key: cord-0716507-3bx96bnp
authors: Li, You; Hodgson, David; Wang, Xin; Atkins, Katherine E; Feikin, Daniel R; Nair, Harish
title: Respiratory syncytial virus seasonality and prevention strategy planning for passive immunisation of infants in low-income and middle-income countries: a modelling study
date: 2021-09-03
journal: Lancet Infect Dis
DOI: 10.1016/s1473-3099(20)30703-9
sha: 8f21b55dc1ad7acf1bd0d7bee75ff7524bf84b25
doc_id: 716507
cord_uid: 3bx96bnp

BACKGROUND: Respiratory syncytial virus (RSV) represents a substantial burden of disease in young infants in low-income and middle-income countries (LMICs). Because RSV passive immunisations, including maternal vaccination and monoclonal antibodies, can only grant a temporary period of protection, their effectiveness and efficiency will be determined by the timing of the immunisation relative to the underlying RSV seasonality. We aimed to assess the potential effect of different approaches for passive RSV immunisation of infants in LMICs. METHODS: We included 52 LMICs in this study on the basis of the availability of RSV seasonality data and developed a mathematical model to compare the effect of different RSV passive immunisation approaches (seasonal approaches vs a year-round approach). For each candidate approach, we calculated the expected annual proportion of RSV incidence among infants younger than 6 months averted (effectiveness) and the ratio of per-dose cases averted between that approach and the year-round approach (relative efficiency). FINDINGS: 39 (75%) of 52 LMICs included in the study had clear RSV seasonality, defined as having more than 75% of annual RSV cases occurring in 5 or fewer months. In these countries with clear RSV seasonality, the seasonal approach in which monoclonal antibody administration began 3 months before RSV season onset was only a median of 16% (IQR 13–18) less effective in averting RSV-associated acute lower respiratory infection (ALRI) hospital admissions than a year-round approach, but was a median of 70% (50–97) more efficient in reducing RSV-associated hospital admissions per dose. The seasonal approach that delivered maternal vaccination 1 month before the season onset was a median of 27% (25–33) less effective in averting hospital admissions associated with RSV-ALRI than a year-round approach, but was a median of 126% (87–177) more efficient at averting these hospital admissions per dose. INTERPRETATION: In LMICs with clear RSV seasonality, seasonal approaches to monoclonal antibody and maternal vaccine administration might optimise disease prevention by dose given compared with year-round administration. More data are needed to clarify if seasonal administration of RSV monoclonal antibodies or maternal immunisation is programmatically suitable and cost effective in LMICs. FUNDING: The Bill & Melinda Gates Foundation, World Health Organization.

. Year-to-year variations in relative effectiveness and relative efficiency for each monoclonal antibodies candidate approach in countries with ≤5 epidemic months .................... 13 Table S6 . Year-to-year variations in the effectiveness and relative efficiency for each maternal vaccine candidate approach in countries with ≤5 epidemic months .. Table S9 . Year-to-year variations in relative effectiveness and relative efficiency for each monoclonal antibodies candidate approach in countries with ≤5 epidemic months, with a monthly efficacy decay rate of 0. 8 Table S10 . Year-to-year variations in relative effectiveness and relative efficiency for each maternal vaccine candidate approach in countries with ≤5 epidemic months with a monthly efficacy decay rate of 0. 8 

The list of low and middle income countries are extracted from the World Bank Classifications by Income. 1 

The RSV burden data among infants in LMICs (as one region) were obtained from our previously published RSV global burden estimates. 19 The data were available in the following age groups: <28 days, 1-<3 months, 3-<6 months, 6-<9 months and 9-<12 months; and by two outcomes: RSV-ALRI incidence rate in the community and RSV-ALRI hospitalisation rate. For the present study, we used the aggregated regional level percentage of RSV cases among infants <1y for each group as the model input (as shown in the table below). 

For monoclonal antibody immunisation, data on BCG and Hepatitis B vaccines coverage were included from the World Health Organization (WHO). 20 The average coverage between the two vaccines was calculated for each country. If coverage was missing for one vaccine for a country, then the coverage of the other vaccine was used.

As limited data were available on the maternal influenza vaccine coverage in LMICs, we used the WHO ANC4+ indicator for the maternal vaccine coverage, defined as the percentage of women aged 15-49 with a live birth who received antenatal care (ANC) four or more times. 21 WHO did not report a separate indicator for each of the ANC visits.

We used the ResVax efficacy data from its phase 3 clinical trial results among third-trimester pregnant women: 39·4% (95% CI: 5·3-61·2) for medically significant RSV-ALRI and 44·4% (95% CI:

19·6-61·5) for RSV-ALRI hospitalisation by day 90 after birth. 22 Calculations related to the effectiveness and relative efficiency

We calculated the proportion of monthly of incidence for age group a among annual incidence in <6 month using the formula,

For each candidate approach c, we determined whether each month and age group pair (a,m) is protected by the prophylactic treatment. If (a,m) is protected then it is a "benefit group", if it is not protected then it is a "non-benefit group". Therefore, by defining an indicator function 1 c (a,m) = 1 if (a,m) is a benefit group and 0 otherwise, we calculated the effectiveness of a candidate approach ( ) with coverage and efficacy through the formulae, Month of birth 1:Jan, 2:Feb, …., 12:Dec

Annual incidence of RSV outcome in age group a Annual average percentage of RSV activity in month m , Proportion of monthly incidence for each age group among annual incidence in <6m Efficacy of prophylactic in candidate approach c Coverage of prophylactic in candidate approach c Calculating proportion of annual incidence in <6m that can be averted by an RSV prophylactic if assuming 100% efficacy and 100% coverage Effectiveness of candidate approach c including coverage and efficacy Number of live births per month Number of months treatment is given for candidate approach c Per-dose effectiveness of candidate approach c Relative effectiveness of candidate approach c compared to the year-round approach = To determine the per-dose effectiveness for each candidate approach ( ), we calculated the ratio of the effectiveness and the number of doses given, resulting in the formula,

To determine the relative efficiency (R c ), we calculated the ratio of the per-dose effectiveness between each candidate approach and the year-round approach. That is,

To calculate the proportion of RSV-ALRI hospitalisations in <3m by birth month, b, we used the formula,

Where ( + − 1) 12 is the value of ( + + 1) modulus 12. Results are presented as median (IQR) among the included countries. Seasonal approach A administers mAb in each epidemic month, while seasonal approaches B-D begin administration of mAb 1, 2 and 3 months prior to the onset of the first epidemic month, respectively. Results are presented as median (IQR) among the included countries. Seasonal approach A is designed to protect infants born in each epidemic month, while seasonal approach B protects infants whose first three months of life include at least two RSV epidemic months. Results are presented as median (IQR) among the included countries. Seasonal approach A is designed to protect infants born in each epidemic month, while seasonal approach B protects infants whose first three months of life include at least two RSV epidemic months. Reference Results are presented as median (IQR) among all the study years. Seasonal approach A is designed to protect infants born in each epidemic month, while seasonal approach B protects infants whose first three months of life include at least two RSV epidemic months. Countries are arranged by the duration of RSV epidemics from short (more seasonal) to long (less seasonal). Seasonal approach A administers mAb in each epidemic month, while seasonal approaches B-D begin administration of mAb 1, 2 and 3 months prior to the onset of the first epidemic month, respectively. Countries are arranged by the duration of RSV epidemics from short (more seasonal) to long (less seasonal). Seasonal approach A is designed to protect infants born in each epidemic month, while seasonal approach B protects infants whose first three months of life include at least two RSV epidemic months. Figure S9 . Country-specific results of effectiveness and relative efficiency in averting RSV-ALRI for monoclonal antibodies Number after each country indicates duration of RSV epidemics (in months). Effectiveness is defined by annual proportion averted among infants under six months of age; relative efficiency is defined by the ratio between per-dose effectiveness of a seasonal approach and that of the year-round approach. Approaches in the upper right quadrant would be considered those with optimal effectiveness and relative efficiency. Figure S10 . Country-specific results of effectiveness and relative efficiency in averting RSV-ALRI hospitalisation for maternal vaccine Number after each country indicates duration of RSV epidemics (in months). Effectiveness is defined by annual proportion averted among infants under six months of age; relative efficiency is defined by the ratio between per-dose effectiveness of a seasonal approach and that of the year-round approach. Approaches in the upper right quadrant would be considered those with optimal effectiveness and relative efficiency. Figure S11 . Country-specific results of effectiveness and relative efficiency in averting RSV-ALRI for maternal vaccine Number after each country indicates duration of RSV epidemics (in months). Effectiveness is defined by annual proportion averted among infants under six months of age; relative efficiency is defined by the ratio between per-dose effectiveness of a seasonal approach and that of the year-round approach. Approaches in the upper right quadrant would be considered those with optimal effectiveness and relative efficiency. Figure S12 . Year-to-year variations of effectiveness and relative efficiency in averting RSV-ALRI hospitalisation for monoclonal antibodies Countries are arranged by the duration of RSV epidemics (in months, shown next to country name). Each dot represents an approach in a single year. Effectiveness is defined by annual proportion averted among infants under six months of age; relative efficiency is defined by the ratio between per-dose effectiveness of a seasonal approach and that of the year-round approach. Approaches in the upper right quadrant would be considered those with optimal effectiveness and relative efficiency. Linear relationship between effectiveness and relative efficiency within each approach and country is due to the fact that relative efficiency is a function of effectiveness and number of dosing months; the latter is a constant for each approach and country. Degree of year-on-year variations can be reflected by the distance between dots of the same colour. Figure S13 . Year-to-year variations of effectiveness and relative efficiency in averting RSV-ALRI for monoclonal antibodies Countries are arranged by the duration of RSV epidemics (in months, shown next to country name). Each dot represents an approach in a single year. Effectiveness is defined by annual proportion averted among infants under six months of age; relative efficiency is defined by the ratio between per-dose effectiveness of a seasonal approach and that of the year-round approach. Approaches in the upper right quadrant would be considered those with optimal effectiveness and relative efficiency. Linear relationship between effectiveness and relative efficiency within each approach and country is due to the fact that relative efficiency is a function of effectiveness and number of dosing months; the latter is a constant for each approach and country. Degree of year-on-year variations can be reflected by the distance between dots of the same colour. Figure S14 . Year-to-year variations of effectiveness and relative efficiency in averting RSV-ALRI hospitalisation for maternal vaccine Countries are arranged by the duration of RSV epidemics (in months, shown next to country name). Each dot represents an approach in a single year. Effectiveness is defined by annual proportion averted among infants under six months of age; relative efficiency is defined by the ratio between per-dose effectiveness of a seasonal approach and that of the year-round approach. Approaches in the upper right quadrant would be considered those with optimal effectiveness and relative efficiency. Linear relationship between effectiveness and relative efficiency within each approach and country is due to the fact that relative efficiency is a function of effectiveness and number of dosing months; the latter is a constant for each approach and country. Degree of year-on-year variations can be reflected by the distance between dots of the same colour. Figure S15 . Year-to-year variations of effectiveness and relative efficiency in averting RSV-ALRI for maternal vaccine Countries are arranged by the duration of RSV epidemics (in months, shown next to country name). Each dot represents an approach in a single year. Effectiveness is defined by annual proportion averted among infants under six months of age; relative efficiency is defined by the ratio between per-dose effectiveness of a seasonal approach and that of the year-round approach. Approaches in the upper right quadrant would be considered those with optimal effectiveness and relative efficiency. Linear relationship between effectiveness and relative efficiency within each approach and country is due to the fact that relative efficiency is a function of effectiveness and number of dosing months; the latter is a constant for each approach and country. Degree of year-on-year variations can be reflected by the distance between dots of the same colour.

Item # Checklist item Reported on page # Objectives and funding 1 Define the indicator(s), populations (including age, sex, and geographic entities), and time period(s) for which estimates were made.

List the funding sources for the work. 7

For all data inputs from multiple sources that are synthesized as part of the study: 3

Describe how the data were identified and how the data were accessed.

Specify the inclusion and exclusion criteria. Identify all ad-hoc exclusions.

Provide information on all included data sources and their main characteristics. For each data source used, report reference information or contact name/institution, population represented, data collection method, year(s) of data collection, sex and age range, diagnostic criteria or measurement method, and sample size, as relevant.

Identify and describe any categories of input data that have potentially important biases (e.g., based on characteristics listed in item 5).

For data inputs that contribute to the analysis but were not synthesized as part of the study: 7

Describe and give sources for any other data inputs. N/A For all data inputs: 8 Provide all data inputs in a file format from which data can be efficiently extracted (e.g., a spreadsheet rather than a PDF), including all relevant meta-data listed in item 5. For any data inputs that cannot be shared because of ethical or legal reasons, such as third-party ownership, provide a contact name or the name of the institution that retains the right to the data.

Data analysis 9 Provide a conceptual overview of the data analysis method. A diagram may be helpful. Figure S1 10 Provide a detailed description of all steps of the analysis, including mathematical formulae. This description should cover, as relevant, data cleaning, data preprocessing, data adjustments and weighting of data sources, and mathematical or statistical model(s).

6 & Appendix 8-9

Describe how candidate models were evaluated and how the final model(s) were selected.

Provide the results of an evaluation of model performance, if done, as well as the results of any relevant sensitivity analysis.

Describe methods for calculating uncertainty of the estimates. State which sources of uncertainty were, and were not, accounted for in the uncertainty analysis.

State how analytic or statistical source code used to generate estimates can be accessed.

7

Provide published estimates in a file format from which data can be efficiently extracted. Table 1 &  Table S1 -S 16

Report a quantitative measure of the uncertainty of the estimates (e.g. uncertainty intervals).

Interpret results in light of existing evidence. If updating a previous set of estimates, describe the reasons for changes in estimates.

18

Discuss limitations of the estimates. Include a discussion of any modelling assumptions or data limitations that affect interpretation of the estimates.

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