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. 2019 Nov 14;4(6):e001862.
doi: 10.1136/bmjgh-2019-001862. eCollection 2019.

BCG vaccination is associated with reduced malaria prevalence in children under the age of 5 years in sub-Saharan Africa

Mike Lt Berendsen  1   2   3   4 , Sjors Wl van Gijzel  1 , Jeroen Smits  5 , Quirijn de Mast  1 , Peter Aaby  4 , Christine S Benn  2   3 , Mihai G Netea  1   6   7 , Andre Jam van der Ven  1
Affiliations

BCG vaccination is associated with reduced malaria prevalence in children under the age of 5 years in sub-Saharan Africa

Mike Lt Berendsen et al. BMJ Glob Health. .

Abstract

Introduction: Malaria continues to be a major cause of morbidity and mortality in sub-Saharan Africa (SSA) without effective interventions. Bacillus Calmette-Guérin (BCG) vaccine possesses protective non-specific effects, which extend beyond protection against tuberculosis. This study explores whether BCG is associated with protection against malaria in children under the age of 5 years in SSA.

Methods: We used data from the Demographic Health Survey programme, including 34 206 children from 13 SSA countries. BCG status was taken from vaccination cards when present; if not, mother's recall was used. Presence of malaria was defined as a positive rapid diagnostic test. Maternally reported presence or absence of fever in the previous 2 weeks defined symptomatic status. Multilevel logistic regression was used to account for the two-stage cluster sampling method.

Results: Of the 34 206 children, 12 325 (36.0%) children were malaria positive and 29 766 (87.0%) were BCG vaccinated. After correction for relevant child, maternal and household factors, BCG vaccination was associated with a lower malaria prevalence (adjusted OR (aOR)=0.94, 95% CI 0.90 to 0.98), especially among children of whom BCG information was retrieved from a vaccination card (aORcard=0.88, 95% CI 0.82 to 0.94). Restricting the analysis to children from regions with suboptimal BCG coverage increased the association (aORcard=0.81, 95% CI 0.73 to 0.89). We observed an increasingly beneficial association with each month of age of the child (aORcard=0.996, 95% CI 0.993 to 0.999). BCG associations were similar for asymptomatic (aORcard=0.86, 95% CI 0.81 to 0.92) and symptomatic (aORcard=0.89, 95% CI 0.78 to 1.01) malaria.

Conclusions: BCG vaccination is associated with protection against malaria. This protection is highest in regions with suboptimal BCG coverage. These results indicate a possible role for timely BCG vaccination in the protection of malaria and its elimination by reducing the transmission reservoir. If confirmed in further research, our findings have substantial implications for global efforts to reduce malaria burden.

Keywords: DHS; bacillus Calmette-Guérin; heterologous effects; malaria.

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Conflict of interest statement

Competing interests: All authors have completed the Unified Competing Interest form (www.icmje.org/coi_disclosure.pdf) and declare no support from companies for the submitted work; no financial relationships with companies that might have an interest in the submitted work in the previous 3 years; their spouses, partners or children have no financial relationships that may be relevant to the submitted work; no non-financial interests that may be relevant to the submitted work.

Figures

Figure 1
Figure 1
BCG coverage and malaria prevalence distribution between and within 13 sub-Saharan African countries. (A) Distribution of both BCG vaccination coverage and malaria prevalence per country are depicted. (B) Overlay chart of BCG coverage (bars) and malaria prevalence (line) per included region of Angola. BCG, bacillus Calmette-Guérin. ISO codes: ago, Angola; BEN, Benin; BFA, Burkina Faso; CIV, Ivory Coast; CMR, Cameroon; cod, Democratic Republic of the Congo; GHA, Ghana; Gin, guinea; MLI, Mali; MOZ, Mozambique; RWA, Rwanda; TZA, United Republic of Tanzania; TGO, Togo.
Figure 2
Figure 2
Associations between BCG vaccination and malaria prevalence. (A) aOR of BCG vaccination on malaria prevalence, overall and subdivided by the source of BCG data (NO vaccination as reference). (B) Sensitivity analyses of BCG vaccination data derived from card with thick-smear microscopy as diagnostic, removal of children likely protected by maternal antimalarial antibodies (age ≤6 months), removal of areas with a BCG coverage of ≥90% and a combination of the latter two. (C,D) Time dependency of the association between BCG vaccination and malaria prevalence with a continuous variable (C) and a categorical variable (D) of timing. (E) Association between BCG vaccination derived from card and malaria prevalence related to the age of the child (interaction term age of child in months×BCG vaccination). (F) Association between BCG vaccination derived from card and malaria prevalence, overall and separate for symptomatic and asymptomatic malaria (symptomatic malaria was based on positive rapid diagnostic test and maternal recall of fever in the past 2 weeks). All results are depicted as aORs±95% CIs retrieved from multilevel logistic regression analyses with four levels (child, cluster, region and country) with correction for age, birth order, sex, twin, place of delivery, size at birth, preceding birth interval, weight-for-age z-score, breastfeeding, other vaccinations, vitamin A supplementation, use of bed nets, maternal age, maternal body mass index, number of births by the mother in the last 5 years, maternal level of education, maternal partner, household size, quality of drinking water, quality of toilet facility, international wealth index and urbanisation level. **P<0.01, ***P<0.001. aOR, adjusted OR; BCG, bacillus Calmette-Guérin.
Figure 3
Figure 3
Possible targets via which BCG could influence malaria infection. BCG vaccination induces increased innate immune activation and a Th1/Th 17 cell biassed immune response which could affect the malaria parasite in both liver and blood stages. Stimulation of Tc and NK cells can clean up infected hepatocytes. Furthermore, production of IL-22 by Th17 cells increases innate immune responses of hepatocytes, and BCG-trained Kupffer cells can reduce sporozoite development. Direct and Th1/Th17 promoted activation of monocytes also leads to increased production of proinflammatory cytokines IFN-γ and TNF-α and has been linked to the production of IgG-2a antibodies for neutralisation of merozoites. At their turn, proinflammatory cytokines induce killing of infected red blood cells by promoting macrophages to produce reactive oxygen species. BCG, bacillus Calmette-Guérin; IFN-γ, interferon gamma; IL, interleukin; Kup, Kupffer cell; Mϕ, macrophage; NK, natural killer cell; Tc, cytotoxic T-cell; th, T-helper cell; TNF-α, tumour necrosis factor alpha.
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