Streptococcus pneumoniae (Spn) is a gram-positive, encapsulated coccus; the World Health Organization (WHO) has identified diseases caused by Spn as a serious public health concern [1]. Indeed, Spn infection is a major cause of morbidity and mortality worldwide and is a leading cause of bacterial meningitis in children [2]. There were an estimated 103,000 cases of Spn globally with a case-fatality ratio (CFR) of 59% in 2000 [3]. With the introduction of pneumococcal conjugate vaccines (PCVs), the most recent study into the global burden of Spn in 2015 reported a decrease in burden to 83,900 cases (range 36,100-169,000) of pneumococcal meningitis with a CFR of 44% in children regardless of HIV status [4].

In 2007, the WHO recommended including the 7-valent polysaccharide-protein conjugate vaccine (PCV7) in national immunization programs, particularly in countries with high mortality rates from pneumococcal disease in children under 5 years [1]. PCV7 has been widely used for providing protection against 65%-85% of serotypes associated with invasive pneumococcal disease in young children [1]. However, since 2009, the WHO has recommended PCV10 or PCV13 depending on the country’s serotype prevalence, financial budget, and vaccine supply; thus, PCV7 is no longer in use [5]. Multiple notable trials worldwide have been conducted and are currently ongoing [6-11] to provide evidence for the preferred product and dosage schedule, which is currently recommended to be 3+0 or 2+1 [12]. As of December 2021, 147 countries (114 with PCV13, 26 with PCV10, and 7 with PCV10&PCV13) have implemented PCV into their national immunization programs, 60 of which are financially supported by the Global Alliance for Vaccines and Immunization [13]. The universalization of PCV has been estimated to have prevented 250,000 deaths in children from 2000 to 2015 [4].

Despite such continuous endeavors to globally implement PCV, the emergence of COVID-19 and associated pandemic measures affected a shift in the paradigm of Spn meningitis. The mass distancing measures contributed to a sharp decline in pneumococcal infections at the start of the pandemic [14]; however, disruption of vaccination programs has become prevalent and concerning [15,16]. Evidence forecasts that this phenomenon will lead to a detrimental increase in the cases of Spn meningitis [17]. The true impact of COVID-19 on the current Spn disease burden is yet to be determined. Therefore, an updated estimation of Spn meningitis will be an important comparator for future investigations and guide strategies to mitigate the pandemic’s negative impacts on Spn immunization programs.

Although the introduction of the vaccine has contributed to a decreasing trend in the burden of pneumococcal meningitis, the reported figures show a marginal reduction within the 15-year period [3,4]. Recent evidence highlights a concerning outlook for the future burden of the disease. Although vaccination has reduced the incidence of Spn for PCV serotypes, there has not been a uniform decrease in the incidence and CFR of Spn meningitis, revealing an issue of serotype replacement [18-21]. This predicament is exacerbated by the increasing antibiotic resistance to Spn meningitis [20,22,23]. Heterogeneity of serotypes and antibiotic resistance are persistent challenges facing other causes of bacterial meningitis, which demands the Spn burden to be scrutinized to a similar degree [24]. Ultimately, Wahl et al [4] reported that their study did not account for the outbreaks of pneumococcal meningitis, possibly leading to an underestimation. Furthermore, the current literature concurs with these authors’ concern about the countries that are yet to implement a national pneumococcal immunization program [4,14]. These problems call for further rigorous efforts in determining and monitoring the disease burden to direct policies to counter the numerous cases and deaths [4].

This review aims to provide the most up-to-date estimate of the global and regional burden of Spn meningitis in children under the age of 5 years. Our objective is to provide meaningful data regarding the global and regional incidence, CFR, and risk factors to guide policies in preventing and minimizing the burden of the disease.

The search from 4 databases resulted in 9295 articles, as shown in the PRISMA flowchart in Figure 1.

A total of 3213 articles were removed as duplicates and 326 studies were further removed due to the participants being adults or nonhuman or the articles being case reports. After the screening process, we included a total of 117 articles that met our eligibility criteria. We are currently undergoing the data extraction process, which will soon be followed by a meta-analysis. The expected completion date for extraction and analysis is January 2025 and the results are planned to be published by March 2025. The results of the completed study will be disseminated through international conferences and publication in a peer-reviewed journal.

This systematic review will identify the most recent global burden of Spn meningitis in children under 5 years of age, while providing important insights into factors that may contribute to a greater or lesser disease burden. Moreover, considering the frequency of sequelae following Spn meningitis, our study will comprehensively capture the types and incidence of the long-term clinical consequences associated with Spn meningitis in children [35].

Findings from our previous systematic review on Haemophilus influenzae type B (Hib) meningitis concurred with a long-standing challenge in the epidemiological literature [36,37], which is the scarcity of surveillance data in countries where such data are most needed. The least amount of data were acquired from the Southeast Asia Region and Eastern Mediterranean Region, which may have impacted the accuracy of our estimation. Therefore, this review will aim to assess and highlight the gaps in the evidence of Spn meningitis in children. For the same reason, we will include an assessment of outcomes and the body of evidence through the GRADE approach, using the GRADEpro Guideline Development Tool. Two independent reviewers (JJP and SN) will assess the quality of the outcomes. The third reviewer will adjudicate any disagreements that are unsettled between the two reviewers.

Although recent evidence indicates the decrease in language bias due to the trend of studies being published in English [37], our review on Hib meningitis had 6 studies that were published in a non-English language out of the 33 studies that were included. As a result, one of the major strengths of this review is including studies of all languages. We will be using Google Translate to acquire data from non-English studies and, similar to our previous review, we will seek advice from external individuals who speak the corresponding languages as necessary. This is to improve the accuracy of extracting data by understanding subtle nuances within the publication.

There are, however, some limitations to this review. We will not be including unpublished data from registers such as the WHO Invasive Bacterial Disease Surveillance Network, which may lead to an underestimation of the disease burden. In addition, we will focus on providing a crude estimate, which may be different from the adjusted values when factors such as HIV prevalence and vaccination have been considered. Nevertheless, this systematic review and meta-analysis will provide data that are comparable to the burden reported in the previous literature and will further expand our knowledge of the current global disease burden of Spn meningitis in children and the impact of universal vaccination programs.

With a specific focus on Spn meningitis in the pediatric population, this review is positioned to offer deeper insights into the disease burden and provide valuable guidance for managing Spn at a policy level for this vulnerable patient group.