Real-life paediatric immunisation practices and the safety of vaccine co-administrations in children

Introduction: Paediatric immunisation schedules are designed to protect children against vaccine-preventable diseases early in life. Thereby, vaccines are often scheduled for co-administration to facilitate the delivery of a growing number of vaccines. However, it may not always be possible for children to adhere to the immunisation schedule. Thus, vaccinations may be delayed, given too early, or missed. Shifted vaccinations may lead to vaccine co-administrations that aren’t listed in the schedule. Currently, available information about the safety of real-life vaccine co-administrations versus separate vaccinations is limited and inconclusive. This uncertainty about the safety of co-administered vaccines may nourish vaccine hesitancy and consequently negatively affect immunisation rates. We analysed real-life paediatric immunisation patterns and assessed the relative safety of routine paediatric vaccine co-administration to fill the existing knowledge gap.
Methods: Our retrospective, dynamic, population-based cohort study included 1’005’827 children between 0 and 18 years, registered with a General Practitioner in England, participating in the Oxford Royal College of General Practitioners’ Research and Surveillance Centre database, between 1 January 2008 and 31 December 2018. We studied 6’257’828 routine childhood vaccinations as recommended in Public Health England’s paediatric immunisation schedules during the study period: DTaP/IPV/Hib/HepB, DTaP/IPV/Hib, DTaP/IPV, dTaP/IPV, Td/IPV, MMR, PCV, MenB, MenC, MenACWY, Hib/MenC, RV, HPV. We analysed the timeliness of these vaccinations, characterised co-administration practices, and compared the differences in relative incidences of adverse events following immunisation between separate vaccination and real-life vaccine co-administration using the self-controlled case series method.
Results: Seventy-five percent of first vaccine doses were administered on time, 19% too late and 6% too early. Fifty-one percent of second and 45% of third doses of a series were given timely after the preceding dose, 36% of second and 37% of third doses sooner, and 13% of second and 18% of third doses after a longer time. Socio-economic deprivation was associated with poorer schedule adherence for most vaccines and doses.
Seventy-nine percent of all routine paediatric vaccines were co-administered: two vaccines were co-administered in 36%, three in 33%, and four in 9% of co-administrations. Seventy-five percent of vaccine co-administrations were given as recommended in the immunisation schedule, while 4% were never recommended and 21% deviated from the actual schedule (i.e. shifted doses, fewer vaccines, or according to an outdated schedule). Untimely vaccinations were the major determinant for never recommended co-administrations.
Seventeen percent of adverse events following immunisation occurred less and 11% more after co-administrations. Five co-administrations of three vaccines led to amplifying interaction effects. After DTaP/IPV/Hib + MenC + PCV there was an increase in fever, rash, gastrointestinal, and respiratory events. After DTaP/IPV/Hib + MenC + RV there was an increase in gastrointestinal events, and after DTaP/IPV/Hib + PCV + RV there was an increase in fever and respiratory events. After MMR + Hib/MenC + PCV there was an increase in gastrointestinal and respiratory events. After MMR + MenC + PCV there was an increase in gastrointestinal events and general symptoms. Among co-administrations of two vaccines, MMR + PCV led to more fever, rash, and neurological events, MMR + MenC to more fever, and DTaP/IPV/Hib + MMR to more musculoskeletal events compared to separate vaccinations.
Discussion: The timeliness of routine paediatric vaccinations was suboptimal and decreased for subsequent doses, particularly after the first year of life. Similarly, the proportions of vaccines co-administered as well as the proportions of recommended co-administrations decreased later in life. Assessing the timeliness of vaccinations in addition to coverage rates is likely to optimise protection and decrease co-administrations without recommendation. Families in lower socio-economic status might particularly benefit from adequate monitoring. We detected no interaction effects following vaccine co-administration for most of the adverse events following immunisation. Routine paediatric vaccine co-administrations that were never recommended weren’t less safe than recommended co-administrations according to our analyses of relative incidence ratios. Co-administering two vaccines led to inhibitory interaction effects for more than a quarter of the studied adverse events. Some amplifying interaction effects after co-administering two vaccines were found for adverse events that occurred less after vaccinations than in the control periods, thus making these events less rare after co-administration than after separate vaccinations. Overall, half of the analysed vaccine co-administrations had an increased relative incidence for at least one adverse event, particularly after co-administrations of three vaccines. These previously undetected interaction effects indicate a safety signal for such co-administrations. Adding a fourth vaccine wasn’t associated with further interaction effects for any of the adverse events following immunisation studied.
Conclusions: Children are at risk of suboptimal protection against vaccine-preventable disease during specified periods in their childhood due to untimely vaccinations. Poor immunisation schedule adherence also negatively affects vaccine co-administration practices, forgoing the benefits of co-administering vaccines. We found that real-life co-administrations of two vaccines are at least equally safe as giving the same vaccines separately, while adding a third vaccine may increase the relative incidence of adverse events following immunisation. Building on these findings, we propose enhanced surveillance for a continued and comprehensive evaluation of the burden of adverse events following vaccine co-administrations.