Arch Dis Child 2014 Murray Archdischild 2013 303764

8/13/2019 Arch Dis Child 2014 Murray Archdischild 2013 303764

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Preventing severe respiratory syncytial virus disease:passive, active immunisation and new antivirals

Joanna Murray,1 Sonia Saxena,2 Mike Sharland3

1Department of Primary Careand Public Health, ImperialCollege London, London, UK2Department of Primary Careand Public Health, ImperialCollege London, London, UK3Paediatric Infectious DiseasesUnit, St Georges NHS TrustLondon, London, UK

Correspondence toProfessor Mike Sharland,Paediatric Infectious DiseasesUnit, St Georges NHS TrustLondon, London SW17 0QT,UK; [email protected]

Received 8 October 2013Revised 29 December 2013Accepted 30 December 2013

To cite:Murray J, Saxena S,Sharland M.Arch Dis ChildPublished Online First:[please includeDay Month

Year] doi:10.1136/archdischild-2013-303764

ABSTRACTIn most high-income countries palivizumab prophylaxis isconsidered safe, efcacious and cost-effective forpreventing respiratory syncytial virus (RSV) hospitaladmissions among specic subgroups of infants bornpreterm, with chronic lung disease or with congenitalheart disease. Virtually all babies acquire RSV duringinfancy and previously healthy babies are not eligible toreceive palivizumab. Emerging evidence suggests somebenet of palivizumab use in reducing recurrent wheezeamong infants born preterm. Better longitudinal studiesare needed to examine its clinical and cost-effectivenesson recurrent and chronic respiratory illness andassociated healthcare burden on resources in the

community and hospitals. Since 99% of child deathsattributed to RSV occur in resource poor countries whereexpensive prophylaxis is not available or affordable,palivizumab has limited potential to impact on thecurrent global burden of RSV lower respiratory tractinfection (LRTI). A range of candidate vaccines for activeimmunisation against RSV are now in clinical trials. Twopromising new antivirals are also currently in phase I/IItrials to test their effectiveness in preventing severe RSVLRTI. These agents may be effective in preventing severedisease and phase III studies are in development. In theabsence of effective active immunisation against RSVinfection, population level approaches to prevent severe

RSV LRTI should continue to focus on reducing prenataland environmental risk factors including prematurity,smoking and improving hygiene practices.

INTRODUCTIONRespiratory syncytial virus (RSV) infection is amajor cause of acute respiratory infection world-wide and each year results in an estimated 33.8million new episodes of lower respiratory tractinfections (LRTIs) among children aged less than5 years.1 Mortality estimates vary from 66 000 to199 000 child deaths annually thought to be attrib-uted to RSV, 99% of these occurring in resourcepoor countries.1 In the UK the RSV-attributeddeath rate in infants has been estimated to be 8.4per 100 000.2

Most children will have been infected with RSV by2 years of age and approximately 10% of these epi-sodes are severe enough to require hospital admis-sion.1 In the UK, RSV infection is the leading causeof hospitalisation in children under 1 year of age,with an estimated admission rate of 31 per 1000 chil-dren under 1 year admitted in England.35 Someinfants are at increased risk of hospital admission,including those who are born preterm or have con-genital heart defects or chronic lung disease.6

Extensive systematic review evidence suggeststhere are no available treatments that clearly

shorten the natural course of infection or provideclinical improvements in RSV bronchiolitis symp-toms.711 Hence, the mainstay of management forinfants infected with RSV remains supportive careincluding nasogastric feeding, oxygen therapy andintensive care for a small proportion (approxi-mately 3%) of more severely affected infants.4 7 1 2

There is currently no effective vaccine against RSVinfection. The only product currently licensed forprophylactic use to provide short-term protectionagainst serious RSV infection among certain highrisk infants, is passive immunotherapy withPalivizumab (Synagis, MedImmune), a humanisedmouse monoclonal antibody against RSV infection,

which targets the surface RSV fusion glycoprotein,preventing RSV entry into host cells and therebypreventing or reducing the severity of RSV infec-tion.13 14 The aim of this article was to review theevidence of the safety, ef cacy and cost-effectiveness of palivizumab immunoprophylaxisfor the prevention of RSV hospital admissionsamong high-risk infants in the UK and discuss newoptions under development.

METHODSRelevant articles were identied by searching TheCochrane Library, EMBASE, MEDLINE, Google

Scholar and PUBMED databases for studies pub-lished from 1 January 1990 to 30 April 2013.Searches were carried out using MeSH terms andvarious combinations of the following keywords:respiratory syncytial virus, RSV, respiratory syn-cytial virus infections, bronchiolitis, bronchio-litis, viral, palivizumab, Synagis,immunoprophylaxis, efcacy, safety, cost-effectiveness, cost benet analysis, cost analysis,economic analysis, hospital admission. Relevantpublications were identied by title and abstract andfull text where required. We included ndings fromclinical trials, observational studies and postmarket-ing studies but excluded articles that were not pub-

lished in English and abstracts that were not availableas complete publications. Reference lists fromselected papers and recent review articles were alsoexamined.

EFFICACY OF PALIVIZUMABThe efcacy and safety of palivizumab was estab-lished through two large randomised, double-blind,placebo-controlled trials, which found palivizumabsafely and effectively reduces RSV hospitalisationrates and serious complications among high-riskinfants.1517 The IMpact study was a multicentre,randomised, double-blind placebo-controlled trial

in infants aged less than or equal to 35 weeksges-

tational age or those with chronic lung disease aged

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less than 24 months (n=1502) were randomised to receive veinjections of palivizumab (15 mg/kg) or equivalent volume ofplacebo every 30 days. The trial found that those receiving pali-vizumab (n=500) had a highly signicant 55% reduction inRSV hospital admissions compared to the placebo group(n=1002).15 In addition, secondary outcomes reported showedinfants receiving palivizumab spent fewer days in hospital andrequired fewer days of supplemental oxygen than those receiv-

ing placebo, but there was no statistically signicant differencein requirement for intensive care or ventilation between the twogroups. Another randomised controlled trial (RCT) comparedpalivizumab use (n=639) to placebo (n=648) among childrenaged up to 24 months with haemodynamically signicant con-genital heart disease.14 16 This study reported a 45% reductionin RSV hospital admissions among those receiving palivizumab(5.3% compared with 9.7%). Mortality was also examined as asecondary outcome in both these RCTs, with infants in controlgroups found to have slightly higher mortality rates, thoughneither trial was sufciently powered for examining thisoutcome.

A recent Cochrane systematic review analysed data from threeRCTs (including those described above) comparing palivizumabwith placebo (n=2831) and four RCTs comparing palivizumabwith motavizumab (n=8265), among infants born preterm,with congenital heart disease or chronic lung disease.18 Theyconcluded that prophylaxis compared to placebo was associatedwith a 51% reduction in risk of RSV hospitalisation (RR=0.4995% CI 0.37 to 0.64) and a 50% reduction in admissions tointensive care units (RR=0.50 95% CI 0.30 to 0.81). In add-ition, pooled analysis revealed a reduction in all-cause mortality,though this was statistically non-signicant (RR=0.69 95% CI0.42 to 1.15).18 It is perhaps most useful though to consider thenumber of children that need to be treated to prevent a hospitalepisode. It is estimated that 17 preterm infants need to receiveprophylaxis to prevent a single RSV hospital admission.19

Methodological limitations of these trials also need to be con-sidered, since some were not designed with sufcient statisticalpower to conrm efcacy.

MOTAVIZUMABMotavizumab, another humanised monoclonal IgG antibody,was developed as an alternative passive immunotherapeutic topalivizumab, with the aim of achieving improved binding afn-ity and virus neutralising activity.20 A phase III double-blindedRCT found motavizumab was non-inferior when compared topalivizumab, with a 26% reduction in RSV hospital admissionscompared with palivizumab.21 However, recipients of motavizu-mab were at increased risk of adverse skin reactions comparedwith those receiving palivizumab. Motavizumab has thereforenot been licensed for use in any country due to concerns overits safety regarding the increased hypersensitivity reactions.15 16

MedImmune have discontinued development of its use forprophylaxis against RSV but are continuing research into itspossible use for treatment of RSV infection.17 20

UK GUIDANCEGuidance for the use of palivizumab in the UK is provided bythe Joint Committee for Vaccination and Immunisation ( JCVI)RSV subgroup. In 2010 the group released recommendationsfor palivizumab use but also highlight the limited evidence baseon which their decisions were based.17 Current JCVI guidancestates that palivizumab is only cost-effective and recommended

for use in particular subgroups of infants at most risk of severedisease (see box 1).17

COST-EFFECTIVENESSDespite evidence of the safety and efcacy of palivizumab prophy-laxis, it remains expensive and difcult to deliver, requiring 5monthly intramuscular injections. The estimated cost for a singledose of palivizumab for an infant aged 6 months, weighing 7.5 kg,is 1023, meaning the total estimated cost per patient receivingthe requiredve doses is just over 5000 each.14 22

Several economic evaluations have examined the cost-

effectiveness of palivizumab prophylaxis in high risk children.The most recent review of the economic evidence concludedthat the cost-effectiveness of palivizumab is inconsistent acrossdifferent studiesdepending on the threshold used and the con-sumption of healthcare resources taken into consideration.18 Inaddition, when interpreting cost-effectiveness studies the differ-ent average weights of infants used in the analysis should becarefully examined as this can have a considerable effect on theconclusions reached.

A Health Technology Assessment considered population sub-groups with different combinations of risk factors for whom theuse of palivizumab may be cost-effective. The study reportedthat at a willingness-to-pay threshold of 30 000 per qualityadjusted life year (QALY), prophylaxis with palivizumab is onlycost-effective among subgroups of children with no chroniclung disease or congenital heart disease ifthey have at least twoother risk factors besides gestational age at birth (includingbeing male, multiple births, siblings at school, smoking exposureand household overcrowding).23 A Canadian cost-effectivenessstudy mirrored these recommendations, also concluding thatimmunoprophylaxis was most cost-effective for infants born at agestational age of 3235 weeks with more than two other riskfactors for RSV hospital admission.24 Elsewhere in Europe, theundiscounted incremental cost-effectiveness ratio (ICER) for useof palivizumab varies. The ICER is estimated to be 6142 perQALY among all high risk infants in Spain and in theNetherlands is estimated to be 12 738/QALY in infants born

preterm or with bronchopulmonary dysplasia and 4256 forinfants with congenital heart complications.25 26 We wereunable to nd any formal cost-effectiveness studies from loweror middle income countries, as the considerable costs prohibiteven minimal use in many countries.

OTHER HIGH-RISK I NFANTSIt is notable that none of the RCTs testing the impact of palivi-zumab prophylaxis to date have included children with

Box 1 Recommended recipients of palivizumabimmunoprophylaxis in the UK.

Children aged


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immunodeciency, chronic neuromuscular diseases, HIV infec-tion or other congenital anomalies. Though these infants athigher risk of RSV infection may benet from prophylaxis, theimpact of passive immunotherapy in these potentially high-riskgroups has not been studied, mostly due to the costs of suchresearch and practical limitations of conducting and recruitingfor an RCT among infants with such rare conditions. Expertsfrom the American Academy of Pediatrics have highlighted the

insufciency of current evidence for the benets of prophylaxisparticularly in immunocompromised infants (such as solid organor haematopoietic stem cell transplant recipients, HIV-infectedinfants and children with other primary and secondary immunedeciencies).27 Experimental studies are currently evaluating theuse of palivizumab in infants with cystic brosis and immuno-suppressed bone marrow transplant recipients.13 23

A large prospective study of over 5000 children in the USA,reported that most children (79%) with severe RSV infection arepreviously healthy.28 So palivizumab prophylaxis targeting onlyhigh risk infants will have a limited impact on total RSV diseaseburden, as most admissions are babies born at term.28 29 Hallet al28 highlighted the importance of prophylaxis being part of abroader package of care aimed at preventing the spread of viralinfections, including the promotion of careful handwashing toreduce child exposure. They conclude that at its current price andclinical outcomes, palivizumab when given in accordance withcurrent recommendations has limited impact on the overallburden of RSV illness seen by hospital paediatricians.28

POTENTIAL LONGER-TERM IMPACT OF PALIVIZUMABIt is not possible to determine from observational studies thecomplex relationship between RSV infection, recurrent wheezeand pre-existing pulmonary vulnerability.30 The recently pub-lished double-blind, placebo-controlled MAKI trial has pro-vided interesting and robust evidence on this association. A totalof 429 healthy preterm infants born at between 33 and

35 weeks gestation were randomly assigned to receive eithermonthly placebo (n=215) or palivizumab (n=214) injectionsduring the winter RSV season.30 Overall, they reported a 10%lower proportion of infants with recurrent wheeze during therst year of life among those receiving palivizumab (11%) com-pared with the placebo (21%) group (p=0.01).30 There was arelative reduction in the total number of wheezing days of 61%in the intervention group compared with the controls (95% CI56% to 65%). Some caution in interpretation of these ndingsis required, since the primary outcome relied on parental report-ing of wheeze rather than a more denitive clinical diagnosis.However, the reduction in wheezing days beyond the periodwhere treatment was received does appear to suggest RSV playsan active role in the mechanism underlying infant wheeze.Though palivizumab reduced recurrent wheezing by 10%,30 thenumber needed to treat is estimated to be 24. 31 Although thishas important implications for the cost-effectiveness of prophy-laxis and further health economic analyses measuring all directand indirect costs are now required, the costs of wheezing in thecommunity are unlikely to be signicant compared to currentdrug costs.

ACTIVE IMMUNISATIONA key target in reducing the scale and severity of RSV LRTIamong children worldwide is widespread active immunisation.However, this remains a challenge because of the difculty ineliciting immunity in such young infants and problems with

attenuation of live viral vaccine candidates to date.32 33

Furthermore, in this age group waning maternal antibody levels

are not sufcient to protect against disease, but can decreasevaccine immunogenicity.34 Considerable safety concerns aboutinactivated vaccine candidates exist, following the failure of aformalin-inactivated RSV vaccine trialled in the 1960s, whichresulted in more severe RSV disease in those who had receivedthe vaccine, and led to two infant deaths due to enhanceddisease symptoms.13 35 36

MedImmune37 have developed some potentially promising

RSV vaccine candidates. MEDI-559 has been tested in a phaseI/2a multicentre, randomised, double-blind, placebo-controlledtrial to evaluate the safety, immunogenicity, tolerability, viralshedding and stability of the vaccine.38 The trial includedhealthy infants aged 1 or 2 months of age irrespective of RSVserostatus and healthy RSV seronegative infants aged 523months. Three doses were given, on a 0, 2 and 4-month sched-ule, with all enrolled infants being followed up for a full year toensure they are monitored during an RSV season.38 Results ofthis trial are not yet publicly available.

A phase I study of a single dose, recombinant live-attenuatedRSV vaccine (NS2 1313 I1314L) is currently enrolling parti-cipants to evaluate vaccine safety and immunogenicity, initiallyamong healthy RSV seropositive infants aged 1259 monthsand then also among healthy seronegative infants aged 624months.39 Another phase I study of a recombinantlive-attenuated RSV vaccine (RSVM2-2) is also recruiting par-ticipants.40 This trial will evaluate the safety of the vaccine indifferent target groups including adults, RSV-seropositive chil-dren aged 1259 months and healthy RSV-seronegative infantsand children aged 624 months. Though each of these candi-date vaccines is in the early stages of development, these (andother candidate vaccines under development) may representimportant advances in the population approaches to the preven-tion of severe RSV disease. The potential impact of an RSVvaccine in the Netherlands has been modelled, with the resultssuggesting it could be a cost-effective intervention, although in

the absence of clinical trial data many different assumptionsabout the potential characteristics of an active vaccine had to bemade in their analysis.41

ANTIVIRALSTrials of two new antivirals for RSV infection may providepromising new options to prevent severe LRT disease, whileother pharmaceutical companies are in the early stages of devel-oping specic antivirals targeting RSV. RSV infects host cells byfusing its envelope with the host cell membrane.42 Attachmentis achieved by the actions of the fusion (F) glycoprotein and theG glycoprotein,43 so these proteins are popular targets in thequest to discover and develop new antiviral compounds againstRSV. Preliminary trials are under way in healthy adults andinfants. Broadly the strategic approach of the new antivirals isprimarily focussed on previously healthy babies with early RSVinfection, with the aim of secondary prevention of severe LRTIrequiring hospital admission. A phase Ib randomised, double-blind, placebo-controlled trial is currently recruiting, to evaluatethe safety and tolerability and pharmacokinetics of the Gileadfusion inhibitor GS-5806 in healthy children


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the community. At present there is a paucity of data reportingrates of progression to severe RSV LRTI requiring admissionamong infants with early mild RSV infection presenting ingeneral practices and emergency departments. More evidencefrom observational studies to quantify the community burden ofRSV illness is needed to consider the potential impact of theseagents and to assist in phase 3 study design.

IMPLICATIONS FOR FUTURE RESEARCHAs yet no studies have examined the impact of passive immuno-therapy beyond the rst year of life. Although there is still somedebate surrounding the specic relationship between RSV infec-tion in infancy and subsequent wheeze and asthma in child andearly adulthood, longer follow-up of infants receiving immuno-prophylaxis could help to improve our understanding of theassociation. Prospective cohort studies are now needed toexamine the longer-term effects of palivizumab use on otherclinical outcomes including wheezing, as well as asthma andmortality.18

Some evidence of the burden of RSV illness in resource poorcountries exists, though this is rarely derived from active case

ascertainment so is likely to underestimate incidence in settingswith limited access to health services.1 It is estimated that 96%of RSV episodes occur in children living in developing countries,where 90% of the global population of children aged less than5 years live.1

In the absence of an effective active vaccination or antiviral toprevent RSV LRTI at a population level, prevention effortsshould also focus on reducing known environmental risk factorsincluding smoking,46 overcrowded housing and improvinghygiene practices to limit transmission among people caring forinfants.1 2 2 3 The primary focus for reducing nosocomial RSVtransmission, particularly in hospital settings, is encouraginggood handwashing techniques or glove and gown use among

healthcare professionals and those in contact with infected indi-viduals.47 48 This is particularly important for high-risk infantsin neonatal units.49 Greater emphasis should be placed on redu-cing modiable risk factors for preterm birth including maternalsmoking, alcohol consumption and illicit drug use in pregnancy,as well as improved management of chronic health conditionssuch as diabetes during pregnancy.

CONCLUSIONAlmost all babies acquire RSV during infancy and previouslyhealthy babies are not eligible to receive palivizumab. Since99% of child deaths attributed to RSV occur in resource poorcountries where expensive prophylaxis is not available or afford-

able, palivizumab has limited potential to impact on the currentglobal burden of RSV LRTI. Two new antivirals are currently inphase I/II trials to test their effectiveness in preventing severeRSV LRTI and a range of candidate vaccines for active immun-isation against RSV are also now in clinical trials. Until a safeand effective active immunisation against RSV infection iswidely available, population level approaches to prevent severeRSV LRTI should continue to focus on reducing prenatal andenvironmental risk factors including prematurity, smoking andimproving hygiene practices.

Contributors JM wrote the rst draft. All authors reviewed the literature, editedthe manuscript and approved the nal draft.

Competing interests None.

Provenance and peer review Commissioned; internally peer reviewed.

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https://www.medimmune.com/http://clinicaltrials.gov/ct2/show/NCT00767416?term=MEDI-559&rank=1http://clinicaltrials.gov/ct2/show/NCT01893554?term=rsv+children+vaccine&rank=2&submit_fld_opt=http://clinicaltrials.gov/ct2/show/NCT01893554?term=rsv+children+vaccine&rank=2&submit_fld_opt=http://clinicaltrials.gov/ct2/show/NCT01893554?term=rsv+children+vaccine&rank=2&submit_fld_opt=http://clinicaltrials.gov/ct2/show/NCT01893554?term=rsv+children+vaccine&rank=2&submit_fld_opt=http://clinicaltrials.gov/ct2/show/NCT01459198?term=RSv+children&rank=1http://clinicaltrials.gov/ct2/show/NCT01797419?term=Safety+Study+of+GS-5806+to+Treat+Respiratory+Syncytial+Virus&rank=1http://clinicaltrials.gov/ct2/show/NCT01797419?term=Safety+Study+of+GS-5806+to+Treat+Respiratory+Syncytial+Virus&rank=1http://www.aliosbiopharma.com/news_room/press_releases/alios_biopharma_initiates_phase_1_clinical_trial_for_rsv_infectionhttp://www.aliosbiopharma.com/news_room/press_releases/alios_biopharma_initiates_phase_1_clinical_trial_for_rsv_infectionhttp://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://adc.bmj.com/http://adc.bmj.com/http://group.bmj.com/http://adc.bmj.com/http://www.aliosbiopharma.com/news_room/press_releases/alios_biopharma_initiates_phase_1_clinical_trial_for_rsv_infectionhttp://www.aliosbiopharma.com/news_room/press_releases/alios_biopharma_initiates_phase_1_clinical_trial_for_rsv_infectionhttp://www.aliosbiopharma.com/news_room/press_releases/alios_biopharma_initiates_phase_1_clinical_trial_for_rsv_infectionhttp://clinicaltrials.gov/ct2/show/NCT01797419?term=Safety+Study+of+GS-5806+to+Treat+Respiratory+Syncytial+Virus&rank=1http://clinicaltrials.gov/ct2/show/NCT01797419?term=Safety+Study+of+GS-5806+to+Treat+Respiratory+Syncytial+Virus&rank=1http://clinicaltrials.gov/ct2/show/NCT01797419?term=Safety+Study+of+GS-5806+to+Treat+Respiratory+Syncytial+Virus&rank=1http://clinicaltrials.gov/ct2/show/NCT01797419?term=Safety+Study+of+GS-5806+to+Treat+Respiratory+Syncytial+Virus&rank=1http://clinicaltrials.gov/ct2/show/NCT01459198?term=RSv+children&rank=1http://clinicaltrials.gov/ct2/show/NCT01459198?term=RSv+children&rank=1http://clinicaltrials.gov/ct2/show/NCT01893554?term=rsv+children+vaccine&rank=2&submit_fld_opt=http://clinicaltrials.gov/ct2/show/NCT01893554?term=rsv+children+vaccine&rank=2&submit_fld_opt=http://clinicaltrials.gov/ct2/show/NCT01893554?term=rsv+children+vaccine&rank=2&submit_fld_opt=http://clinicaltrials.gov/ct2/show/NCT00767416?term=MEDI-559&rank=1http://clinicaltrials.gov/ct2/show/NCT00767416?term=MEDI-559&rank=1http://clinicaltrials.gov/ct2/show/NCT00767416?term=MEDI-559&rank=1https://www.medimmune.com/https://www.medimmune.com/


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doi: 10.1136/archdischild-2013-303764published online January 24, 2014Arch Dis Child

Joanna Murray, Sonia Saxena and Mike Sharlandand new antiviralsvirus disease: passive, active immunisationPreventing severe respiratory syncytial

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References

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