Epidemiology of yellow fever virus in humans, arthropods, and non-human primates in sub-Saharan Africa: A systematic review and meta-analysis.

Yellow fever (YF) has re-emerged in the last two decades causing several outbreaks in endemic countries and spreading to new receptive regions. This changing epidemiology of YF creates new challenges for global public health efforts. Yellow fever is caused by the yellow fever virus (YFV) that circulates between humans, the mosquito vector, and non-human primates (NHP). In this systematic review and meta-analysis, we review and analyse data on the case fatality rate (CFR) and prevalence of YFV in humans, and on the prevalence of YFV in arthropods, and NHP in sub-Saharan Africa (SSA). We performed a comprehensive literature search in PubMed, Web of Science, African Journal Online, and African Index Medicus databases. We included studies reporting data on the CFR and/or prevalence of YFV. Extracted data was verified and analysed using the random effect meta-analysis. We conducted subgroup, sensitivity analysis, and publication bias analyses using the random effect meta-analysis while I2 statistic was employed to determine heterogeneity. This review was registered with PROSPERO under the identification CRD42021242444. The final meta-analysis included 55 studies. The overall case fatality rate due to YFV was 31.1% (18.3-45.4) in humans and pooled prevalence of YFV infection was 9.4% (6.9-12.2) in humans. Only five studies in West and East Africa detected the YFV in mosquito species of the genus Aedes and in Anopheles funestus. In NHP, YFV antibodies were found only in members of the Cercopithecidae family. Our analysis provides evidence on the ongoing circulation of the YFV in humans, Aedes mosquitoes and NHP in SSA. These observations highlight the ongoing transmission of the YFV and its potential to cause large outbreaks in SSA. As such, strategies such as those proposed by the WHO's Eliminate Yellow Fever Epidemics (EYE) initiative are urgently needed to control and prevent yellow fever outbreaks in SSA.

Introduction

Today and throughout history, animals have been an important source of pathogens transmitted to humans [1]. Between 1940 and 2004, over 60% of emerging infectious diseases in humans were due to pathogens from wildlife or domestic animals [2]. Some animal pathogens must be transmitted through an insect vector in order to infect humans [3,4]. A good example of such an animal pathogen requiring an insect vector to infect humans is the yellow fever virus (YFV) that causes yellow fever (YF) in humans. The YFV is an enveloped, positive-sense, single-stranded RNA virus that belongs to the genus of Flavivirus of the family Flaviviridae [5].

In a majority of humans, infection with the YFV may be asymptomatic or present with mild fever, headache, muscle pain and nausea. However, in about 20% of infected humans, the infection will progress to a severe form characterized by high fever, bleeding, jaundice, shock and, multiorgan failure and about 50% of these severe patients die within 7 to 10 days [6,7]. According to the World Health Organization (WHO), each year, about 200,000 YF cases and 30,000 deaths are reported of which nearly 90% of cases and death occur in Africa [8]. Clinically, YF presents with signs and symptoms similar to those of other diseases such as viral hepatitis and malaria and could easily be misdiagnosed for these diseases. As such, the actual number of YF cases could be several times higher than the reported number of cases [9].

YF is endemic in tropical and sub-tropical countries of South America and Africa [10]. In Africa, the YFV is spread through three transmission cycles: the sylvatic (or jungle) cycle, the intermediate (savannah) cycle and the urban cycle [11]. The sylvatic cycle is the primary cycle and spread of the YFV occurs between non-human primates (NHP) as reservoir hosts and forest dwelling mosquitoes such as Aedes africanus, Aedes opok, Aedes simpsoni, Aedes luteocephalus, Aedes taylori, Aedes vittatus. The YFV can then be passed from NHPs to humans when they visit or work in the jungle. The savannah cycle involves transmission of the YFV by an anthropo-zoophilic mosquito such as Aedes albopictus to humans living or working at the fringes of the jungle area. Aedes albopictus feeds on both animals and humans and serves as a bridge vector transferring YFV from animals to humans. In the urban cycle, domestic mosquitoes such as Aedes aegypti facilitates human-to-human transmission of the YFV [11-13].

The existence of an effective YF vaccine since the 1930s has greatly helped to contain YF outbreaks in Africa and beyond. However, since the mid-2000s, an upsurge in YFV transmission events have been reported throughout YF endemic countries especially in Africa [14-16]. Giving this unusual resurgence of YF transmission and the likelihood of major outbreaks, information on the burden and prevalence of YF in Africa is necessary for the development and deployment of counter measures [15]. We conducted a systematic review and meta-analysis to provide information in sub-Saharan Africa (SSA) on the prevalence and case fatality rate of YF in humans and on the prevalence of YF in arthropods and NHP.

Methods

Protocol and inclusion criteria

This systematic review was designed and conducted using the Preferred Reporting Items for Systematic Reviews and Meta–analyses (PRISMA) checklist (S1 Table) [17]. The protocol of this systematic review was published in the international database PROSPERO under the identification CRD42021242444. As this review reports on previously published data, ethical clearance was not required.

In this review, we considered cross-sectional studies, community and hospital-based studies and outbreak reports carried out in SSA. We included studies that reported on the prevalence and case fatality rate of YFV in humans, arthropods, NHP, and other animal species in SSA. Humans were further classified according to age, gender, disease state (healthy individuals and suspected YFV cases) and grouped according to the inclusion criteria of the selected studies. Arthropods were mosquitoes of the Diptera order. Other animal species and NHP were classified into their specific taxonomic orders.

To determine YF prevalence within the human populations, we included all studies reporting i) the detection of YFV specific IgM, ii) the detection of YFV specific IgG and/or IgM, iii) detection of YFV specific neutralizing antibodies, iv) detection of YFV by RT-PCR or viral isolation, v) detection of YFV specific antigens. As such, we included studies that utilize a wide range of methods for detection such as indirect immunofluorescence, complement fixation, culture, RT-PCR or ELISA, next-generation sequencing, or western blot.

Studies carried out of SSA or with inappropriate study design (comments, case reports, reviews, systematic reviews, and meta-analyses) as well as studies using positive YF samples or with sample size ≤ 10 were excluded. All studies from which data on YFV prevalence and case fatality rate (CFR) could not be obtained were also excluded. Studies published in neither the English nor French language or for which full text and abstract were either not available or could not be retrieved were also excluded.

Article search method to identify studies for inclusion

A comprehensive strategy was designed to enable a search of relevant studies in the following databases: PubMed, Web of Science, African Journal Online, and African Index Medicus. These databases were searched for studies published in English or French languages from January 2000 until February 2021 and updated in March 2022 to have contemporary data on YF. Main search strategy (S2 Table) was developed and used to search the databases. The literature search was supplemented by a review of the reference list of identified articles to find additional potential studies. Names of SSA countries and regional groupings were also used to search for studies indexed under these names.

Study selection and data extraction

After removing duplicates from the list of studies, titles and abstracts of the eligible studies were independently examined by two study authors (JETB and SK) for the selection of relevant studies. Data from the included studies was extracted using the online google form by 10 study authors and verified by SK and MGO. The extracted data were: the name of the first author, the year of publication, the study design, country, study period, sampling method, the study population (ill or apparently healthy humans, individual mosquitoes or negative pools, and NHP), age range of study population, YFV vaccine status, WHO Region, UNSD Region, country income level, YFV detection assay, YFV marker detected (virus, antigen, RNA, IgM or IgG), type of sample used for YFV detection, infection status (current, recent or past infections), sample size, number of positive for YFV, and number of deaths within YFV positive. For studies with less than 10 participants in animals and mosquitoes tested in pools and reporting a positive result, the names of the positive species were retained. Any difference in opinion with regards to the selection and inclusion of studies and extracted data were resolved by discussion, consensus, or by a third author.

Evaluation of the quality of studies

The quality of the studies considered was assessed using the tool of Hoy et al. (S3 Table) [18]. This tool consists of 10 questions that evaluates the external and internal validity of the study. The expected answers for each question were “yes”, “no”, “unclear” and “not applicable” depending on the content of the articles. A score of 1 was assigned for all “yes” answers and 0 for the other ones. Articles with a total score of 0–3, 4–6, and 7–10 were considered to be respectively at high, moderate, and low risk of bias.

Data synthesis

Data analysis was performed using R version 4.1.0 software [19]. We described without meta-analysis the positive YFV species of mosquitoes, NHP, and other animal species. The random effect model was performed to estimate combined prevalence of YFV and/or CFR in humans [20]. The Freeman-Tukey Double arcsine transformation was performed for the prevalence calculation [21]. The prevalence were represented as a forest plot with their corresponding 95% confidence intervals (CI). For the plot of the forest plot, a weighting according to the size of the sample was carried out to determine the size of the diamonds [22]. The Clopper-Pearson method was performed to calculate the 95% confidence interval of the prevalences [23,24]. Prevalences for future studies were determined by calculating a prediction interval [22,25]. The Cochran Q test and the I test statistic were used to measure the magnitude of heterogeneity between the included studies. The value of I more than 50%, was an indication of significant heterogeneity in the studies [26,27]. Sources of heterogeneity were investigated by subgroup analysis, and the sensitivity analysis that included only cross-sectional and low risk of bias studies was performed. Visual inspection of a funnel plot and the Egger test were used to estimate the risk of publication bias [28].

Results

Study selection

The literature search through databases provided a total of 3888 potentially relevant articles. After removing 1287 duplicate articles and excluding 2389 articles based on a careful review of the titles and abstracts, the remaining 212 articles were assessed for eligibility. Of the 212 articles, 157 full text articles were excluded for multiple reasons with absence of data on YFV prevalence or case fatality rate being the predominant reason (Fig 1 and S4 Table). We include a final total of 55 articles (151 datapoint on prevalence and/or CFR) in the qualitative and quantitative synthesis for this review [3-9,14,29-75].

Fig 1

PRISMA flow diagram.

Assessment of study quality

The majority of studies included were at moderate risk of bias, 119/151 (78.8%); a few had a low risk of bias 32/151 (21.2%), and none of the included studies had a high risk of bias (S5 Table).

Baseline characteristics of included studies

The summary and individual data of the included studies are presented in S6 and S7 Tables. The studies were published between 2001 and 2022 and the participants were recruited between 1990 and 2021. From the 151 data reported, 4/151 (2.8%) data reported CFR of YFV in humans, 71/151 (45.1%) reported prevalence of YFV in humans, 65/151 (43.0%) in mosquitoes, 7/151 (4.9%) in NHP, and 4/151 (2.8%) in other animal species. Data were majority recorded on cross-sectional studies 135/151 (88.7%), non-probabilistic 137/151 (90.7%), prospective 134/151 (88.7%), multicenter 136/151 (90.1%), and community-based 115/151 (76.2%). The included studies were conducted in 18 SSA countries with the highest number of studies conducted in Senegal 43/151 (28.5%) and the Central African Republic 33/151 (21.9%). Countries in West Africa 63/151 (41.7%) and Central Africa (49/151; 32.5%) had the largest number of studies. The predominant detection assays used to detect YFV in the included studies were sandwich ELISA 38/151 (25.2%), real-time RT-PCR 37/151 (24.5%), and infection of cellular cultures 35/151 (23.2%). The majority of studies found current YFV infection evidenced by the detection of viral RNA or live virus 89/151 (58.9%) and recent infection evidenced by the detection of IgM antibodies 32/151 (21.2%). With respect to studies among humans 64/63 (98.4%), NHP 5/7 (71.4%) and other animals 4/4 (100%), most of them found YFV in serum sample.

Prevalence of yellow fever virus in mosquitoes, non-human primates, and other animal species in sub-Saharan Africa

The mosquitoes tested in the pool were from the Culicidae family. Individually tested mosquitoes from the genus Aedes 28/65 (43.1%), Culex 14/65 (21.5%), and Anopheles 13/65 (20.0%) were predominantly represented. Only five articles reported the detection of YFV in individually tested mosquitoes with prevalence ranging from 0.0 to 12.0%. The mosquito species that were positive for YFV included Aedes aegypti, Aedes africanus, Aedes centropunctatus, Aedes dalzieli, Aedes furcifer, Aedes Luteocephalus, Aedes mcintoshi, Aedes taylori, Aedes vittatus, and Anopheles funestus [29,39,41,42,46]. All studies involving mosquitoes were detection of the ongoing presence of YFV either by virus isolation or RT-PCR. Mosquito samples positive for YFV were only reported in Senegal and Kenya. Only two articles reported the detection of YFV antibodies in NHP with prevalence ranging from 1.8 and 48.0%. The family of Cercopithecidae 6/7 (85.7%) was the most represented NHP. YFV antibodies were detected in Gabon and in the Central African Republic in Cercopithecidae of the species Mandrills, Chlorocebus, Cercopitheque, Cynocephalus, and Erythrocebus [4,70]. None of the studies detected the YFV RNA (current infection) in NHP tested. Other animal species studied to date belong to the order of Artiodactyla 2/4 (50%), Chiroptera 1/4 (25.0%) and Proboscidea 1/4 (25.0%). Only one sample from bats in eastern Africa (Uganda) was found to be positive for YFV antibodies [51]. No sample from other animal species (Buffalo, Duike and Elephant) from countries in Central Africa region were positive for YFV or YF antibodies.

Results of the meta-analysis

Case Fatality Rate of Yellow Fever Virus infection in humans in sub-Saharan Africa

A case fatality rate of YFV infection was recorded in 4 studies conducted in four Africans countries: Democratic Republic of the Congo [76], Nigeria [62], Uganda [5] and Sudan [6] (Fig 2a and 2b). A total of 128 YFV suspected cases were recruited in the 4 studies giving an overall CFR of 31.1% (95% IC: 18.3–45.4) and data presented no heterogeneity (I = 48.6%, [95% CI = 0.0%–83.0%], P = 0.1197) (Fig 3). This estimated CFR of YFV varied across infection status with 29.8% [95% CI = 12.7–49.9] in people with current infection, and 37.0% [95% CI = 19.6–56.6] in people with recent infection. Based on the funnel plot (S1 Fig) and Egger’s regression test, there was a good symmetry and no evidence of potential publication bias (P = 0.382) for determining the CFR of YFV in humans.

Fig 2

Case fatality rate and prevalence estimate of yellow fever virus in humans in sub-Saharan Africa.

The letters (A and B) show the case fatality rate in humans with current and recent yellow fever virus exposures, respectively. The letters (C, D, and E) denote current, recent and past yellow fever virus exposures, respectively. The base map was taken from (https://www.naturalearthdata.com/) and modified with Qgis software.

Fig 3

Case fatality rate estimate of yellow fever virus infections in humans in sub-Saharan Africa.

Prevalence of Yellow Fever Virus infection in humans in sub-Saharan Africa

Studies on humans recruited mostly YFV suspected cases 22/71 (34.4%), apparently healthy individuals 22/71 (31.0%) and febrile patients 14/71 (19.7%). None of the studies considered, reported on the vaccination status of the enrolled participants. The overall prevalence of YFV recorded in 67098 human participants recruited from 71 datapoints prevalence was 9.4% (95% CI = 6.9–12.2) with a substantial heterogeneity between studies (I2 = 99.1% [95% CI = 99.0%–99.2%], p <0.001) (Figs 2c, 2d, 2e and 4, and S2 Fig). Regardless of the type of infection, the prevalence of YFV was 18.8% (95% CI = 11.8–27.0; 15578 participants), 6.0% (95% CI = 3.4–9.2; 29267 participants), and 5.3% (95% CI = 2.7–8.5; 22053 participants) in human participants with past, recent, and current infection respectively. Funnel plot (S3 Fig) and Egger’s regression test (Table 1) showed the existence of publication bias for studies of all types of YFV infections (p<0.001).

Fig 4

Prevalence estimates of yellow fever virus infections in humans in sub-Saharan Africa.

Table 1

Summary of meta-analysis results for case fatality rate and prevalence of yellow fever virus in humans in sub-Saharan Africa.

	Prevalence. % (95%CI)	95% Prediction interval	N Studies	N Participants	¶H (95%CI)	§I2 (95%CI)	P heterogeneity
YFV case fatality rate in humans
Current infection
Overall	29.8 [12.7–49.9]	[0–100]	3	101	1.5 [1–2.9]	57.7 [0–87.9]	0.094
Cross-sectional	23.1 [14.3–33.1]	NA	1	78	NA	NA	1
Recent infection
Overall	37 [19.6–56.2]	NA	1	27	NA	NA	1
YFV prevalence in humans
Current infection
Overall	5.3 [2.8–8.5]	[0–23.8]	19	22253	6.7 [6–7.4]	97.8 [97.2–98.2]	<0.001
Cross-sectional	3.6 [1.3–6.8]	[0–20.8]	12	21313	7.7 [6.8–8.8]	98.3 [97.8–98.7]	<0.002
Low risk of bias	0.8 [0–3.1]	[0–19.2]	4	18272	6.8 [5.3–8.9]	97.9 [96.4–98.7]	<0.003
Past infection
Overall	18.8 [11.8–27]	[0–64.9]	22	15578	11.7 [10.9–12.6]	99.3 [99.2–99.4]	<0.001
Cross-sectional	18 [11.2–26]	[0–62.4]	21	14973	11.3 [10.5–12.2]	99.2 [99.1–99.3]	<0.002
Low risk of bias	12.7 [5–23.3]	[0–65.7]	13	10297	13.5 [12.4–14.6]	99.4 [99.3–99.5]	<0.003
Recent infection
Overall	6.1 [3.5–9.3]	[0–29.4]	30	29267	8.3 [7.7–8.9]	98.5 [98.3–98.7]	<0.001
Cross-sectional	4.3 [2.1–7.2]	[0–24.1]	25	28353	8.2 [7.5–8.9]	98.5 [98.2–98.7]	<0.002
Low risk of bias	2.1 [0.9–3.9]	[0–11.1]	11	24532	6.4 [5.5–7.5]	97.6 [96.7–98.2]	<0.003

CI: confidence interval; N: Number; 95% CI: 95% Confidence Interval; NA: not applicable.

¶H is a measure of the extent of heterogeneity. a value of H = 1 indicates homogeneity of effects and a value of H >1indicates a potential heterogeneity of effects.

§: I2 describes the proportion of total variation in study estimates that is due to heterogeneity. a value > 50% indicates presence of heterogeneity

Subgroup analysis of meta-analysis results for case fatality rate and prevalence of yellow fever virus in humans in sub-Saharan Africa

Subgroup analyses of case fatality rate and prevalence of YFV in humans, mosquitoes, NHP, and other animal species in SSA is summarize in S8 Table and Fig 2. Analysis of the data showed that YFV CFR was significantly higher in community-based studies (42.3%; 95%CI: 27.0–58.4; p = 0.031). Community-based studies (10.4%; 95%CI: 6.9–14.4; p = 0.015), conducted in Nigeria (44.7%; 95%CI: 36.3–53.2), Cameroon (26.1%; 95%CI: 12.0–43.1), and Sudan (25.6%; 95%CI: 5.8–52.5; p < 0.015), recruiting hospitalized participants (27.1%; 95%CI: 11.3–46.5; p = 0.014), suspected YFV cases (11.4%; 95%CI: 7.7–15.7), YFV positive case contacts (10.6%; 95%CI: 0.0–34.2), and apparently healthy individuals (10.8%; 95%CI: 6.1–16.7; p < 0.001) were more likely to show higher YFV prevalence.

Discussion

The present study is the first systematic review and meta-analysis on the prevalence and CFR of YFV in humans, and YFV prevalence in arthropods, NHP, and other animal species in SSA. Overall, our analysis reports a computed pooled CFR estimate due to YF of 31.1% in humans and an overall prevalence of 9.4% of YFV in humans. Mosquitoes positive for YFV included several species of the genus Aedes and Anopheles funestus. Only NHP of the Cercopithecidae family showed serological evidence of exposure to YFV.

The estimated CFR of YFV in humans identified in this review is consistent with that recently reported in a global review with a CFR of 36% for Africa [77]. Such a high CFR could be due to delays or deterrents in seeking care during the early less sever phase of the disease or delayed clinical diagnosis of cases [62,76]. It should also be noted that African population is more at risk of contracting the yellow fever virus and of developing severe forms and death due to a low rate of vaccination coverage and daily activities that bring them closer to vectors such as agriculture, livestock, hunting, and deforestation [77-80]. Also, the existence in Africa of other health conditions such as malnutrition, tuberculosis, malaria and, HIV are other factors that could be associated with this high of YFV CFR [81-83]. About 1/5th (18.8%) of sampled human participants included in this review had IgG antibodies against YFV (past infection). YF IgG antibodies could be naturally acquired following an infection with the virus or following vaccination with the YF vaccine [84]. It is unclear if participants in the included studies had received the YF vaccine as participant’s vaccination history was not reported in most studies. However, the estimated seroprevalence level is slightly reflective of naturally acquire IgG antibodies as the value is comparable to values reported by individual studies conducted on non-vaccinated persons in subgroup analysis. Even so, we cannot rule out the contribution of the YF vaccine on the seroprevalence levels. Most of the included studies were conducted in countries with moderate to high levels of YF vaccine coverage [85]. Despite reports of a good vaccine coverage in SSA including countries incorporated in this review, YF infection continues to persist. The prevalence rates of current and recent infection were 5.3% and 6.0% respectively. This prevalence levels could even be higher if not of the inherent limitation in detecting YF viral RNA and/or antigen (current infection) and YF IgM antibodies (recent infection). Identifying these infection biomarkers is totally dependent on the timing of sample collection and if the studied area is endemic to other flaviviruses such as Dengue, Zika [86]. YF viral RNA and/or antigen can be detected in serum of symptomatic patients only during the first 7 days of illness or for longer periods in severe cases (30% of patients). As such, in the 70% of patients presenting mild symptoms, if this period of sample collection is missed, testing for viral RNA and/or antigen may not be clinically useful. Generally, YF diagnosis relies on the detection YF IgM antibodies as IgM antibodies can be detected for up to 3 months following infection. However, in patients with a prior history of infection with other flaviviruses, IgM antibodies may absent or present briefly (<1 month) thereby hampering IgM detection [87-89]. Among the included studies, high numbers of current and recent YF infections were predominantly detected in studies in Nigeria, Cameroon, and Sudan and among hospitalized patients who were most likely exhibiting severe symptoms.

Mosquitoes or the genus Aedes are the primary vectors responsible for the transmission of the YFV in all transmission cycles [13]. Surprisingly, despite evidence of YF infection in humans, very few of the included individual studies were able to identify YFV in mosquitoes. Broadly, mosquitoes of the Aedes genus specifically Aedes africanus, Aedes furcifer, Aedes luteocephalus, Aedes taylori, and Aedes vittatus in rural settings and Aedes aegypti in an urban setting were found to be positive for YFV. The relatively low detection of YFV in mosquitoes could be due to the low viral load in mosquitoes making detection by direct isolation or RT-PCR very challenging. Also, collected mosquitoes need to be transported at low temperatures to prevent degradation of viral RNA [90]. New techniques and technological advances such as mosquito traps with inserted FTA nuclei acid preservation cards could help bypass some of these challenges in sampling mosquitoes for YF detection [91,92]. NHP are generally considered as competent reservoir hosts of the YFV and are responsible for maintaining the sylvatic YFV transmission cycle [13]. In this review, we found a low rate of YFV antibodies exposure among NHP. Among the NHP, YFV antibodies were detected in mandrills from Gabon and Cercopithecidae from the Central Africa Republic, although the number of studies on NHP were limited. The scanty evidence of acute and/or recent infection of YFV in NHP makes it difficult to understand their role as reservoir host and in maintaining the sylvatic and intermediate transmission cycle in SSA. Although antibodies to YFV were detected in a bat in Uganda, the role of bats as a reservoir could not be ascertained and this would probably be the result of a cross-reaction with another virus [89].

Overall, this systematic review and meta-analysis provides evidence on the ongoing circulation of the YFV in humans, Aedes mosquitoes and NHP in SSA. Our analysis reports on the prevalence of the YFV among the different studied populations. The high number of studies included in this review increases the accuracy of reported estimates. However, there are at least two limitations to our study. First, we observed substantial heterogeneity among the included studies that still existed even when subgroup analyses were done. Secondly, most of the reported pooled estimates had significant publication bias. Despite these limitations, our analyses revealed: the presence of YFV in humans with a relatively high CFR especially during outbreak, one family of NHP (Cercopithecidae) served as a potential reservoir host and Aedes species as main vector of YFV in SSA. These observations highlight the ongoing transmission of the YFV and its potential causing large outbreaks in SSA. As such, strategies such as those proposed by the WHO’s Eliminate Yellow Fever Epidemics (EYE) initiative are urgently needed to control and prevent YFV outbreaks [93].

Preferred reporting items for systematic reviews and meta-analyses checklist.

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Search strategy in PubMed.

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Items for risk of bias assessment.

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Main reasons of exclusion of eligible studies.

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Risk of bias assessment.

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Characteristics of included studies.

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Individual characteristics of included studies.

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Subgroup analyses of case fatality rate and prevalence of yellow fever virus in humans in sub-Saharan Africa.

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Funnel chart for publications of the yellow fever virus case fatality rate in sub-Saharan Africa.

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Prevalence estimate of yellow fever virus infections in humans in sub-Saharan Africa.

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Funnel chart for publications of the yellow fever virus prevalence in humans in Africa.

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24 May 2022

Dear Dr Kenmoe,

Thank you very much for submitting your manuscript "Epidemiology of yellow fever virus in humans, arthropods, and non-human primates in sub-Saharan Africa: a systematic review and meta-analysis." for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

The review and meta-analyzed article were well received by the reviewers; however, some issues require more attention. Additional details are needed in the statistical methods section

The discussion maybe improved by expanding the section that compared the meta-analyzes with recent reports and the section pointing to the limitations of this study

Fig-2) It would may help to link the maps of Fig-2 with the graphs of Fig-3

Fig-3) Fig-3 is mostly a table, the graph shown is redundant with the data.

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The review and meta-analyzed article were well received by the reviewers; however, some issues require more attention. Additional details are needed in the statistical methods section

The discussion maybe improved by expanding the section that compared the meta-analyzes with recent reports and the section pointing to the limitations of this study

Fig-2) It would may help to link the maps of Fig-2 with the graphs of Fig-3

Fig-3) Fig-3 is mostly a table, the graph shown is redundant with the data.

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The objectives of the study are clearly stated.

The systematic review and meta-analysis design adopted in this study is appropriate to address the study objectives.

The study area covered, study population was explicitly described.

Sample size was not necessary for this study, since this was a systematic review of published literature.

The descriptive, and meta-analysis methods were appropriate to analyze the data. Sensitivity and publication analyses were appropriate to address heterogeneity and publication bias.

there are no concerns about ethical requirements. The review reports on previously published data, ethical clearance was not required.

Reviewer #2: 1)- The objectives of the study were generally articulated

2)- In general the section Mthods needs further imporvements. For exemple, the authors should:

a) describe in depth the statistical method of the meta-analysis (ex. fixed effect or rendom effect estimation).

b) provide sensitvity analysis to show the robustness of the results.

c)- provide the criteria and summary table (or figure) showing the quality of the studies should be given in the manuscript. This help to assess the comparability of the studies before performing the meta-analysis.

Reviewer #3: The methodology followed sufficient analysis. Clearly describing the entire methodology.

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: the analysis presented marched the analysis plan

Risk of bias: was well conducted to clearly ascertain the quality of included studies.

Baseline description: the summary and individual data of the included studies was clearly presented as stated in the analysis plan

Random effect model: clearly done to estimate the CFR of YFV and the prevalence of YFV among humans and the results presented in forest plot

Cochran Q test and the I2 test statistic: results clearly reported as described in the analysis plan

Sensitivity analysis: sub-group analysis was conducted as stated in the analysis plan

publication bias and analysis: Funnel plots and Egger's regression test are presented as stated in analysis plan

the results and figures are clearly and completely presented

the figures are of sufficient quality, well labeled and clear

Reviewer #2: 1)- The results fairly matched with the plan analysis

2)- The results should be compared with current results observed in the litterature.

3)- The quality of figures may be improved.

Reviewer #3: The analyzes followed the methodological planning and presented very interesting results.

I emphasize that these results are of paramount importance for public health worldwide.

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: All the conclusions are supported by the data presented

Limitations of the analysis are clearly stated (L356-L359)

Detailed discussion of how the data advances our understanding of the topic is clearly elaborated.

the public health relevance of the study is addressed

Reviewer #2: 1)- The conclusions were generally clear.

2)- However, beyond the classical limits (heterogeneity, publication bais), the authors may provide others specific limitations of the study

Reviewer #3: The conclusion is supported by the data presented conclusively. The limitations of the study are clearly presented. This is a very important study for global public health as it is the first review in the region.

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: The data was clearly presented in this article and there are modifications am suggesting to the authors.

Reviewer #2: (No Response)

Reviewer #3: I suggest accepting the article without changes.

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: The authors followed all the necessary steps laid out in the PRISMA guideline and the systematic review and meta-analysis was clearly conducted.

All results were systematically presented reporting pooled and heterogeneity results.

Issues around publication bias were reported and highlighted as part of the limitations

Reviewer #2: (No Response)

Reviewer #3: (No Response)

--------------------

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Thamiris D'Almeida Balthazar

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References

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article's retracted status in the References list and also include a citation and full reference for the retraction notice.

3 Jun 2022

Submitted filename: Response to Reviewers - PNTD-S-22-00548.doc

Click here for additional data file.

27 Jun 2022

Dear Dr Kenmoe,

We are pleased to inform you that your manuscript 'Epidemiology of yellow fever virus in humans, arthropods, and non-human primates in sub-Saharan Africa: a systematic review and meta-analysis.' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Ernesto T. A. Marques, M.D./Ph.D

Associate Editor

PLOS Neglected Tropical Diseases

Scott Weaver

Deputy Editor

PLOS Neglected Tropical Diseases

***********************************************************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The objectives of the study are clearly stated.

The systematic review and meta-analysis design adopted in this study is appropriate to address the study objectives.

The study area covered, study population was explicitly described.

Sample size was not necessary for this study, since this was a systematic review of published literature.

The descriptive, and meta-analysis methods were appropriate to analyze the data. Sensitivity and publication analyses were appropriate to address heterogeneity and publication bias.

there are no concerns about ethical requirements. The review reports on previously published data, ethical clearance was not required.

Reviewer #2: I have no additional comments. The responses of the authors to me responses are acceptable

Reviewer #3: All considerations were accepted and reviewed, and I am satisfied with the article.

**********

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: the analysis presented marched the analysis plan

Risk of bias: was well conducted to clearly ascertain the quality of included studies.

Baseline description: the summary and individual data of the included studies was clearly presented as stated in the analysis plan

Random effect model: clearly done to estimate the CFR of YFV and the prevalence of YFV among humans and the results presented in forest plot

Cochran Q test and the I2 test statistic: results clearly reported as described in the analysis plan

Sensitivity analysis: sub-group analysis was conducted as stated in the analysis plan

publication bias and analysis: Funnel plots and Egger's regression test are presented as stated in analysis plan

the results and figures are clearly and completely presented

the figures are of sufficient quality, well labeled and clear

Reviewer #2: I have no additional comments. The responses of the authors to my comments are acceptable.

Reviewer #3: All considerations were accepted and reviewed, and I am satisfied with the article.

**********

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: All the conclusions are supported by the data presented

Limitations of the analysis are clearly stated

Detailed discussion of how the data advances our understanding of the topic is clearly elaborated.

the public health relevance of the study is addressed

Reviewer #2: I have no additional comments. The responses of the authors to my comments are acceptable.

Reviewer #3: All considerations were accepted and reviewed, and I am satisfied with the article.

**********

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: The data was clearly presented in this article

no modifications suggested as in previous submission

Reviewer #2: Accept

Reviewer #3: I recommend accepting the article.

**********

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: The authors followed all the necessary steps laid out in the PRISMA guideline

All results were systematically presented

Issues around publication bias were reported

Reviewer #2: I have no additional comments. The responses of the authors to my comments are acceptable.

Reviewer #3: (No Response)

**********

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

7 Jul 2022

Dear Dr Kenmoe,

We are delighted to inform you that your manuscript, "Epidemiology of yellow fever virus in humans, arthropods, and non-human primates in sub-Saharan Africa: a systematic review and meta-analysis.," has been formally accepted for publication in PLOS Neglected Tropical Diseases.

We have now passed your article onto the PLOS Production Department who will complete the rest of the publication process. All authors will receive a confirmation email upon publication.

The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Editorial, Viewpoint, Symposium, Review, etc...) are generated on a different schedule and may not be made available as quickly.

Soon after your final files are uploaded, the early version of your manuscript will be published online unless you opted out of this process. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers.

Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases