Introduction

Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide, especially in children under 5 years of age, and it was estimated to cause about 294,000 deaths in children aged 1–59 months in 2015 [1, 2]. Pneumococcus is capable of colonizing the nasopharyngeal region; carriage can last from weeks to years [3]. Although colonization with pneumococcal strains is asymptomatic, it can lead to respiratory and systemic disease and is a source of spread within the community [3]. Young children are considered the most important vector for the dissemination of pneumococci within the community because of their high frequency of nasopharyngeal carriage [3].

Pneumococcal conjugated vaccines (PCVs) were licensed in 2000 and their use has a substantial impact on the burden of pneumococcal disease leading to a significant reduction in invasive pneumococcal disease through direct and indirect protection [4,5,6]. Different amounts of pneumococcal antibodies are required to protect against systemic disease and colonization, with higher titers needed for protection against certain serotypes and mucosal colonization [7,8,9].

While the contribution of pneumococcal vaccines to public health is indisputable, their administration is associated with mild adverse events such as decreased appetite, irritability, or local reactions (swelling and pain) in almost half of the recipients [10]. The incidence of some events like febrile seizures seems to occur more frequently when PCVs are co-administered with other routine vaccines [11]. There are concerns, also, that the reactogenicity of PCVs may increase by the insertion of more serotypes in the new conjugated vaccine formulations, created to deal with the “serotype replacement” phenomenon [12,13,14].

Although the adverse events of PCVs are mild and transient, they decrease parents’ acceptance and trust [15, 16]. Antipyretic analgesics are widely used to ameliorate vaccine adverse reactions and decrease parental anxiety, but their use has been associated with blunted vaccine immune responses to specific pneumococcal serotypes [17]. As two new PCVs (15-valent and 20-valent) are currently in phase 3 clinical trials, the effect of antipyretics on the antibody titer to specific serotypes will be crucial [18].

The objective of the present study is to systematically review the existing literature on the effect of prophylactic administration of antipyretics on the immune response of PCVs and provide a recommendation on the use of prophylactic antipyretics around the time of pneumococcal immunization.

Materials and methods

Literature search and study selection

In accordance with PRISMA guidelines, we conducted a systematic review to identify the impact of antipyretic use on the immune response of pneumococcal vaccination [19]. We searched the PUBMED and SCOPUS databases for English-language publications indexed through 1 November 2020. The search strategy was based on the utilization of two major groups of keywords: Paracetamol, Acetaminophen, Ibuprofen, Fever, prophylaxis, Antipyretic (Group 1) and Immune response, Antibody response, Immunity, Immunogenicity, Immunization, Immunization, Vaccination, Vaccine (Group 2). These two categories were combined by the Boolean ‘AND’ and the terms utilized within these search categories were combined by the Boolean ‘OR’. The Medical Subject Headings (MeSH) database was used for the identification of synonyms. After compilation of articles from the database and duplicate deletion, the titles and abstracts of articles were manually screened for topic relevance. A full-text review of the articles and their reference lists were then checked by two investigators. Any discordance was resolved through discussion. The reference lists of all relevant articles originally selected for inclusion in the review and relevant reviews were also searched manually to identify potentially relevant articles that were not identified by the original electronic search.

Inclusion/exclusion criteria

Studies in English that evaluated the effect of prophylactic administration of antipyretics (paracetamol and ibuprofen) on the immunogenicity of PCVs (any type) in healthy infants/children ≥2 months by measuring serum anti-pneumococcal IgG concentrations (Geometric mean concentration-GMC) or serotype-specific opsonophagocytic activity (OPA)- Geometric mean titers (GMTs), were selected for inclusion in the present review. Randomized control studies and observational studies were eligible for inclusion as opposed to review papers, clinical guidelines, case reports, and case series. Studies concerning children with comorbidities (immunodeficiency, chronic disorders, chronic use of analgesics, or other medications) or adults were excluded. Moreover, studies where therapeutic use of antipyretics occurred were also excluded.

Data extraction

A data extraction form was developed for this review to collect general information (authors, setting, publication year, design), participants’ baseline characteristics (number of participants, age, vaccine type and manufacturer, vaccine dosing schedule, time between receipt of vaccine and antibody testing, GMT point estimates), intervention elements (kind of antipyretic, administration schedule-time of administration) and record all significant findings.

Methodological quality assessment

Quality assessment of studies was undertaken using the Critical Appraisal Skills Program Tool for cohort and randomized controlled trials studies (CASP) (Table 1) [20].

Table 1 Quality assessment of studies
Full size table

Results

Search results

The literature search generated a total of 3956 studies, of which 186 were duplicates. Further, 3728 studies were removed due to the irrelevance of the title and abstract to the topic of the review. A full-text review of the remaining 42 studies led to the exclusion of 37, and the identification of 5 studies which fulfilled the inclusion criteria. Details of the literature search strategy are shown in Fig. 1.

Fig. 1
figure 1

PRISMA 2009 Flow Diagram

Full size image

Characteristics of the selected studies

Five studies were designed to evaluate the impact of the prophylactic use of antipyretics on the immunogenicity of pneumococcal vaccines in children [17, 21,22,23,24] (Table 2). All studies were randomized control trials (RCT), non-blinded and were performed in European Countries: three in Czech Republic, one in Poland, and one in Romania in the 2009–2017 period.

Table 2 Characteristics of the included studies
Full size table

Included studies had a total of 2775 participants. In four studies, the study population was 2–3 months of age at the time of enrollment and 12–15 months at the time of boosting [21,

Conclusions

Although the use of antipyretics, especially paracetamol, at the time of vaccination appears to reduce the side effects of vaccines, there is a decrease in antibody titers for some PCV antigens. This may raise doubts about the practice of antipyretic administration around vaccination time. This effect differs depending on the antipyretic agent used and may have a time-dependent administration component. The clinical significance of these findings is questionable, especially between primary and booster doses where antibody titers wane. However, after the booster doses, most participants developed protective antibody titers against vaccine antigens.

The small number of studies included in the above review does not allow us to draw certain conclusions. Especially after the near future possible introduction of 15 and 20-valent PCVs, questions regarding the effect of antipyretics on the immunogenicity of vaccines concerning the dose, frequency, and timing should be clarified. More well-designed future studies need to be conducted to provide clear evidence regarding the underlying mechanism and the possible association of immunogenicity with the type of antipyretics and the time of administration.