Safety and Immunogenicity of Early Bacillus Calmette-Guérin Vaccination in Infants Who Are Preterm and/or Have Low Birth Weights: A Systematic Review and Meta-analysis

Shiraz Badurdeen, Andrew Marshall, Hazel Daish, Mark Hatherill, James A Berkley, Shiraz Badurdeen, Andrew Marshall, Hazel Daish, Mark Hatherill, James A Berkley

Abstract

Importance: Bacillus Calmette-Guérin (BCG) vaccination is commonly delayed in infants who are preterm and have low birth weights (LBW) despite the association of early vaccination with better vaccination coverage and potentially nonspecific benefits for survival.

Objective: To determine the safety, immunogenicity, and protective efficacy against tuberculosis (TB) of BCG vaccination given at or before 7 days after birth vs vaccination more than 7 days after birth among infants who are preterm and/or had LBW.

Data sources: Searches of Medline, Embase, and Global Health databases were conducted from inception until August 8, 2017.

Study selection: Clinical trials, cohort studies, and case-control studies that included infants who were preterm and/or had LBW and reported safety, mortality, immunogenicity, proxies of vaccine take, and/or efficacy against TB.

Data extraction and synthesis: Two authors independently extracted data and assessed the quality of the studies. Data extracted included demographics, covariates, sources of bias, and effect estimates. Meta-analysis was performed using a random-effects model.

Main outcomes and measures: Safety, mortality, immunogenicity, or other proxies of vaccine take, such as tuberculin skin test (TST) conversion and efficacy against tuberculosis.

Results: Forty studies were included in a qualitative synthesis; infants who were preterm (born at 26-37 weeks' gestational age) and/or had LBW (0.69-2.5 kg at birth) were included. The BCG vaccine was administered at or before 7 days to 10 568 clinically stable infants who were preterm and/or had LBW; vaccination was administered to 4310 infants at varying times between 8 days and 12 months after birth. Twenty-one studies reporting safety found no cases of BCG-associated death or systemic disease in 8243 infants. Four studies reported no increase in all-cause mortality for infants who had LBW and who received early BCG vaccination compared with infants who had LBW with later vaccination or BCG-vaccinated infants of normal birth weight. Four studies reported lymphadenitis incidence; combined, these reported 0% to 2.9% incidence of vaccination within 7 days and 0% to 4.2% of vaccination after 7 days. Meta-analysis of 7 studies revealed no differences between early and delayed BCG vaccination for scar formation (n = 515; relative risk [RR], 1.01 [95% CI, 0.95-1.07]) or TST conversion (n = 397; RR, 0.97 [95% CI, 0.84-1.13]). Published data were insufficient to assess immunogenicity or protective efficacy against TB disease.

Conclusions and relevance: Early BCG vaccination in healthy infants who are preterm and/or had LBW has a similar safety profile, reactogenicity, and TST conversion rate as delayed vaccination. Based on current evidence, early BCG vaccination in stable infants who are preterm and/or have LBW to optimize uptake is warranted.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.. Flow Diagram of Study Selection
Figure 1.. Flow Diagram of Study Selection
BCG indicates bacillus Calmette-Guérin vaccine; LBW, low birth weight.
Figure 2.. Meta-analyses
Figure 2.. Meta-analyses
A, Meta-analysis of the risk of developing a bacillus Calmette-Guérin (BCG) scar. B, Meta-analysis of tuberculin skin test conversion in infants who are preterm and/or had low birth weights for BCG vaccination within 7 days or at a later point.
Figure 3.. Responses to BCG Vaccination From…
Figure 3.. Responses to BCG Vaccination From Included Studies
A and B, Comparisons of vaccination responses in infants who are preterm vs full-term and comparisons of vaccination responses in infants who have low birth weight vs normal birth weight. Each circle represents the ratio of responses for a specific outcome from a single study. The size of each circle is proportional to the number of infants who were preterm and/or had low birth weights. No estimate of variability is given, and pooling of results was not justified. Ratios of mean diameter (pink circles) or reported adjusted odds ratios were used in preference to unadjusted ratios of proportions (purple circles), where available. Mean stimulation index outcomes are represented by orange circles. Circles with a solid outline represent responses from studies that included vaccination after 7 days postbirth of infants who were preterm and/or had low birth weights (eTable 2 in the Supplement). BCG indicates bacillus Calmette-Guérin; IFN-γ, interferon γ; LMIT, leukocyte migration inhibition test; TNF, tumor necrosis factor; TST, tuberculin skin test.

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