Skip to main content
PLOS Medicine logoLink to PLOS Medicine
. 2023 Jul 17;20(7):e1004250. doi: 10.1371/journal.pmed.1004250

The age profile of respiratory syncytial virus burden in preschool children of low- and middle-income countries: A semi-parametric, meta-regression approach

Marina Antillón 1,2,3,*, Xiao Li 1, Lander Willem 1, Joke Bilcke 1; RESCEU investigators, Mark Jit 4, Philippe Beutels 1
PMCID: PMC10389726  PMID: 37459352

Abstract

Background

Respiratory syncytial virus (RSV) infections are among the primary causes of death for children under 5 years of age worldwide. A notable challenge with many of the upcoming prophylactic interventions against RSV is their short duration of protection, making the age profile of key interest to the design of prevention strategies.

Methods and findings

We leverage the RSV data collected on cases, hospitalizations, and deaths in a systematic review in combination with flexible generalized additive mixed models (GAMMs) to characterize the age burden of RSV incidence, hospitalization, and hospital-based case fatality rate (hCFR). Due to the flexible nature of GAMMs, we estimate the peak, median, and mean incidence of infection to inform discussions on the ideal “window of protection” of prophylactic interventions. In a secondary analysis, we reestimate the burden of RSV in all low- and middle-income countries. The peak age of community-based incidence is 4.8 months, and the mean and median age of infection is 18.9 and 14.7 months, respectively. Estimating the age profile using the incidence coming from hospital-based studies yields a slightly younger age profile, in which the peak age of infection is 2.6 months and the mean and median age of infection are 15.8 and 11.6 months, respectively. More severe outcomes, such as hospitalization and in-hospital death have a younger age profile. Children under 6 months of age constitute 10% of the population under 5 years of age but bear 20% to 29% of cases, 28% to 39% of hospitalizations, and 38% to 50% of deaths.

On an average year, we estimate 28.23 to 31.34 million cases of RSV, between 2.95 to 3.35 million hospitalizations, and 16,835 to 19,909 in-hospital deaths in low, lower- and upper middle-income countries. In addition, we estimate 17,254 to 23,875 deaths in the community, for a total of 34,114 to 46,485 deaths. Globally, evidence shows that community-based incidence may differ by World Bank Income Group, but not hospital-based incidence, probability of hospitalization, or the probability of in-hospital death (p ≤ 0.01, p = 1, p = 0.86, 0.63, respectively). Our study is limited mainly due to the sparsity of the data, especially for low-income countries (LICs). The lack of information for some populations makes detecting heterogeneity between income groups difficult, and differences in access to care may impact the reported burden.

Conclusions

We have demonstrated an approach to synthesize information on RSV outcomes in a statistically principled manner, and we estimate that the age profile of RSV burden depends on whether information on incidence is collected in hospitals or in the community. Our results suggest that the ideal prophylactic strategy may require multiple products to avert the risk among preschool children.


Marina Antillon and colleagues use updated statistical models to estimate the burden of RSV in low- and middle-income countries with the aim of improved targeted prevention strategies.

Author summary

Why was this study done?

  • Respiratory syncytial virus (RSV) is the most common cause of acute pulmonary infections in children. The RSV disease burden is high, especially in the nearly 600 million children under 5 living in 121 low-income (LIC) and middle-income countries (MICs) on which this study focuses.

  • Evidence on the age distribution of RSV infections in these countries is based on sparse data using age breakdowns that are not always comparable.

  • Different pharmaceutical products are becoming available that can reduce the RSV burden. Given that the immunity these products confer differs and wanes over time, it is essential to understand well at which months of age RSV infections drive the RSV disease burden.

  • This study uses improved statistical models to estimate in depth the age profile of RSV cases, hospitalizations, and in-hospital deaths in young children.

What did the researchers do and find?

  • We calculated the distributions of the age of infection, hospitalization, and in-hospital deaths. Depending on whether we use hospital-based or community-based incidence studies to inform our methods, we estimate the peak age of infection at 2.6 to 4.8 months, the mean age at 15.8 to 18.9, and the median age at 11.6 to 14.7 months.

  • We estimate that on an average year, there are 28.23 to 31.34 million cases of RSV, 2.95 to 3.35 million hospitalizations, and 34,114 to 46,485 deaths in children under 5 in LICs and MICs. About half the deaths occur in the community, outside of hospital settings.

  • More severe outcomes, such as hospitalizations and in-hospital deaths have a younger age profile. Children under 6 months of age constitute 10% of the population under 5 years of age but bear 20% to 29% of cases, 28% to 39% of hospitalizations, and 38% to 50% of deaths.

What do these findings mean?

  • Our results support strategies using passive immunity products, such as maternal vaccines and monoclonal antibodies, to protect infants and active vaccination strategies for children over one, who also bear a large proportion of the burden.

  • These results improve the choice of strategies offering the best value for money from a given budget.

  • This study may enable modelers to make improved estimates thus allowing policymakers to gain a better understanding of the potential impact that new pharmaceutical products could have.

Introduction

Respiratory syncytial virus (RSV) infections are responsible for the largest proportion of acute lower respiratory infections (ALRIs) in low- and middle-income countries, and by extension, it is among the top 5 causes of death in children under 5 years of age [1,2]. Among severe ALRIs in children under 5 years of age in low-income countries (LICs), lower-middle-income countries (LMICs), and upper-middle-income countries (UMICs), RSV is the single largest cause of pneumonia, accounting for 31% of cases [2]. RSV transmission is determined by various factors, maternally conferred immunity [35], social contact patterns [610], and the short duration of immunity from infection [1113].

Epidemiological questions surrounding RSV in early life are now more pressing because of (1) ongoing research and development of multiple prophylactic products—ranging from vaccines administered to mothers and children to monoclonal antibodies administered to infants [1420]; and (2) ongoing policy discussions for optimal use of prophylaxis in resource-constrained settings [2126]. Maternally derived antibodies of RSV have a half-life of 36 to 38 days [4,5]. Chu and Englund’s systematic review found maternal vaccines—against any disease—protect children no longer than 4 months [27]. A currently licensed short-acting monoclonal antibody, palivizumab, requires monthly administrations [16,17]. Newer antibodies with “extended” half-lives last between 62 to 150 days [18,19]. Recently announced topline results for Pfizer’s ongoing trial of a RSVpreF maternal vaccine showed 69% reduction in medically attended lower-respiratory tract infections through 6 months of age. An additional set of products under development are active immunizations or childhood vaccines, which could work as a follow-up product to maternal vaccines or monoclonal antibodies administered in the first few weeks of life [20,28,29]. In light of the importance of the duration of protection and the presence of a potential high cost, it is imperative to develop detailed age-specific estimates of incidence, hospitalization, and mortality that can be incorporated with careful economic analyses that weigh the costs and the benefits of options for using these products.

The current evidence on the age distribution of RSV infections in low- and middle-income countries is based on sparse data. While the systematic review by Shi and colleagues and updated by Li and colleagues found data from numerous (previously unpublished) hospital-based studies, the age profile of RSV incidence remains elusive because studies present the data in broad differing age bands, making comparison and synthesis a challenge [30,31]. Among studies that presented sufficient data to evaluate the age profile of RSV burden (data stratified in 3 or more age groups), there were only 18 community-based incidence studies in low and middle-income countries and, of these, only 8 studies presented the probability of hospitalization among cases in the community. Therefore, although there are numerous studies on the age profile of hospitalized cases in many settings, the age-specific relationship between community and hospital incidence remains unclear.

Moreover, the epidemiological data as it is presented in the literature is often discretised using 1 to 7 age groups under the age of 5 years [30,31] rendering the incidence across early childhood as only a partially observed process which could be interpolated by employing a strong assumption of monotonicity [3034]. The interpolation of RSV incidence, hospitalization, and deaths throughout early childhood for different settings requires potentially influential assumptions with consequences for health policy [21].

An alternative approach has been carried out to inform vaccine interventions. Rather than estimating absolute incidence, one study based in Kenya estimated the ideal “vaccine window” using a combination of serological data and nested catalytic models to estimate the optimal age for prophylaxis [35]. However, the vaccine window has not been estimated across different settings or reexamined using community and clinical outcome data.

In the current study, we leverage the data collected by Shi and colleagues and Li and colleagues in combination with an alternative statistical approach to present estimates that circumvent the shortcomings listed above. We use random-effects generalized additive models, a family of semi-parametric models to construct nonlinear and non-monotonic piece-wise defined functions that characterize the trends of RSV across early childhood. By characterizing the age distribution of RSV incidence, hospitalization, and death among young children across different settings, we reestimate the peak, median, and mean age of infection, therefore, informing discussions on the ideal “vaccine window” of a prophylactic drug with a defined duration of protection. In a secondary analysis, we reestimate and reconsider the burden of RSV for different countries and country groups.

Methods

Data

Data on RSV cases in the community, hospitals, and in-hospital deaths were extracted from Shi and colleagues’ and Li and colleagues’ systematic reviews, restricting to studies carried out with an end date in 2000 or later, as this reflects more recent disease patterns, diagnostic practices, and treatment success rates [30,31]. Table 1 shows an overview of the studies available by country income group and outcome of interest—community- and hospital-based incidence, the probability of hospitalization, and the probability of death. We used studies that reported age-specific incidence in at least 3 mutually exclusive age groups for the estimation and studies that used fewer age groups for out-of-sample validation. Modifications to the data provided by Shi and colleagues and Li and colleagues for the purpose of computational compatibility with our approach are detailed in Section S1.1 in S1 Text. These modifications are primarily to distill the data to mutually exclusive age groups and to transform reported incidence and confidence intervals to counts of cases and denominator (population-time).

Table 1. Number of studies available for each RSV-related outcome, in total and broken down by World Bank income category.

All countries Low income Low-middle income Upper-middle income
Spline I: Community-based incidence
Estimation dataset 18 (S:15, VS:4) 0 12 (S:11, VS:4) 6 (S:4)
Validation dataset 2 0 2 0
Spline II: Hospital-based incidence
Estimation dataset 37 (S:15, VS:13) 5 (S:2, VS:3) 14 (S:5, VS:4) 18 (S:8, VS:6)
Validation dataset 15 (S: 1, VS: 1) 2 8 (S: 1, VS: 1) 5
Spline III: Probability of hospitalization among cases in the community
Estimation dataset 8 0 5 3
Validation dataset 3 0 2 1
Spline IV: Probability of death among hospitalized cases
Estimation dataset 58 9 24 25
Validation dataset 30 3 8 19

For outcomes I and II, the numbers in parentheses indicate the number of studies that have additional information regarding severe (S) and very severe cases (VS). Studies where the outcome was stratified for at least 3 age groups were used to estimate the splines, and studies for which the outcome was presented for only 1 or 2 age groups were used as a form of out-of-sample validation. For a visual of the geographic distribution of different data types, see Fig A in S1 Text.

Model of RSV epidemiology

Since the data on RSV epidemiology in infants and preschool children is usually presented in age groups spanning several months or up to a year, making the month-by-month age-specific epidemiology a partially observed process, we sought a method to estimate monthly interpolations of incidence, hospitalization, and mortality before the age of 5. However, not all of the measures of interest are available from all settings where studies were run, resulting in a fragmented understanding of how cases, hospitalizations, and deaths are related. Therefore, we adopted an approach that leverages the age-specific data on each of these outcomes where available, integrating the extant age-specific data on RSV epidemiology into a burden model (BM) that assumes that community, hospitalized, and fatal cases in hospitals follow a multiplicative relationship, as shown in Fig 1. In other words, within this framework, the probability that a case in the community becomes a case in the hospital and that the hospitalized case becomes a fatality is itself age dependent. Moreover, we compare 2 outcomes models (OMs): OM I, in which the starting point is community-based incidence, and then the conditional probability of hospitalization given infection and in-hospital death are applied, and the second, OM II, in which the starting point is hospital-based incidence, and the conditional probability of hospitalization is used to back-calculate community incidence and the probability of death is applied to calculate fatalities. In the absence of any reason to choose one model over another, we look at the results of both side-by-side.

Fig 1. Relationship between cases, hospitalizations, and deaths in children from birth to 59 months of age.

Fig 1

(A) OMs (age-specific). There are 2 ways to construct outcomes splines of the number of cases, hospitalizations, and deaths from the data in the literature, corresponding to OM I and II. The boxes show incidence and the ovals show the probability of progressing from a case in the community to a case in the hospital or from a case in the hospital to a fatal case. It should be noted that the product of incidence and probability yields an incidence. The colored boxes show the splines (splines I–IV) that we estimated from data in the literature, and the black boxes show incidence derived as products of our splines. In OM I, we use the incidence of community-acquired RSV cases (spline I) and the probability of hospitalization given infection (spline III) and deaths among inpatients (spline IV) and we derive the incidence of hospitalizations and the incidence of death due to RSV. In OM II, we use the incidence of RSV cases from hospital-based studies (spline II) and the probabilities of hospitalization and inpatient death and we back-calculate the community-based incidence and the incidence of death due to RSV. From these spline models, we also estimated the peak, median, and mean age of infection. (B) BMs of disease in population. There are 2 ways to calculate the burden of disease in one country: for BM I, we apply the country population size to the incidences derived in (A) and aggregate cases into subgroups according to age; for BM II, we take the number of cases in the country as calculated by Li and colleagues’ risk-factor model, apply the proportion of cases that occur in each month of age according to our splines, and aggregate cases into subgroups according to age. Because there are 2 ways to calculate age-specific incidence in part (A) and 2 ways to calculate burden in part (B), 4 sets of burden estimates result. A full mathematical derivation of this is found in Section S1.4 in S1 text. BM, burden model; OM, outcomes model; RSV, respiratory syncytial virus.

Because RSV outcomes do not necessarily have linear or monotonous relationships with age, we estimated interpolation splines within the generalized additive mixed model (GAMM) framework, a semi-parametric approach [36,37]. Unlike fully parametric models in which the predictors and the outcomes are assumed to have a linear or a linear-transformed relationship—potentially a strong or unwarranted assumption—GAMMs sum polynomials to produce an interpolation spline, yielding a highly flexible modeling framework. Four predictive functions were estimated:

  • Spline I: age-specific incidence as measured in community-based studies.

  • Spline II: age-specific incidence as measured in hospital-based studies.

  • Spline III: age-specific conditional probability of hospitalization given (measured in community-based studies).

  • Spline IV: age-specific conditional probability of death given hospitalization (hCFR) (measured in hospital-based studies).

Furthermore, we tested the significance of the income group (as designated by the World Bank in 2020) as a modifier of the age-dependent spline. Our baseline model was one that included a single (global) spline to explain the relationship between the outcome and age. Then, we tested whether a fixed-effect spline stratified by income group was enough to capture the differences between countries or whether both a fixed-effect and study-specific random-effect splines stratified by income group were necessary to capture the trends. Models were compared using the generalized likelihood ratio test using the χ2 statistic. Further details are found in Section S1.4 in S1 Text.

We projected each of the splines by sampling 5,000 times from a multivariate normal distribution described by the model coefficients to the link function (log for incidence, logit for probability) and back-transformed to present incidence or probabilities as appropriate. This allowed us to propagate the uncertainty of each of the splines throughout the outcome and burden models described below. Further details on our estimates of uncertainty are found in Sections S.1.5.1 to S1.5.2 in S1 Text.

Outcome models: Cases, hospitalizations, and deaths among hospitalizations

The information from the literature can be used in 2 different ways to calculate the number of cases, hospitalizations, and deaths, corresponding to outcome models (OMs) I and II (Fig 1). In OM I, we use the age-specific incidence from community-acquired RSV cases and the age-specific probabilities of hospitalization and death to derive the incidence of hospitalizations and in-hospital death due to RSV, respectively. In OM II, we back-calculate community-based cases in each age group by dividing the incidence of hospitalized cases by the age-specific probability of hospitalization, and we calculate the number of in-hospital deaths in each age group among hospitalized cases using the incidence from hospital-based studies and the probability of death in hospitalized cases. For further details on our construction of the splines, see Section S1.4 in S1 Text.

Age profile of RSV burden

To inform prophylactic interventions against RSV, to provide policy-relevant summaries of the key ages of the burden of RSV disease, and hence to define the ideal “window of protection”, we chose to present 3 measures of the full age distribution of disease: the mean age of infection (often presented in studies), the median age of infection (when half of the cases under 5 have already occurred), and the peak age of infection (the age in which incidence, hospitalizations, and deaths were highest). These 3 measures were calculated for each sample projection of the predictive model of the splines. The accumulated mean, median, and peak from each sample then allowed us to calculate credible intervals for the mean, median, and peak age of infection for the 3 epidemiological outcomes of interest: RSV incidence, hospitalizations, and hospital-based deaths. Further details on our calculations are found in Section S1.7 in S1 Text.

Burden models: Global model and country-specific model

The burden of disease can be estimated using 2 approaches. In BM I, we apply the country population size to the derived incidence as described in Section S1.6 in S1 Text and aggregate cases into subgroups according to age. For BM II, we take the number of cases in children under 5 in each country as calculated by Li’s risk-factor model, and we disaggregate that total by applying the proportion of cases that occur in each age group according to our splines (see Fig 1 for a heuristic illustration and Section S1.6 in S1 Text for a mathematical derivation of the approach).

We calculate cases, hospitalizations, and incidence of deaths—in the hospital and in the community—for 121 countries, which are the number of LIC, LMIC, and UMIC countries in Li’s risk-factor model. Of those countries, 27 were LICs (GNI per capita ≤$1,045) in 2020 with 103 M children under 5, 53 were LMICs (GNI per capita $1,046 to $4,095) with 335 M children under 5, and 41 were UMICs (GNI per capita $4,096 to $12,695) with 161 M under 5, for a total of 598 M children under 5. For more information on the World Bank country income group and included countries, see Section S1.9 in S1 Text.

Deaths in the community

The data on community-based deaths—in other words, the deaths outside of health facilities’ purview—is too sparse to develop splines as above. As an exercise to understand the total magnitude of this burden, albeit not the age-specific magnitude, we have followed the procedure outlined by Shi and colleagues [30]. The number of inpatient deaths was multiplied by 1.5 to 2.9, which were estimates from 3 datasets of the total ALRI mortality as a factor to healthcare attended ALRI mortality (see Shi and colleagues [30] for the data). The mortality was then further multiplied by a factor of 0.9 to 1.0, which accounts for the possible proportion of influenza-related ALRI that may be misclassified as a result of co-occurring influenza and RSV seasons in the 3 studies (see Shi’s supplementary tables 22 to 24 in pages 65 to 66) [30]. The more recent method of Li and colleagues also could not do age profiling from the data that looked at the proportion of all-cause deaths that were attributable to RSV, as these data were only available from the group of 0 to 60 month olds as a single age group.

Scenario analysis: Severity of RSV

There is an incomplete picture of how hospitalization and subsequent death are related to the incidence of severe RSV disease—defined by the WHO’s Integrated Management of Childhood Illnesses as the presence of chest indrawing, difficulty breathing, or very severe in the presence of canonical pediatric danger signs of distress [38,39] (further explanation on what constitutes a severe or very severe infection is found in Section S1.8 in S1 Text). We found no study in the literature that could describe the impact of severity on the entire cascade of care as depicted in Fig 1; in particular, we did not find the probability of death conditional on severe or very severe categorization within the community or the hospital. Our model of severity from the community- or hospital-based incidence is shown in Fig B in S1 Text. There are indications that some hospitalizations are non-severe, and some severe cases do not access care [30].

Therefore, for our main analysis, we chose hospitalization as a dual metric of the severity of disease as we are interested in the resource use expended on RSV-attributable disease. However, we applied our approach to the available data on the probability of severe and very severe cases in the community and in the hospital as this could be constructive, and these results are presented in the appendix.

Results

To estimate the relationship between age and RSV cases, hospitalization, and mortality, we used 18 studies of community-based incidence, 37 studies of hospital-based incidence, 8 studies for the probability of hospitalization among cases in the community, and 58 studies for hCFR among hospitalized patients (Table 1). These studies presented 38,488 person-months of observation 1,943 cases in the community, almost 5 M person-months of observation and 27,822 cases in the hospitals, 121 hospital admissions among 609 cases in the community, and 347 deaths among 27,467 inpatient cases; further details and the number of age groups are in Table A in S1 Text.

We analyzed the incidence of “severe” and “very severe” cases separately based on 15 and 4 community-based studies and 15 and 13 hospital-based studies, respectively (Table 1). Further details on person-years of observation, events, and age groups are in Table A in S1 Text.

When we stratified these studies by World Bank income group, we found that there was a dearth of information for LICs, including no studies to examine the burden from community-based studies nor the probability of hospitalization. Among studies with data on 3 or more age groups, there were 2 studies in LICs reporting hospital-based incidence (reporting both cases and catchment population) and 9 studies in LICs reporting hospital-based deaths. In LMICs and UMICs, there was more data for all categories.

Splines of incidence and probabilities

We tested for the statistical significance of World Bank income group as a predictor of the outcome (Table 2). The income group was a significant predictor for incidence only for community-based incidence (Splines I). Income group was not significant for hospital-based incidence (Spline II), the probability of hospitalization (Spline III), or of death among hospitalized cases (Spline IV).

Table 2. Model selection via the generalized likelihood ratio test.

Income group FE Income group FE and RE
Spline I: Community-based incidence P = <0.01 (DF = 2, χ2 = 13.67) P = 0.6 (DF = 3, χ2 = 1.85)
Spline II: Hospital-based incidence P = 1 (DF = 4, χ2 = 0) P = 0.16 (DF = 7, χ2 = 10.53)
Spline III: Probability of hospitalization P = 0.86 (DF = 2, χ2 = 0.3) P = 0.82 (DF = 3, χ2 = 0.91)
Spline IV: Probability of death among hospitalized cases P = 0.63 (DF = 4, χ2 = 2.56) P = 0.14 (DF = 7, χ2 = 10.9)

DF, degrees of freedom; FE, fixed-effects; RE, random-effects.

The splines for each outcome are shown in Fig 2. We have opted for graphical representations of the splines rather than tables because GAMs do not have an explicit, closed-form; the R objects for each spline are provided in S1 Data along with code for interested users.

Fig 2.

Fig 2

Splines of (A) community-based incidence, (B) hospital-based incidence, (C) probability of hospitalization, and (D) probability of death among hospitalized cases by income group designation. The bands correspond to the 95% confidence intervals of each parameter at each age. The pink bands present the “global” splines—derived from GAMMs with no income group predictor—and the blue bands present the “income group” splines—derived from GAMMs that include a predictor for the World Bank’s country income group designation. For the community-based incidence spline and the probability of hospitalization spline, the LIC estimates are identical to the LMIC estimates because no data exists from LIC settings. GAMM, generalized additive mixed model; hCFR, hospital-based case fatality rate; LIC, low-income countries; LMIC, lower-middle-income countries; UMIC, upper middle-income countries.

Incidence in community- and hospital-based studies

We found that the incidence among community-based studies is lowest among newborns, peaks before 6 months of age, and then decreases, and the overall incidence is higher in UMICs than in LMICs (Fig 2). As there were no studies among LICs and only 6 studies among UMICs in the training dataset, the global trend (in pink) is driven by the trend among LMICs, for which there were 12 studies in the training dataset. Among neonates (<28 days of age), the incidence is 14 (95% CI: 3, 35) per 1,000 person-years in LICs and LMICs, and 68 (95% CI: 13, 217) person-years in UMICs. The peak incidence is 108 (95% CI: 67, 166) per 1,000 person-years at 5.3 (95% CI: 3.5, 7.3) months in LICs and LMICs, and 106 (95% CI: 53, 187) at 5.8 (95% CI: 0.1, 60.0) months per 1,000 person-years in UMICs (Fig 2). The peak incidence at UMICs was difficult to ascertain because of the heterogeneity of age profiles across countries.

Among hospital-based incidence studies, we find a similar pattern but with an earlier peak than community-based incidence, and the incidence is lowest after the age of 2. The neonatal and peak hospital-based incidence is about a tenth as high as that of the community-based incidence. Among neonates (<28 days of age), the incidence is 5 (95% CI: 3, 11) per 1,000 person-years in all regions. The peak of hospital-based incidence is 24 (95% CI: 15, 36) per 1,000 person-years in all regions.

Probability of hospitalization among cases in the community

The highest probability of hospitalization is among newborns, at 25% (95% CI: 13%, 41%), decreasing to 13% (95% CI: 7%, 20%) by 6 months of age, 11% (95% CI: 6%, 17%) by 12 months of age, and 7% (95% CI: 3%, 13%) by 5 years of age (Fig 2).

Case fatality rates among hospitalized individuals (hCFR)

The highest probability of hospital-based case fatality rate (CFR) is among neonates, at 1.27% (95% CI: 0.65%, 2.18%), decreasing to 0.64% (95% CI: 0.40%, 0.95%) by 6 months of age, 0.53% (95% CI: 0.33%, 0.81%) by 12 months of age, and 0.64% (95% CI: 0.19%, 0.62%) by 5 years of age (Fig 2).

Within-sample and out-of-sample validation

Randomly sampled curves drawn from the spline models were graphed against the data that was used to estimate the models (see S2-1.1 to S2-1.4 in S2 Text) and against the studies used for out-of-sample validation (see Sections S2-2.1 to S2-2.4 in S2 Text). Visual inspection revealed no overwhelming lack-of-fit nor signaled that our specifications were inappropriate.

Age profile of RSV burden

We have combined the splines (Fig 2) as described in Fig 1 and in Section S1.4 in S1 Text to characterize the number and the age profile of RSV cases per 1,000 person-years in the community, in hospitals, and as in-hospital deaths (see Fig 3). To describe the age profile of RSV burden (Fig 3), we show the peak, median, and mean age of each outcome in Fig 4. Overall, the incidence of any outcome had more uncertainty when the incidence came from community-based data (Spline I; OM I) than when the incidence came from hospital-based data (Spline II; OM II).

Fig 3. RSV cases, hospitalizations, and deaths per 1,000 person-years according to OM I and II.

Fig 3

95% confidence intervals of cases, hospitalizations, and deaths per 1,000 person-years according to OM I and II, detailed in Fig 1 and Section S1.4 in S1 Text. The orange bands arise from OM I, calculated by taking the splines of community-based incidence (Spline I), probability of hospitalization (Spline III), and probability of death among hospitalized cases (Spline IV). The purple bands arise from OM II, calculated by taking the splines of hospital-based incidence (Spline II), probability of hospitalization (Spline III) to back-calculate cases in the community, and probability of death among hospitalized cases (Spline IV). LIC, low-income countries; LMIC, lower-middle-income countries; OM, outcomes model; RSV, respiratory syncytial virus; UMIC, upper middle-income countries.

Fig 4. Mean age, median age, and peak age of infection, hospitalization, and deaths due to RSV.

Fig 4

The segments correspond to 95% confidence intervals of each of the summaries and the dots correspond to the median estimate of each of the summaries; these are shown in orange when calculated using OM I and in purple when calculated using OM II. LIC, low-income countries; LMIC, lower-middle-income countries; OM, outcomes model; RSV, respiratory syncytial virus; UMIC, upper-middle-income countries.

In all regions, the metrics of the age profile (the mean, median, and peak age) of cases in the community were later than that of hospitalizations and deaths; therefore, both models confirm the hypothesis that more severe outcomes have a younger age profile than RSV cases in general (Fig 4). Throughout the regions, the peak of all outcomes was earlier than the median age of the disease, which itself was lower than the mean age of the disease. All metrics of the age profile of all outcomes overlapped markedly between OM I and OM II, indicating that the uncertainty within models was larger than the uncertainty between models. However, the distribution of the window tends to be lower in OM II than in OM I, indicating that hospital-based incidence studies will bias the age profile of RSV outcomes down.

To quantify the proportion of cases that are contained within key age groups targetted by prophylactics in development, we have quantified the proportion of cases under the age of 5 that fall in age-groups of 3 months in the first year of life in Fig 5. The model based on community-based incidence indicates that a lower proportion of hospitalizations and deaths occur in the 0–<3 month olds, who bear 11% of hospitalizations and 18% of deaths under 5 years of age, than in the 3–<6 month olds, who bare 17% of hospitalizations and 20% of deaths under 5. However, this relationship is reversed in the model based on hospital-based incidence, where 0–<3 month olds account for 20% to 29% of hospitalizations and deaths under 5 and 3–<6 month olds account for 19% to 21% of all hospitalizations and deaths under 5. The difference between models is not statistically significant (Fig A in S3 Text), and there is no evidence that the burden in infants 0–<3 months and 3–<6 months of age is different. Together, these figures indicate that children under 6 months of age—who make up 10% of the population of children under 5 (see Table B in S1 Text)—bear 20% to 29% of cases, 28% to 39% of hospitalizations, and 38% to 50% of deaths.

Fig 5. Proportions of each outcome that fall under key age brackets.

Fig 5

Uncertainty intervals are presented in Fig A in S3 Text. LIC, low-income countries; LMIC, lower-middle-income countries; OM, outcomes model; UMIC, upper middle-income countries.

Severe and very severe cases

The incidence of severe and very severe cases in community-based and hospital-based surveillance was modeled against age (Figs B and C in S3 Text). While the country-level income group was not a significant predictor for the probability of severe and very severe cases in the community or severe disease in hospitals, the country-level income group was a significant predictor of the probability of very severe disease in hospitalized cases (see Table A in S3 Text). For the probability that hospitalized cases are very severe, the model shows a similar mean for LIC and LMIC, but more uncertainty among LMICs, and in UMICs, the model shows a lower distribution and more uncertainty that hospitalized cases are very severe (see Fig B in S3 Text). The incidence of very severe cases among hospitalizations is different across country income groups due to both the underlying incidence in cases and the probability that those cases turn out to be very severe (see Fig C in S3 Text).

There were no statistically significant differences between the mean, median, and peak age of severe and non-severe disease within each model, although the point estimate and the uncertainty bounds indicate that severe cases have a younger age distribution than non-severe cases (compare Fig D in S3 Text to Fig 4). While children under 6 months of age make up 10% of the population of children under 5 (Table B in S1 Text), the share of severe cases borne by this age group is 30% to 42% and 31% to 42% of all severe and very severe cases in the community, and 32% to 44% and 33% to 45% of the severe and very severe cases in hospitals. While the severity as a proportion of community and hospital cases was modeled, the ultimate outcomes of severe cases (convalescence or death) could not be modeled because these relationships were not clearly reported in the literature [30,31].

Burden estimates

Among the 27 LICs, 53 LMICs, and 41 UMICs in our analysis, the population of children under 5 years of age numbered 103 million, 335 M, and 161 M in LICs, LMICs, and UMICs, respectively, for a total of 598 M children under 5. Collectively, there were 61 M children under 6 months of age, 60 M children between 6–<12 months of age, and 468 M children between ages 1–<5 years (a cross-tabulation of the population by income group and age is found in Table B in S1 Text). Fig 6 shows the burden of disease in each income region, and Fig 7 shows the burden of disease by age group for each OM and BM combination.

Fig 6. Burden of RSV cases, hospitalizations, and deaths in low- and middle-income countries, by World Bank income group classification.

Fig 6

Number and 95% confidence intervals of cases, hospitalizations, and deaths per 1,000 person-years according to OMs I and II and BMs I and II, as detailed in Fig 1 and Sections S1.4 and S1.6 in S1 Text. Because we used Li’s country-specific model as the basis for the number of cases in BM II, the cases do not differ between OM I and OM II; hospitalization and in-hospital death outcomes differ due to the different ways in which conditional probability splines were applied in OM I vs. OM II. Burden stratified by age group can also be found in the supplement (see S3 Text, Figs F–H). BM, burden model; LIC, low-income countries; LMIC, lower-middle-income countries; OM, outcomes model; RSV, respiratory syncytial virus; UMIC, upper-middle-income countries.

Fig 7. Burden of RSV cases, hospitalizations, and deaths in low- and middle-income countries, by age group.

Fig 7

Number and 95% confidence intervals of cases, hospitalizations, and deaths per 1,000 person-years according to SMs I and II and BMs I and II, as detailed in Fig 1 as well as Sections S1.4 and S1.6 in S1 Text. Burden stratified by age group can also be found in the supplement (see Figs F–H in S3 Text). BM, burden model; RSV, respiratory syncytial virus; SM, spline model.

The point estimates of the total number of cases in all low- and middle-income countries across all models (BM I/OM I, BM I/OM II, BM II/OM I, and BM II/OM II) ranged between 24.83 M (95% CI: 12.20 M, 44.43 M) and 31.34 M (95% CI: 28.92 M, 34.05 M) cases (Fig 6). Estimates for hospitalizations ranged between 2.62 M (95% CI: 1.81 M, 3.68 M) and 3.57 M (95% CI: 1.98 M, 5.83 M), and estimates for in-hospital deaths ranged between 16,326 (95% CI: 9,018, 26,972) to 22,229 (10,328, 41,763). Furthermore, the uncertainty within each model surpasses the uncertainty across models. Notably, there is more variance in each outcome with BM I/OM II than with BM I/OM I, attributable to the greater variance in the hospital-based incidence studies, which are the basis for OM II (see Figs 2, 3 and 6).

Burden stratified by income group

According to BM I, the plurality of cases are in LMICs, followed by UMICs, followed by LICs. We used the country-specific burden model estimates developed by Shi and colleagues and updated by Li and colleagues (the basis for BM II/OM I and BM II/OM II). The trends in BM II are similar to those of BM I: the plurality of cases are in LMICs, followed by UMICs, and lastly by LICs. Because their model did not estimate other outcomes (hospitalization or hCFR), the estimates of these outcomes differ between BM II/OM I and BM II/OM II although both outcome models begin by assuming same number of total cases (see Fig 6, right column).

Burden stratified by age group

The different models predict cases ranging from 24.83 M to 31.34 M, and out of those, from 4.89 M to 8.21 M cases will occur in the first 6 months of life, while another 5.77 M to 7.34 M cases will occur in the ages of 6 to 11.9 months (see Fig 7). The country-specific burden model by Shi and colleagues (and more recently by Li and colleagues) did not assign cases to any age group; therefore, the distribution of cases among age groups differs between BM II/OM I and BM II/OM II even if the total number of cases does not. Our models then yield between 752,882 to 1.30 M hospitalizations in the first 6 months of life and between 626,867 and 865,469 hospitalizations between the ages of 6 to 11.9 months. In-hospital deaths were then estimated at 6,100 to 10,611 in the first 6 months of life and between 3,684 and 5,132 in the ages of 6 to 11.9 months.

Burden stratified by age group and income group

The incidence stratified by both age and country income group is shown in Figs F to H in S3 Text. All regions follow similar age-related patterns. Country-specific burden estimates by month of age for OMs I and II and BMs I and II assumptions can be found in S1 Data where one can find 1 spreadsheet for each country.

Estimates of deaths in the community and total deaths

Although there was no data to look at the deaths outside of healthcare by age, and therefore there was no data to construct splines, we performed a simple estimate of the number of total deaths—both inside and outside of healthcare facilities (see Table B in S3 Text). Overall, we estimate a mean of between 34,116 total deaths (BM I/OM II) and 46,485(BM II/OM II) deaths, but the uncertainty within the models outpaces the uncertainty between models, featuring confidence intervals as low as 13,589 (BM I/OM II) and as high as 94,423.

Discussion

Understanding the burden of RSV disease across LICs, LMICs, and UMICs is possible thanks to the extensive amount of data that has been collected across the literature and the work of systematic reviews like that of Shi and colleagues and updated by Li and colleagues [30,31]. Yet, not all these data are amenable to synthesis and the data sometimes point to distinct patterns that must be interrogated in order to inform policy. In this paper, we have set forward a principled framework to leverage the extant data.

Constructing splines from outcomes of community- and hospital-based incidence, probability of hospitalization, and in-hospital death, there is enough evidence to show that community-based incidence differs by World Bank Income Group, but there is no statistically significant evidence for a difference by World Bank Income Group for hospital-based incidence, probability of hospitalization, or the probability of in-hospital death (p ≤ 0.01, p = 1, p = 0.86, 0.63, respectively). In supplemental analysis—examining the probability of severe and very severe disease among cases in the community and in the hospital—we found that there is enough evidence to adjust splines for World Bank Income Group when modeling very severe disease in hospitalized cases (p ≤ 0.01) but not other outcomes (see Table A in S3 Text).

The peak age of community-based incidence is 4.8 months, and the mean and median age of infection is 18.9 and 14.7 months, respectively (Fig 2). Estimating the age profile using the incidence coming from hospital-based studies yields a slightly younger age profile, in which the peak age of infection is 2.6 months and the mean and median age of infection are 15.8 and 11.6 months, respectively. Children under 6 months of age bear 20% to 29% of cases, 28% to 39% of hospitalizations, and 38% to 50% of deaths despite constituting only 10% of the population under 5. Moreover, this share is a bit more concentrated among children 3–<6 months old than among those 0–<3 months old for cases and hospitalizations—likely as maternal-derived immunity wanes, although deaths are more concentrated in 0–<3-month-olds rather than the 3-<6 month-olds (18% to 29% versus 20% to 21%, respectively, Fig 5).

More severe outcomes, such as hospitalization and in-hospital death have a younger age profile. Unlike the results of the model without severity (Fig 4), the age profile of severity does not seem to be younger in the hospital than in the community when restricting to the population of severe and very severe disease (Fig E in S3 Text). Children under 6 months of age bear about the same proportion of severe cases as hospitalized cases overall; they bear 30% to 42% and 31% to 42% of all severe and very severe cases in the community, while they bear 32% to 44% and 33% to 45% of the severe and very severe cases in hospitals.

Throughout all low- and middle-income countries, there were between 21.83 M to 31.34 M cases, between 2.62 M and 3.57 M hospitalizations, and between 16,326 to 22,229 in-hospital deaths. Overall deaths—in the community as well as in the hospital—were estimated at 34,111 to 46,485, although the uncertainty within models is larger than the uncertainty between models. The largest share of cases were in LMICs, followed by UMICs, and lastly by LICs.

Modeling semi-parametric splines provides more accurate estimates of per-month incidence than conventional meta-analyses of the age-specific incidence reported in the literature. Semi-parametric splines leverage literature from the field where different age group breakdowns are presented. The combination of a semi-parametric approach and simulation was able to quantify the mean, median, and peak age of all outcomes along with their uncertainty in order to stimulate conversations to define the key window of protection. While the focus on the overall burden is important, an additional target metric ought to be the capacity of the prophylaxis to protect children through the key window of infection, hospitalization, and death. One advantage of our approach is the capacity to present the percentage of children that could be protected by products of different durations (Fig 5).

To understand the impact of different ways of interpreting the data and the extant estimates of burden (from Shi and colleagues’ and Li and colleagues’ risk factor model), we devised 2 outcome models (OM I and OM II) and applied each of them to 2 burden models (BM I and BM II), for a total of 4 models listing cases in the community, hospitalizations, and in-hospital deaths. Because there is no way to weigh these models in a statistically principled manner (unless one arbitrarily assigns equal weights), we did not combine the models. Though prediction intervals between the models overlap substantially (Figs 6 and 7), indicating that both methods of assessing burden were not significantly different at a level of 95% confidence, distributions with a lower or higher mean might be enough to influence a cost-effectiveness analysis. Our approach also examined the robustness of the assumption that a country’s income group is an adequate proxy to interpolate epidemiological patterns of RSV for countries that lack data. We found that the country income group was only useful for community-based incidence (Table 2).

Our findings imply that prophylactics that offer protection until 4 to 6 months of age will target the peak age of deaths but are unlikely to avert even 50% of deaths (indicated by the median in Fig 4 and Fig 5). The longest lasting form of passive immunity—in the form of a monoclonal antibody, Nivursimab—so far protects for 150 days or 5 months [19]. As protection from such a product wanes in the fifth and sixth month, our findings indicate that a second product would be helpful as well. This is consistent with cost-effectiveness analyses, which show that the use of a single prophylactic must be priced competitively in order to prove cost-effective in most low- and middle-income settings [21,24]. While the data on severity was less clear and was relegated to supplemental analysis, severe RSV disease showed a higher concentration in younger infants as well (Fig D and E in S3 Text).

Notably, Li and colleagues found that the RSV-associated acute lower respiratory infection incidence rate peaked in children aged 0–<3 months in LICs and LMICs, whereas the rate peaked in children aged 3–<6 months in UMICs. This tends to be younger than our point estimates based on community-based incidence (OM I) but not hospital-based incidence (OM II), presumably because hospitalized cases are younger than the average case observed in the community. However, it should be noted that Li an colleagues calculated the incidence in 3-month age bands for the first year, which may lead to a masking of the increases and decreases in those first months of life, a shortcoming that our approach has overcome. For cost-effectiveness analysis for which conclusions are reached on the balance of all uncertainties in parameters, the lower age profile could change decisions, especially due to shifts in mortality, which accounts for the majority of all disability-adjusted life-years. In particular, Shi and colleagues found that 45% of deaths appear to occur in the first 6 months of life, which agrees with the estimates of Li and colleagues (45,000 deaths among 0–<6 months compared to 100,500 among 0 to 60 months), and also agrees with our estimates of 38% to 50% (Fig 7). We showed, however, that accounting for model assumptions casts doubt on estimating a mean age of death at 6 months of age, which depends on trusting data coming from hospital-based incidence studies over the data coming from community-based studies (Figs 4 and 5).

Our results are similar to those of Nyiro and colleagues [35], who used a catalytic model of infection on data on RSV-binding IgG serostatus. Nyiro and colleagues showed that the mean age of infection is 15 months (95% CI 13, 18 months) and that the most vulnerable period for infection was between the time when maternal antibodies wane, at 4.7 months, and 11 months of age. Like Nyiro and colleagues [35], we found that the peak age at infection ranged between 3.3 months and 5.8 months (Fig 4) across income groups.

Another study focused on determining the mean age of death from RSV by online questionnaire from Scheltema and colleagues [34] estimated median ages of 5.0 (IQR: 2.3 to 11.0) months in LICs, 4.0 (IQR: 2.0, 10.0) months in LMICs, and UMICs: 7.0 (95% CI: 3.6, 16.8) months. While our estimates do not differ in a statistically significant manner against those of Scheltema and colleagues, the distribution of our estimate of median age of death is slightly higher: 8.9 (95% CI: 5.7, 13.1) and 6.0 (95% CI: 4.3, 8.1) in LICs, 8.9 (95% CI: 5.8, 13.3) and 6.0 (95% CI: 4.3, 8.2) in LMICs, and 9.6 (95% CI: 2.3, 21.4) and 6.1 (95% CI: 4.3, 8.3) in UMICs (Fig 4).

Overall, our conclusions and those of Li and colleagues’ [31] came to qualitatively similar conclusions regarding the overall burden of disease. Li and colleagues’ [31] generalized linear mixed model (GLMM)—similar to our GAMMs but without the versatile splines—calculated 31.4 M (23.2 M, 42.6 M) cases of RSV in countries designated as “developing” by UNICEF (closely equivalent to the World Bank’s LICs, LMICs, and UMICs together), which was close to our estimates between 24.67 M to 28.23 M in BM I (which, unlike BM II, was not based on their risk factor model). Among hospitalizations, our estimates differed more markedly but were in the same order of magnitude; while they estimated 3.1 M (95% CI: 2.4 M, 4.2 M) hospitalizations in developing countries, we estimated between 2.95 M and 3.57 M cases across models, with uncertainty ranges between 1.45 M and 5.83 M. Our in-hospital deaths arrived at comparable conclusions to those of Li an colleagues: our point estimates ranged from 16,326 to 22,229 compared to their 25,900 and showed similar credible intervals—7,333 to 41,763 compared to their 14,500 to 48,600 (Table B in S3 Text) [31].

One key difference between the burden models is that our total deaths—both in-hospital and in the community—34,116 to 46,485 lie much closer to those of GBD 2015 estimate of 36,400 (95% CI: 20,000, 61,500) for developing countries than those of Li and colleagues at 100,500 (95% CI: 83,600, 124,500) and Shi and colleagues of 117,964 (95% CI: 94,545, 147,164) [30,31,40]. Shi and colleagues estimated a higher hCFR in neonates (≤28 day olds) of 6.3% (3.3%, 12.1%) and 1.0% (95% CI: 0.1%, 7.2%) (see their supplementary table 20) than ours, which were 1.28% (95% CI: 0.66%, 2.22%) (Fig 2). For the age group 0–<6 months, Shi and colleagues calculated 2.2% (95% CI: 1.8% to 2.7%) for all developing countries (loosely equivalent to LICs, LMICs, and UMICs), whereas Li and colleagues’ update and reanalysis estimated an hCFR of 1.1% (95% CI: 0.8%, 1.6%). Li and colleagues also estimated 1.9% (95% CI: 1.5%, 2.4%) in sensitivity analyses. Therefore, we suspect that part of the difference between our study and that of Shi and colleagues is that they used only studies that showed neonates (≤28 day olds) specifically and, unlike our framework, had no framework to “borrow” or inform their estimate of ≤28-day mortality with the implicit information from studies for children 0–<3 months or 0–<6 of age (see their appendix page 62). Our framework allowed for “borrowing” between incomparable age breakdowns in order to be more precise about our final estimate of hCFR [30,31].

Despite the ambitious efforts of RSV GEN led by Shi and colleagues [30], and more recently by Li and colleagues [31], key gaps remain in the literature that our analysis could not address. Because we required incidence estimates from 3 nonoverlapping age groups in order to calculate the splines, there was no calculation of community-based incidence in LICs. Therefore, the assessments of incidence in this country group must rely on hospital-incidence studies, leaving a formidable question around the cases in the community in LICs and underestimating the impact of future prophylactics in these settings. Second, data on the hospitalization probability among cases in the community are sparse in all country groups, and, therefore, it is difficult to understand how hospitalization incidence compares to community incidence; community-based mortality studies have shown a lower median age than hospital-based mortality [41]. Third, severity data was difficult to interpret, but the patterns indicate that the mean and median age of severe infection is situated at a younger age than the mean and median age of all cases, consistent with the main model (see Figs D and E in S3 Text versus Fig 4). Severity itself is not always defined the same way, and therefore, the continuum between a mild case, a severe case, and a very severe case is not entirely clear (see Section S1.8 in S1 Text). Lastly, the existing heterogeneity between World Bank income groups detected for severity in our analysis pointed to the need for more geographically comprehensive surveillance, in particular, with regard to community-based incidence, severity, care-seeking, and hospitalization in LICs.

Different demand and accessibility characteristics by income group could explain why the incidence—both from the community and hospital-based studies—was found to be higher in UMICs than in LMICs or LICs (see Fig 2). LIC hospital incidence is likely underestimated because patients do not reach health facilities, or when they do, they have to be turned away due to overcapacity [42]. Many of the original studies retrieved by Shi and colleagues, as well as Li and colleagues, were previously unpublished (now available at [43,44]), and the circumstances under which patients were admitted are unknown, thus leaving the degree of underestimation unclear. Given the positive association between country-level income and healthcare accessibility, the overall burden may have been understated in poorer locations. Healthcare use surveys alongside RSV incidence studies would help estimate the size of the underreporting, as is done for other diseases [45].

Four last gaps remain in the data we examined. First, subtype identification (RSV A versus RSV B) was so poorly characterized in the extant literature as to disallow a meta-analytic analysis like the one performed here. If prophylactics are not equally effective against both subtypes, then further surveillance on the incidence of subtypes would be necessary. Second, there was no seasonality examined in these data, though some policies in high-income countries are being designed to target very young children around the peak RSV season of the year. Third, the period we used for the data, i.e., studies published between 2000 and 2020, included the introduction of pneumococcal vaccine in many countries after 2008, which may have modified the CFR patterns, but it was beyond the scope of this study to examine time variation in the CFR. Fourth, the RSV seasonality has been impacted by the COVID-19 pandemic, and continuous surveillance is essential to monitor the global RSV seasonal pattern across global regions [4648].

To date, there are 13 pediatric vaccines in development and our analysis serves to highlight the use-case for these vaccines [20]. Although the incidence of hospitalization and death has waned by the time a child is 12 months of age, we show that between 38% and 47% of RSV-related hospitalizations and between 28% and 37% of deaths among preschool children occur over the age of 1 (Fig 5). A product that can be immunogenic in children at 9 months of age could prevent an additional 9% to 10% hospitalizations and deaths which occur between 9–<12 months when children are scheduled to begin taking childhood vaccinations for other commonly administered antigens like measles.

In conclusion, the fact that the median and mean age of infection—and of severe disease—is higher than the peak of infection indicates that an ideal strategy may be a combination of passive immunity for the first months of life followed by active immunization at 9 to 12 months of age. Although the RSV pediatric vaccine is still in the early stage of clinical development, the new long-acting monoclonal antibody (Nirsevimab, by AstraZeneca) and the RSV prefusion maternal vaccine (RSVpreF, by Pfizer) are likely to be marketed soon in high-income countries [49]. Depending on the price, the country’s RSV pattern, and the implementation strategies, Nirsevimab and RSVpreF might also be able to substantially avoid RSV infections among young children in LMICs. The larger uncertainty bounds in our analysis are not a drawback of the analysis, but rather an advantage of the framework, which is steadfast in showing the uncertainty that we are confronted with in the data. As long as gaps in the epidemiological literature remain and are not examined rigorously, decision-making must be done after considering all uncertainty.

Supporting information

S1 Text. Supplementary Methods.

Section S1.1. Extraction of the Shi and colleagues and Li and colleagues data. Section S1.1.1. Modifications to incidence data from Shi and colleagues. Section S.1.1.2. Modifications to fatality (hCFR) data from Shi and colleagues. Section S1.2. Descriptive summaries of all data. Section S1.3. Generalized additive mixed models (GAMM). Section S1.4. Outcome Models (OM) I and II. Section S1.7. Characterizing the age profile of RSV burden (mean, median, and the peak age of each outcome). Section S1.6. Burden Models (BM) I and II. Section S1.9. Countries included, World Bank Income Group, population, and life tables. Section S1.3. Generalized additive mixed models (GAMM). Section S1.5.1. Spline specifications and computational considerations. Section S1.5.2. Predictions of the outcome model and uncertainty. Section S1.8. Severe and very severe disease. Table A. Characteristics of the studies included in the main splines and in the supplemental severity splines. Table B. Country income groups and population age <5 in 2020. Fig A. Geographic distribution of the available data. Fig B. Relationship between cases, hospitalizations, and severity from birth to 60 months of age.

(PDF)

S2 Text. Supplementary Results: Spline Validation.

Section 2–1.1. Fit-vs-observed: Community-based incidence. Section 2–1.2. Fit-vs-observed: Hospital-based incidence. Section 2–1.3. Fit-vs-observed: Probability of hospitalization among cases in the community. Section 2–1.4. Fit-vs-observed: Probability of death among hospitalized cases. Section 2–2.1. Out-of-sample validation: Community-based incidence. Section 2–2.2. Out-of-sample validation: Hospital-based incidence. Section 2–2.3. Out-of-sample validation: Probability of hospitalization among cases in the community. Section 2–2.4. Out-of-sample validation: Probability of death among hospitalized cases.

(PDF)

S3 Text. Supplementary Results: Additional Projections.

Fig A. Splines of the probability of severe and very severe disease among community-based and hospital-based cases. Fig B. Splines of the probability of severe and very severe disease among community-based and hospital-based cases. Fig C. RSV cases, hospitalizations of severe and very severe disease per 1,000 person-years according to Spline Models (SM) I and II. Table A. Model selection via the generalized likelihood ratio test for severe and very severe disease. Fig D. Mean, median, and peak age of each severe and very severe disease among community-based and hospital-based cases. Fig E. Proportions of each outcome that fall under key age brackets for severe and very severe case burden. Fig F. Sensitivity analysis of the burden of RSV cases, hospitalizations, and deaths by age in low-income countries (LICs). Fig G. Sensitivity analysis of the burden of RSV cases, hospitalizations, and deaths by age in low-income countries (LMICs). Fig H. Sensitivity analysis of the burden of RSV cases, hospitalizations, and deaths by age in low-income countries (UMICs).

(PDF)

S1 Data. Excel files with projections for each country of the burden of cases, hospitalizations, in-hospital and community deaths for each age group and by 1-month age groups, as well as peak, median, and mean age of each outcome.

(ZIP)

Acknowledgments

The authors would like to thank Philipp Tellenbach for help with data cleaning. Rescue Investigators include: Philippe Beutels (University of Antwerp); Veena Kumar (Novavax), Louis Bont (University Medical Center Utrecht); Harish Nair and Harry Campbell (University of Edinburgh); Andrew Pollard (University of Oxford); Peter Openshaw (Imperial College London); Federico Martinon-Torres (Servicio Galego de Saude), Terho Heikkinen (University of Turku and Turku University Hospital); Adam Meijer (National Institute for Public Health and the Environment); Thea K Fischer (Statens Serum Institut); Maarten van den Berge (University of Groningen); Carlo Giaquinto (PENTA Foundation); Michael Abram (AstraZeneca); Kena Swanson (Pfizer); Bishoy Rizkalla (GlaxoSmithKline); Charlotte Vernhes and Scott Gallichan (Sanofi Pasteur); Jeroen Aerssens (Janssen); and Eva Molero (Team-It Research). This publication was also supported through PATH by Gavi, the Vaccine Alliance.

Abbreviations

ALRI

acute lower respiratory infection

BM

burden model

CFR

case fatality rate

DF

degrees of freedom

FE

fixed-effects

GAMM

generalized additive mixed model

GLMM

generalized linear mixed model

hCFR

hospital-based case fatality rate

LIC

low-income country

LMIC

lower-middle-income country

OM

outcomes model

RE

random-effects

RSV

respiratory syncytial virus

UMIC

upper-middle-income country

Data Availability

All coding files are available from the following github repository https://github.com/Marina-Antillon/rsv_splines_lmics.

Funding Statement

Respiratory Syncytial Virus Consortium in Europe (RESCEU) has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 116019 (XL, LW, JB, MJ, PB). which receives support from the European Union’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). MA has received funding from a post-doctoral fellowship of the Belgian-American Education Foundation. PB also received support through PATH by Gavi, the Vaccine Alliance. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

References

  • 1.Hotez PJ, Bottazzi ME, Strych U. New vaccines for the world’s poorest people. Annu Rev Med. 2016;67:405–417. doi: 10.1146/annurev-med-051214-024241 [DOI] [PubMed] [Google Scholar]
  • 2.O’Brien KL, Baggett HC, Brooks WA, Feikin DR, Hammitt LL, Higdon MM, et al. Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study. Lancet. 2019;394(10200):757–779. doi: 10.1016/S0140-6736(19)30721-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Ochola R, Sande C, Fegan G, Scott PD, Medley GF, Cane PA, et al. The level and duration of RSV-specific maternal IgG in infants in Kilifi, Kenya. PLoS ONE. 2009;4(12):4–9. doi: 10.1371/journal.pone.0008088 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Nyiro JU, Sande C, Mutunga M, Kiyuka PK, Munywoki PK, Scott JAG, et al. Quantifying maternally derived respiratory syncytial virus specific neutralising antibodies in a birth cohort from coastal Kenya. Vaccine. 2015;33(15):1797–1801. doi: 10.1016/j.vaccine.2015.02.039 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Chu HY, Steinhoff MC, Magaret A, Zaman K, Roy E, Langdon G, et al. Respiratory Syncytial Virus Transplacental Antibody Transfer and Kinetics in Mother-Infant Pairs in Bangladesh. J Infect Dis. 2014;210(10):1582–1589. doi: 10.1093/infdis/jiu316 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Hodgson D, Pebody R, Panovska-Griffiths J, Baguelin M, Atkins KE. Evaluating the next generation of RSV intervention strategies: a mathematical modelling study and cost-effectiveness analysis. BMC Med. 2020;18(1):1–14. doi: 10.1186/s12916-020-01802-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Korsten K, Adriaenssens N, Coenen S, Butler CC, Pirçon JY, Verheij TJM, et al. Contact With Young Children Increases the Risk of Respiratory Infection in Older Adults in Europe—the RESCEU Study. J Infect Dis. 2021. doi: 10.1093/infdis/jiab519 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Mossong J, Hens N, Jit M, Beutels P, Auranen K, Mikolajczyk R, et al. Social contacts and mixing patterns relevant to the spread of infectious diseases. PLoS Med. 2008;5(3):0381–0391. doi: 10.1371/journal.pmed.0050074 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.van Hoek AJ, Andrews N, Campbell H, Amirthalingam G, Edmunds WJ, Miller E. The Social Life of Infants in the Context of Infectious Disease Transmission; Social Contacts and Mixing Patterns of the Very Young. PLoS ONE. 2013;8(10):1–7. doi: 10.1371/journal.pone.0076180 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Mousa A, Winskill P, Watson OJ, Ratmann O, Monod M, Ajelli M, et al. Social contact patterns and implications for infectious disease transmission: A systematic review and meta-analysis of contact surveys. Elife. 2021;10. doi: 10.7554/eLife.70294 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Sande CJ, Cane PA, Nokes DJ. The association between age and the development of respiratory syncytial virus neutralising antibody responses following natural infection in infants. Vaccine. 2014;32(37):4726–4729. doi: 10.1016/j.vaccine.2014.05.038 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Ohuma EO, Okiro EA, Ochola R, Sande CJ, Cane PA, Medley GF, et al. The natural history of respiratory syncytial virus in a birth cohort: The influence of age and previous infection on reinfection and disease. Am J Epidemiol. 2012;176(9):794–802. doi: 10.1093/aje/kws257 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Hall CB, Walsh EE, Long CE, Schnabel KC. Immunity to and frequency of reinfection with respiratory syncytial virus. J Infect Dis. 1991;163(4):693–698. doi: 10.1093/infdis/163.4.693 [DOI] [PubMed] [Google Scholar]
  • 14.Powell K. The new wave of vaccines for a killer respiratory virus. Nature. 2020;600. [DOI] [PubMed] [Google Scholar]
  • 15.Madhi SA, Polack FP, Piedra PA, Munoz FM, Trenholme AA, Simões EAF, et al. Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants. N Engl J Med. 2020;383(5):426–439. doi: 10.1056/NEJMoa1908380 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Meissner HC, Groothuis JR, Rodriguez WJ, Welliver RC, Hogg G, Gray PH, et al. Safety and pharmacokinetics of an intramuscular monoclonal antibody (SB 209763) against respiratory syncytial virus (RSV) in infants and young children at risk for severe RSV disease. Antimicrob Agents Chemother. 1999;43(5):1183–1188. doi: 10.1128/AAC.43.5.1183 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Resch B. Product review on the monoclonal antibody palivizumab for prevention of respiratory syncytial virus infection. Hum Vaccin Immunother. 2017;13(9):2138–2149. doi: 10.1080/21645515.2017.1337614 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Domachowske JB, Khan AA, Esser MT, Jensen K, Takas T, Villafana T, et al. Safety, Tolerability and Pharmacokinetics of MEDI8897, an Extended Half-life Single-dose Respiratory Syncytial Virus Prefusion F-targeting Monoclonal Antibody Administered as a Single Dose to Healthy Preterm Infants. Pediatr Infect Dis J. 2018;37(9):886–892. doi: 10.1097/INF.0000000000001916 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Hammitt LL, Dagan R, Yuan Y, Baca Cots M, Bosheva M, Madhi SA, et al. Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants. N Engl J Med. 2022;386(9):837–846. doi: 10.1056/NEJMoa2110275 [DOI] [PubMed] [Google Scholar]
  • 20.Comerlato Scotta M, Tetelbom Stein R. Current strategies and perspectives for active and passive immunization against Respiratory Syncytial Virus in childhood. J Pediatr (Rio J). 2023;99(S1):S4–S11. doi: 10.1016/j.jped.2022.10.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Li X, Willem L, Antillon M, Bilcke J, Jit M, Beutels P. Health and economic burden of respiratory syncytial virus (RSV) disease and the cost-effectiveness of potential interventions against RSV among children under 5 years in 72 Gavi-eligible countries. BMC Med. 2020;18(1):1–16. doi: 10.1186/s12916-020-01537-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Baral R, Li X, Willem L, Antillon M, Vilajeliu A, Jit M, et al. The impact of maternal RSV vaccine to protect infants in Gavi-supported countries: Estimates from two models. Vaccine. 2020;38(33):5139–5147. doi: 10.1016/j.vaccine.2020.06.036 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Baral R, Higgins D, Regan K, Pecenka C. Impact and cost-effectiveness of potential interventions against infant respiratory syncytial virus (RSV) in 131 low-income and middle-income countries using a static cohort model. BMJ Open. 2021;11(4):1–10. doi: 10.1136/bmjopen-2020-046563 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Laufer RS, Driscoll AJ, Baral R, Buchwald AG, Campbell JD, Coulibaly F, et al. Cost-effectiveness of infant respiratory syncytial virus preventive interventions in Mali: A modeling study to inform policy and investment decisions. Vaccine. 2021;39(35):5037–5045. doi: 10.1016/j.vaccine.2021.06.086 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Pouwels KB, Bozdemir SE, Yegenoglu S, Celebi S, McIntosh ED, Unal S, et al. Potential cost-effectiveness of RSV vaccination of infants and pregnant women in Turkey: An illustration based on bursa data. PLoS ONE. 2016;11(9):1–15. doi: 10.1371/journal.pone.0163567 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Poletti P, Merler S, Ajelli M, Manfredi P, Munywoki PK, James Nokes D, et al. Evaluating vaccination strategies for reducing infant respiratory syncytial virus infection in low-income settings. BMC Med. 2015;13(1):1–11. doi: 10.1186/s12916-015-0283-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Chu HY, Englund JA. Maternal immunization. Clin Infect Dis. 2014;59(4):560–568. doi: 10.1093/cid/ciu327 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Abbasi J. RSV Vaccines, Finally Within Reach, Could Prevent Tens of Thousands of Yearly Deaths. JAMA. 2022;327(3):204–206. doi: 10.1001/jama.2021.23772 [DOI] [PubMed] [Google Scholar]
  • 29.World Health Organisation. Characteristics for Respiratory Syncytial Virus (RSV) Vaccines. Department of Immunization, Vaccines and Biologicals. 2017; p. 16. [Google Scholar]
  • 30.Shi T, McAllister DA, O’Brien KL, Simoes EAF, Madhi SA, Gessner BD, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet. 2017;390(10098):946–958. doi: 10.1016/S0140-6736(17)30938-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Li Y VRS Study Group in Lyon, Respiratory Virus Global Epidemiology Network, RESCEU. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2019: a systematic analysis. SSRN preprint. 2022; p. 1–35. [Google Scholar]
  • 32.Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet. 2010;375(9725):1545–1555. doi: 10.1016/S0140-6736(10)60206-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Troeger C, Blacker B, Khalil IA, Rao PC, Cao J, Zimsen SRM, et al. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect Dis. 2018;18(11):1191–1210. doi: 10.1016/S1473-3099(18)30310-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Scheltema NM, Gentile A, Lucion F, Nokes DJ, Munywoki PK, Madhi SA, et al. Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series. Lancet Glob Health. 2017;5(10):e984–e991. doi: 10.1016/S2214-109X(17)30344-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Nyiro JU, Kombe IK, Sande CJ, Kipkoech J, Kiyuka PK, Onyango CO, et al. Defining the vaccination window for Respiratory syncytial virus (RSV) using ageseroprevalence data for children in Kilifi, Kenya. PLoS ONE. 2017;12(5):1–14. doi: 10.1371/journal.pone.0177803 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Wood SN. Generalized Additive Models. Chapman and Hall/CRC; 2017. Available from: https://www.taylorfrancis.com/books/9781498728348. [Google Scholar]
  • 37.James G, Witten D, Hastie T, Tibshirani R. An Introduction to Statistical Learning with Applications in R. Springer Texts in Statistics. New York, NY: Springer New York; 2013. Available from: http://link.springer.com/10.1007/978-1-4614-7138-7. [Google Scholar]
  • 38.World Health Organization. Integrated Management of Childhood Illness (IMCI): Chart Booklet. March. WHO Press; 2014. [Google Scholar]
  • 39.World Health Organization. Integrated Management of Childhood Illness: management of the sick young infant aged up to 2 months. Geneva, Switzerland: World Health Organization; 2019. Available from: https://www.who.int/publications/i/item/9789241516365. [Google Scholar]
  • 40.Flaxman AD, Vos T, Murray CJ. An Integrative Metaregression Framework for Descriptive Epidemiology. University of Washington Press; 2015. [Google Scholar]
  • 41.Mazur NI, Löwensteyn YN, Willemsen JE, Gill CJ, Forman L, Mwananyanda LM, et al. Global Respiratory Syncytial Virus-Related Infant Community Deaths. Clin Infect Dis. 2021;73:S229–S237. doi: 10.1093/cid/ciab528 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Saha S, Santosham M, Hussain M, Black RE, Saha SK. Perspective piece rotavirus vaccine will improve child survival by more than just preventing diarrhea: Evidence from Bangladesh. Am J Trop Med Hyg. 2018;98(2):360–363. doi: 10.4269/ajtmh.17-0586 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Nair H, Global regional and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015, 1995–2015 [dataset]; 2017. Available from: https://datashare.ed.ac.uk/handle/10283/2115 [cited 2022 Aug 20]. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Li Y, Nair H. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2019: a systematic analysis, 2017–2020 [dataset]; 2021. Available from: https://datashare.ed.ac.uk/handle/10283/4025 [cited 2022 Aug 20]. [Google Scholar]
  • 45.Phillips MT, Meiring JE, Voysey M, Warren JL, Baker S, Basnyat B, et al. A Bayesian approach for estimating typhoid fever incidence from large-scale facility-based passive surveillance data. Stat Med. 2021;40(26):5853–5870. doi: 10.1002/sim.9159 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Mosscrop LG, Williams TC, Tregoning JS. Respiratory syncytial virus after the SARS-CoV-2 pandemic—what next? Nat Rev Immunol. 2022;22(10):589–590. doi: 10.1038/s41577-022-00764-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Mohebi L, Karami H, Mirsalehi N, Ardestani NH, Yavarian J, Mard-Soltani M, et al. A delayed resurgence of respiratory syncytial virus (RSV) during the COVID-19 pandemic: An unpredictable outbreak in a small proportion of children in the Southwest of Iran, April 2022. J Med Virol. 2022;94(12):5802–5807. doi: 10.1002/jmv.28065 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Billard MN, van de Ven PM, Baraldi B, Kragten-Tabatabaie L, Bont LJ, Wildenbeest JG. International changes in respiratory syncytial virus (RSV) epidemiology during the COVID-19 pandemic: Association with school closures. Influenza Other Respi Viruses. 2022;16(5):926–936. doi: 10.1111/irv.12998 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Pfizer, Inc. Pfizer Announces Positive Top-Line Data of Phase 3 Global Maternal Immunization Trial for its Bivalent Respiratory Syncytial Virus (RSV) Vaccine Candidate. 2022. Available from: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-positive-top-line-data-phase-3-global [cited 2023 Apr 14]. [Google Scholar]

Decision Letter 0

Callam Davidson

24 Jan 2023

Dear Dr Antillón,

Thank you for submitting your manuscript entitled "The burden of respiratory syncytial virus in infants of low- and middle-income countries: A semi-parametric, meta-regression approach" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by Jan 26 2023 11:59PM.

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Callam Davidson

Associate Editor

PLOS Medicine

Decision Letter 1

Callam Davidson

9 Mar 2023

Dear Dr. Antillón,

Thank you very much for submitting your manuscript "The burden of respiratory syncytial virus in infants of low- and middle-income countries: A semi-parametric, meta-regression approach" (PMEDICINE-D-23-00070R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We hope to receive your revised manuscript by Mar 30 2023 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Callam Davidson,

PLOS Medicine

plosmedicine.org

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

Comments from the Academic Editor:

Please rewrite the text a bit to make it less technical and add a bit more interpretation of the results.

I found it a bit confusing that in the methods section there was a section entitled "Window of protection" and in the results section "Window of infection". Is that the same? Also, term window seemed a bit misleading, as it is about certain aspects of a distribution. I think the authors could do more to clarify what they mean by window of protection and how the results can be interpreted in that way.

One of the reviewers remarked on that the estimates were for the year 2020 and that the authors should comment on the impact of the pandemic. It was not clear for me that the estimates were meant to be for 2020, I thought that the authors implicitly assumed a sort of endemic (albeit seasonal) state. But I agree that some comments on the impact of the pandemic would be important.

Another reviewer suggested to not use two ways to calculate outcomes, but I found this actually good, because it gives additional validity to the estimates.

Requests from the Editors:

Please ensure that all numbers presented in the abstract are present and identical to numbers presented in the main manuscript text.

In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

Please remove the Code Availability, Role of the funding source, and Author Contributions sections from the main text and ensure the relevant information is captured in the Submission Form questionnaire.

For internet-derived references, please include the date accessed.

S1 Supporting Text, Figure A: Please confirm that the appropriate usage rights apply to the use of this map. Please see our guidelines for map images: https://journals.plos.org/plosmedicine/s/figures#loc-maps

Comments from the reviewers:

Reviewer #1: Antillon and colleagues reported a secondary analysis of the burden of RSV infections in infants of LMICs based on two global systematic reviews published in 2017 and 2022. The authors leveraged flexible generalized additive mixed models (GAMM) to estimate the age-dependent incidence and mortality of RSV infections, which would allow more flexibility for understanding the age distribution of RSV infections of different severity. The authors went ahead and estimated the global number of RSV infections and deaths in 2020, and compared those estimates with the two global systematic reviews. The authors showed that depending on the study settings, the peak, mean and median age of RSV infections could vary; these findings could help optimize the timing (of age) for RSV immunisation products given the anticipated short duration of protection.

Overall, this analysis has its merits for an improved understanding of the age distribution of RSV cases and potentially deaths. The methodology for estimating the age-specific incidence and probability appears to be sound in general. However, the second part that estimated the absolute number of infections and deaths was problematic (see the comments below), and reading through the manuscript, it looks more like a validation of the model rather than a formal estimate; it is not essential to the main message of the manuscript.

Comments for Part 1 - age distribution

* The authors assumed in their base model that the probability that a case in the community becomes a case in the hospital and that the hospitalized case becomes a fatality is itself age-dependent. This holds partly true - the probability is also expected to be dependent on country's income.

o Accessibility and availability of hospital care is likely to be different across income groups (e.g., UMICs better than the other two), so is quality of health-care that is associated with in-hospital CFR. Although the authors explored income group as a fix effect in secondary model (and tested the added value albeit not being able to rule out false negative), I would consider swapping the two models and making income-specific splines the primary model. This is important especially if the age distribution of RSV cases and deaths differed by income (as seen in RSV GOLD studies).

o I appreciate that the authors might have limited data from certain income regions (e.g., LIC) but that should not be the sole reason for not going for income-specific model as the primary model. If necessary, LIC and LMIC can be combined.

* Deaths in the community - I would leave out the deaths in the community (or move to the appendix at least) for two reasons. First, as the authors pointed out, data are sparse (compared to incidence and hospitalisation data) and are not suitable for GAMM models. Second, the alternative approach (that applied an inflation factor, Shi et al.) was based on an additional assumption about the proportion of RSV episodes that could access hospital care. The resulted estimates would not be as robust as the estimates of incidence and hospitalisations and undermined the overall quality of the work.

Comments for Part 2 - estimation of absolute number

* I am confused by the decision to estimate the absolute number of global and regional RSV infections in the year of 2020 - the COVID-19 pandemic year when RSV epidemiology changed substantially (e.g., incidence, severity and age distribution). I do not see any additional efforts for accounting for the impact of the pandemic nor any justifications.

o Reading through the manuscript, this part looks more like an informal validation of the GAMM models used above - then I would use the years of 2015 and 2019, respectively for validating the estimates by Shi et al and Li et al. This part could potentially go to the appendix.

Comments for "window of protection"

* I believe this is the meat of the paper and deserves more attention and work. Can the authors consider estimating the proportion of the overall burden in <1y or <5y for different RSV prophylactic products and for different schedules (e.g., birth dose or later in life)? This provides more straightforward practical information for decision-makers in addition to peak, mean and median age.

Other comments

* Writing style - while I appreciate that the authors described their methodology in great details, the overall text looks a bit too technical, especially considering the readerships of PLoS Med. This is for both the method and discussion sections. I spent almost half a day each to navigate through the amount of technical details.

o In the discussion section, I saw large amount of texts that compared numbers but few interpretation and appraisal of the estimates.

Reviewer #2: This study addresses an important research question about the age profile of RSV disease burden in developing countries. It has relevance for understanding the potential impact of various RSV vaccination strategies. Overall, the study is well-done and clearly written. The manuscript is lengthy and presents multiple results. However, this manuscript can be better summarized and emphasize on the most important findings. Specific comments are as follows:

Major comments:

- Lack of a clear description of the methods for different outcome models. Figure 1 panel A is very condensed, but the figure legend is more informative enough. The method description on page 6 is still not clear why the authors chose two different outcome models. I recommend the authors to phrase this part, including the following two burden models, as a base model and sensitivity analyses.

- The section window of protection and the burden stratified by age in results should be combined and emphasized. This is the most significant and innovative finding this paper compared with others. Instead of presenting point estimates like mean, median, and peak age of infection, the authors should consider describing the distribution of the age profile and the impact of different vaccination strategies. Many previous papers already concluded the mean and median age of infection. In my opinion, what the author wrote in page 14 to 15, "…about a quarter to a half of all hospitalizations happen in the first 6 months of life…", is the most important finding for this manuscript. The author should consider expanding this part and discussing what percentage of children at risk can be protected with different type of vaccination strategy.

Minor comments:

- The current title does not reflect the content of the manuscript. I would suggest changing the title to "The detailed age distribution of RSV burden in infants of low- and middle-income countries: a generalized additive mixed effect model approach"

- The background of the abstract is disjoint from the following abstract. I would suggest adding a sentence to explain why estimate the age profile of RSV burden will help optimize the upcoming vaccination strategies.

- The probability of hospitalization is a conditional probability. The author should make it clear in the first place. It should be "the probability of hospitalization given infection".

- Page 2 line 17, statement: "maternal vaccines protect children no more than four months". Pfizer announced the results of a phase 3 clinical trial on maternal RSV vaccine and the protection is beyond 150 days.

- Page 2 line 25: The word "temporal resolution" is confusing. This paper does not measure RSV burden over calendar time as a time-series analysis but provide the detailed age profile of RSV burden.

- Page 4 line 81: The author should clarify that the "month-specific epidemiology" is age in month in pediatric populations.

- Page 8: "The scenario analysis: severity of RSV' seems to be disjoint from the main manuscript. The author should consider moving this section into the supplementary document and acknowledging the lack of severity measures as a limitation.

- Page 9 line 245 is unclear. What is the meaning of "the trend overall is higher"?

- Page 9 line 254. Large "amount".

- Page 9 line 259. What is the peak incidence? Hospitalization incidence? Community-based incidence?

- Page 9 line 263. For "12,77%", the decimal symbol should use the same format across the paper.

Reviewer #3: Thanks for the opportunity to review your manuscript. My role is as a statistical reviewer, so my review concentrates on the study design, data, and analysis that are presented. I have put general questions first, followed by queries relevant to a specific section of the manuscript (with a page/line reference).

This manuscript estimates incidence of RSV (community, hospitalisations, and deaths from) across early childhood across a selection of lower and middle-income countries. Suitable data (with sufficient numbers of age-groups and from 200 onwards) were taken from a previous systematic review. An interesting approaching using generalised additive mixed models was applied - this enabled a country specific estimate of age-specific incidence of RSV with a random parameter for the spline effect of age. Sub-group effects were considered in the incidence and probability parts of the model, e.g. heterogeneity by country income group. Aggregated age-group data was dealt with my considering the total incidence/probability for an age-group to be representative of the mid-point of the interval. That is probably a reasonable approach for population level data. Shrinkage was employed to find an optimal number of knots for each of the splines. Two approaches to estimating burden were considered - these give very similar point estimates with OM generally having wider CI than OM I. This is a fairly complex approach - the detailed appendices (and github repository) were a great help for this review. The explanation and figures are well presented in terms of explaining the approach. The GAMMs used are a good way to estimate the target epidemiological model (e.g. incidence in community->hosp->death), but whether this model of burden is reasonable representation of the process, or if the underlying data from the systematic review is of sufficient quality to be used in this way is something I don't have the expertise to judge myself.

I have worked with population level RSV data (a long time ago) and at the time I was surprised by the discrepancy between the burdens it represented in my own country compared to the relative level of attention paid towards this disease. I think that the overall aims and research questions proposed here are good (albeit this judgement comes from someone without substantial subject-matter expertise on RSV).

One query I had was around generalisability of the findings from the included countries to all low and middle-income countries, e.g. good amounts of coverage for Central America, but limited data available for North Africa and Central Asia. The results should be internally valid to the countries included in the data, but I wonder if some of the language that generalises the results to all LMICs might not be appropriate?

Abstract, Methods and findings. I would reword the description of the secondary analysis so that it's clear that total RSV burden was estimated, at the moment the difference between the primary and secondary analyses is hard to distinguish because the phrases 'across different settings 'and 'across settings' look similar but actually mean completely different things.

S.1.4 For the incidence part of the model, was over dispersion checked? Were residuals also examined for excess 0's? Given population is an offset I would guess this would unlikely to be an issue

S1.4.1 "…we excluded studies that fewer than three studies…" - should the last 'studies' here be 'age-groups'?

S.1.4.2 What is the advantage of 5,000 draws from the MVN distribution compared to taking predictions directly from 5 and 95th percentile (or whatever limits are appropriate)?

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 2

Philippa C Dodd

16 May 2023

Dear Dr. Antillón,

Thank you very much for re-submitting your manuscript "The age profile of respiratory syncytial virus burden in pre-school children of low- and middle-income countries: A semi-parametric, meta-regression approach" (PMEDICINE-D-23-00070R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by 2 reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

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.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.  

We look forward to receiving the revised manuscript by May 23 2023 11:59PM.   

Sincerely,

Philippa Dodd, MBBS MRCP PhD

PLOS Medicine

plosmedicine.org

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

Requests from Editors:

GENERAL

Thank you for detailed and considered responses to previous editor and reviewer comments. Please see below for further comments which we require that you address prior to publication.

Please start your numbering at line 1 of the abstract (as opposed to the introduction).

ABSTRACT

Final paragraph of methods and findings and the beginning of the conclusions, please temper the language used when reporting your results, the phrase, ‘we estimate...’ or similar may be helpful.

AUTHOR SUMMARY

Thank you for including an author summary. The author summary should consist of 2-3 succinct bullet points under each of the following headings:

• Why Was This Study Done? Authors should reflect on what was known about the topic before the research was published and why the research was needed.

• What Did the Researchers Do and Find? Authors should briefly describe the study design that was used and the study’s major findings. Do include the headline numbers from the study, such as the sample size and key findings.

• What Do These Findings Mean? Authors should reflect on the new knowledge generated by the research and the implications for practice, research, policy, or public health. Authors should also consider how the interpretation of the study’s findings may be affected by the study limitations. In the final bullet point of ‘What Do These Findings Mean?’, please describe the main limitations of the study in non-technical language.

We encourage you to review published articles on our website for examples. Please also see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

STATISTICAL REPORTING

Page 9 onwards - when reporting 95% CIs, we suggest the use of commas to separate upper and lower bounds instead of hyphens as these can be confused with the reporting of negative values. Please check and amend throughout including all sections of the main manuscript text, figures (and tables) and supplementary files where relevant.

FIGURES

Please consider using/confirm usage of a colour palette suitable to those with colour blindness (i.e. avoiding red and/or green) to improve accessibility of your figures.

DISCUSSION

Please revise the structure of your discussion which should begin with a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion. Please do not include any sub-headings in the text such that your discussion reads as a single piece of continuous prose.

REFERENCES

For in-text reference callouts please remove spaces between citations, for example, line 24 (introduction) ‘…[20, 28, 29]…’ should read ‘…[20,28,29]…’ Please check and amend throughout all sections of the manuscript.

SUPPORTING INFORMATION

S1.4.1 and S1.8 – contains red text which may not be accessible to those with colour blindness. Please consider revising the use of red (and/or green).

S1 page 19 – please ensure that referencing format follows that of PLOS Medicine’s guidance which can be found here https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references

Please ensure that journal name abbreviations are those found in the National Center for Biotechnology Information (NCBI) databases.

Please ensure that up to but no more than 6 author names are listed followed by et al, if more than 6 authors contribute to an individual study.

Please ensure that all web references include an access date.

SOCIAL MEDIA

If not already done so, to help us extend the reach of your research, please detail any Twitter handles you wish to be included when we tweet this paper (including your own, your co-authors’, your institution, funder, or lab) in the manuscript submission form when you re-submit the manuscript.

Comments from Reviewers:

Reviewer #1: No further comments.

Reviewer #3: Thanks for the revised manuscript and responses to my original queries. The updates and clarifications cover my original review - no further questions from me.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 3

Philippa C Dodd

30 May 2023

Dear Dr Antillón, 

On behalf of my colleagues and the Academic Editor, Professor Mirjam Kretzschmar, I am pleased to inform you that we have agreed to publish your manuscript "The age profile of respiratory syncytial virus burden in pre-school children of low- and middle-income countries: A semi-parametric, meta-regression approach" (PMEDICINE-D-23-00070R3) in PLOS Medicine.

Prior to publication please ensure that you make the following revisions:

1) Author Summary

i) Line 53 – please split this statement as follows, ‘This study uses improved statistical models to estimate in

depth the age profile of RSV cases, hospitalizations, and in-hospital deaths in young children.’

ii) If you wish to include the latter half of the statement, suggest the following – ‘This study may enable modellers

to make improved estimates thus allowing policymakers to gain a better understanding of the potential impact

that new pharmaceutical products could have.’ and placing as a final bullet point under ‘what do these findings

mean’.

2) Discussion

Line 474 (and onwards) please change ‘is’ to ‘was’ or ‘was estimated at…’

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process. 

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper. 

Best wishes,

Pippa 

Philippa Dodd, MBBS MRCP PhD 

PLOS Medicine

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Text. Supplementary Methods.

    Section S1.1. Extraction of the Shi and colleagues and Li and colleagues data. Section S1.1.1. Modifications to incidence data from Shi and colleagues. Section S.1.1.2. Modifications to fatality (hCFR) data from Shi and colleagues. Section S1.2. Descriptive summaries of all data. Section S1.3. Generalized additive mixed models (GAMM). Section S1.4. Outcome Models (OM) I and II. Section S1.7. Characterizing the age profile of RSV burden (mean, median, and the peak age of each outcome). Section S1.6. Burden Models (BM) I and II. Section S1.9. Countries included, World Bank Income Group, population, and life tables. Section S1.3. Generalized additive mixed models (GAMM). Section S1.5.1. Spline specifications and computational considerations. Section S1.5.2. Predictions of the outcome model and uncertainty. Section S1.8. Severe and very severe disease. Table A. Characteristics of the studies included in the main splines and in the supplemental severity splines. Table B. Country income groups and population age <5 in 2020. Fig A. Geographic distribution of the available data. Fig B. Relationship between cases, hospitalizations, and severity from birth to 60 months of age.

    (PDF)

    S2 Text. Supplementary Results: Spline Validation.

    Section 2–1.1. Fit-vs-observed: Community-based incidence. Section 2–1.2. Fit-vs-observed: Hospital-based incidence. Section 2–1.3. Fit-vs-observed: Probability of hospitalization among cases in the community. Section 2–1.4. Fit-vs-observed: Probability of death among hospitalized cases. Section 2–2.1. Out-of-sample validation: Community-based incidence. Section 2–2.2. Out-of-sample validation: Hospital-based incidence. Section 2–2.3. Out-of-sample validation: Probability of hospitalization among cases in the community. Section 2–2.4. Out-of-sample validation: Probability of death among hospitalized cases.

    (PDF)

    S3 Text. Supplementary Results: Additional Projections.

    Fig A. Splines of the probability of severe and very severe disease among community-based and hospital-based cases. Fig B. Splines of the probability of severe and very severe disease among community-based and hospital-based cases. Fig C. RSV cases, hospitalizations of severe and very severe disease per 1,000 person-years according to Spline Models (SM) I and II. Table A. Model selection via the generalized likelihood ratio test for severe and very severe disease. Fig D. Mean, median, and peak age of each severe and very severe disease among community-based and hospital-based cases. Fig E. Proportions of each outcome that fall under key age brackets for severe and very severe case burden. Fig F. Sensitivity analysis of the burden of RSV cases, hospitalizations, and deaths by age in low-income countries (LICs). Fig G. Sensitivity analysis of the burden of RSV cases, hospitalizations, and deaths by age in low-income countries (LMICs). Fig H. Sensitivity analysis of the burden of RSV cases, hospitalizations, and deaths by age in low-income countries (UMICs).

    (PDF)

    S1 Data. Excel files with projections for each country of the burden of cases, hospitalizations, in-hospital and community deaths for each age group and by 1-month age groups, as well as peak, median, and mean age of each outcome.

    (ZIP)

    Attachment

    Submitted filename: Reviewer comments FINAL.docx

    Attachment

    Submitted filename: Reviewer comments.docx

    Data Availability Statement

    All coding files are available from the following github repository https://github.com/Marina-Antillon/rsv_splines_lmics.


    Articles from PLOS Medicine are provided here courtesy of PLOS

    RESOURCES