5.1 RSV vaccines (1).pdf

5.1 RSV vaccines Content 1. RSV virus, infection and burden of disease 2. Overview of RSV vaccine development 3. RSV vaccines (in phase 3 and/or authorized) 1. RSV virus, infection and burden of disease Respiratory Syncytial Virus (RSV) RSV is an enveloped, negative-sense RNA virus1 Initial...

5.1 RSV vaccines Content 1. RSV virus, infection and burden of disease 2. Overview of RSV vaccine development 3. RSV vaccines (in phase 3 and/or authorized) 1. RSV virus, infection and burden of disease Respiratory Syncytial Virus (RSV) RSV is an enveloped, negative-sense RNA virus1 Initial stages of infection are facilitated by two surface glycoproteins2 Single-strand RNA virus in the Pneumoviridae family1 F: surface fusion protein • Essential for viral entry2,3 • Mediates fusion between the viral envelope and airway epithelial cells4 • Highly conserved between RSV-A and RSV-B6 Protein F also mediates fusion of infected cells with other cells, forming large multinucleated cells called syncytia4 G: attachment glycoprotein • Heavily glycosylated2 • Targets ciliated cells of the airways2 • Variable between RSV-A and RSV-B6 There are two antigenic subgroups of RSV: 1. Rima B et al. J Gen Virol 2017;98:2912–2913; 2. McLellan JS et al. Curr Top Microbiol Immunol 2013;372:83–104; 3. Graham BS et al. Curr Opin Immunol 2015;35:30–38; 4. Tian J et al. J Gen Virol Syncytium A B Variations in protein G account for much of the antigenic differences between these subgroups2,3,5 2013;94:1691–1700; 5. Battles MB, McLellan JS. Nat Rev Microbiol 2019;17:233–245; 6. Mejias A et al. Ann Allergy Asthma Immunol 2020;125:363–346 RSV is a highly contagious seasonal virus that co-circulates with other respiratory viruses Seasonality Transmission • RSV is transmitted by inhalation of or contact with infected people’s respiratory secretions1 Seasonal RSV epidemics lasting up to 5 months occur concurrently with epidemic seasons of other respiratory viruses6,7 Northern Hemisphere6 Temperate zone Tropical zone RSV can spread within households2 0,3 Frequency Frequency 0,3 0,2 0,1 0 Infected person Infected people are typically contagious for 3−8 days,1 although older adults may shed virus for longer periods of time5 *Meaning that, in a fully susceptible population, on average each infected person infects three other people. COVID-19, coronavirus disease 2019 For references, please see notes page Jan Mar May Jul Observations Sep Nov Jan Mar May Jul Peak month Curve fitting The graphs are reproduced from Bloom-Feshbach K et al. 20136 where they were published, free of copyright, under Creative Commons CCO public domain dedication R0 ~ 3 R0 estimate = 2.82 (at peak timing)4 R0 estimate = 3.02 (on last week)4 Nov Peak month Mean basic reproduction number (R0)*,3 0,1 0 Sep RSV spreads easily 0,2 • • Normal RSV seasonality was disrupted by COVID-19 mitigation measures, increasing the possibility of out-of-season outbreaks post-pandemic8–11 During the 2022–23 season, a rise in viral respiratory diseases was observed due to increased circulation of RSV and influenza early in the season, co-circulating with other respiratory viruses e.g. SARS-CoV-2.12,13 5 RSV is a disease of all ages Burden of RSV Natural immunity is short-lived, and RSV causes repeated infections throughout life, not only in childhood Virtually all children will have been infected with RSV by age 2 years1 Immune response after natural infection is incomplete and is short-lived2,3 RSV reinfections occur throughout life3 Older adults are at high risk of severe RSV infection. Those with certain comorbidities are at even greater risk4,5 1. Centers for Disease Control and Prevention (CDC), 2022. Respiratory syncytial virus infection (RSV): symptoms and care. http://www.cdc.gov/rsv/about/symptoms.html (accessed June 2023); 2. Openshaw PJM et al. Annu Rev Immunol 2017;35:501–532; 3. Walsh E et al. Clin Chest Med 2017;38(1):29–36; 4. Branche AR et al. Clin Infect Dis 2022;74(6):1004–1011; 5. Centers for Disease Control and Prevention (CDC), 2022. RSV in older adults and adults with chronic medical conditions. https://www.cdc.gov/rsv/high-risk/older-adults.html (accessed June 2023) 6 RSV burden of disease in children younger than 5 years Globally (2019 estimates): For children (0-60 months) • 33 million RSV-associated acute lower respiratory tract infection (LRTI) episodes (Uncertainty range (UR): 25,4-44,6 million) • 3,6 million RSV-associated acute LRTI hospital admissions (UR: 2,69-4,6 million) • 26 300 RSV-associated acute LRTI in-hospital deaths (UR: 15 100 – 9 100) • 101 400 RSV-attributable overall deaths (UR: 84 500-125 200) For infants (0-6 months) • 6,6 million RSV-associated acute LRTI episodes (UR: 4,6-9,7 million) • 1,4 million RSV-associated acute LRTI hospital admissions (UR: 1,0-2,0 million) • 13 300 RSV-associated acute LRTI in-hospital deaths (UR: 6800-28 100) • 45 700 RSV-attributable overall deaths (UR: 38 400-55 900) Li et al. Lancet 2022; 399: 2047-64 RSV burden of disease in children younger than 5 years - 2% of deaths in children aged 0-60 months (UR: 1,6-2,4%) and 3,6% of deaths in children aged 28 days to 6 months (UR: 3,0-4,4%) were attributable to RSV - More than 95% of RSV-associated acute LRTI episodes and more than 97% of RSV-attributable deaths across all age bands were in low- and middle income countries (LMIC) Li et al. Lancet 2022; 399: 2047-64 https://www.youtube.com/watch?v=6pX5kvZGrYo November 2019; https://www.youtube.com/watch?v=6pX5kvZGrYo Clinical burden of RSV in older adults in Europe Incidence 1.62% (95% CI: 0.84, 3.08) or >3 million cases of RSV-ARI*1 Hospitalization 0.15% (95% CI: 0.09, 0.22) In-hospital case fatality rate 7.13% (95% CI: 5.40, 9.36) or ~274,000 hospitalizations*1 or ~20,000 deaths* An unknown number of people die outside of hospital1 RSV is currently not covered by the European community network for surveillance of communicable diseases2 The ECDC currently collects data on RSV and has launched an integrated surveillance strategy for respiratory diseases in the EU/EEA countries3 *Calculated using the European population aged ≥60 years old in 20191 ARI, acute respiratory infection; EEA, European Economic Area; ECDC, European Centre for Disease Prevention and Control; EU, European Union 1. Savic M et al. Influenza Other Respir Viruses 2023;17(1):e13031; 2. ECDC, 2015. Workshop on burden of RSV disease in Europe November 23–24. https://www.ecdc.europa.eu/sites/portal/files/media/en/press/events/Documents/Meeting%20report%20ECDC%20RSV%20surv%20and%20burden%20of%20disease%20workshop%2023-24%20Nov.pdf (accessed June 2023); 3. ECDC, 2022. Communicable disease threats report, week 46, November 13–19. https://www.ecdc.europa.eu/en/publications-data/communicable-disease-threats-report-13-19-november-2022-week-46 (accessed June 2023) 9 RSV pathogenesis in the human respiratory tract Carvajal et al. Frontiers Immunol 2019; https://www.frontiersin.org/articles/10.3389/fimmu.2019.02152/full Severe RSV disease and risk factors in young children • Complications of RSV infection: – Pneumonia – Hospitalization – Death • Risk factors: – History of prematurity, young age below 6 months at the beginning of RSV season – Underlying disease, e.g. immunodeficiency, bronchopulmonary dysplasia (BPD), congenital heart disease (CHD) – Low socioeconomic status and parental education, crowded living conditions, young siblings, maternal smoking and indoor smoke pollution, malnutrition/small for gestational age, family history of atopy or asthma, low cord serum RSV antibody titers, and living at altitude. Signs and symptoms of RSV infection in adults RSV infection is typically mild, but may lead to serious complications and poor outcomes Typically, RSV infection in healthy adults results in mild, cold-like symptoms1,2 However, RSV can lead to serious conditions1,3: Lower respiratory tract infection (eg, pneumonia) Hospitalization Exacerbation of certain comorbidities Death Symptoms can be similar to those of other respiratory pathogens2,3 Cardiovascular complications 1. Centers for Disease Control and Prevention (CDC), 2023. RSV in older adults and adults with chronic medical conditions. https://www.cdc.gov/rsv/high-risk/older-adults.html (accessed June 2023); 2. Nam HH and Ison MG. BMJ 2019;366:l5021; 3. Branche AR, Falsey AR. Drugs Aging 2015;32:261–269 12 Risk factors for severe RSV-associated disease in adults Risk of severe RSV-associated disease increases with age and certain comorbidities Older age1,2 Comorbidities1,3,4 Weak immune status1 Especially for those aged ≥60 years Adults at increased risk include those with certain comorbidities Adults with weakened immune systems are also at increased risk of severe RSV disease (eg, asthma, COPD, CHF, CAD, diabetes, CKD) CAD, coronary artery disease; CHF: congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease 1. Centers for Disease Control and Prevention (CDC), 2022. RSV in older adults and adults with chronic medical conditions. https://www.cdc.gov/rsv/high-risk/older-adults.html (accessed June 2023); 2. Belongia EA et al. Open Forum Infect Dis 2018;27;5:ofy316; 3. Branche AR et al. Clin Infect Dis 2022;74:1004–1011; 4. Wyffels V et al. Adv Ther 2020;37(3):1203–1217 13 Older age and susceptibility to RSV infection Older adults are particularly susceptible to severe RSV-associated disease due to age-related decline in immunity, aging of the lung, and high rates of comorbidities Age-related decline in immunity • Negative changes in the quality and quantity of immune cells, particularly T-cells1,2 Inflammaging • Chronic, low-grade inflammation, contributing to dysfunction and imbalance in immune responses1-3 Age-related changes in lung tissue • Physiological changes reduce pulmonary function affecting4: • Health surveys conducted in the US found5: • Epithelial barrier integrity • >30% of adults 45–64 years had ≥2 chronic condition • Mucociliary clearance • Tissue elasticity T-cells play a critical role in viral clearance and controlling RSV disease progression1 Thought to contribute to older adults developing more severe forms of respiratory diseases1–3 Aging and comorbidities May enhance susceptibility to severe respiratory infections4 • >60% of adults ≥65 years had ≥2 chronic conditions Certain comorbidities increase the risk of severe RSV-associated disease6,7 1. Stephens LM and Varga SM. Vaccines (Basel) 2021;9(6):624; 2. Watson A and Wilkinson TMA. Ther Adv Respir Dis 2021;15:1753466621995050; 3. Torrelles JB et al. Front Aging 2022;3:818700; 4. Cho SJ et al. Annu Rev Physiol 2020;82:433–459; 5. Boersma P et al. Prev Chronic Dis 2020;17:E106; 6. CDC, 2022. Older adults are at high risk for severe RSV https://www.cdc.gov/rsv/factsheet-older-adults.pdf (accessed June 2023); 7. Branche AR et al. Clin Infect Dis 2022;74(6):1004–1011 14 Respiratory viral infections are a major factor in the worsening of COPD and asthma COPD Asthma Longer hospitalization1–3 Accelerated lung function decline1,3 Greater hypoxemia2,3 Greater airway inflammation3–5 Hospital admissions6 11.6 ± 0.6 days for infective* exacerbations vs 8.8 ± 0.8, P<0.02 for non-infective exacerbations3 Greater decreases in FEV1 (0.25 ± 0.03 L vs 0.12 ± 0.04 L, P<0.05) in infective* vs noninfective exacerbations3 A trend for a greater decrease in PaO2 (15.3 ± 1.35 vs. 11.92 ± 1.86 mm Hg, P=0.078) in infective* vs non-infective exacerbations3 Higher airway eosinophils and serum IL-6 levels in virusassociated exacerbations than nonviral exacerbations, P=0.0643,4 RSV infection accounted for 7.2% of asthma hospitalizations in adults ≥65 years of age6 Enhanced responsiveness to allergens7,8 8/10 vs 1/10 patients had FEV1 decline after exposure to a combination of allergen and rhinovirus vs allergen alone7 Altered antiviral immune response in asthmatics is associated with asthma worsening6,7,9,10 Positive association between rhinovirus load and CD45+,CD68+, CD20+, neutrophils and eosinophils at 4 days post-infection10 *Viral and/or bacterial infection CD, cluster of differentiation; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; IL, interleukin; PaO2, partial pressure of oxygen in arterial blood 1. Linden D et al. Eur Respir Rev 2019;28:180063; 2. Mohan A et al. Respirology 2010;15(3):536–426; 3. Papi A et al. Am J Respir Crit Care Med 2006;173(10):1114–1121; 4. Seemungal T et al. Am J Respir Crit Care Med 2001;164(9):1618–1623; 5. Aghapour M et al. Am J Respir Cell Mol Biol 2018;58:157–169; 6. Westerly BD, Peebles RS. Immunol Allergy Clin North Am 2010;30:523–539; 7. Adeli M et al. J Family Med Prim Care 2019;8(9):2753–2759; 8. Ojanguren I et al. Arch Bronconeumol. 2022;58(9):632–634; 9. Hewitt R et al. Ther Adv Respir Dis 2016;10:158–174; 10. Zhu J et al. Chest. 2014;145(6):1219–1229 15 Interplay between respiratory infections and cardiovascular disease Viral respiratory infections may exacerbate existing cardiovascular disease and trigger new cardiovascular events1 People with chronic CV diseases are at increased risk of severe outcomes from respiratory tract infections2,3 ARIs are associated with CV complications, such as CHF, myocardial ischemia and infarction, and atrial fibrillation1,4 • Heart failure, myocardial infarction and atrial fibrillation cause significant, long-term, morbidity and mortality1,5–7 ARI, acute respiratory infection; CHF, congestive heart failure; CV, cardiovascular. 1. Franczuk P et al. Biomedicines 2023;11(1):71; 2. Centers for Disease Control and Prevention (CDC), 2023. RSV in Older Adults and Adults with Chronic Medical Conditions. https://www.cdc.gov/rsv/high-risk/older-adults.html; 3. Rosenthal N et al. JAMA Netw Open 2020;3(12):e2029058; 4. Ivey KS et al. J Am Coll Cardiol 2018;71(14):1574–1583; 5. Centers for Disease Control and Prevention(CDC), 2023. Heart Failure. https://www.cdc.gov/heartdisease/heart_failure.htm; 6. Centers for Disease Control and Prevention (CDC), 2022. Heart Attack Symptoms, Risk, and Recovery. https://www.cdc.gov/heartdisease/heart_attack.htm; 7. Centers for Disease Control and Prevention (CDC), 2022. Atrial Fibrillation. https://www.cdc.gov/heartdisease/atrial_fibrillation.htm. All URLs accessed September 2023. 16 Systemic inflammation due to respiratory viral infections such as RSV can trigger the release of pro-inflammatory cytokines1–3 The inflammatory response may lead to disruption and rupture of arterial plaques and increased risk of acute coronary syndrome such as myocardial infarction1 Acute infection Coronary arteries become inflamed and restricted Arterial linings are damaged Clotting begins to occur Oxygen levels and blood pressure decrease Pro-inflammatory cytokines such as IL-6, IL-1β and TNF-α Pre-existing vulnerable plaque (fatty deposit) Plaque rupture Thrombosis Increased risk of CV event There is evidence that RSV may share some of the mechanisms by which other viral infections contribute to cardiovascular injury2 The figure is for illustrative purposes only CV, cardiovascular; IL, interleukin; TNF, tumor necrosis factor 1. Corrales-Medina VF et al. Lancet Infect Dis 2010;10:83–92; 2. Ivey KS et al. J Am Coll Cardiol 2018;71:1574–1583; 3. Franczuk P et al. Biomedicines 2023;11(1):71 17 2. RSV vaccine development RSV vaccine development • Search for a safe and effective RSV vaccine is ongoing since > 60 years • RSV is identified in 1956 • 1960’s: formalin-inactivated RSV vaccine for young infants withdrawn because of safety issues • Enhanced RSV disease (ERD) • Th2, non neutralising antibodies • Other vaccine candidates unsuccesfull as well • What are the immune correlates of protection? o High concentrations of neutralising antibodies o Cellular immunity (Th1, CD4, CD8 T cells) o Mucosal IgA • Main target antigen = Fusion proteine o Major breakthrough in 2013: structure-based vaccine design RSV vaccine development: importance of the right conformation of the fusion proteine Only prefusion F RSV can bind to host cells to infect them. Antibodies directed against prefusion F are most effective to prevent infection. Barney S. Graham. N Engl J Med 2023; 388:579-581 Overview of RSV vaccines by approach and target population Mazur et al. Lancet Infect Dis 2023; 23: e2-21 Overview of RSV vaccines (and mAbs) by approach and target population Mazur et al. Lancet Infect Dis 2023; 23: e2-21 3. RSV vaccines (in phase 3 and/or licensed) Comparison of RSV vaccines in late stage development Vaccine RSVPreF3 OA RSVPreF mRNA-1345 Company GSK Pfizer Moderna Antigen + dose RSV prefusion protein 120 µg RSV-A RSV prefusion protein 120 mg (2 x 60 µg) Bivalent RSV-A, RSV-B RSV prefusion mRNA 120 µg Nr doses + administration route 1 IM injection 1 IM injection 1 IM injection Other components Adjuvant AS01E (liposomes + MPL + QS21) No adjuvant Lipid nanoparticles (LNP) Phase 3 RCT (ongoing) 1:1 (vaccine vs placebo) Phase 3 RCT (ongoing) 1:1 (vaccine vs placebo) Phase 3 RCT (ongoing) 1:1 (vaccine vs placebo) Number and age of participants ~25.000 ≥ 60 years ~34.000 ≥ 60 years ~37.000 ≥ 60 years Brand name and EMA approval date Arexvy 07/06/2023 Abrysvo 23/08/2023 Not licensed yet Study name and design (pivotal efficacy trial) RSVPreF3: phase I/II dose finding study After dose 1 in older adults (60–80 years), humoral and cellular immune responses were evident 10 T-cell response Fold-increase in RSV-A nAb titres at 30 days post-vaccination vs pre-vaccination Increase in frequency of RSVPreF3-specific, CD4+ T cells* at 30 days post-vaccination vs pre-vaccination RSVPreF3 plain AS01E 3000 AS01B Frequency (Q1–median–Q3)* Geometric mean of fold increase 12 Antibody response Nearly 10-fold increase in antibodies with highest dose of RSVPreF3 8 6 4 2 P<0.0001 P<0.0001 2500 Increased T-cell responses with both adjuvanted formulations vs non-adjuvanted RSVPreF3 2000 1500 1000 500 Baseline values 0 0 30 µg 60 µg 120 µg Pre-specified success criteria: antibody response: ≥6-fold increase in RSV-A nAbs; T-cell response: statistically demonstrated superiority of AS01 adjuvanted vs plain formulations Plain AS01E AS01B *Expressing at least two markers among IL-2, CD40L, TNFα, IFNγ AS01, Adjuvant System 01; CD, cluster of differentiation; IFN, interferon; IL, interleukin; nAb, neutralising antibody; OA, older adults; TNF, tumour necrosis factor 120 µg RSVPre3 + AS01E selected for further development Leroux-Roels I et al. J Infect Dis 2023; 227: 761-72 GSK’s RSV older adult vaccine The combination of RSVPreF3 (120 µg) and AS01E is designed to induce a robust humoral and cellular immune response, to help protect older adults and those with comorbidities RSVPreF3 OA vaccine RSVPreF3 antigen (120 µg) Antigen* engineered to preferentially maintain the prefusion conformation and display potent neutralizing epitopes to boost humoral immune response in older adults1,2 AS01E adjuvant system Boosts cellular immune response and restores the RSVPreF3 CD4+ T-cell level in older adults2 *RSV fusion (F) glycoprotein is highly conserved between RSV-A and RSV-B subtypes1 Image of F protein reproduced from Graham BS et al. Curr Opin Immunol 2015;35:30–38, Copyright 2015, with permission from Elsevier AS01E, Adjuvant System 01E (25 µg Quillaja saponaria Molina, fraction 21, 25 µg 3-O-desacyl-4’- monophosphoryl lipid A, combined in a liposomal formulation); CD, cluster of differentiation 1. Graham BS et al. Curr Opin Immunol 2015;35:30–38; 2. Leroux-Roels I et al. J Infect Dis 2022; Epub ahead of print (doi: 10.1093/infdis/jiac327) 26 AReSVi-006 Ongoing AReSVi-006 Phase 3 trial design1–4 A randomized, placebo-controlled, observer-blind, multi-country efficacy study RSV season 1 (2021–22) RSVPreF3 OA Placebo Re-randomization (1:1) Randomization (1:1) RSV season 2 (2022–23) RSV season 3 (2023–24) RSVPreF3 OA RSVPreF3 OA (annual group, dose 2) (annual group, dose 3) Placebo Placebo (RSVPreF3 OA single dose) (RSVPreF3 OA single dose) RSVPreF3 OA N=12,467 R D1 R Older adults aged ≥60 years N=24,966 Placebo Placebo Placebo N=12,499 D1 Study initiation (in NH): May 2021 End of S1 Analysis (in NH; Apr 2022) End of S2 Analysis (in NH; 31 Mar 2023) Published in NEJM2 IDweek oral presentation4 Primary endpoint: To demonstrate the efficacy of RSVPreF3 OA in the prevention of RSV* LRTD† in adults ≥60 years of age during the first season2,3 Confirmatory secondary endpoint: To demonstrate the efficacy of RSVPreF3 OA in the prevention of RSV* LRTD† in adults ≥60 years of age over 2 seasons, following a single dose of RSVPreF3 OA and following annual revaccination dose4 All RSV-LRTD† cases were adjudicated by an independent external adjudication committee Figure adapted with permission from Ison MG et al. A respiratory syncytial virus (RSV) prefusion F protein candidate vaccine (RSVPreF3 OA) is efficacious in adults ≥60 years of age (YOA). Presented at IDWeek, October 19−23, 2022, Washington, DC, USA . *RT-PCR confirmed; †LRTD defined as ≥2 lower respiratory symptoms/signs for ≥24 hours including ≥1 lower respiratory sign OR ≥3 lower respiratory symptoms for ≥24 hours D, day; LRTD, lower respiratory tract disease; NH, Northern Hemisphere; RT-PCR, reverse-transcriptase polymerase chain reaction; S, season 1. ClinicalTrials.gov, 2022. NCT04886596. https://clinicaltrials.gov/ct2/show/NCT04886596; 2. Papi A et al. N Engl J Med 2023;388(7):595–608; 3. Ison MG et al. A respiratory syncytial virus (RSV) prefusion F protein candidate vaccine (RSVPreF3 OA) is efficacious in adults ≥60 years of age (YOA). Presented at IDWeek, October 19−23, 2022, Washington, DC, USA; 4. Ison M. et al. Oral presentation IDweek congress 11-15 October 2023, Boston, MA 27 RSVPreF3: vaccine efficacy Study results: vaccine efficacy Median follow-up time: 6,9 months Papi A et al. N Engl J Med. 2023 Feb 16;388(7):595-608. doi: 10.1056/NEJMoa2209604. AReSVi-006 Vaccine efficacy against (severe) RSV-LRTD after a single dose of RSVPreF3 OA produced sustained vaccine efficacy over 2 full seasons1 Number of participants with ≥1 RSV-LRTD / N 82.6% Season 1* RSVPreF3 OA Placebo 7 / 12,466 40 / 12,494 30 / 12,469 139 / 12,498 1 / 12,466 17 / 12,494 7 / 12,469 48 / 12,498 RSV-LRTDa 67.2% Season 1+2† 94.1% Season 1* Severe RSV-LRTDb 78.8% Season 1+2† 0 20 40 60 Vaccine efficacy (% [CI]c) 80 100 definition of LRTD: presence of ≥2 lower respiratory symptoms/signs for ≥24 hours including ≥1 lower respiratory sign OR ≥3 lower respiratory symptoms for ≥24 hours, with ≥1 RSV-positive swab detected by qRT-PCR. RSV-LRTD according to either of the 2 case definitions (based on clinical signs/investigator assessment or based on supportive therapy). c96.95% CI for RSV-LRTD Season 1, 97.5% CI for RSV-LRTD Season 1+2 and 95% CI for severe RSV-LRTD for both seasons. *Up to end of Season 1 in the Northern Hemisphere (April 2022 analysis); median follow-up . †From 15 days post-Dose 1 up to end of Season 2 in the Northern Hemisphere (March 2023 analysis). The dotted line indicates the criteria of confirmatory objectives (lower limit of CI >20%). N, number of participants in the modified exposed set (mES). CI, Confidence Interval. 1. Ison M. et al. Oral presentation IDweek congress 11-15 October 2023, Boston, MA aCase bSevere 29 AReSVi-006 Vaccine efficacy against RSV-LRTD after a single and an annual dose of RSVPreF3 OA over 2 full seasons; future data will inform optimal timing of revaccination1 Number of participants with ≥1 RSV-LRTD / N RSVPreF3 OA Placebo 7 / 12,466 40 / 12,494 67.2% 30 / 12,469 139 / 12,498 67.1% 30 / 12,469 139 / 12,498 82.6% Season 1* Season 1+2† RSV-LRTDa Single dose Season 1+2† Annual doseⱡ Vaccine efficacy (% [CI]b) definition of LRTD: presence of ≥2 lower respiratory symptoms/signs for ≥24 hours including ≥1 lower respiratory sign OR ≥3 lower respiratory symptoms for ≥24 hours, with ≥1 RSV-positive swab detected by qRT-PCR. CI for RSV-LRTD Season 1, 97.5% CI for RSV-LRTD Season 1+2 and 95% CI for severe RSV-LRTD for both seasons. *Up to end of Season 1 in the Northern Hemisphere (April 2022 analysis). †From 15 days postDose 1 up to end of Season 2 in the Northern Hemisphere (March 2023 analysis). ⱡAnnual dosing, 2 doses ~12 months apart. The dotted line indicates the criteria of confirmatory objectives (lower limit of CI >20%). N, number of participants in the modified exposed set (mES). CI, Confidence Interval. 1. Ison M. et al. Oral presentation IDweek congress 11-15 October 2023, Boston, MA aCase b96.95% 30 RSVPreF3: vaccine safety Papi A et al. N Engl J Med. 2023 Feb 16;388(7):595-608. doi: 10.1056/NEJMoa2209604; https://stacks.cdc.gov/view/cdc/122369 Use of Arexvy in older adults • Indication: Prevention of lower respiratory tract disease caused by RSV in adults aged 60 years and older • Administration: 1 dose, intramuscular injection • Storage: refridgerator (2-8°C) • Preparation: Powder and suspension need to be reconstituted prior to administration • Price: 206,3 euro • Co-administration: simultaneous administration with influenza vaccine is possible. Simultaneous administration with other vaccines (SARS-CoV-2, PCV20) is being investigated. • The duration of protection and optimal timing of revaccination are being investigated. PCV: pneumococcal conjugated vaccine Pfizer’s RSVpreF vaccine Two recombinant stabilized RSV prefusion F antigens representing subgroups RSV-A and RSV-B RSVPreF vaccine formulation1,2 Stabilized prefusion F protein antigen (RSVPreF) from RSV-A (60 µg) Stabilized prefusion F protein antigen (RSVPreF) from RSV-B (60 µg) 1. European Medicines Agency (EMA), 2023. Abrysvo Summary of Product Characteristics (SmPC). 2. Falsey AR et al. J Infect Dis 2022;225:2056–66 33 RENOIR Ongoing RENOIR Phase 3 trial design1,2 Randomized, placebo-controlled study of the efficacy, immunogenicity, and safety of RSVpreF in adults ≥60 years Season 1 RSVpreF Adults ≥60 years Current enrollment1: n= 37634 7 countries: Argentina, Canada, Finland, Japan, Netherlands, South Africa, United States1 Season 2 R 1:1 Study start date Aug 31, 2021 Placebo Interim analysis2 Data cutoff: July 14, 2022 Efficacy follow-up Up to 2 RSV seasons Primary endpoints2: • • To demonstrate the efficacy of RSVPreF vaccine in preventing RSV-related LRTI* with ≥2 signs or symptoms To demonstrate the efficacy of RSVPreF vaccine in preventing RSV-related LRTI* with ≥3 signs or symptoms *RT-PCR confirmed; LRTI defined as ARI with ≥2 or ≥3 LRT signs/symptoms (new or worsened); ARI defined as 1 respiratory infection symptom (new or worsened from baseline), lasting >1 day R, Randomization; LRTI, lower respiratory tract Illness; RT-PCR, reverse-transcriptase polymerase chain reaction 1. ClinicalTrials.gov. NCT05035212. https://classic.clinicaltrials.gov/ct2/show/NCT05035212; 2. Walsh E et al. N Engl J Med. 2023 Apr 20;388(16):1465-1477; 34 RENOIR Vaccine efficacy against RSV-associated illness during the first RSV season1 Number of events Season 1 - Exposed set RSVPreF N=17,215 Placebo N=17,069 22 58 11 33 2 14 62.1% RSV-ARI LL of the 2-sided CI for vaccine efficacy was >20% 66.7% RSV-LRTI ≥2 signs/symptoms Primary endpoint 85.7% RSV-LRTI ≥3 signs/symptoms Primary endpoint 0 20 40 60 80 100 Vaccine efficacy (% [CI†]) Figure adapted from Walsh E et al. N Engl J Med. 2023 Apr 20;388(16):1465-1477 LRTI defined as ARI with ≥2 or ≥3 LRT signs/symptoms (new or worsened); ARI defined as 1 respiratory infection symptom (new or worsened from baseline), lasting >1 day. All RSV cases confirmed by RT-PCR; †96.66% CI for primary endpoint, 95% for all secondary endpoints ARI, acute respiratory Illness; CI, confidence interval; LRTI, lower respiratory tract Illness; RT-PCR, reverse-transcriptase polymerase chain reaction 1. Walsh E et al. N Engl J Med. 2023 Apr 20;388(16):1465-1477 35 RENOIR RSVPreF reactogenicity profile1 Solicited AEs reported within 7 days of vaccination Season 1 Median duration: 1–2 days 100 90 Most frequent local AE Pain: 11% Participants, % 80 70 Most frequent systemic AE Fatigue: 16% RSVPreF (n=3621) Placebo (n=3539) 60 50 40 30 20 16 14 11 10 3 8 6 2 <1 1 13 12 10 7 1 8 1 3 4 6 5 1 1 0 Erythema Pain Local Swelling Arthralgia Fatigue Fever Headache Myalgia Nausea Vomiting Systemic *with onset of 7 and 8 days, respectively, after receiving RSVPreF vaccine. ƚ14 months after administration Figure adapted from Walsh E et al. N Engl J Med. 2023 Apr 20;388(16):1465-1477 AE, Adverse Event; 1. Walsh E et al. N Engl J Med. 2023 Apr 20;388(16):1465-1477. 2. European Medicines Agency (EMA), 2023. Abrysvo Summary of Product Characteristics (SmPC). Abrysvo, INN-respiratory syncytial virus vaccine (bivalent, recombinant) (europa.eu) . Diarrhea 36 mRNA-1345: phase 3 study Study design • Randomized, placebo-controlled (1:1) phase 3 trial • In 22 countries. • 37 000 participants aged 60 years and older • Persons with stable chronic medical conditions were eligible Study objectives Vaccine efficacy against RSV-associated Lower Respiratory Tract Disease • With 2 or more symptoms • With 3 or more symptoms 120 µg mRNA encoding for RSVPreF In LNP Single IM injection Results • VE against RSV-LRTD with ≥ 2 symptoms: 83,7% (CI: 66,1-92,2%) • VE against RSV-LRTD with ≥ 3 symptoms: 82,4% (CI: 34,8-95,3%) • Adverse events: grade 3 symptoms: 4% in vaccine group vs 2,8% in placebo group https://investors.modernatx.com/news/news-details/2023/Moderna-Announces-mRNA-1345-an-Investigational-Respiratory-Syncytial-Virus-RSV-Vaccine-Has-Met-Primary-Efficacy-Endpoints-in-Phase-3-Trial-in-Older-Adults/default.aspx Kampmann et al. N Engl J Med 2023; 388: 1451-1464 Maternal vaccination with RSVPreF • Phase 3 placebo controlled study (n = 7392; 1:1) • Objective: Evaluate safety and efficacy of maternal vaccination (between 24-36 weeks gestational age (GA)) to prevent RSVassociated infection in the infant • Results: • ‘Medically attended’ RSV-associated lower respiratory tract infection (tachypnoea, SpO2 < 95%, tirage) • ‘Medically attended’ RSV-associated severe lower respiratory tract infection (tachypnoea, SpO2 < 93%, high flow nasal cannula or mechanical ventilation, ICU, non responsive) Kampmann et al. N Engl J Med 2023; 388: 1451-1464 Monoclonal antibodies to prevent RSV-associated disease Nirsevimab: • mAb directed against preF epitope Ø • Extended half life (through modification of the Fc region): 63 to 73 days (as a comparison: palivizumab licensed in 1998, has a half life of 18-20 days) Langedijk & Bont. Nat Rev Microbiol 2023; 21: 734-9 Nirvesimab Hammitt et al. N Engl J Med 2022; 386: 837-46 Implementation RSVPreF vaccination vs nirsevimab mAb? • Advice of Superior Health Council (Belgian NITAG) and cost-effectivity analysis in preparation • USA: unanimous advice of CDC/ACIP with regard to nirsevimab • All infants < 8 months right before the RSV season • Children 9-19 months with risk factors right before the second RSV season • 495 USD per dose • At this price the intervention is deemed to be costeffective • Canada: other conclusion of the cost-effectiveness analysis (next slide) Isabel Leroux-Roels, MD PhD Center for Vaccinology, Ghent University Hospital [email protected]