In a first-of-its-kind study, researchers have found that antibiotic use in young children is associated with lower vaccine-induced antibody responses to several childhood vaccines.
The study, published yesterday in Pediatrics, found that children 2 years of age and younger who had received antibiotics had lower levels of antibody protection from the diphtheria-tetanus-acellular pertussis (DTaP) and pneumococcal conjugate vaccine (PCV) than those who received no antibiotics. They also found that antibiotic courses that were accumulated over time were negatively associated with vaccine-induced antibody levels.
While previous studies in mice and adult humans have suggested a link between antibiotics and the immune response to vaccination, the study is the first to find such a link in children. The study authors say the findings suggest an outcome that could leave children vulnerable to vaccine-preventable diseases and highlight the need for more research on antibiotics and vaccine-induced immunity.
Lower vaccine-induced antibody levels
The findings are based on a retrospective, secondary analysis of a cohort study of children ages 6 to 24 months in Rochester, New York, that focused on respiratory infections in the primary care setting, especially acute otitis media (ear infection). The children in the study—all of whom had followed the recommended vaccine schedule—had blood collected at well-child visits at 6, 9, 12, 15, 18, and 24 months of age.
Researchers with Rochester General Hospital Research Institute and the Rochester Institute of Technology reviewed the medical records of the children, questioned parents about illnesses and antibiotic prescriptions, and measured antibody response to the DTaP, PCV, inactivated polio (IPV), and Haemophilus influenzae type b (Hib) vaccines from the provided blood samples. They then compared antibody levels in children who had received antibiotics with those who had received no antibiotics.
A total of 560 children met the criteria for inclusion. Of these children, 342 had received 1,678 antibiotic courses, and 218 received no antibiotic courses. The predominant antibiotics prescribed were amoxicillin, amoxicillin-clavulanate, cefdinir, and ceftriaxone. Receipt of antibiotics was heavily associated with daycare attendance.
The analysis found that from 9 to 24 months of age, the children who had received antibiotics had a higher frequency of vaccine-induced antibody levels for several DTaP and PCV antigens that were below the protective threshold, compared with the children who received no antibiotics. When the researchers compared all vaccine-induced antibody levels at all ages, they found that children who took antibiotics had a higher frequency of antibody levels below the protective threshold at 9 and 12 months; differences between the two groups were not statistically significant at other time points.
Among the antibiotics the children had received, cefdinir (odds ratio [OR], 1.58), ceftriaxone (OR, 1.39), and amoxicillin-clavulanate (OR, 1.58) were associated with lower antibody levels, but amoxicillin (OR, 1.26) was not.
The researchers also found that the number of antibiotic courses received in the first year of life had an impact on subsequent vaccine-induced antibody levels. Each antibiotic course received over the first year was associated with a 5.8% reduction in median antibody levels to DTaP, a 6.8% reduction in antibody levels for Hib, an 11.3% reduction in antibody levels for IPV, and a 10.4% reduction in PCV antibodies.
After booster shots of those vaccines (18 to 24 months), the impact on accumulated antibiotics was even greater: each antibiotic prescription was associated with a reduction in vaccine-induced antibody levels of 18.1% for DTaP, 21.3% for Hib, 18.9% for IPV, and 12.2% for PVC.
"The results reveal that antibiotic use is associated with lower antibody levels to several vaccine antigens and a frequency-dependent effect of antibiotic courses over time in the first 2 years of life," the authors wrote.
In a video abstract that accompanies the study, senior author Michael Pichichero, MD, of Rochester General Hospital Research Institute says that while the study is small and limited to children in one city, the findings nonetheless further highlight the need for careful use of antibiotics in children.
"This is new information for pediatricians, and yet again more reason for judicious antibiotic prescribing," Pichichero said.
The role of the gut microbiome
The findings also add to the growing body of research that suggests antibiotic exposure at an early age has impacts on children's health as they get older. In recent years, studies have found correlations between antibiotic exposure in the first 2 years of life and increased risk of obesity, allergies, and type 2 diabetes later in life.
While the mechanism behind these associations has not been identified, the emerging hypothesis, based mainly on research conducted in mice, is that it's likely tied to the effect that antibiotics can have on the composition and diversity of bacteria in the gut microbiome, which in young children is still developing.
A study of adults given broad-spectrum antibiotics before seasonal influenza vaccination found reduced bacterial load and a significant reduction in neutralizing antibody responses to the vaccine—a finding that bolsters the case that antibiotic alteration of the gut microbiome may have an impact on vaccine immune response.
While their study did not include an analysis of stool samples to study the potential impact of antibiotics on the gut microbiomes of the enrolled children, Pichichero and his colleagues say future studies should do so.
In an editorial in the same journal, Octavio Ramilo, MD, and Asuncion Mejias, MD, PhD, of Nationwide Children's Hospital in Ohio, called the findings "remarkable."
"Their observations could have major implications for clinical practice and should stimulate larger prospective multicenter studies involving more diverse populations to confirm these findings," they wrote. "Future studies should also include mechanistic analyses that permit understanding the origin of these reduced antibody responses, and eventually design approaches to mitigate their potential clinical impact."
