On the verge of  RESPIRATORY SYNCYTIAL VIRUS  - PowerPoint Presentation

1. On the verge of RESPIRATORY SYNCYTIAL VIRUS disease preventionAn immunization pipeline to protect in early life

2. Respiratory syncytial virus (RSV) is the world's top cause of severe respiratory infections and hospitalization in infants and young children—with no widely available interventions to prevent it.Now is the time to raise awareness and support global, regional, and country decision-making around RSV prevention, policy, and implementation preparedness.New, game-changing tools for preventing RSV in early life are now achieving or on the pathway to licensure.long-acting monoclonal antibodies given to newbornsvaccine given in pregnancyAdding RSV to the immunization toolkit couldkeep children out of the hospitalsave many young livesfree up resources for other health prioritiesAn overdue chance to address an under-recognized cause ofWhy focus on RSV? And why now?millions of hospitalizationsthousands of deathsstrain on health systems and livelihoodsOriginal slide developed by the World Health Organization and PATH

3. RSV disease burdena huge, under-recognized, public health problemForthcoming prevention productslong-acting mAbs and maternal vaccines to protect the youngest childrenThe road to RSV preventionpriorities and opportunitiesAgendaOriginal slide developed by the World Health Organization and PATH

4. RSV disease burdena huge, under-recognized public health problem

5. Controlling RSV is critical in the larger pneumonia fight because itis the most common cause of infant pneumonia and bronchiolitisis a leading cause of pneumonia deaths in the first 6 months of lifecauses up to 40% of severe pneumonia cases before 1 year of age2increases vulnerability to pneumonia caused by other viruses and bacteriaPneumonia is the #1 cause of child mortality worldwidePNEUMONIA IS RESPONSIBLE FOR 15% OF ALL-CAUSE <5 MORTALITY(> 700,000 deaths per year)11 Interim WHO-MCEE cause of death for children under-5 years (September 2019) updated using cause fractions from 2017 and applying them to UN-IGME estimates for 2018.2 Pneumonia Etiology Research for Child Health (PERCH) Study Group. Lancet. 2019.Pneumonia 15%Other causesKilling more children than malaria, measles, and diarrhea combined.Original slide developed by the World Health Organization and PATH

6. Annual global pediatric RSV disease burden (< 5 years of age)LEADING CAUSE OF SEVERE RESPIRATORY INFECTION33,000,000episodes3.6 millionhospitalizationsReference: Li Y, et al. Lancet 2022.< 6 months20%6 months to 5 years80%6 months to 5 years61%LEADING CAUSE OF PEDIATRIC HOSPITALIZATIONIMPORTANT CAUSE OF PEDIATRIC MORTALITY< 6 months39%6 months to 5 years54%< 6 months46%101,000deathsTOTAL GLOBAL CHILD MORTALITY DUE TO RSV3.6%< 6 MONTHS  2.3%< 5 YEARS  Nearly half of RSV deaths are before 6 months of ageOriginal slide developed by the World Health Organization and PATH

7. What is RSV?Often mild, like a cold, but can be severe (or deadly) for infants.Sneezing, coughing, quiet breathing, touching contaminated surface and then eyes, nose, or mouthInfection-induced immunity not fully protectiveRepeated lifelong infectionsAny child can get severely ill and be hospitalized, but some factors raise the risks:< 6 months old or born prematurelyComorbidities (e.g., underlying heart/ lung disease)Living in socioeconomically disadvantaged areasRSV is so widespread that almost all children contract the virus before 2 years of age.PRESENTATIONTRANSMISSIONPARTIAL IMMUNITYPOPULATIONS AT HIGH RISKOriginal slide developed by the World Health Organization and PATH

8. About the virusSingle stranded RNA virus.Airway obstruction may occur due to sloughed epithelium and inflammatory cells with mucus and fibrin that get into small airways.Immune target  RSV fusion (F) proteinF protein on surface of virus fuses with host epithelial cells in the lung, enabling infectionSimilar to spike protein in SARS-CoV-2Fusion (F) proteinOriginal slide developed by the World Health Organization and PATH

9. RSV’s biggest risks are in the youngest childrenReference: PERCH Study Group. Lancet. 2019.6 months1 IN EVERY 28 DEATHSbefore 6 months of age globally is due to RSV1Most severe in first few months of life due to easily blocked small airways.Original slide developed by the World Health Organization and PATH

10. Many children in low-income economies never make it to a hospital.24xas many children die from RSVin the community than in the hospital98% of pediatric RSV mortality occurs in low- and middle-income economies1LOW-INCOMEHIGH-INCOME1 Li Y, et al. Lancet. 2022; 2 Srikantiah P, et al. Clin Infect Dis. 2021.24hospital deaths/ 1,000 RSV cases<1hospital deaths / 1,000 RSV cases109community deaths/ 1,000 RSV cases<1community deaths / 1,000 RSV casesThe disparity in RSV mortality between low- and high-income contexts is substantial.In children < 6 months of age, RSV is responsible for:Original slide developed by the World Health Organization and PATH

11. Testing and surveillance—current statusPCR and antigen tests can diagnose RSV infection.Most RSV data are from high-income areas, though data are available from all WHO regions.RSV as common in low- and middle-income areas as high.More data needed on disease burden nuances at country levels.Many places don’t test for RSV in clinical care. More RSV testing and surveillance needed, including in low- and middle-income areas.WHO is leveraging the Global Influenza Surveillance and Response System (GSIRS) to help, but additional Original slide developed by the World Health Organization and PATH

12. SUPPORTIVE CARE (e.g., hydration, nutritional support, oxygen, and ventilation)No licensed antivirals for RSVInappropriate antibiotic use poses antimicrobial resistance threatPALIVIZUMAB (EXISTING)Short-lasting mAb that can prevent severe RSV in high-risk infantsUse is limited to high-income countriesRequires up to 5 monthly dosesExpensive/ impractical for low- and middle-income marketsNIRSEVIMAB (NEW)Long-acting mAb given at birth or soon thereafter (approved in Europe in late 2022)Price and supply may be early barriers to access, requiring market shaping to overcomeNO VACCINE yet licensed to prevent RSVA first-in-class RSV maternal vaccine showed positive Phase 3 clinical trial results in November 2022 and licensure submission is underwayCurrent treatment and prevention for young infantsTREATMENT/MANAGEMENTMONOCLONAL ANTIBODY (MAB) PREVENTIONVACCINE PREVENTIONOriginal slide developed by the World Health Organization and PATH

13. RSV31.1%(28.4, 34.2)Rhinovirus 7.5%(5.3, 10.1)hMPV 7.5%(5.9, 9.5)Parainfluenza 7.4%(5.8, 9.3)Pneumococcus 6.7%(5.1, 8.5)TB 5.9%(3.9, 8.3)P. jirovecii2.0%(0.9, 3.3)H. influenzae5.9%(3.8, 8.5)Staph 2.7%(1.5, 4.3)Influenza 2.0%(1.1, 3.2)VIRUSESBACTERIATBFUNGISites in Bangladesh, Gambia, Kenya, Mali, South Africa, Thailand, ZambiaReference: PERCH Study Group; Lancet, 2019.Pneumonia Etiology Research for Child Health (PERCH) studyTop 10 causes of severe pneumonia before 5 years of age in 7 countries in Africa and AsiaOriginal slide developed by the World Health Organization and PATH

14. RSV6.48% (5.81-7.59)Ureaplasma spp2.82 (1.93-3.77)Other blood culture2.57 (2.05-3.11)Klebsiella pneumonaiae1.79 (1.17-2.49)Escherichia coli1.71 (1.05-2.62)Enterovirus or rhinovirus1.36 (0.83-2.37)Salmonella spp1.28 (0.53-2.52)Streptococcus pneumoniae1.15 (0.70-1.98)Group B Streptococcus1.12 (0.65-1.71)Staphyloccocus aureus1.05 (0.63-1.68)Aetiology of Neonatal Infections in South Asia (ANISA) studyTop 10 causes of community-acquired serious infections in neonates in 3 countries in South Asia3 4 5Proportion of pSBI episodes (%)012678Reference: Saha, S. et al. Lancet, 2018.Sites in Bangladesh, India, and PakistanOriginal slide developed by the World Health Organization and PATH

15. RSV prevention strategies may need to account for seasonalitySeasonal virus activity observed in many areas around the world but can be year-round in others.1Timing of seasonal RSV circulation can vary year-to-year, adding complexity to prevention efforts.Some prevention and treatment strategies could be calibrated to times of year when people are most at risk.EQUATORIALyear round circulation1Li Y et al, Lancet Global Health. 2019. TEMPERATEwell-circumscribed seasonalitySUBTEMPARATE / SUBTROPICALseasonal peaks withlow level year-round circulationOriginal slide developed by the World Health Organization and PATH

16. RSV illness strains health systems and livelihoods 1Baral R, et al. J Pediatric Dis Soc. 2020. 2Bhuiyan MU, et al. J Glob Health. 2017. 3PERCH Study Group. Lancet. 2019. Lack of prevention measures means that health systems and households must bear the costs of managing RSV cases and complications.Economic burden is substantial in high-income countries, where most data has been generated. Available data in low- and middle-income economies show substantial burden on health systems and households.More health economics data are needed to inform decision-making around RSV prevention.32% OF TOTAL MONTHLY HOUSEHOLD INCOME PER RSV EPISODE24% OF MONTHL INCOME FOR FAMILIES PERRSV HOSPITALIZATIONImpacts on livelihoods32% OF MONTHLY INCOME FOR POORER FAMILIES PER RSVHOSPITALIZATIONBangladesh2Malawi15-10% OF HOSPITAL ADMISSIONS OF CHILDREN < 5 YEARS OLD DUE TO RSVImpacts on health system$10M USD MEDIAN ANNUAL DIRECT COST OF RSV HOSPITALIZATIONGambia, Mali, Kenya, South Africa3Bangladesh2Original slide developed by the World Health Organization and PATH

17. Forthcoming prevention productslong-acting mAbs and maternal vaccines to protect the youngest children

18. New hope of preventing RSV in infants—a product development renaissance1960s1998RSV vaccine development stalls Short-acting mAb licensed Palivizumab 2013Key technology—RSV pre-fusion (F) protein2022Pre-F products for early-life RSV prevention approved or on the pathway to licensure1956RSV discoveredPre-fusion conformation of the F protein discovered as safe and promising immune targetNeutralizing antibodies target pre-F protein and prevent virus from fusing to and infecting host cellsRemoves risk of causing enhanced diseaseFormalin-inactivated, pediatric RSV vaccine candidate shown to cause enhanced respiratory disease in RSV-naïve infants during first natural infectionMaternal vaccinepositive Phase 3 results / submitted for US licensureLong-acting mAb in Phase 2b/3Long-acting mAb licensed in Europe2010sBreakthroughs in RSV understanding spark product development renaissancewww.path.org/resources/rsv-vaccine-and-mab-snapshot/Original slide developed by the World Health Organization and PATH

19. New products likely here soon for prevention in early lifeMonoclonal antibodyMaternal vaccineDirectly immunizing neonates soon after birth provides antibodies for critical protection in early life.Vaccination in pregnancy can directly enhance the pregnant vaccinee’s immunity and increase natural antibody transfer to baby across the placenta for protection in early life.mAbs are manufactured antibodies to the RSV pre-F protein that neutralize the virus.Pre-F protein in the vaccine induces antibodies that neutralize the virus. At birth with other birth dose vaccinations (e.g., hepatitis B; BCG, OPV) or at first Expanded Program on Immunization (EPI) visit.Vaccination in late second or third trimester of pregnancy to optimize transfer of antibodies to infant.Given in one doseAt least 5-6 months protection after administration (longer lasting than palivizumab) Given in one doseAt least 5-6 months protection after birthRATIONALEHOW IT WORKSTIMINGPRODUCT CHARACTERISTICSOriginal slide developed by the World Health Organization and PATH

20. Leading product progress for RSV prevention in early lifeNirsevimab (mAb)1 AstraZeneca / Sanofi Pasteur79.5%(95%, 65.9 to 87.7)Medically attended RSV lower respiratory tract infection (LRTI) through 150 daysPooled Phase 2b/3 analysis Approved in Europe in November 2022Price and supply access barriers anticipated, at least in early yearsMarket shaping needed for low-income market accessSingle-dose pre-filled syringe77.3%(95%, 50.3 to 89.7)RSV-LRTI with hospitalization through 150 daysPre-fusion Fmaternal vaccine2Pfizer69.4%(44.3% to 84.1%)Severe medically attendedRSV-LRTI from birth through 180 daysSubmission for US licensure in 2022Earliest potential WHO prequalification estimated in 2024Single-dose vial (current); multi-dose vial (in development)51.3%(29.4% to 66.8%)Medically attendedRSV-LRTI from birth through 180 days1Simoes E. International RSV Symposium. Belfast, Ireland. September 30, 2022. 2Pfizer press release, November 1, 2022, at www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-positive-top-line-data-phase-3-global .Additional long-acting mAbs for delivery to neonates are in development and have potential for low- and middle-income markets. Merck (Phase 2b/3)The Bill & Melinda Gates Medical Research Institute (Phase 1) PRODUCT /DEVELOPEREFFICACY (%)(CONFIDENCE INTERVAL)OUTCOME MEASUREDCOMMENTSOriginal slide developed by the World Health Organization and PATH

21. Timelines for lead RSV candidates aimed at protecting infantsMerck mAbAstraZeneca/Sanofi nirsevimab2022202320242025Pfizer maternalvaccinePhase 3 completedFDA filingsEMAapprovalEarliest regulatory decisionsFDAdecisionEarliest possibleSAGEreviewEarliest possible SAGEreviewFDAdecisionsEarliest PQ single-dose maternal vaccineEarliest SAGE/PQEarliest PQ multi-dose vial maternal vaccineMONOCLONAL ANTIBODIESMATERNAL VACCINESEMA=European Medicines Agency FDA=US Food and Drug AdministrationSAGE=WHO Scientific Advisory Group of Experts PQ=WHO prequalificationEMA filingsOriginal slide developed by the World Health Organization and PATH

22. The road to RSV preventionpriorities and opportunities

23. Global access will depend on support from Gavi, the Vaccine AllianceGavi is an international organization created in 2000 to improve access to new and underused vaccines for children living in the poorest parts of the world.As of 2022, 54 countries are eligible for Gavi support.1RSV product costs are still unclear; however, the leading products are not anticipated to be affordable for LMICs without subsidies.Gavi approved RSV prevention in infants as part of its Vaccine Investment Strategy (VIS) for 2021-2025 funding.RSV to be revisited at 2023 VIS.1. Availability of licensed productWHO prequalificationSAGE recommendationCost within predicted rangeAvailable funding2018 VIS RECOMMENDATIONSNEXT VIS 2023SUPPORT FOR RSV MATERNAL IMMUNIZATION OR MABPRODUCTS CONTINGENT ON:1www.gavi.org/types-support/sustainability/eligibilityOriginal slide developed by the World Health Organization and PATH

24. Delivering products will depend on coordination across two platformsCross-cutting engagement across antenatal care, obstetric, pediatric, and immunization programs and experts will be needed, regardless of product(s) chosen.RSV preventionEPIMaternal, newborn, child health programs / antenatal care (ANC)Original slide developed by the World Health Organization and PATH

25. MATERNAL VACCINECOMMON ACROSS PRODUCTSDelivered similarly to BCG, hepatitis B, OPV birth dose vaccinesIntramuscular injection, like many vaccinesRobust immunization infrastructure and systems in placeSkilled workforce familiar with nuances of immunizationExisting tetanus, COVID-19, and other maternal immunization programs may be leveragedOpportunity to leverage resources to improve ANC and vaccine service deliveryOffering RSV vaccine during ANC to protect infants may also benefit ANC coverage, uptake, and perceived quality of careVaccine safety monitoring systems could also track pregnancy and other maternal/child health outcomesRSV vaccine would be first-ever vaccine licensed with an indication for use in pregnancy to protect infants—paving the way for other maternal vaccinesBoth products will protect babies during the most critical first six months of lifeProvide passive protection against RSV Only one dose needed, which simplifies deliveryPotential to be cost-effective in low- and middle-income economies (context dependent)MATERNAL VACCINECOMMON ACROSS PRODUCTSProgrammatic considerations: likelyLONG-ACTING MABadvantagesOriginal slide developed by the World Health Organization and PATH

26. Programmatic considerations: potentialMATERNAL VACCINECOMMON ACROSS PRODUCTSIdentifying and reaching infants born outside formal healthcare settingsmAbs may be new policy and regulatory territory for some countriesCost and supply barriers to accessAlthough designed to require only one dose, two doses may be needed based on weightANC/EPI coordination and readiness needs may be uncharted in some countries (e.g., safety monitoring, logistics, training)Reaching pregnant patients in target gestational age window and approaches to protect preterm infants that miss the windowExpanding pregnancy registry surveillance/linking mother-infant recordsSeasonal dosing could be logistically challengingAwareness gaps or reluctance/hesitancy about new RSV products given to neonates or in pregnancy may affect demand/acceptability/uptakeAdditional services may strain certain health system componentsCompeting priorities for immunization and maternal, child health programsMATERNAL VACCINECOMMON ACROSS PRODUCTSLONG-ACTING MABchallengesOriginal slide developed by the World Health Organization and PATH

27. Adding RSV as a new disease target to the public health agendaThe goal will be for RSV prevention to complement other public health initiatives and strategies.RSVImmunizationImmunization Agenda 2030 goals (life course vaccination, tailored country programs, gender equity, new technologies)Existing maternal immunization implementation (tetanus, pertussis, COVID-19)Future maternal vaccines (Group B Streptococcus)ANCImplementing updated recommendations for 8 ANC contacts per pregnancyANC platform optimizationQuality of care improvementExpanding reach/impact of existing interventionsOriginal slide developed by the World Health Organization and PATH

28. Getting to public health impact What success could look likeImproved infant health and survival through introduction and wide-scale use of RSV prevention tools(mAb and/or maternal immunization) What’s needed to reach the goalEvidence-based decisions support RSV prioritization and product adoptionHealth systems & services deliver RSV prevention product(s) routinely, efficiently, and equitablyOUTCOMESElements for achieving objectivesEvidence supports case for vaccine adoptionIncreased stakeholder awareness of RSV disease and forthcoming productsSupportive policies and financing are in placeCoordination established between EPI and ANC programs around RSV preventionOperations and logistics in place to procure and deliver prevention product(s) as well as monitor implementationImplementers empowered to deliver prevention product(s)Capacity building underway to track vaccine safety and impactGOALOBJECTIVESOUTCOMESOriginal slide developed by the World Health Organization and PATH

29. Country decision-making and implementationWhat preparations are needed?The case for prioritizing RSVDisease surveillance / safety monitoringProduct choiceWorkforce readinessDelivery platform(s)FinancingAwareness / acceptance / demandGlobal / country policyOriginal slide developed by the World Health Organization and PATH

30. Progress is underway but more work is neededAreas of ongoing efforts include, but are not limited to:Further characterizing disease burden, by regionHealth economics researchService delivery research and supportAwareness raisingAcceptance/demand researchSafety monitoring system reviewsOriginal slide developed by the World Health Organization and PATH

31. What can countries be doing now?Begin by thinking through decision-making and implementation questions.Where does RSV prevention fit in our public health agenda amidst other priorities?What additional information do we need to make decisions?Which RSV prevention product(s) could best suit our context (e.g., cost/benefit)?How can we optimize delivery and across which programs/platforms? How can we best raise awareness and product acceptability (e.g., among healthcare workers, parents)?Who needs to be engaged and informed (e.g., maternal, child health and EPI stakeholders)?Who will be champions for RSV prevention and take the lead in raising awareness?Original slide developed by the World Health Organization and PATH

32. Thank you!