MAJOR ARTICLE

Reduced-Dose Schedule of Prophylaxis Based on

Local Data Provides Near-Optimal Protection
Against Respiratory Syncytial Virus
Daniel M. Weinberger,1 Joshua L. Warren,2 Claudia A. Steiner,3 Vivek Charu,4 Cécile Viboud,4 and Virginia E. Pitzer1
Departments of 1Epidemiology of Microbial Disease, and 2Biostatistics, Yale School of Public Health, New Haven, Connecticut; 3Healthcare Cost and
Utilization Project, Center for Delivery, Organization and Markets Agency for Healthcare Research and Quality, Rockville, and 4Division of International
Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, Bethesda, Maryland

(See the Editorial Commentary by Panozzo and Hampp on pages 515–6.)

Background. Respiratory syncytial virus (RSV) is a major cause of respiratory infections among young children and
can lead to severe disease among some infants. Infants at high risk for severe RSV infection receive monthly injections of a
prophylactic monoclonal antibody during the RSV season based on national guidelines. We considered whether a re-
duced-dose schedule tailored to the local RSV season in the continental United States would provide adequate protection.
Methods. Hospitalization data for 1942 counties across 38 states from 1997 to 2009 were obtained from the State
Inpatient Databases (Agency for Healthcare Research and Quality). We assessed the timing of RSV epidemics at the coun-
ty and state levels using a 2-stage hierarchical Bayesian change point model. We used a simple summation approach to
estimate the fraction of RSV cases that occur during the window of protection provided by initiating RSV prophylaxis
during different weeks of the year.
Results. The timing of RSV epidemic onset varied significantly at the local level. Nevertheless, the national recom-
mendations for initiation of prophylaxis provided near-optimal coverage of the RSV season in most of the continental
United States. Reducing from 5 to 4 monthly doses (with a later initiation) provides near-optimal coverage (<5% decrease
in coverage) in most settings. Earlier optimal dates for initiating 4 doses of prophylaxis were associated with being farther
south and east, higher population density, and having a higher percentage of the population that was black or Hispanic.
Conclusions. A 4-dose schedule of prophylactic injections timed with local RSV epidemics could provide protection
comparable to 5 doses and could be considered as a way to improve the cost-effectiveness of prophylaxis.
Keywords. RSV; respiratory syncytial virus; prophylaxis; palivizumab; spatial variation.

Respiratory syncytial virus (RSV) is a leading cause of
hospitalizations among young children in the United
States and globally [1]. The virus infects most children
by the age of 2 years [2]. Premature infants and those
with certain underlying cardiopulmonary conditions
have a particularly high risk for severe lower respiratory
Received 30 September 2014; accepted 21 March 2015; electronically published
22 April 2015.
Correspondence: Daniel M. Weinberger, PhD, Yale University, Department of Ep-
idemiology of Microbial Diseases, PO Box 208034, New Haven, CT 06520-8034
(daniel.weinberger@yale.edu).
Clinical Infectious Diseases® 2015;61(4):506–14
© The Author 2015. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/cid/civ331
disease [3–5]. No vaccine is available to protect children
from RSV, but infants at risk for severe disease can receive
monthly injections of a prophylactic monoclonal antibody
(palivizumab) during the RSV season [6, 7]. The initiation
of the monthly injections needs to be timed so that
the child is protected for the duration of the RSV season
[8]—starting too late or ending too early will result in
the child being unprotected, while doses administered
before or after the RSV season are not cost-effective.
In the United States, up to 5 doses of palivizumab are
recommended for high-risk infants, typically beginning
in November; fewer doses may be administered depend-
ing on when during the RSV season a child is born [9].
Spatiotemporal variations in RSV epidemics make it
difficult to determine when to initiate the monthly

506 • CID 2015:61 (15 August) • Weinberger et al

series of prophylaxis and to determine how many doses to use
[8]. The earliest epidemics in the United States occur in summer
in southern Florida and in autumn in northern Florida and other
parts of the southeast. In other parts of the United States, epidem-
ics occur later throughout the fall and winter [10–14]. In some
regions, epidemics have a biennial pattern with large, early
epidemics one year followed by mild, late epidemics the next
year [15, 16], which might be linked to the strength of seasonal
variations in environmental conditions [17]. Nearby locations
can have different epidemic start times [12–14], and epidemic
duration can differ with population characteristics [15, 16].
We used data from a comprehensive nationwide hospitaliza-
tion database to estimate local variations in the timing of RSV
epidemics and to determine whether a reduced-dose prophylax-
is schedule would provide adequate protection if appropriately
timed with local epidemic patterns. Our results, combined with
cost-effectiveness analyses, can be used to inform recommenda-
tions for the use of RSV prophylaxis across the continental
United States.
METHODS
Data Sources on RSV Hospitalizations and Demographics
Weekly hospitalization data were obtained from the State Inpa-
tient Databases of the Healthcare Cost and Utilization Project,
maintained by the Agency for Healthcare Research and Quality
through an active collaboration. This database contains all hos-
pital discharge records from community hospitals in participat-
ing states [18]; we used data from July 1997 to June 2009. Cases
were identified by the presence of the RSV diagnostic discharge
codes (International Classification of Diseases, Ninth Revision
[ICD-9] codes 079.6, 466.11, 480.1) listed anywhere in the pa-
tient’s record. Weekly time series were created for all RSV cases
among children aged 0–23 months. All counties that contribut-
ed data for at least 3 RSV seasons (July–June) were included in
the analyses. Information about population size and correlates
of socioeconomic status (including proportion of the popula-
tion that is black or Hispanic) for each county was obtained
from Census Bureau statistics compiled by the Surveillance,
Epidemiology, and End Results program (http://seer.cancer.
gov/popdata/singleages.html). The urban–rural classifications
of the counties (2006 version) were obtained from the National
Center for Health Statistics (NCHS; http://www.cdc.gov/nchs/
data_access/urban_rural.htm). All analyses were performed
using SAS software, version 9.3 (SAS Institute, Cary, North
Carolina) or WinBUGS [19].
Estimating Epidemic Onset and Duration at the County
and State Levels
We estimated the start (onset) and end of the RSV epidemics as
well as epidemic duration (end week ‒ beginning week) in each
Reduced-Dose Schedule of RSV Prophylaxis
July–June season using a 2-stage Bayesian hierarchical model.
The first stage consisted of a Bayesian change point model
that estimated the start date, end date, and duration of the ep-
idemic separately in each year and county. The second stage was
a hierarchical Bayesian model that borrowed information across
the estimates from individual locations and years to obtain a
stabilized estimate of the epidemic onset and duration in each
year and state or county. These models were fit to either state-
level or county-level data. The first-stage model was fit using
PROC MCMC in SAS version 9.3, and the second-stage models
were fit using WinBUGS. Further details on the models are
shown in the Supplementary Appendix.
Identifying Optimal Dates for the Initiation of Prophylaxis
With 4 or 5 Doses
National recommendations stipulate that 5 monthly doses of
RSV prophylaxis should be initiated in southeast Florida on 1
July; in north-central and southwest Florida on 15 September;
and in most other areas of the United States on 1 November [7,
9]. Once prophylaxis begins, we assume the period of protection
lasts for 24 weeks (5 doses, spaced 1 month apart) [9]. This is a
conservative estimate, as the recommendations state that pro-
tection lasts for at least 24 weeks [9]. We calculated the percent-
age of cases occurring within the 24-week window beginning on
the recommended start date and compared this to the percent-
age of cases occurring within an optimal window of protection.
We also evaluated the potential coverage of a 4-dose series of
monthly shots, which would provide protection for 20 weeks.
Therefore, the goal was to identify the 24- or 20-week window
in each county that covers the greatest fraction of all RSV cases
across all years. We estimated the fraction of all RSV cases that
would occur within different 24- or 20-week windows begin-
ning between July and December (95% of epidemics at the
state level began before the end of December). The optimal win-
dow was considered to be the one that included the greatest
fraction of the total cases during the year:
0 1
ð j¼iþ23Þ
X ðX
j¼52Þ
Max@ ðRSVj Þ= ðRSVj ÞA;
ð j¼iÞ ð j¼1Þ
where i represents the number of weeks since the beginning of
July, ranging from 1 to 26, with the optimal week i being the one
resulting in the maximum fraction. This statistic was estimated
separately for each July–June period and for each state or
county.
Optimal Initiation of Prophylaxis at the State Level
For each state, we calculated the average optimal start week
across all available years. The optimal window of protection
began in this week and lasted for 24 weeks. We then estimated
the percentage of cases that occur during this optimal window
• CID 2015:61 (15 August) • 507
in each year and took the mean of this value across all available
years. Because some states exhibit biennial epidemic patterns
(strong, early epidemic one year followed by a weak, late epi-
demic the next), we also tested whether the average optimal
week differed significantly between odd and even years using
linear regression.
Identifying Correlates of Optimal Dates for the Initiation of
Prophylaxis at the County Level
We first evaluated the univariate associations between the opti-
mal week for initiating RSV prophylaxis and a variety of demo-
graphic and geographic factors, including the proportion of the
population that was black or Hispanic (logit transformed), pop-
ulation density (log-transformed), and latitude and longitude of
the county (PROC CORR, SAS version 9.3). We also evaluated
whether the optimal week differed by the NCHS urban–rural
classification scheme (6 levels ranging from large central metro-
politan areas to noncore areas) (linear regression, PROC GEN-
MOD, SAS version 9.3). The observations were weighted by the
number of cases of RSV occurring in each county and July–June
period.
Next, we built a model to estimate the optimal week to initiate
prophylaxis in each county based on demographic and geo-
graphic characteristics. We randomly selected 80% of the coun-
ties with available data to form a training dataset and reserved
the remaining 20% as a validation dataset. Using the training
dataset, we fit 22 different candidate models, each of which con-
tained a different set of variables (Supplementary Data), includ-
ing state dummy variable (ie, state average), latitude and
longitude (cubic spline), county-level characteristics alone (as
in univariate regression) or in combination, a dummy variable
for being an odd or even year, and interactions among the var-
iables. Observations were weighted by the number of RSV cases
in each county and year. The Bayesian Information Criteria
were compared to evaluate model fit. To evaluate predictive
performance, we estimated the correlation between the ob-
served values in the validation dataset and the predicted values
(weighted by the observed number of RSV cases in each county
and year), and we calculated the percentage of all cases that fell
within the predicted optimal window.
RESULTS
RSV Hospitalization Patterns
There were 769 301 RSV hospitalizations among children aged
0–23 months that occurred between July 1997 and June 2009
and were captured in our dataset. These data were drawn
from hospitals in 1942 counties across 38 states (Supplementary
Figure 1). There was an average of 59 381 cases of RSV per year
across the available states, drawn from an average population of
5.1 million children aged <2 years.
508 • CID 2015:61 (15 August) • Weinberger et al
Variations in Epidemic Onset and Duration at the State and County
Levels
Consistent with previous reports, there was considerable vari-
ability in the average timing of RSV epidemics between states.
The earliest epidemic onsets occurred in Florida, and, in gene-
ral, the epidemic onsets occurred later in the northern and west-
ern states (Figure 1A). The latest epidemic onsets, on average,
occurred in Oregon and Maine, 7–10 weeks after the epidemics
in the southeastern states (Figure 1A and 1B). Epidemic onset
varied substantially between years (Figure 1B).
In addition to the variations in epidemic onset between states,
there was variability in the average onset of epidemics at the
county level within a state (Figure 1C). Epidemics lasted longer
in large central metro counties (16.0 [95% confidence interval
{CI}, 15.3–16.7] weeks) and large fringe metro counties (15.8
[95% CI, 15.3–16.4] weeks), compared with medium metro
counties (15.5 [95% CI, 15.0–16.1] weeks), small metro counties
(15.1 [95% CI, 14.5–15.6] weeks), micropolitan counties (14.1
[95% CI, 14.9–15.9] weeks), and nonurban counties (14.4 [95%
CI, 14.0–14.9] weeks). The epidemics in the large central metro,
large fringe metro, medium metro, small metro, and micropoli-
tan counties were significantly longer than the epidemics in the
nonurban counties (95% credible intervals for differences did not
include zero; Supplementary Results).
Optimal Timing for the Initiation of RSV Prophylaxis With 5 Doses
At the state level, the national recommendations provided good
coverage of the RSV season—94% of cases that occurred within
the optimal 5-dose window of protection also occurred within
the window of protection based on the national recommenda-
tions (Figure 2A, Table1). Notably, a range of start dates for
each state and county would provide near-optimal coverage of
the RSV season (Figure 2A and 2B).
Because RSV epidemics have a biennial pattern, we also con-
sidered whether the optimal date for initiating prophylaxis
differed between odd and even years. Eleven states (Colorado,
Iowa, Kansas, Kentucky, Maine, Maryland, Minnesota, Missouri,
Nebraska, South Dakota, and Utah) showed some evidence of
biennial variations (P < .1 comparing average onset in even and
odd years), with 3–5.5 weeks between the optimal date of initia-
tion in even and odd years (Supplementary Table 1).
Effect of Eliminating 1 Dose of Prophylaxis on Protection
We considered whether the use of 4 doses of palivizumab, rath-
er than 5 doses, would provide adequate coverage of the typical
RSV season. Across all states and counties, 90%–98% of the
cases occurring within the optimal 24-week window of protec-
tion also occurred during the optimal 20-week window of pro-
tection (Table 2, Figure 2C and 2D). With the reduced-dose
series, the optimal start date for initiating prophylaxis would
be 1–3 weeks later in the season compared with the optimal
start date for 5 doses (Table 2).
Figure 1. A, Average weekly incidence of respiratory syncytial virus (RSV) hospitalizations in each state. The black bar represents the 24-week period
when a child would be protected by prophylaxis, based on the national guidelines of 5 doses beginning 1 November. B, Year-to-year variations in the
estimated week of epidemic onset at the state level. The states are ordered by latitude, with the southernmost states at the bottom. C, Variations in
the estimated week of epidemic onset between counties and years in each state, with each bubble representing an estimate from each county and
year. The estimates are obtained using a 2-stage model, where onset is estimated separately for each state/county and year, then entered into a hierarchical
model that borrows information between years and geographic areas to obtain stabilized (shrinkage) estimates. The size of the bubbles in (A) and (B) is
proportional to the inverse posterior variance of the estimate. Darker shading indicates that multiple bubbles are overlapping.

Reduced-Dose Schedule of RSV Prophylaxis • CID 2015:61 (15 August) • 509

Figure 2. Percentage of cases that occur during the 24-week or 20-week window of protection provided by respiratory syncytial virus (RSV) prophylaxis if
the dosing series is started in each week between the beginning of July (week 0) and the end of December. The maximum on each curve indicates the
average optimum week for initiating prophylaxis in that state or county. The curves are calculated separately by year and state/county and then averaged
across all available years. A and B, Protection provided by 5 doses at the state (A) and county (B) level. C and D, Protection provided by either a 5-dose series
(blue) or a 4-dose series (red) at the state level (C) or county level (D). The vertical dotted lines are placed at 1 November, when the national recommen-
dations suggest starting prophylaxis for most states. The horizontal dashed line represents 90% coverage. Only counties with an average of at least 25 cases
are shown in (B) and (D). Counties in Florida are excluded from (B) and (D).

Predictors of Optimal Week of Initiation of RSV Prophylaxis at the
County Level
Because not all counties had available hospitalization data
(Figure 3A), we developed and validated a model of the optimal
timing for the initiation of RSV prophylaxis with a 4-dose series
for all counties in the continental United States to obtain an
estimate of epidemic timing for counties with and without data
(Figure 3B). In univariate analyses, an earlier optimal initiation
date was associated with several socioeconomic indicators,
including higher urbanization, having a higher percentage of
black or Hispanic residents, higher population density, being
further south or east, and being an odd vs even year (Table 1).
The best multivariate model (Figure 3B) included latitude and
longitude of the county (spline), correlates of socioeconomic
status ( population density, percentage of the population that
was Hispanic, percentage of the population that was black),
being an odd vs even year, and interaction terms (Supplementary
Data). There was a moderate correlation between the optimal
date predicted from the best model and the optimal date observed
in the training and validation samples (ρ = 0.75 and ρ = 0.65,
respectively). If a 4-dose prophylaxis series was initiated based
on the predicted optimum start dates in each county, 90.1% of
all cases would occur within the window of protection (90.0%
in the training set, 90.7% in the validation set), compared with
93.2% if the nationally recommended start date for 5 doses was
used (92.9% in the training set, 93.8% in the validation set).
DISCUSSION
We present evidence that despite large variations in RSV epidem-
ic timing across the continental United States, national recom-
mendations for the initiation of a 5-dose series of prophylaxis

510 • CID 2015:61 (15 August) • Weinberger et al

Table 1. Average Optimal Start Date for 5 or 4 Doses of Prophylaxis and the Percentage of Respiratory Syncytial Virus Cases Occurring
Within the Window of Protection for Each Schedule

Optimal Date of First Dose Cases Occurring Within

of Prophylaxisa Optimal Window of Protectionb, %
Proportion of Cases
National 5 Doses 4 Doses Covered
State 5 Doses 4 Dosesc Recommendationd (Optimal) (Optimal) by 4 vs 5 Doses
Arizona 9-Nov 23-Nov 97.3 97.9 95.8 0.98
Arkansas 26-Oct 2-Nov 94.6 95 91.6 0.96
California 2-Nov 16-Nov 94.8 95 92 0.97
Colorado 16-Nov 30-Nov 94.3 96.1 93.2 0.97
Florida 31-Aug 14-Sep 77.7 77.7 70.4 0.9
Georgia 5-Oct 19-Oct 89.3 91.2 86 0.94
Illinois 9-Nov 16-Nov 94.4 94.6 90.9 0.96
Indiana 9-Nov 23-Nov 95.3 95.7 92.6 0.97
Iowa 23-Nov 30-Nov 91 93.4 89.9 0.96
Kansas 16-Nov 30-Nov 93.9 95 92.2 0.97
Kentucky 9-Nov 23-Nov 92.2 92.4 87.9 0.95
Maine 30-Nov 21-Dec 90.7 96.2 92.6 0.96
Maryland 2-Nov 9-Nov 93 93 88.7 0.95
Massachusetts 2-Nov 16-Nov 95.1 95.1 91.5 0.96
Michigan 16-Nov 30-Nov 93 94.7 91.6 0.97
Minnesota 9-Nov 23-Nov 94.3 94.8 91.2 0.96
Missouri 2-Nov 23-Nov 93.9 94.6 90.9 0.96
Nebraska 16-Nov 30-Nov 92.7 94.1 90.1 0.96
Nevada 16-Nov 23-Nov 88.8 89.9 86.2 0.96
New Hampshire 9-Nov 30-Nov 95.9 96 94 0.98
New Jersey 19-Oct 26-Oct 92.4 92.8 88.1 0.95
New York 19-Oct 2-Nov 91.2 91.5 85.7 0.94
North Carolina 26-Oct 2-Nov 93.8 93.7 89.4 0.95
Ohio 16-Nov 23-Nov 94.6 95.7 92.2 0.96
Oklahoma 2-Nov 16-Nov 96.5 96.5 94.2 0.98
Oregon 30-Nov 14-Dec 91.2 95.5 92.6 0.97
Pennsylvania 9-Nov 30-Nov 95.1 96.1 92.6 0.96
Rhode Island 2-Nov 9-Nov 96.4 96.4 92.3 0.96
South Carolina 19-Oct 26-Oct 90.1 90 84.9 0.94
South Dakota 23-Nov 30-Nov 88.9 92.1 86.8 0.94
Tennessee 26-Oct 16-Nov 93.5 93.5 89.1 0.95
Texas 5-Oct 19-Oct 92.4 93.1 87.2 0.94
Utah 23-Nov 7-Dec 93.9 96.4 93.7 0.97
Vermont 23-Nov 7-Dec 94.9 96.6 93.9 0.97
Virginia 26-Oct 9-Nov 92.4 92.4 87.9 0.95
Washington 16-Nov 30-Nov 91.5 93.7 89.5 0.96
West Virginia 16-Nov 30-Nov 92.8 93.7 90 0.96
Wisconsin 16-Nov 7-Dec 95.3 97 94.6 0.97

Analysis based on hospitalization data from the State Inpatient Databases of the Healthcare Cost and Utilization Project (Agency for Healthcare Research and
Quality).
a
The week beginning on this date.
b
Average across all years of the percentage of cases that occur during the 24- or 20-week window starting on the optimal start date for 5 doses or 4 doses,
respectively.
c
The standard error for the 4-dose optimal start dates ranged from 0.4 to 4.4 weeks, with an average standard error of 1.9 weeks.
d
Date of 1 November, except for Florida (15 September). All dates are based on the 2014 calendar.

Reduced-Dose Schedule of RSV Prophylaxis • CID 2015:61 (15 August) • 511

Table 2. Univariate Associations Between Optimal Week more complete picture of the geographic patterns of RSV activ-
for Initiating a 4-Dose Prophylaxis Series and Urban–Rural ity in the United States than analyses based on laboratory data.
Characteristics (N = 1407 Counties) Practically, the start dates provided in the tables provide an
approximation of the optimal date to initiate prophylaxis at
Difference in
the state or county level. There is some flexibility in when to
Characteristic Optimal Weeka 95% CI
start prophylaxis, and in most cases, starting the 4-dose series
Urban–rural classification
a few weeks earlier or later than the optimal date would have
Large central metro Ref Ref
a fairly small impact on protection (Figure 2). Due to the com-
Large fringe metro −0.03 −.21 to .14
Medium metro 0.88 .71 to 1.05
plexity of using county-level recommendations, the optimal
Small metro 2.03 1.84–2.23 start date at the state level (Table 2) would provide a good ap-
Micropolitan 2.86 2.65–3.07 proximation of the optimal start date at the county level. For
Noncore 4.76 4.44–5.08 states without data, the optimal start dates predicted from the
Even vs odd years county-level model could provide a reasonable approximation
Odd year Ref Ref of the best start date (Supplementary Table).
Even year 0.29 .18–.41 The cost-effectiveness of RSV prophylaxis has been debated
Correlationb (ρ) [20–22]. To evaluate the impact of changing from a 5-dose
Latitude (north) 0.41 .39–.42 schedule to a 4-dose schedule based on local timing, a formal
Longitude (east) −0.23 −.25 to −.21
cost-effectiveness analysis is needed that takes into account fac-
Percentage black (logit) −0.43 −.45 to −.42
tors such as the incidence rate in the target population, the ef-
Percentage Hispanic (logit) −0.28 −.29 to −.26
ficacy of prophylaxis, and the relationship between infant
Population density (log) −0.38 −.40 to −.37
Percentage of population <5 y −0.09 −.11 to −.07
weight and dosage. However, we can approximate the impact
using previous estimates of the incremental cost-effectiveness
Analysis based on hospitalization data from the State Inpatient Databases of
the Healthcare Cost and Utilization Project (Agency for Healthcare Research ratio (ICER). The optimal 4-dose schedule would capture
and Quality). 96.2% of hospitalized cases captured by the optimal 5-dose
Abbreviations: CI, confidence interval; Ref, reference. schedule (Table 2). Assuming that average dosage remains
a
Estimated with linear regression, with a dummy variable for each category.
b
approximately the same, and that the administration and other
Pearson correlation.
costs are equally distributed across each dose, the total cost of
prophylaxis under the 4-dose schedule should be 80% of what
it would be under the 5-dose schedule. Therefore, the total effect
of switching from a 5-dose to 4-dose schedule can be approxi-
provide good coverage of the RSV epidemic period in most set- mated by multiplying the ICER by 0.83 (=0.8/0.962). This is un-
tings. Moreover, we find that eliminating 1 of the 5 monthly likely to alter the conclusions of Hampp et al, who estimated the
doses and initiating this reduced-dose series later in the season ICER to be US$302 103 among premature infants <6 months of
would not result in a substantial decline in protection if the ini- age in the Florida Medicaid population [20]. However, other
tiation of prophylaxis accounts for variations in RSV epidemic studies have reported more favorable ICERs (eg, [21, 22]).
timing between states and counties. Our study is subject to several limitations. The county infor-
These results build on previous studies of RSV epidemic tim- mation assigned to each case is based on the county where the
ing and prophylaxis and make several key advances. A previous hospital is located rather than the county of residence. This
study based on laboratory surveillance in 19 select US locations could lead to some misclassification, particularly for rural
[8] compared the number of weeks a child would be unprotect- areas with limited healthcare facilities. Furthermore, we lacked
ed during the RSV season if prophylaxis was initiated based on data for states in the Northern Plains and the South; our results
the national recommendations vs the average onset date. How- may not be generalizable to these regions. Our analyses of
ever, because RSV transmission and disease risk will be greatest epidemic onset assumed that there was a single RSV epidemic
at the peak of the epidemic and lower at the beginning and end, in each year. However, in some rural areas, the epidemics could
simply counting the number of weeks of the RSV season when a instead be characterized by multiple, independent, and localized
child is unprotected can be misleading. Our method allowed us outbreaks. This would lead to less precise estimates of epidemic
to identify the optimal week for initiating prophylaxis and to onset, but would not influence our analyses of optimal timing of
demonstrate that a reduced-dose schedule, with a later start initiation of prophylaxis. We assumed that a child has equal risk
date, could provide adequate coverage of the RSV season in of developing disease outside the window of protection at the
most locations. Additionally, our analyses used data from a beginning or end of the RSV season. However, antibody protec-
comprehensive hospitalization database, which provides a tion wanes gradually, so an individual might have some residual

512 • CID 2015:61 (15 August) • Weinberger et al

Figure 3. A, Optimal week for initiating respiratory syncytial virus (RSV) prophylaxis among counties for which data were available. B, Predicted optimal
week for initiating RSV prophylaxis in each county in the continental United States, based on county-level characteristics. Darker colors indicate later
weeks. The color scale indicates the number of weeks since the beginning of July.

protection at the end of the RSV season. There was a moderate
correlation between the observed and expected optimal start
dates estimated from the regression model, but other factors
are not accounted for in the model, including waning of popu-
lation-wide immunity, viral changes, and stochastic introduc-
tions. Finally, we relied on ICD-9 codes to define a case as
being caused by RSV. This approach might be more sensitive
but less specific for detecting RSV cases compared with a defi-
nition based on viral testing. However, the strong correlation
[23] between hospitalizations coded as “RSV” and those
coded as “bronchiolitis” (a syndromic definition) suggests that
the epidemic patterns are not due to testing biases.
The key question is when to administer prophylaxis to high-
risk infants. Our results suggest that although national recom-
mendations provide good coverage of the RSV season for most
US counties, a 4-dose series based on local epidemic timing
would perform nearly as well in most settings. Such a change
in the dosing schedule would represent a significant cost savings
with little effect on the impact of the intervention.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online
(http://cid.oxfordjournals.org). Supplementary materials consist of data
provided by the author that are published to benefit the reader. The posted
materials are not copyedited. The contents of all supplementary data are the
sole responsibility of the authors. Questions or messages regarding errors
should be addressed to the author.
Notes
Acknowledgments. We thank Dr Eugene Shapiro for discussion of the
analyses. We thank the Healthcare Cost and Utilization Project/State Inpa-
tient Databases data partners for contributing data for this analysis: Arizona
Department of Health Services, Arkansas Department of Health, California

Reduced-Dose Schedule of RSV Prophylaxis • CID 2015:61 (15 August) • 513

Office of Statewide Health Planning and Development, Colorado Hospital
Association, Florida Agency for Health Care Administration, Georgia Hos-
pital Association, Illinois Department of Public Health, Indiana Hospital
Association, Iowa Hospital Association, Kansas Hospital Association, Ken-
tucky Cabinet for Health and Family Services, Maine Health Data Organi-
zation, Maryland Health Services Cost Review Commission, Massachusetts
Center for Health Information and Analysis, Michigan Health and Hospital
Association, Minnesota Hospital Association, Missouri Hospital Industry
Data Institute, Nebraska Hospital Association, University of Nevada Las
Vegas School of Community Health Sciences, New Hampshire Department
of Health and Human Services, New Jersey Department of Health,
New York State Department of Health, Cecil G. Sheps Center for Health
Services Research University of North Carolina at Chapel Hill, Ohio Hospi-
tal Association, Oklahoma State Department of Health, Oregon Association
of Hospitals and Health Systems, Pennsylvania Health Care Cost Contain-
ment Council, Rhode Island Department of Health, South Carolina Revenue
and Fiscal Affairs Office, South Dakota Association of Healthcare Organi-
zations, Tennessee Hospital Association, Texas Department of State Health
Services, Utah Department of Health, Vermont Association of Hospitals
and Health Systems, Virginia Health Information, Washington State De-
partment of Health, West Virginia Health Care Authority, and Wisconsin
Department of Health Services.
Author contributions. D. M. W. conceived of the analyses and wrote
the first draft of the manuscript. D. M. W., J. L. W., and V. E. P. performed
the analyses. C. V., V. E. P., J. L. W., and V. C. consulted on the analyses and
revisions of the manuscript. C. A. S. provided the data and contributed to
revisions of the manuscript. All authors have seen and approved the final
draft of the manuscript.
Disclaimer. No funding sources had any role in the design, analysis, de-
cision to publish, or the writing of the manuscript.
Financial support. C. V. was supported by the Division of International
Epidemiology and Population Studies, Fogarty International Center, Na-
tional Institutes of Health (NIH). V. E. P. was supported by the Bill & Me-
linda Gates Foundation and the RAPIDD program of the Science and
Technology Directorate, Department of Homeland Security, and the Fo-
garty International Center, NIH. D. M. W. is a Pepper Scholar with support
from the Claude D. Pepper Older Americans Independence Center at Yale
University School of Medicine (grant number P30AG021342 NIH/National
Institute on Aging), and acknowledges support from UL1TR000142 as well
as support from the Bill & Melinda Gates Foundation and Pfizer.
Potential conflicts of interest. D. M. W. has received research support
through a Pfizer grant to Yale University and has received consulting fees
from Merck. All other authors report no potential conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the con-
tent of the manuscript have been disclosed.
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