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

Abstract

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.

Available evidence on the co-administration of the four-component meningococcal B vaccine (4CMenB) with three vaccines at the same visit among pediatric individuals

“…Studies that reported safety data for pentavalent vaccines (DTaP-IPV-Hib) co-administered with 4CMenB were also included, due to the similarity in safety profiles compared to hexavalent vaccines. 18 No geographical or language restrictions were applied in the literature search.…”

Trivalent outer membrane vesicles-based combination vaccine candidate induces protective immunity against Campylobacter and invasive non-typhoidal Salmonella in adult mice

“…According to the World Health Organization (WHO), combination vaccines are divided into two types: (a) vaccines that contain multiple antigens in a single formulation for protection against multiple diseases and (b) those that contain antigens of different strains and serotypes of the same organism, providing protection against a single infectious disease. The advantages of combination vaccines over individual formulations include reduced frequency of clinic visits and injections, decrease in the duration of infant distress, increase in parental willingness for vaccination, lesser operational and stocking costs, and increase in the vaccinepreventable disease coverage rates [21]. Recently, our group developed a combined pentavalent outer membrane vesicles-based vaccine candidate that conferred potent protective immune response against ve major pathotypes of diarrhoeagenic Escherichia coli in a mouse model [22].…”

Cost‐minimization analysis of DTaP‐IPV‐Hib combination vaccine in China: A nationwide cross‐sectional study

“…[8][9][10] A systematic evaluation and meta-analysis also suggested that the DTaP-IPV-Hib combination vaccine and separate vaccines did not differ concerning immunogenicity parameters. 11 World Health Organization (WHO) has promoted the use of combination vaccines for immunization programs in 2017. 12 Countries, notably the US, Canada, and India, have introduced the DTaP-IPV-Hib combination vaccine into the routine childhood immunization program, replacing the separated DTaP, IPV, and Hib vaccines.…”

“…Multiple clinical trials have confirmed the high level of immunogenicity of the DTaP‐IPV‐Hib combination vaccine (>95%) 8–10 . A systematic evaluation and meta‐analysis also suggested that the DTaP‐IPV‐Hib combination vaccine and separate vaccines did not differ concerning immunogenicity parameters 11 . World Health Organization (WHO) has promoted the use of combination vaccines for immunization programs in 2017 12 .…”