Bifidobacterium Abundance in Early Infancy and Vaccine Response at 2 Years of Age

Abstract

Background: The intestinal microbiome in early infancy affects immunologic development and thus may affect vaccine memory, though few prospective studies have examined such associations. We examined the association of Bifidobacterium levels in early infancy with memory responses to early vaccination measured at 2 years of age.

Methods: In this prospective observational study, we examined the association of Bifidobacterium abundance in the stool of healthy infants at 6 to 15 weeks of age, near the time of vaccination, with T-cell and antibody responses measured at 6 weeks, 15 weeks, and 2 years of age. Infants were vaccinated with Bacillus Calmette-Guérin (BCG) (at birth), oral polio virus (at birth and at 6, 10, and 14 weeks), tetanus toxoid (TT) (at 6, 10, and 14 weeks), and hepatitis B virus (at 6, 10, and 14 weeks). Fecal Bifidobacterium was measured at 6, 11, and 15 weeks. Bifidobacterium species and subspecies were measured at 6 weeks.

Results: Mean Bifidobacterium abundance in early infancy was positively associated with the CD4 T-cell responses to BCG, TT, and hepatitis B virus at 15 weeks, with CD4 responses to BCG and TT at 2 years, and with plasma TT-specific immunoglobulin G and stool polio-specific immunoglobulin A at 2 years. Similar associations were seen for the predominant subspecies, Bifidobacterium longum subspecies infantis.

Conclusions: Bifidobacterium abundance in early infancy may increase protective efficacy of vaccines by enhancing immunologic memory. This hypothesis could be tested in clinical trials of interventions to optimize Bifidobacterium abundance in appropriate populations.

Trial registration: ClinicalTrials.gov NCT01583972 NCT02027610.

FIGURE 1

Heat map showing associations (and statistical significance) between early life bifidobacteria abundance and BCG vaccine responses measured at 6 weeks, 15 weeks and 2 years of age determined with multiple regression analysis as described in Methods. BCG vaccine responses include the CD4 T-cell SI and the DTH skin test response. Associations with the SI for the positive control for CD4 T-cell stimulation (SEB) are also shown. Bifidobacteria abundance measures were as follows: (1) mean abundance of the genus Bifidobacterium measured at 6, 11, and 15 weeks and single measures made at 6 weeks for (2) the genus Bifidobacterium; (3) the most abundant species, B longum; (4) the most abundant of 2 subspecies, B longum subspecies infantis; (5) the second subspecies, B longum subspecies longum; and 2 minor species, (6) B breve and (7) B bifidum.

FIGURE 2

Heat map showing associations (and statistical significance) between early life bifidobacteria abundance and TT and HBV responses measured at 15 weeks and 2 years of age determined with multiple regression analysis as described in Methods. Responses include the CD4 T-cell SI, the ALS assay for IgG at 15 weeks, plasma IgG at 2 years, and the IgG AI at 2 years. Bifidobacteria abundance measures were as follows: (1) mean abundance of the genus Bifidobacterium measured at 6, 11, and 15 weeks and single measures made at 6 weeks for (2) the genus Bifidobacterium; (3) the most abundant species, B longum; (4) the most abundant of 2 subspecies, B longum subspecies infantis; (5) the second subspecies, B longum subspecies longum; and 2 minor species, (6) B breve and (7) B bifidum.

FIGURE 3

Association of stool bifidobacteria in early infancy, at 6 to 15 weeks of age, with vaccine responses at 2 years of age. Top row, TT-specific CD4 T-cell SI (top row); middle row, TT-specific plasma IgG; bottom row, stool polio type 2–specific IgA. The asterisk (*) indicates a single, off-scale value (>7.5).

FIGURE 4

Heat map showing associations (and statistical significance) between early life bifidobacteria abundance and OPV vaccine responses measured at 15 weeks and 2 years of age determined with multiple regression analyses as described in Methods. Responses include the CD4 T-cell SI, the ALS assay for IgG at 15 weeks, plasma IgG and IgA at 2 years for the 3 strains of virus included in the vaccine, the IgG AI and IgA AI for all 3 strains at 2 years. Bifidobacteria abundance measures were as follows: (1) mean abundance of the genus Bifidobacterium measured at 6, 11, and 15 weeks and single measures made at 6 weeks for (2) the genus Bifidobacterium; (3) the most abundant species, B longum; (4) the most abundant of 2 subspecies, B longum subspecies infantis; (5) the second subspecies, B longum subspecies longum; and 2 minor species, (6) B breve and (7) B bifidum. s1, strain 1; s2, strain 2; s3, strain 3.