In this column, I recently discussed the impact of the microbiome on childhood vaccine responses. My group has been expanding our research on the topic of childhood vaccine response and its relationship to infection proneness. Therefore, I want to share new research findings.
Immune responsiveness to vaccines varies among children, leaving some susceptible to infections. We also have evidence that the immune deficiencies that contribute to poor vaccine responsiveness also manifest in children as respiratory infection proneness.
Predicting Vaccine Response in the Neonatal Period
The first 100 days of life is an amazing transition time in early life. During that time, the immune system is highly influenced by environmental factors that generate epigenetic changes affecting vaccine responsiveness. Some publications have used the term “window of opportunity,” because it is thought that interventions to change a negative trajectory to a positive one for vaccine responsiveness have a better potential to be effective. Predicting which children will be poorly responsive to vaccines would be desirable, so those children could be specifically identified for intervention. Doing so in the neonatal age time frame using easy-to-obtain clinical samples would be a bonus.
In our most recent study, we sought to identify cytokine biosignatures in the neonatal period, measured in convenient nasopharyngeal secretions, that predict vaccine responses, measured as antibody levels to various vaccines at 1 year of life. Secondly, we assessed the effect of antibiotic exposures on vaccine responses in the study cohort. Third, we tested for induction of CD4+ T-cell vaccine-specific immune memory at infant age 1 year. Fourth, we studied antigen presenting cells (APCs) at rest and in response to an adjuvant called R848, known to stimulate toll-like receptor (TLR) 7/8 agonist, to assess its effects on the immune cells of low vaccine responder children, compared with other children.1
Dr. Michael E. Pichichero
The study population consisted of 101 infants recruited from two primary care pediatric practices in/near Rochester, New York. Children lived in suburban and rural environments. Enrollment and sampling occurred during 2017-2020. All participants received regularly scheduled childhood vaccinations according to the recommendations by US Centers for Disease Control. Nasopharyngeal swabs were used to collect nasal secretions. Antibody titers against six antigens were measured at approximately 1 year of age from all 72 available blood samples. The protective threshold of the corresponding vaccine antigen divided each vaccine-induced antibody level and the ratio considered a normalized titer. The normalized antibody titers were used to define vaccine responsiveness groups as Low Vaccine Responder (bottom 25th percentile of vaccine responders, n = 18 children), as Normal Vaccine Responder (25-75th percentile of vaccine responders, n = 36 children) and as High Vaccine Responder (top 25th percentile of vaccine responders, n = 18 children).
We found that specific nasal cytokine levels measured at newborn age 1 week old, 2 weeks old, and 3 weeks old were predictive of the vaccine response groupings measured at child age 1 year old, following their primary series of vaccinations. The P values varied between less than .05 to .001.
Five newborns had antibiotic exposure at/near the time of birth; 4 [80%] of the 5 were Low Vaccine Responders vs 1 [2%] of 60 Normal+High Vaccine Responder children, P = .006. Also, the cumulative days of antibiotic exposure up to 1 year was highly associated with low vaccine responders, compared with Normal+High Vaccine Responder children (P = 2 x 10-16).
We found that Low Vaccine Responder infants had reduced vaccine-specific T-helper memory cells producing INFg and IL-2 (Th1 cytokines) and IL-4 (Th2 cytokines), compared with Normal+High Vaccine Responder children. In the absence of sufficient numbers of antigen-specific memory CD4+ T-cells, a child would become unprotected from the target infection that the vaccines were intended to prevent after the antibody levels wane.
We found that Low Vaccine Responder antigen-presenting cells are different from those in normal vaccine responders and they can be distinguished when at rest and when stimulated by a specific adjuvant — R848. Our previous findings suggested that Low Vaccine Responder children have a prolonged neonatal-like immune profile (PNIP).2 Therefore, stimulating the immune system of a Low Vaccine Responder could shift their cellular immune responses to behave like cells of Normal+High Vaccine Responder children.
In summary, we identified cytokine biosignatures measured in nasopharyngeal secretions in the neonatal period that predicted vaccine response groups measured as antibody levels at 1 year of life. We showed that reduced vaccine responsiveness was associated with antibiotic exposure at/near birth and with cumulative exposure during the first year of life. We found that Low Vaccine Responder children at 1 year old have fewer vaccine-specific memory CD4+ Th1 and Th2-cells and that antigen-presenting cells at rest and in response to R848 antigen stimulation differ, compared with Normal+High Vaccine Responder children.
Future work by our group will focus on exploring early-life risk factors that influence differences in vaccine responsiveness and interventions that might shift a child’s responsiveness from low to normal or high.
Dr. Pichichero is a specialist in pediatric infectious diseases, Center for Infectious Diseases and Immunology, and director of the Research Institute, at Rochester (New York) General Hospital. He has no conflicts of interest to declare.
References
1. Pichichero ME et al. Variability of Vaccine Responsiveness in Young Children. J Infect Dis. 2023 Nov 22:jiad524. doi: 10.1093/infdis/jiad524.
2. Pichichero ME et al. Functional Immune Cell Differences Associated with Low Vaccine Responses in Infants. J Infect Dis. 2016 Jun 15;213(12):2014-2019. doi: 10.1093/infdis/jiw053.