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1 2 3 Preferred Product Characteristics of Monoclonal Antibodies for Passive Immunization against Respiratory Syncytial Virus (RSV) 4 5 NOTE: 6 7 This draft has been prepared in consultation with the WHO Department of Immunization, Vaccines and Biologicals’ Technical Advisory Group for 8 RSV. 9 10 This document is being posted for the purpose of inviting comments and suggestions on the proposals contained therein, which will then be 11 considered by WHO's Product Development for Vaccines Advisory Committee (PDVAC) . 12 13 Written comments proposing modifications to this text must be received by 10 May 2020 and entered in the Comment Form (available 14 separately), and should be addressed to the Responsible Officer: Ms Erin Sparrow at [email protected]. 15

16 Background and purpose of WHO preferred product characteristics (PPCs)

17 This document describes World Health Organization (WHO) preferences for characteristics of monoclonal antibody (mAb) products used for 18 passive immunization against severe Respiratory Syncytial Virus (RSV) disease in infants. These preferences are shaped by the global unmet public 19 health need in priority disease areas for which WHO encourages the development of vaccines and other preventive interventions suitable for use 20 in low- and middle-income countries (LMICs). While many characteristics are the same as those preferred in high-income countries, there are 21 some characteristics that might be unique to LMIC settings.[1]

22 The primary audience for this document includes all involved in the development of new RSV mAbs intended for global use, that is contemplating 23 eventual WHO policy recommendation and prequalification. This document concerns only RSV mAbs intended to prevent RSV severe disease in 24 young children. PPCs present preferred, rather than required, characteristics of products. Whether or not a product meets the PPC criteria, it can 25 be assessed for policy recommendations by the WHO Strategic Advisory Group of Experts (SAGE) on immunization and for WHO prequalification, 26 which assesses product quality, safety, efficacy, and suitability for use in LMICs.[2] The prequalification process assesses products for programmatic

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27 suitability for use in LMICs, and has a number of mandatory, critical and preferred characteristics that are evaluated (3,4). It is a prerequisite to 28 procurement of a product by United Nations (UN) agencies and by Gavi.[3] Low programmatic suitability of new products may delay or prevent 29 their deployment in LMICs. PPCs are reviewed periodically and updated when necessary considering any changes in scientific knowledge and 30 technology.

31 Research and development on RSV preventive products has increased significantly in recent years.[4] Vaccine development efforts stalled for 32 several decades following clinical trials conducted in the 1960s, in which a formalin-inactivated whole virus vaccine led to enhanced respiratory 33 disease (ERD) in RSV-naïve children upon their first exposure to RSV.[5] [6] Much has been learned about the pathogenesis of ERD since then, 34 and current RSV prevention strategies are designed to minimize the risk of ERD.[7] Several types of RSV vaccines and long-acting mAbs are 35 currently in pre-clinical and clinical stages of development. To date, there is one licensed mAb, used in specified populations of high-risk infants 36 in high-income and some middle-income countries, and there are no licensed RSV vaccines, though several mAbs and vaccines are in late-stage 37 clinical development. The Preferred Product Characteristics for RSV vaccines for use in pregnant women and paediatric populations has been 38 published previously (WHO/IVB/17.11).[8]

39 The case for prevention of RSV disease in young infants 40 RSV is a leading cause of respiratory disease in young children globally. The virus causes infections at all ages, but young infants have the highest 41 incidence of severe disease, peaking at 1–3 months of age.[9] RSV affects children in all countries of the world and by two years of age, virtually 42 all children will have been infected. In 2015, RSV was estimated to cause 33.1 million acute lower respiratory tract infections (LRTIs) in young 43 children under 5 years of age annually, with 3.2 million severe cases requiring hospitalization and up to 118,200 deaths.[10] There were an 44 estimated 1.4 million hospital admissions and 27,300 in-hospital deaths among infants younger than 6 months of age, of which 27,100 occurred 45 in LMICs.[10] Preliminary data from recent mortality surveillance studies in several low resource settings in Africa, South Asia, and South 46 America suggest that 6-10% of all deaths in infants (aged 7 days to 6 months) may be associated with RSV.[11, 12] [13, 14] RSV transmission 47 follows a marked seasonal pattern in temperate countries with winter epidemics; in tropical countries, RSV may have a single seasonal peak,

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48 multiple peaks or circulate year-round in countries near the equator. Different seasonality patterns may have policy and programmatic 49 implications as the protection afforded by monoclonal antibodies is short lived. Two subtypes of RSV, A and B, exist and both may co-circulate in 50 a population in any given year.

51 Context of available interventions 52 The first formulation of passive protection against RSV disease was polyclonal, hyperimmune intravenous immunoglobulin (RSV-IGIV, 53 RespiGam®) [15], manufactured by plasmapheresis from pooled plasma of healthy human donors selected for high titres of protective RSV 54 antibodies as determined by microneutralization.[16] RSV-IGIV was used for RSV prevention in children under 24 months with a chronic lung 55 disease, bronchopulmonary dysplasia, and in children less than 6 months old who were born prematurely.[17] RSV-IGIV was superseded by 56 palivizumab, a more potent intramuscularly administered humanized RSV F mAb (Synagis®), which was approved by the US FDA in 1998. 57 Palivizumab is approved for use at the start of the RSV season for prevention of severe RSV disease in specific high-risk children including those 58 born prematurely or those with moderate to severe bronchopulmonary dysplasia or hemodynamically significant congenital heart disease.[18] 59 [19] Palivizumab is administered during the RSV season in five monthly doses, with a recommended dose of 15mg/kg of body weight. Although it 60 has been registered in 65 countries,[20, 21] it is used in a restricted manner in wealthier countries due to its high cost. As of late 2019, 61 palivizumab is registered in no low income countries, 3 lower-middle-income countries, 18 upper-middle-income countries, and 44 high income 62 countries. A Cochrane review in 2013 concluded that palivizumab might not be cost-effective in LMICs.[22] The efficacy of motavizumab, a 63 second-generation RSV mAb, was compared to palivizumab in a phase 3 clinical trial. Motavizumab did not meet prespecified superiority criteria 64 for the primary endpoint (protection against RSV hospitalization) when compared to palivizumab and cutaneous reactions were more frequently 65 observed in motavizumab recipients than palivizumab recipients. This product was not brought to market.[23, 24] 66 67 Monoclonal antibodies with an extended half-life, which could protect infants during an entire RSV season with a single dose, are currently in 68 development. Such extended half-life mAbs promise to have simplified delivery requirements and to be less costly, making them potentially 69 suitable for use in LMICs and for use in all infants. Such products are the focus of this document.

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70 WHO strategic vision for RSV mAbs 71 To promote the development of high-quality, safe, affordable and effective mAbs that prevent severe RSV disease and RSV-related deaths in 72 young children globally. 73 74 MAbs for RSV – preferred product characteristics. 75 The preferred approach to establish the clinical efficacy of an extended half-life RSV mAb would be in randomized controlled trials (RCTs), in 76 which the product is compared to a placebo in the case of full-term healthy infants or compared to palivizumab in separate trials in high-risk 77 infants where it is available as the standard of care. The primary endpoint of an RSV mAb trial in higher burden LMIC settings would likely be 78 severe RSV disease (Table 1), which is sufficiently common in young infants to allow assessment in a trial of manageable size. A placebo- 79 controlled trial would be justified in healthy term infants in LMICs (as palivizumab is not indicated for this population) and could also be justified 80 in high-risk infants in LMICs if palivizumab is not the standard of care. Additional justification for such a trial is that, currently, there is no licensed 81 RSV vaccine and no immune correlate of protection has been identified.[25] Situations where placebo-controlled trials can be justified have been 82 described by WHO previously.[26] In such trials, sites in more than one LMIC would be desirable for demonstrating efficacy in populations with 83 differing disease epidemiology, seasonality, and demographic characteristics. 84 85 Several protein-based RSV vaccines targeting pregnant women are in clinical development; these vaccines could, if effective, result in 86 transplacental antibody transfer and protection of infants during the first few months of life, potentially up to 6 months of age.[4] Comparative 87 analyses of the relative advantages and disadvantages, including programmatic suitability for LMICs, cost-effectiveness, and interchangeability of 88 long-acting mAbs and maternal immunization will be important for policy making. 89 90 Table 1. Preferred product characteristics Parameter Preferred Characteristic Notes Indication Passive immunization for Objective measures of severity should be used such as elevated respiratory rate by protection against severe RSV age group and documented hypoxemia. These should be measured on a

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disease during the neonatal continuous scale. Clinical signs of hypoxia or increased work of breathing should period and early infancy, the also be collected (e.g. central cyanosis, nasal flaring, grunting, inability to feed). period of highest risk of severe Ideally, an agreed definition of severe RSV disease could be used to compare RSV disease and mortality. outcomes across products and regions. Candidate case definitions were proposed by a WHO expert working group in 2015.[27]

Target population Preterm and full-term neonates RSV mortality peaks at 4-6 months of age, but continues to be elevated and infants through 6 months throughout infancy. of age.

Schedule A one dose regimen is highly Both seasonal and year-round dosing can be considered. preferred. 1. In settings with clearly defined RSV seasonal circulation, dosing can occur at or just before the onset of the RSV season. A single dose can be given as a 2. Year-round dosing may be preferred in settings with continuous and/or birth dose or at any healthcare inconsistent peaks of RSV circulation. visit through 6 months of age. mAb administration, either alone or in combination with other vaccines, can be done at the following time points: 1. Birth dose (or soon after) is preferred for newborns likely to have their first RSV exposure in the first 5 months of life. 2. At any healthcare contact such as scheduled primary series EPI visits. (e.g. with DTP1, DTP2 or DTP3) through 6 months of age.

Policy makers should select a delivery strategy based on local context and programmatic feasibility.

Production platform Produced using a well characterized cell line (e.g. CHO cells).

Safety Safety and reactogenicity at No evidence of greater severity of RSV disease occurring after mAb wanes. least as favourable as other WHO recommended vaccines

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given at the same age (e.g. HepB birth dose).

Efficacy Greater than 70% efficacy A mAb with a lower efficacy and shorter duration of protection could be against RSV-confirmed severe considered for use depending on the epidemiological setting and product- disease for 5 months following attributable disease reduction. administration (the median length of the RSV season). Other efficacy endpoints of public health significance are: • Hospitalized RSV • Non-severe RSV LRTI (e.g. tachypnea or lower-chest wall indrawing without severe hypoxemia or danger signs) • All-cause severe LRTI, up to 1 year • Recurrent wheeze and asthma (would require follow-up for several years (2-6 years) • Antibiotic use

Strain specificity Protects against both RSV A and Prior to efficacy trials, mAbs should demonstrate neutralization capacity in vitro B subtypes. against circulating contemporary A and B subtypes. Potential escape mutants should be mapped based on known epitope structures and mAb binding characteristics. Surveillance for clinical breakthrough cases should be undertaken pre- and post-licensure; identification of breakthrough cases should prompt in- vitro neutralization studies of circulating RSV strains to identify potential escape mutant.

Co-administration No significant negative impact Birth dose of mAb should show non-interference with birth dose of BCG, polio, on immune responses to co- Hepatitis B. mAb administration at EPI visits should show non-interference with delivered vaccines. co-administered EPI vaccines (e.g. DTP, HepB, Hib, PCV.[28] Demonstrated safety of RSV mAb upon co-administration with other recommended pediatric vaccines.

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Route of administration Single intramuscular or 0.5 ml dose preferable for young infants. subcutaneous dose using standard volumes for injection as specified in programmatic suitability for PQ.[2]

Registration, Must be licensed and approved Many principles and criteria of vaccine prequalification will apply to preventive prequalification by national regulatory mAbs.[3] Specific requirements for prequalification of mAbs are outlined in and programmatic authorities in countries of use. Pilot Procedure for Prequalification of Biotherapeutic Products and Similar suitability Biotherapeutic Products, though final guidance on prequalification of mAbs has WHO defined criteria for not yet been issued at this time (2019).[29] programmatic suitability of vaccines and recommendations Prequalification by WHO will facilitate approval and ability to purchase products in on presentation, packaging, LMICs.[3] thermostability, storage volume and disposal should be met, where applicable to mAbs.[2] [25]

Value proposition Dosage, regimen and cost of The impact of RSV mAbs on health systems (such as reduction of hospitalization goods amenable to affordable burden and decrease in antibiotic use) and the immunization programme (such as supply. MAb should be cost- cold storage capacity) should be evaluated pre- and/or post-licensure, as effective in LMICs. practicable. Cost-of-goods should allow the vaccine price to be similar to other new vaccines for feasibility of use in LMIC settings. mAb price should be acceptable to Gavi investment case for use in Gavi-eligible countries.[30]

91 92

93 References

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94 95 [1] WHO Preferred Product Characteristics (PPCs). Geneva: World Health Organization; ( www.who.int/immunization/research/ppc- 96 tpp/preferred_product_characteristics/en/, accessed 15 July 2019). 97 [2] Assessing the programmatic suitability of vaccine candidates for WHO prequalification. Geneva: World Health Organization; 98 2014.(http://apps.who.int/iris/bitstream/10665/148168/1/WHO_IVB_14.10_eng.pdf, accessed 1 August 2019). 99 [3] Procedure for assessing the acceptability, in principle, of vaccines for purchase by United Nations agencies. Geneva: World Health 100 Organisation; 2013 ( 101 www.who.int/immunization_standards/vaccine_quality/TRS_978_61st_report_Annex_6_PQ_vaccine_procedure.pdf , accessed 1 102 August 2019). 103 [4] PATH RSV Vaccine and mAb Snapshot April 2019 (www.path.org/resources/rsv-vaccine-and-mab-snapshot/, accessed on 15 July 104 2019) 105 [5] Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K, et al. Respiratory syncytial virus disease in infants despite 106 prior administration of antigenic inactivated vaccine. Am J Epidemiol. 1969;89:422-34. 107 [6] Graham BS. Vaccines against respiratory syncytial virus: The time has finally come. Vaccine. 2016;34:3535-41. 108 [7] Acosta PL, Caballero MT, Polack FP. Brief History and Characterization of Enhanced Respiratory Syncytial Virus Disease. Clin 109 Vaccine Immunol. 2015;23:189-95. 110 [8] WHO Preferred Product Characteristics for RSV Vaccines, WHO 111 2017.(https://apps.who.int/iris/bitstream/handle/10665/258705/WHO-IVB-17.11-eng.pdf, accessed on 31 July 2019). 112 [9] Saha SK, Schrag SJ, El Arifeen S, Mullany LC, Shahidul Islam M, Shang N, et al. Causes and incidence of community-acquired 113 serious infections among young children in south Asia (ANISA): an observational cohort study. Lancet. 2018;392:145-59. 114 [10] Shi T, McAllister DA, O'Brien KL, Simoes EAF, Madhi SA, Gessner BD, et al. Global, regional, and national disease burden 115 estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and 116 modelling study. Lancet. 2017;390:946-58. 117 [11] Caballero MT, Bianchi AM, Nuño A, Ferretti AJP, Polack LM, Remondino I, et al. Mortality Associated With Acute Respiratory 118 Infections Among Children at Home. J Infect Dis. 2019;219:358-64. 119 [12] Blau D, RSV Burden from the CHAMPS Study, Presentation at 11th International RSV Symposium, 31 October to 4 November 120 2018, Asheville, USA. 121 [13] Gill C, RSV-associated respiratory deaths among Zambian Infants: an interim analysis of the first year of the Zambia Pertussis 122 RSV Infant Mortality Estimation (ZPRIME) Study, Poster at 11th International RSV Symposium, 31 October to 4 November 2018, 123 Asheville, USA. 124 [14] Child Health and Mortality Prevention Surveillance (CHAMPS) Network, available here: https://champshealth.org, accessed on 125 22 November 2019. 126 [15] Oertel MD. RespiGam: an RSV immune globulin. Pediatr Nurs. 1996;22:525-8.

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127 [16] Siber GR, Leombruno D, Leszczynski J, McIver J, Bodkin D, Gonin R, et al. Comparison of antibody concentrations and 128 protective activity of respiratory syncytial virus immune globulin and conventional immune globulin. J Infect Dis. 1994;169:1368-73. 129 [17] Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia 130 using respiratory syncytial virus immune globulin prophylaxis. The PREVENT Study Group. Pediatrics. 1997;99:93-9. 131 [18] US FDA website, approved drug products, available here: www.accessdata.fda.gov/scripts/cder/daf/index.cfm, accessed on 1 132 June 2018. 133 [19] Synagis Product Label, FDA, revised May 2017, available 134 here: www.accessdata.fda.gov/drugsatfda_docs/label/2017/103770s5200lbl.pdf (accessed on 16 October 2019). 135 [20] N drugs - Synagis, https://www.ndrugs.com/?s=synagis%20(medimmune%20inc), accessed on 21 October 2019. 136 [21] Pharma intelligence Informa - Synagis, http://drugprofiles.informa.com/drug_profiles/338-synagis, accessed on 21 October 137 2019. 138 [22] Andabaka T, Nickerson JW, Rojas-Reyes MX, Rueda JD, Bacic Vrca V, Barsic B. Monoclonal antibody for reducing the risk of 139 respiratory syncytial virus infection in children. Cochrane Database Syst Rev. 2013;4:Cd006602. 140 [23] Carbonell-Estrany X, Simoes EA, Dagan R, Hall CB, Harris B, Hultquist M, et al. Motavizumab for prophylaxis of respiratory 141 syncytial virus in high-risk children: a noninferiority trial. Pediatrics. 2010;125:e35-51. 142 [24] The Antiviral Drugs Advisory Committee of the US Food and Drug Administration Review of Motavizumab, Summary Minutes 143 June 2, 2010. 144 (https://wayback.archiveit.org/7993/20170405205426/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMate 145 rials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM241510.pdf, accessed on 2 August 2019). 146 [25] Giersing BK, Karron RA, Vekemans J, Kaslow DC, Moorthy VS. Meeting report: WHO consultation on Respiratory Syncytial 147 Virus (RSV) vaccine development, Geneva, 25-26 April 2016. Vaccine. 2017. 148 [26] Expert Consultation on the Use of Placebos in Vaccine Trials, WHO 2013, available here 149 https://apps.who.int/iris/bitstream/handle/10665/94056/9789241506250_eng.pd , accessed on 22 November 2019. 150 [27] Modjarrad K, Giersing B, Kaslow DC, Smith PG, Moorthy VS, Group WRVCE. WHO consultation on Respiratory Syncytial 151 Virus Vaccine Development Report from a World Health Organization Meeting held on 23-24 March 2015. Vaccine. 2016;34:190-7. 152 [28] Summary of WHO Position Papers - Recommended Routine Immunizations for Children, April 2019, Available here: 153 www.who.int/immunization/policy/Immunization_routine_table2.pdf, accessed on 17 September 2019. 154 [29] Pilot Procedure for Prequalification of Biotherapeutic Products and Similar Biotherapeutic Products, available here: 155 www.who.int/medicines/regulation/biotherapeutic_products (accessed on 18 October 2019). 156 [30] 06a - Annex C: Respiratory Syncytial Virus Investment Case, Vaccine Investment Strategy Programme and Policy Committee 157 Meeting 18-19 October 2018, available here: www.gavi.org/library/gavi-documents/strategy/ppc-meeting-18-19-october-2018---vis- 158 06a---annex-c--respiratory-syncytial-virus-investment-case, accessed on 17 September 2019. 159

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