key: cord-0936183-jr4s2nx0
authors: Ananworanich, Jintanat; Heaton, Penny M.
title: Bringing Preventive RSV Monoclonal Antibodies to Infants in Low- and Middle-Income Countries: Challenges and Opportunities
date: 2021-08-28
journal: Vaccines (Basel)
DOI: 10.3390/vaccines9090961
sha: 2454721760f5fa7f6d9fc3d3ff682883297b2eed
doc_id: 936183
cord_uid: jr4s2nx0

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections (LRTIs) in infants. Most deaths occur in infants under 3 months old, and those living in low and middle-income countries (LMICs). There are no maternal or infant RSV vaccines currently approved. An RSV monoclonal antibody (mAb) could fill the gap until vaccines are available. It could also be used when a vaccine is not given, or when there is insufficient time to vaccinate and generate an antibody response. The only currently approved RSV mAb, palivizumab, is too costly and needs monthly administration, which is not possible in LMICs. It is imperative that a safe, effective, and affordable mAb to prevent severe RSV LRTI be developed for infants in LMICs. Next generation, half-life extended mAbs in clinical development, such as nirsevimab, show promise in protecting infants against RSV LRTI. Given that a single dose could cover an entire 5-month season, there is an opportunity to make RSV mAbs affordable for LMICs by investing in improvements in manufacturing efficiency. The challenges of using RSV mAbs in LMICs are the complexities of integrating them into existing healthcare delivery programs and surveillance systems, both of which are needed to define seasonal patterns, and monitor for escape mutants. Collaboration with key stakeholders such as the World Health Organization and Gavi, the Vaccine Alliance, will be essential for achieving this goal.

Respiratory syncytial virus (RSV) is a global disease that places a high and underappreciated burden on the economy and healthcare services. It is the leading preventable cause of acute lower respiratory tract infection (LRTI) deaths in children 6 months of age or younger; most deaths occur in low-and middle-income countries (LMICs) [1] .

The World Health Organization (WHO) Product Development for Vaccines Advisory Committee (PDVAC) indicates that RSV immunoprophylaxis with vaccines and monoclonal antibodies (mAbs) are priority interventions. There is currently no approved vaccine against RSV. RSV mAbs are proven to prevent RSV LRTI in preterm infants and are currently being used in infants at high risk for severe RSV disease. However, the only type approved is not accessible and affordable for widespread use in LMICs. The high rate of RSV infection, especially among infants and young children, underscores the need for safe, effective, and affordable prevention of RSV disease.

Most children acquire an RSV infection by the time they are 2 years old, causing a mild upper respiratory tract infection within 4 to 6 days after infection. Population-based serologic studies suggest that seroconversion from primary RSV infection occurs in about 30% of infants by 6 months of age, 50% by age one, and 100% by age two. [2, 3] . However, in some children it leads to a more severe illness, such as bronchiolitis or pneumonia. All infants are at risk of RSV-associated acute LRTI, but the highest risk is in the first 6 months of life, and in particular, the first 3 months. During this early infancy period, infants have narrow airways that are easily obstructed by inflammatory infiltrates, and may have low titers of maternally transferred neutralizing antibodies against RSV [4] . Infants who are born prematurely or have chronic lung disease (CLD) or congenital heart disease (CHD) are at the greatest risk of acute LRTI. Gestational age and birth weight are independent risks for hospitalization [5] .

In 2015, RSV was estimated to cause 33.1 million new episodes of acute LRTI in children under 5 years old. Among 3.2 million hospital admissions in this age group, 1.4 million hospitalizations were in children younger than 6 months. Healthy term infants 3 months of age and younger account for more RSV-associated hospitalizations than any other age group [6] . The hospital admission rate from RSV in LMICs is 15.9 per 1000 neonates per year. Incidence rates are three times greater in preterm than term infants [1] . Globally, there are approximately 120,000 RSV-associated acute LRTI deaths among children <5 years of age each year [7] . RSV LRTIs account for a third of all LRTIs [1] . Most deaths occur in LMICs. Approximately 45% of in-hospital deaths due to RSV-associated acute LRTIs occur in children younger than 6 months (median ages of RSV-related deaths are between 4 and 7 months [1, 8] .

Preliminary data from 2019 suggest that in several low-income countries, 6-10% of all deaths in infants up to 6 months of age may be associated with RSV [9] . Data from the Child Health and Mortality Prevention Surveillance (CHAMPS) and ongoing community mortality surveillance platforms in Zambia and India indicate that RSV is associated with approximately 7% of all deaths in infants 7 days to 6 months of age. This suggests a potentially significant number of preventable RSV deaths in young infants. Data from Zambia indicate close to 70% of this RSV-associated mortality in young infants occurs in the first 3 months of life [10] . There is substantial underreporting of community, non-hospital deaths and non-respiratory RSV deaths (e.g., sepsis), indicating that infants in this age group in LMICs constitute a critically important target group for prevention.

RSV is a negative-stranded RNA virus in the Pneumoviridae family. It has 11 known proteins, including envelope spikes (SH, G and F), inner envelope proteins (M), nonstructural proteins (NS1, NS2) and ribonucleocapsid complexes (N, P, L, M2-1, M2-2). RSV has two subtypes, A and B, and these are typically determined by G sequences. F and G proteins are the main targets for vaccine and mAb development because of their direct involvement with infectivity and RSV disease.

The RSV F protein (involved in viral entry), is a superior target to the G protein (involved in attachment to host cell) because of its conserved and highly neutralizationsensitive epitopes. G is an attachment glycoprotein with membrane and secreted forms. The RSV F protein is essential for virus entry into the host cell and mediates membrane fusion of the virus particle and the target cell. Fusion of infected cells with adjacent cells results in the formation of the characteristic syncytia. During membrane fusion, the metastable prefusion (pre-F) undergoes conformational changes to a stable post-fusion F (post-F). There are six antigenic sites (Ø, I, II, III, IV, and V) between pre-F and post-F ( Figure 1 ) [11] . Sites Ø and V are pre-F sites, whereas site I is a post-F site. Site II and site IV are shared by both the pre-F and post-F. Neutralizing antibodies for pre-F are more potent than those targeting post-F due to pre-F being a highly neutralization-sensitive region [12] . The discovery of the pre-F conformation and stabilization to present a fraction of neutralizing-sensitive surfaces as an immunogen has transformed RSV vaccine development and fueled next generation vaccines capable of inducing highly neutralizing polyclonal antibody responses. The identification of the antigenic sites on pre-F has advanced therapies such as vaccine and mAb development to reduce the burden of RSV disease [13] .

Vaccines 2021, 9, 961 3 of 13 ment and fueled next generation vaccines capable of inducing highly neutralizing clonal antibody responses. The identification of the antigenic sites on pre-F has adva therapies such as vaccine and mAb development to reduce the burden of RSV disease 

Development of a therapy to prevent or reduce RSV infection is ongoing, buildi part, on research related to natural RSV immunity. Previous research has shown that naïve infants who receive higher levels of neutralizing antibody from their mothers t placentally and potentially via breastmilk are less susceptible to RSV infection [1 Moreover, infants with ability to generate strong RSV-specific humoral and cellula mune responses during primary RSV infections tend to have faster recovery and le vere RSV [16] . Nevertheless, RSV-naïve infants typically generate innate and adaptiv mune responses against RSV that are suboptimal and short-lived. This could be d their developing and immature immune system, immune tolerance, and RSV-drive cape from host immunity (e.g., downregulation of type I interferon response, imm modulation of secretory G protein, and spontaneously flipping into post-F confirm to avoid neutralization) [11] . Such original antigenic failure may imprint a long-la suboptimal adaptive immune response to RSV. Therefore, natural immunity to R insufficient, and re-infection occurs throughout adulthood, although with milder di severity, until immune senescence and dysregulated responses occur in the elderl sulting in an increased risk of severe RSV disease [17] .

Direct immunization in RSV-naïve infants offers a unique opportunity to elicit lasting, effective innate, humoral, and cellular immune responses at initial exposure virus. The goal of maternal immunization is to boost polyclonal anti-RSV neutralizin tibody titers for antenatal transfer to the infant, whereas RSV mAb blocks viral ent targeting a specific antigenic site on the F protein.

All infants, both full-term and preterm, should be protected from RSV. The mos portant thing for LMICs is to prevent severe RSV LRTI in infants who are ≤6 mont age, and entering their first RSV season. Ideally, the protection should cover a typi month RSV season.

As shown in Figure 2 , there are three main strategies being studied to protect in during this vulnerable period. The priorities are developing maternal RSV vaccine infant RSV mAbs to provide immediate protection to young infants, whereas active i 

Development of a therapy to prevent or reduce RSV infection is ongoing, building in part, on research related to natural RSV immunity. Previous research has shown that RSV-naïve infants who receive higher levels of neutralizing antibody from their mothers transplacentally and potentially via breastmilk are less susceptible to RSV infection [14, 15] . Moreover, infants with ability to generate strong RSV-specific humoral and cellular immune responses during primary RSV infections tend to have faster recovery and less severe RSV [16] . Nevertheless, RSV-naïve infants typically generate innate and adaptive immune responses against RSV that are suboptimal and short-lived. This could be due to their developing and immature immune system, immune tolerance, and RSV-driven escape from host immunity (e.g., downregulation of type I interferon response, immune modulation of secretory G protein, and spontaneously flipping into post-F confirmation to avoid neutralization) [11] . Such original antigenic failure may imprint a long-lasting suboptimal adaptive immune response to RSV. Therefore, natural immunity to RSV is insufficient, and re-infection occurs throughout adulthood, although with milder disease severity, until immune senescence and dysregulated responses occur in the elderly, resulting in an increased risk of severe RSV disease [17] .

Direct immunization in RSV-naïve infants offers a unique opportunity to elicit longlasting, effective innate, humoral, and cellular immune responses at initial exposure to the virus. The goal of maternal immunization is to boost polyclonal anti-RSV neutralizing antibody titers for antenatal transfer to the infant, whereas RSV mAb blocks viral entry by targeting a specific antigenic site on the F protein.

All infants, both full-term and preterm, should be protected from RSV. The most important thing for LMICs is to prevent severe RSV LRTI in infants who are ≤6 months of age, and entering their first RSV season. Ideally, the protection should cover a typical 5-month RSV season.

As shown in Figure 2 , there are three main strategies being studied to protect infants during this vulnerable period. The priorities are developing maternal RSV vaccines and infant RSV mAbs to provide immediate protection to young infants, whereas active infant immunization is focused on protecting infants after 6 months of age as maternal or passive antibody titers wane [18] . Achieving protective efficacy via active immunization may prove difficult for infants less than 3 months of age.

immunization is focused on protecting infants after 6 months of age as maternal or passive antibody titers wane [18] . Achieving protective efficacy via active immunization may prove difficult for infants less than 3 months of age. There is a rapidly expanding landscape of RSV vaccine development. There are more than 20 RSV vaccines in clinical development, including live attenuated/chimeric, proteinbased, nucleic acid, and recombinant vectored vaccines [19] . Two RSV prefusion F protein subunit maternal vaccines are in phase 3 with results anticipated in 2023/2024, by Glax-oSmithKline [20] and Pfizer [21] .

Maternal immunization aims to boost the generation of high potency neutralizing antibodies that are transferred via the placenta to the fetus during the second or third trimester. This would protect infants during the first 3 to 6 months of life. The WHO Preferred Product Characteristics (PPC) for RSV vaccines include a one dose regimen using a well characterized platform with a favorable safety profile in pregnancy, and greater than 70% vaccine efficacy against confirmed severe RSV disease in the offspring from birth to age 4 months or more [22] . For maternal RSV vaccine development, the WHO has defined severe RSV LRTI as polymerase chain reaction (PCR)-confirmed RSV infection with all of the following: respiratory infection (cough or difficulty breathing), LRTI defined as fast breathing by WHO criteria or SpO2 < 95%, and ≥ one of the following features of severe disease: SpO2< 93% and/or lower chest wall in-drawing [23] .

The only completed phase 3 vaccine trial is the Novavax maternal RSV F nanoparticle vaccine trial [24] . This trial enrolled 4636 women in their third trimester of pregnancy. The primary endpoint, reduction in medically-attended RSV LRTI at 90 days, was not met based on the pre-specified success criterion, which had a lower bound of the 97.52% confidence interval (CI) of ≥30% (vaccine efficacy (VE) 39% (97.52% CI of −1 to 63.7)). However, the estimate of VE for reduction of LRTI with severe hypoxemia from RSV was higher, at 48.3% (95% CI of −8.2, 75.3%). Moreover, the vaccine did show benefits in reducing hospitalizations from RSV-associated LRTI (VE 44.4%, 95% CI, 19.6 to 61.5), and from all-cause LRTI (VE 27.8%, 95% CI 4.8 to 45.3).

Administration of a mAbs directly to the infant is a proven RSV preventive therapy [25] that not only bridges the gap before vaccines are available, but will also compliment There is a rapidly expanding landscape of RSV vaccine development. There are more than 20 RSV vaccines in clinical development, including live attenuated/chimeric, protein-based, nucleic acid, and recombinant vectored vaccines [19] . Two RSV prefusion F protein subunit maternal vaccines are in phase 3 with results anticipated in 2023/2024, by GlaxoSmithKline [20] and Pfizer [21] .

Maternal immunization aims to boost the generation of high potency neutralizing antibodies that are transferred via the placenta to the fetus during the second or third trimester. This would protect infants during the first 3 to 6 months of life. The WHO Preferred Product Characteristics (PPC) for RSV vaccines include a one dose regimen using a well characterized platform with a favorable safety profile in pregnancy, and greater than 70% vaccine efficacy against confirmed severe RSV disease in the offspring from birth to age 4 months or more [22] . For maternal RSV vaccine development, the WHO has defined severe RSV LRTI as polymerase chain reaction (PCR)-confirmed RSV infection with all of the following: respiratory infection (cough or difficulty breathing), LRTI defined as fast breathing by WHO criteria or SpO2 < 95%, and ≥ one of the following features of severe disease: SpO2< 93% and/or lower chest wall in-drawing [23] .

The only completed phase 3 vaccine trial is the Novavax maternal RSV F nanoparticle vaccine trial [24] . This trial enrolled 4636 women in their third trimester of pregnancy. The primary endpoint, reduction in medically-attended RSV LRTI at 90 days, was not met based on the pre-specified success criterion, which had a lower bound of the 97.52% confidence interval (CI) of ≥30% (vaccine efficacy (VE) 39% (97.52% CI of −1 to 63.7)). However, the estimate of VE for reduction of LRTI with severe hypoxemia from RSV was higher, at 48 Administration of a mAbs directly to the infant is a proven RSV preventive therapy [25] that not only bridges the gap before vaccines are available, but will also compliment vaccines after they become available for infants who require immediate protection. Refer to Table 1 for a list of completed and ongoing phase 2 and 3 trials of RSV mAb, and to Section 6 for details regarding the approved and candidate mAbs to date. The mAbs would only need to be used in infants 6 months of age and younger, or those at risk of LRTIs during the local RSV season, which would reduce the overall national program cost of RSV disease prevention. Palivizumab is currently the only licensed, short-acting mAb, and is approved for preterm infants, and infants with CLD and CHD. There are several half-life extended RSV mAbs in development, including at least four mAbs in early development and two in late-stage development [19] . Critical success factors intrinsic to a candidate mAb include high potency; a high barrier to mAb-resistant escape mutants; product safety, stability, and adequate pharmacokinetics; and adequate duration of protection. The WHO PPC for RSV mAbs include prevention of severe RSV disease in infants with a one-dose intramuscular or subcutaneous regimen that can be given as a birth dose or at any healthcare visit during the first 6 months of life. The mAb should have safety and reactogenicity profile comparable to other WHO recommended vaccines and have at least 70% efficacy against RSV-confirmed severe disease (due to both RSV A and B subtypes) for 5 months following administration. The mAb should be accessible and affordable to LMICs, and licensed by national regulatory authorities [22] .

The strategy of immunizing infants is more suitable for protecting infants >3 months old, and children. There is insufficient time to vaccinate to generate an effective and protective immune response in infants younger than 3 months with a developing immune system. It would likely require multiple vaccine doses and several months to generate protective immunity, which could be long-lasting. Moreover, studies with formalin-inactivated vaccines in the 1960s suggested an enhancement of RSV disease post-vaccination in the young infants who were RSV seronegative before vaccination [26] . This was likely due to aberrant responses with induction of delayed type cellular responses [27] , and non-neutralizing antibody responses leading to immune complex deposition and complement fixation in the small airways [28] . It should be noted that passively administered serum from formalininactivated RSV vaccinated rodents was not associated with enhanced pathology in the pups that received the sera and subsequently challenged with RSV [29] . Much has been learned since then, and current studies are focused on different types of vaccines that induce high titers of neutralizing antibodies, such as live attenuated, recombinant vectored, and nucleic acid vaccines, and they include seropositive infants and children [19] . 

There is one approved RSV mAb, palivizumab, a prophylactic against LRTI caused by RSV that has been used for the past two decades. Palivizumab is an RSV F-specific immunoglobulin G monoclonal antibody (Synagis ® , Swedish Orphan Biovitrum AB, Stockholm, Sweden) that has a half-life of around 20 days and requires monthly injections. This mAb, mainly used in high-income countries, is cost prohibitive for LMICs, and has limited approval for infants. It is approved by the Food and Drug Administration (FDA) for high-risk children, including (1) preterm infants born at ≤ 35 weeks gestational age and who are ≤ 6 months old at the beginning of RSV season; (2) children with bronchopulmonary dysplasia (BPD) that required medical treatment within the previous 6 months and who are ≤ 24 months old at the beginning of RSV season; and (3) children with hemodynamically significant CHD and who are ≤24 months old at the beginning of RSV season. Among preterm infants, the American Academy of Pediatrics (AAP) issued updated guidance in 2014 to limit its recommendation for palivizumab to preterm infants born before 29 weeks gestational age who are ≤12 months old, who would most likely benefit from this prophylaxis [42] .

After the 2014 AAP policy, the overall palivizumab use declined and RSV-associated hospitalization in the US increased in infants < 6 months old, who had a gestational age of 29 to 34 weeks [43] . Similar increases were also observed in the Province of Quebec, Canada when palivizumab was withdrawn for use in late preterm infants [44] . These data support the need for a RSV immunoprophylaxis strategy for all young infants. Given the altered RSV epidemiology during COVID-19 pandemic-delayed seasonal onset and increases in inter-seasonal RSV activity-the AAP has issued a strong recommendation for palivizumab to be used in eligible patients living in regions that are experiencing high rates of RSV circulation [45] .

Motavizumab, a derivative of palivizumab with higher affinity for RSV, was not pursued by MedImmune for licensure after the phase 3 trials in high-risk children failed to show clear superiority to palivizumab, and noted a trend for a higher rate of skin rashes [30, 46] . Suptavumab (developed by Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA), given as a 2-dose regimen, 8 weeks apart, did not meet trial efficacy endpoints in phase 3 due to its lack of efficacy against the predominantly circulating RSV B strains, and development was discontinued [32] .

Two RSV mAbs are in late-stage clinical development, MEDI8897 (nirsevimab, Astra Zeneca, Gaithersburg, MD, USA) and MK-1654 (Merck, Kenilworth, NJ, USA). Nirsevimab binds to the antigenic site Ø of RSV prefusion F, which is highly sensitive to neutralization [47] . MK-1654 binds to antigenic site IV of RSV pre-and post-fusion F protein, which is considered highly conserved [48] . These mAbs have broad neutralization activity against laboratory-and clinical-circulating strains of RSV A and B. Both have an engineered Fc domain with a half-life extension crystallizable fragment domain M252Y/S254T/T256E (YTE) mutation (European Union numbering) that prolongs the half-life by 3-fold compared to palivizumab, to about 70 days, due to enhanced binding to FcRn that impedes antibody clearance [49] .

Nirsevimab received FDA breakthrough status and the European Medicines Agency (EMA) PRIME (priority medicines) status for its phase 2b trial, which enrolled premature infants 29 to 34 weeks in gestational age who were ≤1 year old. After a single dose of nirsevimab 50 mg via intramuscular (IM) injection, the incidence of RSV-associated medically-attended LRTI (MALRTI) was reduced by 70%, and that of hospitalizations by 78%, compared to placebo [34] .

The ongoing phase 3 study in term and late preterm infants ≥35 weeks gestational age [37] has met its primary endpoint of reducing RSV LRTIs [38] . There is also an ongoing phase 2b/3 in preterm infants ≤ 35 weeks gestational age with either CLD or CHD or BPD [36] . These late-stage studies employ weight-based dosing (50 mg IM for infants weighing < 5 kg (kilogram) and 100 mg IM for those weighing ≥ 5 kg [50] .

The MK-1654 program has begun recruitment into their phase 2b/3 trail in healthy preterm and full-term infants, ≤1 year of age, to evaluate a single IM administration of MK-1654 for preventing RSV-associated MALRTI [41] . The phase 2a study of safety and PK has completed recruitment, and monitoring is ongoing [39] . A phase 2a, controlled human challenge model of MK-1654 in healthy participants was completed, and results as of May 2021 show antiviral activity against RSV [40] . The safety data, to date, from nirsevimab and MK-1654 studies in adults and infants, have been favorable. The overall safety profile in phase 1 studies in adults, with dosing 5 to 10 times the target infant doses, is similar to that of placebo [51, 52] . In the phase 2b study, in which approximately 900 infants received nirsevimab, no anaphylaxis or other notable hypersensitivity reactions were observed. There were no serious adverse events related to the mAb [34] . For both mAbs, anti-drug antibodies (ADA) post-mAb administration were infrequent and were not associated with adverse events. In the phase 1b/2a nirsevimab study, ADA was associated with lower drug exposure, but only between days 150 to 360 in some infants [6] .

The current candidate mAbs in development are targeted primarily for high-income countries, with costs likely to be too high to allow affordable global access to the product, unless successfully addressed by other mechanisms, such as tiered pricing. The Bill and Melinda Gates Foundation (BMGF) has supported the preclinical development of a candidate mAb, RSM01, which is being advanced to clinical development by the Bill and Melinda Gates Medical Research Institute (Gates MRI), a non-profit biotechnology institution. RSM01 is a fully human IgG1 mAb that targets site Ø of the pre-F of RSV and has YTE half-life extended mutations. The BMGF has the primary aim of developing this product for LMICs.

A successful and cost effective implementation will rely on the ability to administer the mAbs at the beginning of the infant's first RSV season. This assumes that a half-life extended mAb could protect infants against severe RSV disease through a typical 5-month RSV season, and that in the LMIC setting, only one dose per infant will be given during the first 6 months of life. In countries with clear RSV seasonality, the mAb could be given at birth or during a scheduled immunization visit, whichever is closest to the beginning of RSV season. A birth dose is ideal as it negates missed opportunities, particularly in areas with poor return rates for immunization visits. However, many LMICs have tropical climates where RSV seasonality may be less pronounced compared to temperate climate countries. A year-round RSV pattern, predominantly seen in countries near the equator, poses a challenge to implementing mAbs.

A recent mathematical modeling study to evaluate seasonality versus a year-round approach for mAb implementation in infants ≤ 4 months of age utilized surveillance data from 52 LMICs across Asia, Africa, Eastern Europe, South America, and the Middle East. The majority of these LMICs (75%) had clear RSV seasonality: more than 75% of annual RSV cases occurred in ≤5 months. In the countries with clear RSV seasonality, a seasonal approach that gives mAbs to eligible infants 1 to 3 months before onset of the RSV season achieved high efficacy without substantially compromising effectiveness compared to the year-round approach, while only utilizing about half of the mAbs (i.e., infants born outside RSV season would not require mAbs) [53] . In countries without clear RSV seasonality, or those without any RSV seasonality data, the mAbs could be given at birth, year-round. This approach could be simpler to implement and may also be considered for countries with RSV seasonality. A birth dose would reduce missed opportunities. However, this approach is likely less cost-efficient if infants are dosed outside the RSV season and the mAb duration of protection is short.

RSV, like other RNA viruses, possesses an error-prone RNA polymerase. Although the F protein, which is the target for most RSV mAbs in development, exhibits relative genetic and antigenic stability, there are potential concerns about the emergence of antibody resistant escape mutants. Resistance to RSV mAb could be due to the pre-existing resistant mutations in circulating RSV strains, as observed in the phase 3 suptavumab trial, or from selective pressure on the virus following mAb administration. Amino acid substitutions Vaccines 2021, 9, 961 9 of 13 in the nirsevimab binding site have been observed in in-vitro experiments, and most did not impact viral replication [54] . However, nirsevimab-resistant mutants were observed in 2 of 25 breakthrough infections in the phase 2b study [34] . Molecular surveillance of the 2017-2018 F sequences from eight countries showed high-frequency polymorphisms at antigenic sites Ø and V of RSV B that included 100% detection of the nonconservative polymorphisms in suptavumab target site V (L172Q/S173L). Conservative polymorphisms in nirsevimab target site Ø (I206M/Q209R) [54] were detected in 77% of RSV B strains, but they retained susceptibility to neutralization by nirsevimab [55] .

It is important for drug developers to conduct database analysis to determine if any new circulating strains exhibit potential for being resistant to their products. There is a risk that mAbs could drive resistant RSV strains (i.e., escape variants) by single point mutations, resulting in loss of binding and protection. However, after two decades of use, no known palivizumab target site II polymorphisms have been observed among 2017-2018 RSV strains. This is encouraging, albeit the limited use of palivizumab may not have put enough pressure on the virus to select for resistant strains.

There is realistic potential for an RSV mAb to be scalable in LMICs. The current drug substance manufacturing processes for mAbs could reasonably yield COGs of under $100 per gram [56] . Assuming that a 50 mg dose would be sufficient to protect most infants <6 months of age, COGs could be less than $5 per dose. Multi-dose vial presentations will also reduce the relative costs of such drug products. With substantial investments toward improving manufacturing process and product presentation, cost, storage and distribution (including last-mile stability at ambient temperature) on par with some vaccines could be achieved.

In order for countries to implement RSV mAbs as a preventive measure for infants, national level data of RSV incidence and the burden on healthcare utilization will be required. However, LMICs often lack such data due to limited infrastructure for conducting surveillance. A recent study showed that RSV burden data in children under 5 years old were only available from 8% of the population in low-income countries, compared to 63% in lower-middle-income countries, 80% in upper-middle-income countries, and 71% in highincome countries [57] . The WHO has built upon the influenza surveillance system to initiate global RSV surveillance in 25 countries to support the introduction of RSV immunization, should it become available. For countries with clear RSV seasonality, a few years of surveillance should be sufficient to inform a country's seasonal RSV mAb administration strategy [53] . Underrepresented estimates of RSV-associated LRTI, hospitalization, and deaths will hinder the adoption of nationwide RSV preventive measures that could save millions of lives.

To facilitate delivery of an effective RSV mAb to LMICs, it would be important for RSV mAb to be on the WHO Pre-Qualification (PQ) list and the Essential Medication List (EML). Cancer therapeutic mAbs have been added to the EML in 2019, so there is precedent for this type of modality to be prequalified. The drug developers' early engagement with different WHO committees (PDVAC, Technical Advisory Group (TAG) and Strategic Advisory Group of Experts (SAGE)) and Gavi, the Vaccine Alliance, will be necessary to obtain guidance on a clinical development plan and PQ process. It will be critical to seek guidance from WHO and other key stakeholders on the feasibility of conducting placebo-controlled studies in LMICs after nirsevimab or other RSV mAbs are approved, but are inaccessible and not yet standard of care [58] .

A non-inferiority trial of a new RSV mAb against nirsevimab would require a very large sample size that may not be feasible. For example, assuming a 1% severe RSV disease rate in the nirsevimab group, a sample size of 140,101 infants/group (80% power) or 187,654 infants/group (90% power) would be needed to show a lower bound on the relative risk >0.9 (i.e., control incidence is lower than RSM01 by at most 10% with 1-sided 97.5% CI). As there are more available data from RSV mAb or vaccine trials, a neutralizing antibody titer may be established as a correlate of protection against RSV, which could allow for a smaller phase 3 to be conducted using biomarker endpoints.

Maternal RSV vaccines require administration during a specific gestational window of 24 to 36 weeks in women who seek antenatal care. Premature birth and late vaccination can result in lower antibody titers and shorter durations of protection in infants. Moreover, infants who have additional risk factors for severe LRTI (e.g., preterm, CLD, or CHD) may require protection beyond the first 3 to 6 months of life, when placentally transferred Ab has waned. In these instances, RSV mAbs could be administered during a wider window to provide immediate protection for infants. A modeling study projected both maternal RSV vaccine and mAb to be independently impactful and cost-effective in LMICs when administered to infants < 6 months old. Compared to no intervention, a maternal vaccine or mAbs (birth dose) are projected to avert 25% or 55% of RSV-related deaths, respectively, based on similar assumptions for efficacy (minimum 30% for 4 months and maximum 90% for 6 months) [59] .

The COVID-19 pandemic has propelled innovations in clinical trials that could be leveraged for RSV mAb studies. In our own experience conducting a COVID-19 treatment trial [60] , an accelerated timeline was achieved for all steps, from study concept to regulatory review, and study start. We demonstrated successful clinical operation using a 100% remote trial model that recruited participants from across the US via a meta-site. This type of process and other innovations (e.g., wearables and a self-collecting blood sample device) could facilitate collection of data and inclusion of participants regardless of where they live, thereby alleviating the travel burden on families and children in RSV mAb trials for post-mAb administration follow-up visits.

RSV is the most common infectious cause of acute LRTI in young children. Death rates are higher in infants < 3 months old and those living in LMICs. An efficacious RSV immunization product provided to all infants in the first 6 months of life as they enter their first RSV season could have significant public health impact by preventing LRTIassociated hospitalizations and deaths. It might also reduce all-cause LRTIs, as shown in the Novavax maternal RSV vaccine trial. There are dozens of maternal and infant RSV vaccines being studied, but none have reached approval. Administering mAbs directly to the infant is the only proven RSV preventive therapy to date. Several next-generation, half-life extended mAbs in development have shown promise as single injections to protect infants from RSV-associated LRTIs for the entire 5-month RSV season. Such RSV mAbs could be scalable in LMICs because of their low dose requirements, and potential for multi-dose vial presentation and further improvements in manufacturing processes. 

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: A systematic review and modelling study

The natural history of respiratory syncytial virus in a birth cohort: The influence of age and previous infection on reinfection and disease

Population-based serology reveals risk factors for RSV infection in children younger than 5 years

Respiratory Syncytial Virus (RSV) Neutralizing Antibodies at Birth Predict Protection from RSV Illness in Infants in the First 3 Months of Life

The influence of birth weight amongst 33-35 weeks gestational age (wGA) infants on the risk of respiratory syncytial virus (RSV) hospitalization: A pooled analysis

tolerability and pharmacokinetics of MEDI8897, an extended half-life single dose respiratory syncytial virus prefusion F-targeting monoclonal antibody administered as a single dose to healthy preterm infants

Respiratory syncytial virus seasonality: A global overview

Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): A retrospective case series

Preferred Product Characteristics of Monoclonal Antibodies for Passive Immunization Against Respiratory Syncytial Virus (RSV). WHO/Draft-V0.1/Mar2020

Senior Program Officer, Global Health (Bill & Melinda Gates Foundation

Human respiratory syncytial virus: Pathogenesis, immune responses, and current vaccine approaches

Immunological lessons from respiratory syncytial virus vaccine development

Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody

Seasonal variation of maternally derived respiratory syncytial virus antibodies and association with infant hospitalizations for respiratory syncytial virus

Breast milk prefusion F immunoglobulin G as a correlate of protection against respiratory syncytial virus acute respiratory illness

The CD8 T cell response to respiratory virus infections

Protective and harmful immunity to RSV infection

Advances in RSV vaccine research and development-A global agenda

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Multi-Country Study to Demonstrate Efficacy of a Single Dose of Unadjuvanted RSV Maternal Vaccine, Administered IM To Pregnant Women 18 to 49 Years of Age, for Prevention of RSV-Associated Lrtis in Their Infants up to 6 Months of Age

A Phase 3, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of a Respiratory Syncytial Virus (Rsv) Prefusion F Subunit Vaccine in Infants Born to Women Vaccinated During Pregnancy

WHO Preferred Product Characteristics for Respiratory Syncytial Virus (RSV) Vaccines. Geneva: WHO, 2021. License: CC BY-NC-SA 3.0 IGO

Vaccine Consultation Expert Group. WHO consultation on respiratory syncytial virus vaccine development report from a World Health Organization meeting held on 23-24

Respiratory syncytial virus vaccination during pregnancy and effects in infants

The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants

Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine

Cell-mediated immunity to respiratory syncytial virus induced by inactivated vaccine or by infection

Involvement of antibody, complement and cellular immunity in the pathogenesis of enhanced respiratory syncytial virus disease

Preclinical assessment of safety of maternal vaccination against respiratory syncytial virus (RSV) in cotton rats

A randomized controlled trial of motavizumab versus palivizumab for the prophylaxis of serious respiratory syncytial virus disease in children with hemodynamically significant congenital heart disease

Respiratory syncytial virus (RSV) Prevention study group. Efficacy of motavizumab for the prevention of respiratory syncytial virus disease in healthy Native American infants: A phase 3 randomized double-blind placebo-controlled trial

Suptavumab for the prevention of medically-attended respiratory syncytial virus infection in preterm infants

Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of a Human Monoclonal Antibody, Suptavumab (REGN2222), for the Prevention of Medically Attended RSV Infection in Preterm Infants

Single-dose nirsevimab for prevention of RSV in preterm infants

Phase 2b Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of MEDI8897, a Monoclonal Antibody with an Extended Half-Life Against Respiratory Syncytial Virus

Phase 2/3 Randomized, Double-Blind, Palivizumab-Controlled Study to Evaluate the Safety of MEDI8897, a Monoclonal Antibody with an Extended Half-Life Against Respiratory Syncytial Virus, in High-Risk Children (MEDLEY)

Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of MEDI8897, A Monoclonal Antibody with an Extended Half-Life Against Respiratory Syncytial Virus, in Healthy Late Preterm and Term Infants (MELODY)

First Potential Passive Immunization to Show Protection Against RSV in the General Infant Population

A Double-Blind, Randomized, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MK-1654 in Preterm and Tull-term Infants

Phase 2a Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of MK-1654 in Healthy Participants Inoculated with Experimental Respiratory Syncytial Virus

Phase 2b/3 Double-Blind, Randomized, Placebo-Controlled Study to Evaluate The Efficacy and Safety of MK-1654 in Healthy Pre-Term And Full-Term Infants

Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection

Update on respiratory syncytial virus hospitalizations among U.S. preterm and term infants before and after the

Impact of the withdrawal of palivizumab immunoprophylaxis on the incidence of respiratory syncytial virus (RSV) hospitalizations among infants born at 33 to 35 weeks' gestational age in the province of Quebec, Canada: The RSV-Quebec study

Interim Guidance for Use of Palivizumab Prophylaxis to Prevent Hospitalization From Severe Respiratory Syncytial Virus Infection During the Current Atypical Interseasonal RSV Spread. American Academy of Pediatrics

Motavizumab Study Group. Motavizumab for prophylaxis of respiratory syncytial virus in high-risk children: A noninferiority trial

A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants

A potent broadly neutralizing human RSV antibody targets conserved site IV of the fusion glycoprotein

An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence

Population pharmacokinetics and exposure-response analysis of Nirsevimab in healthy preterm infants

Safety, tolerability, and pharmacokinetics of MEDI8897, the respiratory syncytial virus prefusion F-targeting monoclonal antibody with an extended half-life, in healthy adults

A phase 1 randomized, double-blind, placebo-controlled trial to assess the safety, tolerability, and pharmacokinetics of a respiratory syncytial virus neutralizing monoclonal antibody MK-1654 in healthy adults

Respiratory syncytial virus seasonality and prevention strategy planning for passive immunization of infants in low-income and middle-income countries: A modelling study

Prevalence and Significance of Substitutions in the Fusion Protein of Respiratory Syncytial Virus Resulting in Neutralization Escape from Antibody MEDI8897

Global molecular epidemiology of respiratory syncytial virus from the 2017−2018 INFORM-RSV Study

Integrated continuous bioprocessing: Economic, operational, and environmental feasibility for clinical and commercial antibody manufacture

National burden estimates of hospitalisations for acute lower respiratory infections due to respiratory syncytial virus in young children in 2019 among 58 countries: A modelling study

Placebo use in vaccine trials: Recommendations of a WHO expert panel

Impact and cost-effectiveness of potential interventions against infant respiratory syncytial virus (RSV) in 131 low-income and middle-income countries using a static cohort model

Controlled, Phase 2b Study to Evaluate Safety and Efficacy of Rivaroxaban (Xarelto ® ) for High Risk People with Mild COVID-19

We thank Debbie Daehnick (DT Medical Writing Corp) for her assistance in preparing this manuscript.

The authors declare no conflict of interest.