Immunogenicity and Safety of Childhood Combination Vaccines: A Systematic Review and Meta-Analysis.

Background: Vaccination is considered the most effective and economical measure for controlling infectious diseases. Although combination vaccines are widely used worldwide, whether any of the combination vaccines is superior to each separate vaccine has yet to be established. This systematic review and meta-analysis aimed to summarize the available evidence on the effectiveness and safety of combination vaccines in children. Methods: A systematic search was conducted from database inception to August 20, 2021, in MEDLINE, Embase, Cochrane, and Scopus. Published randomized clinical trials (RCTs) and open-label trials of immunogenicity and safety of combined vaccines were selected. The results of the studies were quantitatively synthesized. Results: Overall, 25 articles met the inclusion criteria and were included in the meta-analysis. The results indicated that the combined diptheria−tetanus−acellular pertussis (DTaP)−hepatitis B virus (HBV)−Haemophilus influenzae type B (Hib) vaccine group had lower levels of anti-tetanus antibodies than the combined DTaP−HBV and separate Hib vaccinations group (SMD = −0.23; 95% CI: −0.42, −0.05; p = 0.013). Meanwhile, the combined DTaP−HBV−inactivated polio virus (IPV)−Hib vaccine group had higher levels of anti-pertussis (PT) and anti-filamentous hemagglutinin (FHA) antibodies than the combined DTaP−IPV−Hib and separate HBV vaccinations group (anti-PT: SMD = 0.60; 95% CI: 0.45, 0.75; p < 0.0001; anti-FHA: SMD = 0.40; 95% CI: 0.01, 0.78; p = 0.042). The levels of anti-pertactin (PRN) antibodies were lower in the combined DTaP−IPV−Hib vaccine group than in the combined DTaP−IPV and separate Hib vaccinations group (SMD = −0.13; 95% CI: −0.27, −0.00; p = 0.047). The individuals injected with the DTaP−HBV−IPV−Hib vaccine had a lower risk of pain and swelling than those injected with the combined DTaP−HBV−IPV and separate Hib vaccines (pain: RR = 0.79; 95% CI: 0.69, 0.91; p = 0.001; swelling: RR = 0.87; 95% CI: 0.78, 0.98; p = 0.020). However, the group that received the DTaP−HBV−IPV−Hib vaccine had a higher risk of fever than the group that received DTaP−HBV−IPV and separate Hib vaccinations (RR = 1.13; 95% CI: 1.02, 1.26; p = 0.021). Conclusions: This meta-analysis suggests that the combined vaccines (DTaP−IPV−Hib, DTaP−HBV−Hib, DTaP−HBV−IPV−Hib) are safe, well-tolerated, and provide immunogenic alternatives to separate vaccines in children. The combined DTaP−HBV−IPV−Hib vaccine showed a higher incidence of fever, which was lower than the cumulative incidence of fever induced by all vaccines. Future studies should evaluate the cost-effectiveness of using combined vaccines and compare the potency of different formulations to improve routine local or national childhood immunization programs.