance between diagnosis tools for assessing eczema in infants: a challenge for intervention trials. Dermatitis, 2022; 33(3):207–214.
37.
Severity scoring of atopic dermatitis: the SCORAD index. Consensus report of the European Task Force on Atopic Dermatitis. Dermatology, 1993; 186(1):23–31.
38.
ThøstesenLM, NissenTN, KjærgaardJ, et al.Bacillus Calmette-Guérin immunisation at birth and morbidity among Danish children: a prospective, randomised, clinical trial. Contemp Clin Trials, 2015; 42:213–218.
39.
MessinaNL, GardinerK, DonathS, et al.Study protocol for the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR), a randomised controlled trial to determine the non-specific effects of neonatal BCG vaccination in a low-mortality setting. BMJ Open, 2019; 9(12):e032844.
40.
WilliamsHC, BurneyPG, HayRJ, et al. The U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol, 1994; 131(3):383–396.
41.
WilliamsHC, BurneyPG, PembrokeAC, et al. The U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis. III. Independent hospital validation. Br J Dermatol, 1994; 131(3):406–416.
42.
Biering-SørensenS, JensenKJ, MonterioI, et al.Rapid protective effects of early BCG on neonatal mortality among low birth weight boys: observations from randomized trials. J Infect Dis, 2018; 217(5):759–766.
43.
KleinSL, JedlickaA, PekoszA. The Xs and Y of immune responses to viral vaccines. Lancet Infect Dis, 2010; 10(5):338–349.
StraubRH.The complex role of estrogens in inflammation. Endocr Rev, 2007; 28(5):521–574.
46.
MartinPE, KoplinJJ, EckertJK, et al.The prevalence and socio-demographic risk factors of clinical eczema in infancy: a population-based observational study. Clin Exp Allergy, 2013; 43(6):642–651.
47.
Saadatian-ElahiM, AabyP, ShannF, et al.Heterologous vaccine effects. Vaccine, 2016; 34(34):3923–3930.
48.
SongN, ShamssainM, ZhangJ, et al.Prevalence, severity and risk factors of asthma, rhinitis and eczema in a large group of Chinese schoolchildren. J Asthma, 2014; 51(3):232–242.
49.
ZimmermannP, CurtisN. Factors that influence the immune response to vaccination. Clin Microbiol Rev, 2019; 32(2):e00084–e00018.
50.
KleinSL, FlanaganKL. Sex differences in immune responses. Nat Rev Immunol, 2016; 16(10):626–638.
51.
FlanaganKL, PlebanskiM. Sex-differential heterologous (non-specific) effects of vaccines: an emerging public health issue that needs to be understood and exploited. Expert Rev Vaccines, 2017; 16(1):5–13.
52.
AabyP, BennCS, FlanaganKL, et al.The non-specific and sex-differential effects of vaccines. Nat Rev Immunol, 2020; 20(8):464–470.
53.
BennCS, FiskerAB, RieckmannA, et al. Vaccinology: time to change the paradigm?Lancet Infect Dis 2020;20(10):e274–e283.
54.
LundN, AndersenA, HansenASK, et al.The effect of oral polio vaccine at birth on infant mortality: a randomized trial. Clin Infect Dis, 2015; 61(10):1504–1511.
55.
HigginsJPT, Soares-WeiserK, Lopez-LopezJA, et al.Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ, 2016; 355:i5170.
56.
MartinsCL, BennCS, AndersenA, et al.A randomized trial of a standard dose of Edmonston-Zagreb measles vaccine given at 4.5 months of age: effect on total hospital admissions. J Infect Dis, 2014; 209(11):1731–1738.
57.
AabyP, MartinsCL, GarlyM-L, et al.Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ, 2010; 341:c6495.
58.
AabyP, RavnH, FiskerAB, et al.Is diphtheria-tetanus-pertussis (DTP) associated with increased female mortality? A meta-analysis testing the hypotheses of sex-differential non-specific effects of DTP vaccine. Trans R Soc Trop Med Hyg, 2016; 110(10):570–581.
59.
AabyP, MogensenSW, RodriguesA, et al. Evidence of increase in mortality after the introduction of diphtheria-tetanus-pertussis vaccine to children aged 6–35 months in Guinea-Bissau: a time for reflection?Front Public Health 2018;6:79.
60.
MogensenSW, AndersenA, RodriguesA, et al.The introduction of diphtheria-tetanus-pertussis and oral polio vaccine among young infants in an Urban African Community: a natural experiment. EBioMedicine, 2017; 17:192–198.
61.
HanifiSMA, FiskerAB, WelagaP, et al.Diphtheria-tetanus-pertussis (DTP) vaccine is associated with increased female-male mortality. Studies of DTP administered before and after measles vaccine. J Infect Dis, 2021; 223(11):1984–1991.
62.
AabyP, NielsenJ, BennCS, et al.Sex-differential effects on mortality of BCG and diphtheria-tetanus-pertussis vaccines in a rural area with high vaccination coverage: observational study from Senegal. Trans R Soc Trop Med Hyg, 2016; 110(9):527–533.
63.
AabyP, JensenH, SambB, et al.Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: reanalysis of West African studies. Lancet, 2003; 361(9376):2183–2188.
64.
RTS,S Clinical TrialsPartnership.Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet, 2015; 386(9988):31–45.
65.
AabyP, RodriguesA, KofoedPE, et al.RTS,S/AS01 malaria vaccine and child mortality. Lancet, 2015; 386(10005):1735–1736.
66.
KleinSL, ShannF, MossWJ, et al.RTS,S malaria vaccine and increased mortality in girls. MBio, 2016; 7(2):e00514–e00516.
67.
AabyP, FiskerAB, BjörkmanA, et al. WHO's rollout of malaria vaccine in Africa: can safety questions be answered after only 24 months?BMJ 2020;368:l6920.
68.
DoshiP.WHO's malaria vaccine study represents a “serious breach of international ethical standards”. BMJ, 2020; 368:m734.
69.
PrenticeS, DockrellHM. BCG specific and nonspecific effects: different questions, similar challenges. J Infect Dis, 2021; 224(7):1105–1108.
70.
BerendsenMLT, OlandCB, BlesP, et al.Maternal priming: bacillus Calmette-Guerin (BCG) vaccine scarring in mothers enhances the survival of their child with a BCG vaccine scar. J Pediatric Infect Dis Soc, 2020; 9(2):166–172.
71.
Schaltz-BuchholzerF, Bjerregard OlandC, BerendsenM, et al. Does maternal BCG primes for enhanced beneficial effects of neonatal BCG in the offspring?J Inf Secur 2021.
72.
StensballeLG, RavnH, BirkNM, et al.BCG vaccination at birth and rate of hospitalization for infection until 15 months of age in Danish children: a randomized clinical multicenter trial. J Pediatric Infect Dis Soc, 2019; 8(3):213–220.
73.
MawaPA, WebbEL, Filali-MouhimA, et al.Maternal BCG scar is associated with increased infant proinflammatory immune responses. Vaccine, 2017; 35(2):273–282.
74.
BennCS, RothA, GarlyML, et al.BCG scarring and improved child survival: a combined analysis of studies of BCG scarring. J Intern Med, 2020; 288(6):614–624.
75.
Schaltz-BuchholzerF, BerendsenM, RothA, et al.BCG skin reactions by 2 months of age are associated with better survival in infancy: a prospective observational study from Guinea-Bissau. BMJ Glob Health, 2020; 5(9):e002993.
76.
BerendsenM, Schaltz-BuchholzerF, BlesP, et al.Parental bacillus Calmette-Guerin vaccine scars decrease infant mortality in the first six weeks of life: a retrospective cohort study. EClinicalMedicine, 2021; 39:101049.
77.
TurnbullFM, McIntyrePB, AchatHM, et al.National study of adverse reactions after vaccination with Bacille Calmette-Guerin. Clin Infect Dis, 2002; 34(4):447–453.
FekrvandS, YazdaniR, OlbrichP, et al.Primary immunodeficiency diseases and bacillus Calmette-Guérin (BCG)-vaccine–derived complications: a systematic review. J Allergy Clin Immunol Pract, 2020; 8(4):1371–1386.
80.
LotteA, Wasz-HockertO, PoissonN, et al.Second IUATLD study on complications induced by intradermal BCG-vaccination. Bull Int Union Tuberc Lung Dis, 1988; 63(2):47–59.
81.
LotteA, Wasz-HockertO, PoissonN, et al.BCG complications. Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv Tuberc Res, 1984; 21:107–193.
82.
SimpsonEL, KeckLE, ChalmersJR, et al.How should an incident case of atopic dermatitis be defined? A systematic review of primary prevention studies. J Allergy Clin Immunol, 2012; 130(1):137–144.
83.
Lee SCCommittee of Korean Atopic Dermatitis Association forREACH.Various diagnostic criteria for atopic dermatitis (AD): a proposal of Reliable Estimation of Atopic Dermatitis in Childhood (REACH) criteria, a novel questionnaire-based diagnostic tool for AD. J Dermatol, 2016; 43(4):376–384.
84.
JøhnkeH, VachW, NorbergLA, et al.A comparison between criteria for diagnosing atopic eczema in infants. Br J Dermatol, 2005; 153(2):352–358.
85.
ShannF. A live-vaccine-last schedule: saving an extra million lives a year?Clin Infect Dis 2021;72(8):1437–1439.
86.
KuhtreiberWM, FaustmanDL. BCG therapy for type 1 diabetes: restoration of balanced immunity and metabolism. Trends Endocrinol Metab, 2019; 30(2):80–92.
