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The full value of immunisation against respiratory syncytial

virus for infants younger than 1 year: effects beyond
prevention of acute respiratory illness
Daniel R Feikin, Ruth A Karron, Samir K Saha, Erin Sparrow, Padmini Srikantiah, Daniel M Weinberger, Heather J Zar

Respiratory syncytial virus (RSV) is a leading cause of severe respiratory illness and death among children worldwide, Lancet Infect Dis 2023
particularly in children younger than 6 months and in low-income and middle-income countries. Feasible and cost- Published Online
effective interventions to prevent RSV disease are not yet widely available, although two new products aimed at November 21, 2023
https://doi.org/10.1016/
preventing RSV disease—long-acting monoclonal antibodies and maternal vaccines—have been licensed within the
S1473-3099(23)00568-6
past 2 years. The primary target of these products is reduction of the substantial burden of RSV-associated acute lower
Department of Immunization,
respiratory tract infections (LRTI) in infants younger than 1 year. However, other important public health benefits Vaccines and Biologicals, World
might also accrue with the prevention of RSV-associated LRTI during the first year of life. Mounting evidence shows Health Organization, Geneva,
that preventing RSV-associated LRTI in infants younger than 1 year could prevent secondary pneumonia caused by Switzerland (D R Feikin MD,
E Sparrow DrPH); Department
other pathogens, reduce recurrent hospitalisations due to other respiratory diseases in later childhood, decrease all-
of International Health,
cause infant mortality, ameliorate the burden of respiratory diseases on health-care systems, reduce inappropriate Bloomberg School of Public
antibiotic use, and possibly improve lung health beyond infancy. We herein review current evidence and suggest Health, Johns Hopkins
approaches to better assess the magnitude of these potential secondary effects of RSV prevention, which, if proven University, Baltimore, MD, USA
(Prof R A Karron MD); Child
substantial, are likely to be relevant to policy makers in many countries as they consider the use of these new products.
Health Research Foundation,
Dhaka, Bangladesh
Introduction RSV vaccines or monoclonal antibodies suggest that the (S K Saha PhD); Bangladesh
Acute lower respiratory tract infections (LRTI) are a number of infants (or mothers, in the case of the RSV Shishu Hospital and Institute,
Dhaka, Bangladesh (S K Saha);
leading cause of mortality in children younger than maternal vaccine) needed to be immunised to prevent
Bill & Melinda Gates
5 years worldwide.1 Respiratory syncytial virus (RSV) is one severe case of RSV disease among infants is Foundation, Seattle, WA, USA
the most common cause of LRTI and contributes approximately 50–100, which compares favourably to (P Srikantiah MD); Department
substantially to LRTI mortality. In a US surveillance that of other childhood vaccines, such as rotavirus and of Epidemiology of Microbial
Diseases, Yale School of Public
study of children with community-acquired pneumonia pneumococcal conjugate vaccines.7–9,16
Health, New Haven, CT, USA
requiring hospitalisation, RSV was the most commonly The full benefits of immunisation to prevent RSV (D M Weinberger PhD);
diagnosed pathogen, detected in 37% of children disease in infants younger than 1 year on long-term child Department of Paediatrics &
younger than 5 years.2 In a large study of severe and very health and health-care systems that can be accrued by Child Health, Red Cross War
Memorial Children’s Hospital,
severe pneumonia in seven low-income and middle- preventing RSV disease in young children are, however, Cape Town, South Africa
income countries (LMICs), RSV had the greatest likely to go beyond RSV-associated LRTI (hereafter (Prof H J Zar PhD); SA-MRC Unit
aetiological fraction (31·1%) of all pathogens.3 A referred to as RSV-LRTI). The secondary benefits from on Child & Adolescent Health,
systematic analysis of disease burden of acute lower RSV prevention are more challenging to measure and University of Cape Town,
Cape Town, South Africa
respiratory infections estimated that 101 400 deaths in might take years to become manifest, but RSV prevention (Prof H J Zar)
children younger than 5 years in 2019 were attributable might ultimately contribute substantially to public health
Correspondence to:
to RSV, representing 2·0% of all global childhood value and cost-effectiveness of RSV vaccines and Daniel Feikin, Department of
deaths; 45% of these RSV deaths occurred in children monoclonal antibodies, and be crucial to inform Immunization, Vaccines and
younger than 6 months.4 In addition, RSV was estimated decisions by countries about whether and how to Biologicals, World Health
Organization, Geneva,
to cause, in 2019, 33 million episodes of LRTI in children introduce these products in the coming years. In this
Switzerland
younger than 5 years, 3·6 million of which required Personal View, we explore the evidence and potential feikind@who.int
hospitalisation.4 magnitude of the secondary benefits of preventing RSV
After decades of slow progress in preventing RSV disease on child health and health-care systems, as well
disease in children in their first year of life, clinical as describing future research needs to better define these
trials with newer agents,5–10 such as an anti-RSV effects. RSV also causes a substantial burden of disease
monoclonal antibody with extended half-life in older adults,17 and two vaccines are already licensed for
(nirsevimab), and a bivalent RSV prefusion F vaccine this population;18,19 however, prevention of RSV disease in
(known as RSV preF) for maternal immunisation have adults is beyond the scope of this paper.
yielded encouraging efficacy results and regulatory
authorities have evaluated and licensed these products Prevention of all-cause LRTI and bacterial
on the basis of their efficacy11–14 (table 1). Moreover, as pneumonia
RSV is prevalent as a leading cause of severe respiratory The burden of LRTI caused by RSV extends beyond those
disease in children younger than 5 years worldwide, the cases in which RSV is identified. RSV-associated LRTI is
vaccine-preventable burden of LRTI attributable to RSV likely to be underdiagnosed because clinical diag­nostic
disease is expected to be high.15 Clinical trial results of testing for RSV is not routinely done in most

www.thelancet.com/infection Published online November 21, 2023 https://doi.org/10.1016/S1473-3099(23)00568-6 1

 Personal View

Product Product type Antigen RSV-associated LRTI Number of infants or All-cause LRTI Number of infants Regulatory
efficacy (95% CI) at mothers needed to efficacy (95% CI) at or mothers needed status
150 days immunise* to prevent 150 days to immunise* to
one RSV-associated LRTI prevent one all-
case through 150 days cause LRTI case
through 150 days
NCT02624947 RSV F protein Protein subunit RSV F protein, not For RSV MS-LRTI with For RSV MS-LRTI with For all-cause For all-cause Discontinued
(completed) nanoparticle vaccine stabilised in the severe hypoxemia†: severe hypoxemia: 167; MS-LRTI with severe MS-LRTI with severe
(Novavax) (administered to prefusion 48·3% (–1·0 to 73·5); for all RSV MS-LRTI: 111 hypoxemia: 39·0% hypoxemia: 67; for
pregnant women) conformation for all RSV (–13·0 to 57·3); for all-cause MS-LRTI:
MS-LRTI: 31·4% all-cause MS-LRTI: 44
(–1·3 to 53·6)9 20·6% (3·1 to 35·0)9
NCT04424316 RSV preF Protein subunit RSV F protein For severe RSV MA- For severe RSV-MA-LRTI: For severe all-cause For severe all-cause FDA approval
(completed) protein vaccine stabilised in the LRTI: 70·9% 89; for all RSV MA-LRTI, MA-LRTI: NA; for all- MA-LRTI: NA; for all- granted on
vaccine (administered to prefusion (44·5 to 85·9); for all 67 cause MA-LRTI: 5·2% cause MA-LRTI: 200 Aug 21, 202313
(Pfizer) pregnant women) conformation RSV MA-LRTI: 52·5% (–16·5 to 22·8%)7 and EMA
(28·7 to 68·9)7 approval
granted on
Aug 24, 202314
NCT03979313 Nirsevimab Monoclonal IgG extended half- For very severe RSV For very severe RSV MA- For very severe all- For very severe all- EMA approval
(completed) antibody life monoclonal MA-LRTI: 78·6% LRTI: 75; for LRTI requiring cause MA-LRTI: cause LRTI, NA; granted on
(administered to antibody directed (48·8 to 91·0); for hospitalisation: 65; for all NA; for all-cause for all-cause LRTI Oct 31, 202212
infant) against site 0 on F RSV-LRTI requiring RSV MA-LRTI: 24 LRTI requiring requiring and FDA
on RSV prefusion hospitalisation 76·8% hospitalisation: hospitalisation: 70; (biologics
F protein (49·4 to 89·4); for all 38·9% (6·3 to 60·2); for all-cause license)
RSV MA-LRTI: 76·4% for all-cause MA-LRTI: 19 granted on
(62·3 to 85·2)8 MA-LRTI: 38·2% July 17, 202311
(23·7 to 50·0)8
NCT04767373 Clesrovimab Monoclonal IgG extended half- Data pending Data pending Data pending Data pending Phase 2b/3
(ongoing) antibody life monoclonal trial ongoing
(administered to antibody directed
infant) against site IV on
RSV F protein10

EMA=European Medicines Agency. FDA=US Food and Drug Administration. LRTI=lower respiratory tract infections. MA-LRTI=medically attended lower respiratory infections (as defined in the clinical trial).
MS-LRTI=medically significant lower respiratory infections (as defined in the clinical trial). NA=not available. RSV=respiratory syncytial virus. *Number needed to immunise to avert one case was calculated as the
reciprocal of the difference in risk between the intervention group and the placebo group. The number needed to immunise accounts for product efficacy and incidence in the setting where the trial took place.
†Defined as a peripheral oxygen saturation of less than 92% at sea level.

Table 1: Completed or ongoing phase 3 trials of products showing efficacy against RSV-LRTI and all-cause LRTI in infants up to 5 months of age

health-care systems. In addition, RSV can synergistically
interact with other pathogens to cause LRTI, but is often
overlooked because RSV is no longer detectable at the
time of testing or its presence is deemed incidental.
Randomised controlled trials of effective preventive
products might provide an opportunity to estimate the
true disease burden attributable to RSV by comparing
outcome rates in all-cause LRTI (not just LRTI caused by
RSV) between vaccinated and placebo groups. When
looking at the rate reduction caused by vaccination, as
indicated by the number needed to immunise, the study
of the RSV F protein nanoparticle maternal vaccine
(NCT02624947) showed more than twice as a high
disease prevention capacity against all-cause LRTI than
against RSV-associated LRTI outcomes.9 In contrast, the
randomised controlled trial of nirsevimab (NCT03979313)
showed a similar number needed to immunise for all-
cause and RSV-associated LRTI outcomes.8 The
difference in the results from these randomised
controlled trials might be related to more complete
diagnosis of RSV cases in the nirsevimab trial, and it
might also be due to the fact that the nirsevimab trial
took place during the COVID-19 pandemic, when rates
of co-infection with other pathogens might have been
reduced as a consequence of lower circulation of
respiratory pathogens resulting from widespread non-
pharmaceutical interventions (eg, use of facial masks
and physical distancing).20–23 Another trial of the bivalent
RSV prefusion F vaccine7 given to pregnant women
showed a small, non-significant reduction in all-cause
medically attended LRTI, which might be due to the
unusually low attributable fraction of RSV in all-cause
LRTI (22%) during the trial, which was conducted during
the COVID-19 pandemic.
Disruptions related to the COVID-19 pandemic
provided another opportunity to probe the attributable
burden of RSV in all-cause LRTI. RSV, along with several
other respiratory viruses, largely disappeared for over a
year, starting in March, 2020, due to the extensive
implementation of non-pharmaceutical interventions to
prevent the spread of SARS-CoV-2.21 The viruses then
reappeared, but often during the spring and summer
rather than during the typical autumn and winter
epidemic period.24,25 In a study in Israel, an estimate
based on the timing and intensity of these patterns
suggested that 49% of radiologically confirmed alveolar

2 www.thelancet.com/infection Published online November 21, 2023 https://doi.org/10.1016/S1473-3099(23)00568-6


pneumonia in children younger than 5 years was
associated with RSV, along with 21% of other types of
LRTI.22 In addition, 18% of cases of bacteraemic
pneumococcal pneumonia were estimated to be linked to
a preceding RSV infection, whereas no association was
found between RSV infection and non-pneumonia
invasive pneumococcal disease.22 In France, during the
COVID-19 pandemic, a 63% decrease in invasive
pneumococcal disease was observed among children
younger than 15 years; modelling suggested that a
decline in RSV cases probably contributed 40% (95% CI
15–65) of this decrease.23 Similar results were found in
Canada, where a resurgence of RSV was estimated to
contribute to 77% (95% CI 33–100) of the post-pandemic
rebound of invasive pneumococcal disease in late 2021.26
In contrast, in South Africa, where hospitalisation rates
for both RSV and invasive pneumococcal disease
approximately halved during the peak of the pandemic
compared with pre-pandemic rates, RSV rates rebounded
in 2022 while invasive pneumococcal disease rates did
not, suggesting that the relationship between the two
pathogens might be less direct and involve other factors
in some settings.20
The use of pneumococcal conjugate vaccines also
provided an opportunity to better understand the effects
of RSV co-infections on acute LRTI. In a randomised
controlled trial of a nine-valent pneumococcal conjugate
vaccine, South African children who received a
pneumococcal conjugate vaccine had a non-significant
lower rate (22% lower [95% CI –3 to 41]) of RSV-associated
pneumonia than did those who received a placebo;
among HIV-negative children, the rate was 32% lower
(95% CI 6 to 50)]).27 This finding is in agreement with
observational studies; reductions in the incidence of
hospitalisation for RSV and bronchiolitis in children
were temporally associated with the universal intro­
duction of pneumococcal conjugate vaccines in children
in several populations.28–30 For instance, RSV hospi­
talisations among children aged 3–11 months declined by
18% in the USA after the introduction of the pneumo­
coccal conjugate vaccine.31 However, another study in
Australia did not detect a decline in RSV after the
introduction of pneumococcal conjugate vaccines.32
RSV-associated mortality
Prevention of RSV-associated deaths is a major goal of
immunisation programmes in LMICs, wherein more
than 97% of global RSV deaths occur.4 The updated RSV
global mortality analysis for 2019 reported RSV-
attributable mortality in which RSV was in the causal
chain of the death, and RSV-associated mortality where
RSV was detected in the respiratory tract but had an
unclear causal role.4 RSV-attributable mortality in
children younger than 6 months (the target age range for
RSV vaccines and monoclonal antibodies) was estimated
at 45 700 deaths (uncertainty range 38 400–55 900),4 which
translates to 2·1% (uncertainty range 1·7–2·5) of all
www.thelancet.com/infection Published online November 21, 2023 https://doi.org/10.1016/S1473-3099(23)00568-6
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deaths in this age group worldwide, or 3·6% (3·0–4·4)
after exclusion of the first week of life, when birth-related
deaths predominate.4 With the more permissive and less
specific metric of RSV detection among deceased
children younger than 6 months, RSV-associated
mortality in these children was estimated at 102 000 deaths
(uncertainty range 88 800–118 800), which might reflect
the under-recognised contribution of RSV to infant
deaths.4
The updated RSV global mortality estimates incor­
porate new data from community mortality studies in
Zambia, India, Pakistan, and Argentina, where naso­
pharyngeal swabs were obtained from deceased infants
within 48 hours of death to test for presence of RSV.33
Those studies showed that a high proportion of mortality
in children younger than 5 years occurs in the
community rather than in the hospital, and that deaths
in the community accounted for more than 70% of all
deaths in the lowest income settings in Zambia and
India (although the Indian setting was a low-income
rural community that was not representative of most of
India). The studies further uncovered a sizable,
previously unmeasured presence of RSV among these
deaths in the community setting, accounting for 4–27%
of all deaths among children younger than 6 months—
findings that supported the use of all-cause deaths,
rather than just respiratory deaths, as the denominator
for the revised RSV global burden calculations. A
limitation of these community mortality studies was that
a causal link between detection of RSV and its role in the
child’s death was not evaluated.
The global mortality estimates also incorporated data
from the Child Health and Mortality Prevention For the Child Health and
Surveillance (CHAMPS) platform, which assesses Mortality Prevention
Surveillance network see
multiple aetiologies among deceased children by means https://champshealth.org/
of molecular and pathological evaluation of tissue
collected with minimally invasive post-mortem sampling
from multiple organs, and assigns the causal chain for
each death via a standardised process. Among children
younger than 6 months in seven high-mortality CHAMPS
sites, RSV was detected in 4·0% of all deaths and was
identified in the causal chain of 1·7% deaths.34 Among
deaths in the first week of life, RSV was rarely detected
(1·3%), and was never established to be in the causal
chain of death. However, between the ages of 7 days and
6 months, RSV was detected in 8·7% of deaths and
identified in the causal chain of 4·7% of deaths. Notably,
very few deaths were deemed to be caused by RSV
alone—as previously mentioned, RSV can increase the
risk for subsequent bacterial superinfection,27 and thus
serve as the initial pathogenic insult that contributes to
deaths several days or even weeks after onset of RSV
illness.35
Respiratory illnesses subsequent to RSV-LRTI
The Drakenstein Child Health study, a South African
birth cohort study, reported that children with RSV-LRTI
3
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in the first 2 years of life had a three-times higher risk of
subsequent recurrent LRTI due to non-RSV pathogens.36
The incidence of recurrent LRTI was highest following
severe RSV-LRTI requiring hospitalisation, but even
ambulatory RSV-LRTI was associated with a significantly
higher risk of recurrent LRTI compared with ambulatory
non-RSV LRTI. A previous study in Gambian children
with RSV-LRTI requiring hospitalisation and age-
matched controls also reported an increased incidence of
LRTI after hospitalisation for RSV-LRTI,37 as did a study
in Tennessee, USA.38 Despite the association shown in
observational studies, recurrent LRTI has not been
evaluated in randomised controlled trials of RSV
prevention, which would provide more definitive
evidence of the association.
Several studies and meta-analyses have reported a
significant association between RSV-LRTI in the first
year of life (especially severe or RSV-LRTI requiring
hospitalisation) and recurrent wheezing or asthma in
childhood.39–41 In a meta-analysis published in 2020,
children who had RSV-LRTI had 3·4-times (95% CI
2·7–4·2) higher odds of subsequent wheezing, and a
2·6-times (95% CI 1·7–4·0) higher odds of asthma at the
age of 6 years or older.39 Almost all studies were
from high-income country settings; however, in the
Drakenstein Child Health Study in South Africa, early
life RSV-LRTI was also strongly associated with all
wheezing phenotypes (early, late, or recurrent) up to the
age of 5 years.42
Despite the strong association between RSV-LRTI and
subsequent recurrent wheezing or asthma seen in
observational studies, whether RSV is part of a causal
pathway or RSV-LRTI, recurrent wheezing, and asthma
reflect a common underlying genetic or physiological
susceptibility to respiratory illness is unclear.39,43 A
randomised controlled trial of the monoclonal antibody
palivizumab in preterm infants (born at 32–35 weeks of
gestation) reported a significant 10% reduction in
parental report of mild wheezy illness at 1 year and
6 years of age; however, no difference was detected in
physician-diagnosed wheezing or asthma or lung
function as measured by spirometry at the age of 6 years.44
Another randomised controlled trial of motavizumab, an
effective monoclonal antibody that was never licensed,
showed no difference in recurrent wheezing in full-term
Native American children up to the age of 3 years.45
Additional evidence refuting a causal association comes
from genetic studies. The association between RSV-LRTI
with subsequent recurrent wheezing or asthma is
reduced when partly controlling for genetic susceptibility:
the adjusted odds ratio (OR) for the association decreases
from 4·2 (95% CI 2·4–7·4) to 2·5 (1·2–4·9).39 A small
study of monozygotic twins with discordant RSV-LRTI
status showed no association with subsequent recurrent
wheezing or asthma.46
In contrast, several birth-timing studies are more
suggestive of a causal role of RSV. One large
4 www.thelancet.com/infection Published online November 21, 2023 https://doi.org/10.1016/S1473-3099(23)00568-6
epidemiological study over five RSV seasons showed a
30% increase in subsequent asthma risk depending on
birth timing, with the highest risk in those born 13 weeks
before the RSV peak.47 Furthermore, a US birth cohort
that measured RSV infection (which should be
distributed more randomly and less influenced by
genetic susceptibility than severe RSV disease) reported
a 26% lower risk of asthma at the age of 5 years (adjusted
OR 0·74 [95% CI 0·58–0·94]) in children not infected
with RSV during infancy than in children infected with
RSV during infancy (ie, the first year of life); the reduction
in risk was confined to non-atopic asthma subtypes.48
The authors estimated that prevention of RSV infection
during infancy could potentially reduce cases of asthma
at the age of 5 years by 15%; however, current RSV
vaccines and monoclonal antibodies are unlikely to
provide sterilising immunity and prevent all RSV
infections.49 Furthermore, potential mechanisms for the
association of RSV-LRTI with subsequent recurrent
wheezing or asthma have now been shown in several in
vitro and animal experiments (eg, RSV can affect
inflammatory pathways and airway epithelial develop­
ment).50 Early-life RSV-LRTI in South African children
was also associated with development of a recurrent
wheezing phenotype with increased airway resistance at
5 years, independent of baseline function.42
The long-term impact of early-life RSV-LRTI might
extend beyond childhood and into chronic respiratory
illness in adults. Asthma in young adults in Norway was
almost twice as probable in those who had bronchiolitis
during infancy than in demographically matched
individuals who did not.51 A study of a longitudinal cohort
recruited at birth in 1946 in the UK found that respiratory
infection in infancy was associated with both obstructive
and restrictive lung function patterns in adulthood, but
only among smokers.52 A later analysis of the same birth
cohort found a 93% increased risk of early adult
respiratory mortality, particularly from chronic obstruc­
tive pulmonary disease, among those who had a LRTI
episode before the age of 2 years, after adjustment for
childhood socioeconomic factors and adult smoking.53
However, these associations between early-life LRTI and
adult respiratory disease are not specific to RSV and,
importantly, are unable to adjust for an underlying
genetic predisposition for severe respiratory disease.
RSV burden on health-care systems
RSV can have a substantial burden on health-care
systems. In temperate climates, the peak RSV season
usually occurs over several months in autumn and
winter. Even in subtropical climates, approximately
three-quarters of countries have seasonal RSV
circulation.54 These seasonal spikes in RSV disease can
overwhelm hospitals by consuming much of the bed
capacity in paediatric units and placing stress on staffing
requirements. In the USA, discharge data from 2009–19
showed that RSV bronchiolitis was the overall leading

cause of infant hospitalisation in every year, accounting
for approximately 9·5% of all hospitalisations; during
the RSV season, RSV accounted for approximately
16–18% of all hospitalisations among infants.55 In some
high-incidence years, such as the recent 2022–23 season,
the impact of RSV on the health-care system is even
greater.56
RSV’s burden on the health-care system is not confined
to high-income countries, but occurs also in LMICs,
where overall rates of RSV-LRTI are generally higher.57 In
the Pneumonia Etiology Research for Child Health
(PERCH) study of severe and very severe pneumonia,
RSV was found to be the leading cause overall and in
each of the seven participating countries.3 Moreover, in
four PERCH countries with available data (The Gambia,
Mali, Kenya, and South Africa), RSV accounted for
7·5–13·6% of all-cause hospitalisations in children aged
1–59 months.3 In the Drakenstein Child Health Study in
South Africa,35 RSV-associated disease accounted for
15·3% of all-cause hospitalisations (excluding birth
hospitalizations) in the first 2 years, and 22·0% in the
first 6 months of life.58
In LMICs, where paediatric bed shortages tend to be
more acute, the high burden of RSV admissions in
paediatric units can have secondary effects on hospital
systems’ ability to deliver care to children affected by
other health conditions. A study in the largest paediatric
hospital in Bangladesh evaluated nearly 20 000 admitted
children younger than 5 years in 2019. During this time,
RSV-positive cases accounted for 6% of all admissions
and 20–30% of all admissions during the peak RSV
season; the average length of stay for RSV-positive
patients was 5 days.59 65% percent of RSV cases occurred
within the first 6 months of life, which is the age range
for which current RSV products are likely to offer
protection. In the same study, approximately 20% of
children requiring hospitalisation were refused
admission due to the unavailability of inpatient beds, and
30-day mortality was higher among children who were
refused admission, mostly with perinatal complications
and neonatal diseases, than among those admitted. The
researchers modelled that 15% of hospital bed-day
occupancy would be averted by an effective maternal
RSV vaccine, resulting in a 2% reduction in mortality
among children who need to be admitted to hospital,
mostly due to fewer children being turned away for lack
of bed availability.
In the randomised controlled trial of nirsevimab
that took place mostly in high-income settings,
hospitalisations for respiratory illness of any cause were
reduced by 38·9% (95% CI 6·3–60·2) and outpatient
visits for LRTI decreased by 41·9% (25·7–54·6) in infants
receiving nirsevimab.8,60 Beyond its effects on health-care
visits, RSV prevention is also likely to result in decreased
antimicrobial use. In the RSV F protein nanoparticle
maternal vaccine trial (NCT02624947), despite moderate
efficacy, infants in the vaccine group had a 12·9%
www.thelancet.com/infection Published online November 21, 2023 https://doi.org/10.1016/S1473-3099(23)00568-6
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(1·3–23·1) reduction in all antimicrobial prescriptions
through to the age of 90 days compared with infants in
the placebo group, equating to 4·8 (95% CI 0·5–8·6)
antimicrobial courses averted per 100 infants.61 In the
nirsevimab trial, antibiotic use in children up to the age
of 5 months in the intervention group was reduced by
23·6% (3·8–39·3), resulting in 8·2 antibiotic courses
averted per 100 infants.60 The reduction in antibiotic use
might extend beyond prevention of RSV-LRTI—for
example, RSV has been implicated as an important cause
of acute otitis media, which drives a large proportion of
paediatric antibiotic use.62–64 One study found that
RSV-LRTI in the first 6 months of life was associated
with an increased incidence of otitis media and antibiotic
prescriptions in the second half of infancy (6–11 months
of age).38 However, whether RSV prevention in the first
6 months of life can reduce the incidence of acute otitis
media is unclear. Although a small randomised
controlled trial of intravenous RSV immunoglobulin
given to children younger than 2 years at high risk of
severe RSV disease showed a reduction in the incidence
of the otitis media (27% vs 43%; p<0·01),65 a larger
randomised controlled trial of palivizumab, a monoclonal
antibody that more specifically targets RSV, found no
difference in otitis media rates between palivizumab and
placebo recipients (42% vs 40%; p=0·51).66
Given its high global incidence, RSV also incurs a
substantial financial burden on health-care systems. One
meta-analysis estimated that, in 2017, the global cost of
RSV-LRTI management (including both inpatient and
outpatient costs) was €4·82 billion (95% CI 3·47–7·93);
while the cost per RSV episode was several-times higher
in high-income countries than in LMICs, LMICs
accounted for 65% of the global cost.67 This analysis did
not take into account household expenditures. In
Finland, 52% of parents of children younger than 3 years
with an RSV-associated illness missed at least 1 day of
work, with a mean duration of absenteeism of 2·6 days
(SD 1·5).64 Studies in Kenya and South Africa show that,
although direct health-care expenses account for most
costs related to RSV disease in those settings, a
substantial financial burden is placed on households
through out-of-pocket expenses and indirect costs.68,69 A
detailed review of the financial costs of RSV disease is
beyond the scope of this paper; cost-effectiveness
analyses of RSV prevention, including in LMICs, have
been published elsewhere.70,71
Future research to define secondary effects of
RSV disease prevention
As countries introduce new maternal RSV vaccines and
monoclonal antibodies, how might these ripple effects of
prevention best be measured, and over what timeframes?
Some of these outcomes, such as effects on all-cause
LRTI or on health-care system use, might be discernible
in the short term through planned or post-hoc analyses
of the ongoing randomised controlled trials of RSV
5
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Level of pre-licensure evidence Certainty of effect Rapidity of effect demonstration after

Severe RSV-LRTI
All-cause LRTI (including bacterial
pneumonia)
RSV disease-associated mortality
All-cause child mortality
Long-term respiratory illness and lung
function
Health-care system capacity
Health-care system cost
Reductions in antibiotic use
High (efficacy shown for all
products in RCTs)
Medium (efficacy shown as Medium (depends on aetiologic fraction of RSV among
secondary outcome in some RCTs) LRTI cases)
Low (not shown in RCTs)
Low (not measured in RCTs)
Low to medium (mixed evidence
of the causal role of RSV; RCTs
generally have not shown an
effect)
Medium (reduction in
hospitalisations and outpatient
visits for all-cause LRTI shown in
some trials)
Low (no direct evidence that RSV
prevention lowers costs)
High (effects shown in several
RCTs)
High (shown for all products in RCTs)
Medium (preventing severe RSV-LRTI should prevent
RSV mortality in settings with poor access to care)
Low overall (because RSV contributes to small
proportion of child mortality); medium in the
1–5 months age group (in which RSV contributes more
to mortality)
Low to medium (mixed evidence of the causal role of
RSV)
Medium (among children aged 1–5 months during RSV
season); higher in settings of good access to health care
(ie, in high-income countries more than in lower-
income and middle-income countries)
Medium (should be documentable if reductions in
health-care use occur)
Medium (depends on local antibiotic prescribing
practices; less likely in low-income and middle-income
countries, where antibiotic use is lower)
implementation
Rapid (due to high incidence and high product
effectiveness)
Rapid (with high aetiologic fraction of RSV among LRTI
cases in settings with seasonal epidemics)
Medium (will require large post-introduction
populations to document because mortality is rare
outcome)
Medium (will require large post-introduction
populations in high-mortality settings to document)
Slow (many years of follow-up after widescale
introduction needed to show impact on lung health
outcomes)
Medium to rapid (in case of large RSV aetiological
fraction during RSV seasonal epidemics); quicker in
settings of good access to health care
Medium (would probably need several RSV seasons to
document effect on costs)
Medium to rapid (depends on antibiotic prescribing
practice and incidence of RSV)

LRTI=lower respiratory tract infections. RCTs=randomised controlled trials. RSV=respiratory syncytial virus.

Table 2: Outcomes of RSV disease prevention on key outcomes after widespread introduction of RSV vaccines and monoclonal antibodies

vaccines and monoclonal antibodies (table 2, figure).72
However, relatively few participants from LMICs were
enrolled in the randomised controlled trials; secondary
effects on child health and health-care system outcomes
will also need to be measured in LMICs, where both
specific outcomes and magnitude of outcomes might
differ substantially from those in high-income countries.9
Assessment of many of these secondary outcomes will
require evaluations to be done after widespread
introduction of RSV vaccines or monoclonal antibodies.
Measurements of the impact of RSV prevention is likely
to be more efficient in settings with clearly defined RSV
seasons, when the aetiologic fraction of RSV among
LRTI is high. Assessment would ideally occur over at
least two RSV seasons because the severity of RSV
epidemics might vary from year to year.73 Moreover, some
countries show a biennial pattern of alternating severe
and less severe RSV epidemics, which might create the
need for longer follow-ups to capture the full range of
effects of RSV prevention.74 Post-introduction effect
studies could be used not only to define the impact on
biological outcomes, such as all-cause LRTI, severe LRTI,
and otitis media, but also health-care systems outcomes,
such as hospital bed-days used and antibiotic courses
prescribed.75 Moreover, post-introduction studies are
probably the only feasible way to have a large enough
population and a long enough follow-up time to define
effects on rare outcomes (eg, LRTI mortality) or outcomes
that require a long time to manifest (eg, asthma).76
A variety of study designs could be considered. In
areas where a prevention strategy has not yet been
introduced, randomised introduction of a product might
be initiated, such as step-wedge designs in which a
product is introduced in a staggered manner in different
geographical units (eg, subdistrict, district). Randomised
introduction of RSV vaccines and monoclonal anti­
bodies, however, is unlikely to be feasible in many real-
world settings and would probably be done only in
special studies. As such, post-introduction evaluations
can also evaluate effects by means of quasi-experimental
designs, such as an interrupted time series, to estimate
reductions in burden of vaccine-preventable disease
once widespread vaccine introduction has occurred.77,78
Such evaluations require reliable pre-introduction and
post-introduction data regarding the outcome of interest,
as well as adjustment for other secular changes that
might affect surveillance. Synthetic controls analyses,
which use a weighted average of multiple comparison
groups (eg, similar countries who did not introduce RSV
vaccines and monoclonal antibodies), might avoid some
of the potential temporal confounders in other
approaches.79
In addition to post-introduction evaluations of the
positive secondary effects of RSV prevention, monitoring
for population-based adverse effects after widespread
roll-out of these products must also occur. Some potential
risks of these products that will need to be evaluated are
the emergence of viruses with escape mutations to the

6 www.thelancet.com/infection Published online November 21, 2023 https://doi.org/10.1016/S1473-3099(23)00568-6

 Personal View

More than 5 years

Between 6 months and 5 years

Up to 6 months
Reduced incidence Improved lung
of wheezing health
episodes

Reduced all-cause LRTI

Reduced antibiotic use

Improved availability of
hospital beds

Reduced V LR
RSV-LRTI
all-cause deaths

RIP
Potential Potential
reduced reduced
incidence of incidence of
Reduced RSV
asthma COPD
disease deaths

Reduced
recurrent LRTI

Figure: Potential effects of preventing RSV-LRTI in infants younger than 1 year, by duration of impact
Figure created with BioRender.com. COPD=chronic obstructive pulmonary disease. LRTI=lower respiratory tract infections. RSV=respiratory syncytial virus.

epitopes targeted by monoclonal antibodies and pregnancy
outcomes after maternal vaccination.7,80,81 Descriptions of
approaches to monitoring post-introduction safety are
beyond the scope of this paper.
Conclusion
RSV disease is poised to be the next clinically significant
infectious disease of infants to become preventable by
immunisation. After decades of development, two
classes of preventive products, RSV maternal vaccines
and long-acting monoclonal antibodies for infants, are
now licensed in the USA and European Union and
might soon be widely available. The primary focus of
the trials of these products, as well as their use case, is
the prevention of RSV-associated LRTI in infants
younger than 1 year. The effects of preventing RSV
disease, however, are likely to go beyond this important
outcome. We described how preventing RSV disease in
infants younger than 1 year can lead to several other
salient public health gains that can be achieved both in
the short term and later in life. More evidence of the
secondary effects of RSV prevention should be gathered
in clinical trials and post-introduction studies. Such
evidence will be crucial for decision makers to assess
the full public health value of RSV prevention in their
settings. It is this type of evidence on the full value of
these products that led WHO’s Strategic Advisory
Group of Experts on Immunization to call for a large-
scale RSV impact study in LMICs, where many
competing immunisation and health priorities are
pressing.82 The next few years will be a decisive period to
better define how these new preventive products can
reduce the burden of RSV-LRTI, and to assess the ripple
effects of prevention on other important public health
measures.
Contributors
DRF conceptualised the paper. All authors contributed to the original
draft and revised the final paper. ES and DRF produced the figure.

www.thelancet.com/infection Published online November 21, 2023 https://doi.org/10.1016/S1473-3099(23)00568-6 7

 Personal View
Declaration of interests
DMW reports grants or contracts, paid to institution and unrelated to
the subject of this work, from the US National Institutes of Health,
Bill & Melinda Gates Foundation, US Veterans Affairs Department,
Pfizer, and Merck; consulting fees from Merck, Pfizer, and
GSK/Affinivax; and payment or honoraria for lectures, presentations,
participation in speakers’ bureaus, manuscript writing, or educational
events from Pfizer and Merck. HJZ reports funding paid to institution
from the Gates Foundation, US National Institutes of Health, Pfizer,
AstraZeneca, and MSD. RAK reports grants paid to institution from the
US National Institutes of Health and Sanofi Pasteur; and is the chair of
the WHO Product Development for Vaccines Advisory Committee.
DRF and ES report funding paid to institution from the Gates
Foundation for respiratory syncytial virus-related activities. SKS and
PS declare no competing interests.
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