Reactogenicity of hexavalent vaccines modelled in Swedish birth cohorts

In Europe, three hexavalent vaccines are licensed for childhood immunisation: DT3aP-HBV-IPV/Hib (Infanrix hexa, GSK), DT2aP-HBV-IPV-Hib (Hexyon, Sanofi Pasteur) and DT5aP-HBV-IPV-Hib (Vaxelis, MSD). These vaccines combine diphtheria, tetanus, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b, with multiple acellular pertussis antigens (two in Hexyon, three in Infanrix hexa and five in Vaxelis). In Sweden, Hexyon is used for the vaccination of infants. A meta-analysis published in 2021 that used data from head-to-head studies evidenced that the odds ratios of eight solicited adverse reactions (ARs) in infants were significantly lower with Infanrix hexa than with Hexyon.1 Based on these data, a decision support tool was developed to compare the estimated ARs after a primary dose of these vaccines in infants. In the present study, we compared the safety profiles of Infanrix hexa and Hexyon in Swedish children based on published literature and data. Based on the meta-analysis of safety outcomes, odds ratio of ARs occurring after vaccination with Infanrix hexa versus Hexyon was as follows: pain (0.740), redness (0.722), swelling (0.858), fever (0.670), drowsiness (0.817), irritability (0.820), persistent crying (0.717) and anorexia (0.829) (Table S1).1 We assumed a vaccination coverage of 94.3% based on 2022 estimates.2 The below 1-year population in Sweden for the years 2023 to 2042 was extrapolated from the population estimates published by Statistics Sweden.3 The endpoints calculated were the estimated number of ARs by type and the absolute risk reduction (ARR). Univariate sensitivity analyses were also conducted for the ARs avoided for the eight AR types. The impact of the COVID-19 pandemic on the routine vaccination coverage was not considered since it was likely a one-time event that does not affect the long-term projections. The number of children experiencing various ARs after primary vaccination of infants <1 year of age with a single dose of Infanrix hexa versus Hexyon was estimated for the year 2023 (Table 1). In that year, 97 034 of the 102 900 infants were vaccinated. The larger benefit was observed in the number of fever episodes. The number of infants experiencing various ARs after vaccination with Infanrix hexa versus Hexyon was also estimated for the years 2023–2027, and the number of avoided ARs was calculated. The estimated total number of ARs avoided from 2023 to 2027 for the eight AR types ranged from 41 722 in 2023 to 45 330 in 2027. The cumulative number of ARs avoided over these 5 years was 218 542. The ARRs calculated for the eight AR types ranged from 3.0% (95% confidence interval: 2.8%–3.2%) for swelling at injection site to 10.0% (95% confidence interval: 9.5%–10.5%) for fever (Table 1). For example, the 10.0% ARR for any grade of fever indicated that among 97 034 infants vaccinated with Infanrix hexa instead of Hexyon, 9703 fewer infants would experience fever. Sensitivity analyses were performed on AR-specific data, that is the proportion of each AR for Hexyon and Infanrix hexa, and on AR-non-specific data, that is population size and vaccination coverage. The base value for the sensitivity analyses was the number of ARs avoided. Variation of the AR-specific data with ± 2 SD or AR-non-specific data with ±10% did not change the overall outcome that a reduction in estimated ARs could be obtained by vaccinating with Infanrix hexa instead of Hexyon. We found that there was a slightly lower risk of experiencing ARs when vaccinating an infant with Infanrix hexa versus Hexyon that would considerably reduce the number of ARs experienced each year. Cumulatively, over a 20-year period, about 927 067 ARs could be avoided. Hexavalent vaccines are among the first vaccines administered to children and their reactogenicity might influence parents' decisions regarding following vaccination. As ARs can cause health and economic burdens to the patients and their caretaker indirect benefits of reduced ARs may significantly impact the results of cost–benefit analyses for hexavalent vaccines. In addition, safety concerns are known to be a cause of parental refusal of vaccination. Risk of adverse reactions are indeed often cited as a reason for vaccine hesitancy.4, 5 The lower risk of ARs could thus positively impact vaccine acceptance and children protection against vaccine preventable diseases. Our study had several limitations, the main one being that the results were estimates based on projected population sizes from public resources and a meta-analysis of ARs in clinical trials conducted in other countries,1 and thus not based on clinical data from Sweden. In conclusion, applying the results from the published meta-analysis on the Swedish birth cohort evidenced that using Infanrix hexa could lower the number of ARs experienced by Swedish infants. George Marina: Writing – review and editing; writing – original draft; methodology; resources; formal analysis. Lundholm Lotta: Writing – review and editing; writing – original draft; funding acquisition; validation. Silfverdal Sven Arne: Writing – review and editing; validation. The authors would like to thank Marianne Wittrup Larsen for her contributions to the study. The authors would also like to thank Business & Decision Life Sciences Medical Communication Service Center for editorial assistance, writing and design support and manuscript coordination, on behalf of GSK. Esther van de Vosse provided medical writing support. GSK provided funding (number VEO-000328) and was involved in all aspects of the study and paper. MG works for the Hari Group and received funding from GSK during this study. LL is a GSK employee. SAS received a fee from GSK for a lecture on pneumococcal vaccines outside the submitted work and has participated in advisory board meetings on pneumococcal, meningococcal and hexavalent vaccines, and on RSV, for GSK, Pfizer, MSD and Sanofi Pasteur. Infanrix HEXA is a trademark owned by or licensed to GSK. Hexyon is a trademark of Sanofi Pasteur. Vaxelis is a trademark of Merck Sharp & Dohme. Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.