Introduction
Routine childhood vaccination with vaccines against pertussis has been a long-standing immunization program in several countries [
1]. Since the resurgence of pertussis in the early 2010s [
2‐
4], several countries have recommended Tdap/dTap for women between 28 and 38 weeks of pregnancy [
5‐
9]. However, pertussis outbreaks continue to be reported worldwide [
10‐
13], with high increments in incidence among fully vaccinated children [
14‐
16]. This may be due to a lack of antibody protection in new-born infants [
17], or the waning immunity of DTaP over time [
18]. Thus, strategic vaccine schedules for children and timely uptake of boosters are important [
19]. Studies estimating vaccination coverage without investigating the timeliness may mask the delay of vaccination [
20,
21]. The association between vaccine hesitancy – an important factor related to delayed or missed immunizations – and pertussis in infants and children still lacks systematic investigations [
22,
23].
Vaccine hesitancy is a psychological state, vaccination behavior, or decision-making process [
22]. Maternal vaccine hesitancy was associated with lower pertussis-containing vaccine uptake (0–74%) [
24], resulting in fewer newborns receiving maternal antibodies [
25]. Parental hesitancy and non-medical exemptions have contributed to childhood vaccine hesitancy [
15,
26‐
28]. In Northern California, the hazard ratios of pertussis were 13 and 1.9 times higher among the unvaccinated and under-vaccinated children than the fully vaccinated, respectively [
19]. Children in exemption clusters were 2.5 times more likely to develop pertussis than non-exemption clusters [
28]. The COVID-19 pandemic disrupted routine immunization schedules through the reduced availability of vaccine services during lockdowns, emerging confusing messages about vaccinations, and increasing reluctance to receive vaccinations [
24,
29‐
32], leading to decreased childhood and prenatal pertussis vaccine coverage [
33,
34]. Together, higher pertussis risks in infants and children may exist in the post-pandemic period.
Previous meta-analyses and systematic reviews focused only on 1) the effect of childhood unvaccination/under-vaccination on pertussis in specific countries [
18], 2) the effectiveness of maternal vaccinations [
35], or 3) the effectiveness of childhood pertussis-containing vaccinations [
36]. Therefore, we performed a systematic review and meta-analysis assessing the association between maternal and childhood vaccine hesitancy and pertussis at the population level, to investigate the importance of on-time childhood and maternal vaccination worldwide.
Discussion
We found a significant association between vaccine hesitancy and higher pertussis ORs in infants and children. At the population level, maternal and childhood vaccinations are highly effective at reducing the rate and severity of pertussis infection in infants and children.
Childhood vaccine hesitancy is an essential barrier to preventing pertussis in children, regardless of vaccine coverage. Although evidence indicated that the pertussis ORs were higher before 2018, recent studies still advocate that vaccine hesitancy is an important factor behind significantly higher pertussis risks in infants and children. Children with pertussis are more likely to be unvaccinated than under-vaccinated. Several factors may lead to childhood unvaccination, including nonmedical exemptions (such as philosophical, personal belief, or religious exemptions), cultural norms, unavailability of vaccination appointments, and hesitance toward vaccine providers [
18]. Nonmedical exemptions were associated with significantly higher pertussis-related risks in children [
14,
15,
28]. However, meta-analyses on this topic could not be conducted due to the limited number of population-level studies available. Further studies should be conducted to determine the relationship between pertussis and various factors related to childhood unvaccination/under-vaccination. The high heterogeneity in the subgroup analysis regarding the number of unvaccinated doses may be due to different vaccine schedules across different regions. Different recommended ages for children to take their first and fourth dose of vaccines against pertussis in immunization programs in the United States [
45] and New Zealand [
48] may explain the high heterogeneity in the estimated effect of 1 and 4 doses childhood under-vaccination.
The dose–effect relationship exists in childhood pertussis vaccine hesitancy. Pertussis ORs increased gradually as more vaccine doses were missing. Vaccine hesitancy over boosters may lead to more adverse effects in children. VE was the lowest at the first dose and gradually increased with the dose number, indicating a more significant preventive effect of pertussis-containing vaccines for older children. Waning immunity and vaccine hesitancy leading to the absence or late administration of boosters may result in more severe cases of pertussis in older children and higher VE of boosters [
18]. However, for each dose, the effect of waning immunity may be insignificant because of the short follow-up periods of studies included in our analysis. The 4
th dose showed the highest VE, but the population-level data were too limited to conduct a meta-analysis. Delayed early vaccination seemed to be unimportant due to the relatively low VE and dose–effect relationship. However, deferring early vaccines may lead to missed or delayed vaccinations [
61]. Together, we advocate that children should receive up-to-time pertussis-containing vaccinations – both primary series and subsequent boosters – to reduce regional and global pertussis outbreaks.
Maternal vaccine hesitancy was associated with significantly higher pertussis risks in infants. At the population level, maternal vaccination had significant protective effects both on infants too young to be vaccinated (
\(\le\) 2 months) and on infants eligible for their 1
st dose of pertussis-containing vaccination (
\(\le\) 3 months), with higher protective effects in the former group. This notion is also supported by the results of previous clinical trials [
62‐
64]. Barug et al. reported a higher geometric mean concentration of pertussis toxin antibodies in 3-month-old infants whose mothers received maternal Tdap compared to that in those whose mothers declined [
63]. Even when maternal vaccination failed to prevent infants from contracting pertussis, infants whose mothers received the maternal vaccine had a significantly lower risk of hospitalization. Thus, maternal vaccination is important for preventing infants
\(\le\) 3 months old from pertussis infections and reducing the severity of the disease if contracted. Maternal VE was high in infants, regardless of the vaccine administered timing. Previous studies reported no increased risks of adverse events among women who received maternal pertussis-containing vaccines and their infants [
62‐
65]. Together, maximizing pertussis-containing vaccine uptake during pregnancy should be promoted worldwide, particularly in countries with re-emerging pertussis outbreaks.
We observed that vaccine delay was not significantly associated with higher pertussis risks in children. The high heterogeneity of meta-analysis may be explained by different population characteristics and government policies between Taiwan and the United States [
23,
40]. A lower pertussis risk was indicated when the 4
th dose was delayed, but related studies were too limited to perform a full meta-analysis. Delaying childhood pertussis-containing vaccination may reduce the incidence of allergic diseases in infants and children [
66,
67], indicating that delaying childhood vaccination may carry potential benefits. Because maternal vaccinations may reduce pertussis risks in infants
\(\le\) 3 months, infants whose mothers received maternal vaccinations may be able to delay the administration of their 1
st dose of pertussis-containing vaccination. However, further evidence is needed to verify this notion. More studies are needed to determine the specific and accurate associations between vaccine delays, including of different doses, and the risks of pertussis infection in children. We suggest that a clearer and standardized definition of vaccine delay and under-vaccination should be adopted for future studies on the topic, which may help with generating robust and comparable results.
Limitations also exist. First, different countries have different recommended vaccination ages for children, which may introduce high heterogeneity in our meta-analyses. Due to these differences, we were unable to evaluate the association between childhood vaccine hesitancy and pertussis risks in different age groups. Second, few studies investigated the specific effects of vaccine hesitancy during pertussis outbreaks; therefore, we could not assess differences in the effects of vaccine hesitancy on the risks of developing pertussis in children during the outbreak vs. non-outbreak years. Third, seven studies had NOS < 7, indicating potential defects in study design that may affect the accuracy of our meta-analysis. Lastly, the effects of psychological state or decision-making aspects of vaccine hesitancy on pertussis were not investigated because of limited studies in this study.
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