Background: Global pediatric immunization programs with pneumococcal conjugate vaccines (PCVs) have reduced vaccine-type pneumococcal disease, but a substantial disease burden of non-PCV serotypes remains. Methods: This phase 3, randomized (1:1), double-blind study evaluated safety and immunogenicity of 20-valent PCV (PCV20) relative to 13-valent PCV (PCV13) in healthy infants. Participants received 2 infant doses and a toddler dose of PCV20 or PCV13, with diphtheria-tetanus-acellular pertussis combination vaccine at all doses and measles, mumps, rubella and varicella vaccines at the toddler dose. Primary pneumococcal immunogenicity objectives were to demonstrate noninferiority (NI) of PCV20 to PCV13 for immunoglobulin G geometric mean concentrations after infant and toddler doses and percentages of participants with predefined serotype-specific immunoglobulin G concentrations after infant doses. Safety endpoints included local reactions, systemic events and adverse events. Results: Overall, 1204 participants were vaccinated (PCV20, n = 601; PCV13, n = 603). One month after the toddler dose, 19/20 serotypes met NI for immunoglobulin G geometric mean concentrations; serotype 6B narrowly missed NI [PCV20/PCV13 geometric mean ratio: 0.57 (2-sided 95% confidence interval: 0.48–0.67); NI criterion: lower 2-sided 95% confidence interval >0.5]. Sixteen/twenty serotypes met NI for ≥1 primary objective after 2 infant doses. PCV20 induced robust opsonophagocytic activity, and boosting responses were observed for all vaccine serotypes, including those missing statistical NI. The safety/tolerability profile of PCV20 was like that of PCV13. Conclusions: PCV20 3-dose series in infants was safe and elicited robust immune responses. Based on these results and PCV13 experience, PCV20 3-dose series is expected to be protective for all 20 vaccine serotypes. NCT04546425.

Abstract Background The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to expand protection against pneumococcal disease. PCV20 contains conjugates for serotype 6A, which is also in 13-valent PCV (PCV13) and appears to have had a clinical impact on 6C disease, and the additional serotype 15B. An exploratory assessment of cross-reactive functional antibodies to serotypes 6C and 15C elicited by PCV20 in two phase 3 infant studies is described. Methods Two randomized phase 3 studies evaluated immunogenicity and safety of PCV20 relative to PCV13 in infants receiving a 4-dose series (3 infant doses and a toddler dose; NCT04382326) or a 3-dose series (2 infant doses and a toddler dose; NCT04546425). In each study, immunoglobulin G (IgG) concentrations and opsonophagocytic activity (OPA) titers to serotypes 6C and 15C were measured in a randomly selected subset of infants 1 month after the infant doses, and before and 1 month after the toddler dose. IgG geometric mean concentrations, OPA geometric mean titers (GMTs), and percentage of participants with predefined IgG concentrations, and OPA titers greater than or equal to the lower limit of quantitation were calculated with 95% confidence intervals. Results PCV20 elicited IgG and OPA responses to serotype 6C that were generally similar for most endpoints to PCV13 after the 3 infant and toddler doses in the 4-dose series study and after the toddler dose in the 3-dose series study. PCV20 also elicited both IgG and OPA responses to 15C after the infant and toddler doses that were well differentiated from the PCV13 group in both studies. After the toddler dose, OPA GMTs to serotype 6C in the PCV20 and PCV13 groups were 422 and 995, respectively, following a 3-dose series, and 824 and 1090 following a 4-dose series. OPA GMTs to serotype 15C were 67 and 38 and 117 and 38 at the same timepoint in the PCV20 and PCV13 groups, respectively. Conclusion PCV20 elicits cross-reactive IgG and cross-functional OPA responses to serotypes 6C and 15C. The responses to serotype 6C after PCV20 are generally similar to those of PCV13. The epidemiology of disease due to the vaccine-type and vaccine-related serotypes will be monitored after introduction of PCV20 into infant immunization programs. Funded by Pfizer Inc Disclosures Noor Tamimi, MD, Pfizer: Employee|Pfizer: Stocks/Bonds Mary J. Kline, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Kimberly J. Center, M.D., Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Allison Thompson, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Gary Baugher, PharmD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Jelena Drozd, MS, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Ingrid L. Scully, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Peter Giardina, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds James Trammel, MS, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Lanyu Lei, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Yahong Peng, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Daniel Scott, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds William C. Gruber, MD, Pfizer, Inc.: Employee|Pfizer, Inc.: Stocks/Bonds Wendy Watson, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds

Abstract Background The 20-valent pneumococcal conjugate vaccine (PCV20), developed to expand protection against pneumococcal disease, is approved for adults in several countries and for pediatric use in the United States. Tolerability and safety data from PCV20 pediatric studies are described. Methods Five randomized studies in infants (1 Phase 2; 4 Phase 3) assessing the safety of PCV20 relative to 13-valent PCV (PCV13) receiving a 3- or 4-dose series (2 or 3 primary series doses and a toddler dose) were conducted in North America, Europe, South America, and Japan. Study vaccines were given intramuscularly in all studies except in Japan, where a subcutaneous (SQ) route was also evaluated. A single-arm Phase 3 study of 1 PCV20 dose was performed in US children 15 months to 17 years old; children < 5 years old had received ≥ 3 doses of PCV13. All studies assessed local reactions and systemic events within 7 days of vaccination. Adverse events (AEs) were collected through 1 month after the primary series (infant studies) and 1 month after the toddler or single vaccine dose. Serious AEs (SAEs) were collected throughout study participation. Results The safety population across 6 studies totaled 6654 participants; 3276 infants and 831 children received PCV20 and 2547 infants received PCV13. Overall, the most common local reaction was injection site pain, except in the infant study in Japan, where redness was most common, particularly in SQ groups. In the infant studies, the most common systemic events were irritability and drowsiness. The most common systemic events in older children were fatigue (≥ 2- to < 5-year-old age group) and muscle pain (≥ 5- to ≤ 17-year-old age group). Fever > 40°C was uncommon (PCV20, ≤ 0.5%; PCV13, ≤ 0.1% after any dose). AE and SAE rates were similar to the PCV13 group in the infant studies and low in the study in children. Events were consistent with illnesses and medical conditions that may occur in pediatric populations. Conclusion In 6 studies conducted globally, PCV20 was safe and well tolerated in infants and children through 17 years of age. The PCV20 tolerability and safety profile was similar to PCV13 controls in infant studies and consistent with PCV13 studies in children. FUNDING BY PFIZER INC Disclosures Laurence Flint, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Kathleen McElwee, MD, MDH, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds G. Laissa Ouedraogo, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Noor Tamimi, MD, Pfizer: Employee|Pfizer: Stocks/Bonds Mary J. Kline, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Kimberly J. Center, M.D, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Allison Thompson, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Richard de Solom, MBBS, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Masako Yamaji, MS, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds James Trammel, MS, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Lanyu Lei, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Yahong Peng, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds William C. Gruber, MD, Pfizer, Inc.: Employee|Pfizer, Inc.: Stocks/Bonds Daniel Scott, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Wendy Watson, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds

Abstract Background PCV20 contains the 13-valent pneumococcal conjugate vaccine (PCV13) components, and 7 additional conjugates (for serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F), extending pneumococcal serotype coverage. Key data from the pivotal Phase 3 evaluation of PCV20 in adults are presented. Methods Adults naïve to pneumococcal vaccination were enrolled into 3 age cohorts (≥60, 50–59, and 18–49 years of age). Participants ≥60 years received either PCV20 and saline 1 month later, or PCV13 and 23-valent pneumococcal polysaccharide (PPSV23) 1 month later (1:1 randomization, double blind). Participants 50–59 and 18–49 years received either a dose of PCV20 or PCV13 (3:1 randomization, double blind). Tolerability, safety and immunogenicity (opsonophagocytic activity [OPA] responses) were assessed. Results 3889 participants received vaccine. 1507 and 1490 participants ≥60 years received PCV20 or control respectively. All 20 vaccine serotypes induced robust responses and OPA geometric mean titers (GMTs) to all 13 matched serotypes were noninferior to PCV13. In addition, the OPA GMTs to 6 of the 7 additional serotypes 1 month after PCV20 were noninferior compared to the same serotypes in PPSV23. The OPA GMT of serotype 8 missed noninferiority by a very narrow margin (2-sided 95% lower bound of GMT ratio [20vPnC/PPSV23] was 0.49, with noninferiority criterion of >0.5); this is unlikely to be clinically significant given the high geometric mean fold rise of OPA titers after PCV20 (22-fold above baseline). GMTs after PCV20 in each of the younger age cohorts (18–49 years, 50–59 years) were noninferior to adults 60–64 years. The tolerability and safety profile of PCV20 was similar to PCV13. Conclusion Based on the robust immune responses and comparability to licensed pneumococcal vaccines, as well as bridging to the younger age group, these data support that PCV20 will be protective against pneumococcal disease due to the 20 serotypes in adults. Disclosures Charu Sabharwal, MD, MPH, Pfizer (Employee, Shareholder) Xia Xu, PhD, Pfizer (Employee, Shareholder) Vani Sundaraiyer, PhD, MS, Pfizer (Independent Contractor) Yahong Peng, PhD, Pfizer (Employee, Shareholder) Lisa Moyer, BS, Pfizer (Employee, Shareholder) Michael W. Pride, PhD, Pfizer (Employee, Shareholder) Ingrid L. Scully, PhD, Pfizer Inc (Employee, Shareholder) Kathrin U. Jansen, PhD, Pfizer (Employee, Shareholder) William C. Gruber, MD, Pfizer (Employee, Shareholder) Daniel Scott, MD, Pfizer (Employee, Shareholder) Wendy Watson, MD, Pfizer (Employee, Shareholder)

Abstract Background A 20-valent pneumococcal conjugate vaccine (PCV20) is being developed to extend protection against pneumococcal disease beyond that of the 13-valent pneumococcal vaccine (PCV13). This is the first safety and immunogenicity study of PCV20 in healthy infants. Methods This randomized, double-blind study enrolled and randomized (1:1) healthy infants ≥ 42 to ≤ 98 days of age to receive a 4-dose series of either PCV20 or PCV13 (control) at 2, 4, 6, and 12 months of age. Local reactions and systemic events were assessed for 7 days after each vaccination; adverse events (AEs) and serious AEs (SAEs) were collected throughout the study. PCV20 immune responses (serotype-specific immunoglobulin G [IgG] and opsonophagocytic activity [OPA]) were measured in sera 1 month after the third infant dose and the fourth dose at 12 months of age. Results There were 460 subjects enrolled, with 416 and 391 subjects receiving 3 and 4 doses, respectively. Local reactions and systemic events were predominantly mild to moderate in severity and similar among vaccine groups. There were no related SAEs or deaths reported. PCV20 elicited IgG responses 1 month after the third dose with boosting after a fourth dose. OPA responses were also observed. Conclusion PCV20 was well tolerated with a safety profile similar to PCV13. PCV20 elicited immune responses to all 20 vaccine serotypes. Disclosures Shelly Senders, MD, Pfizer (Grant/Research Support) Nicola P. Klein, MD, PhD, GSK group of companies (Research Grant or Support)Merck (Grant/Research Support)Pfizer (Grant/Research Support)Protein Science (now SP) (Grant/Research Support)Sanofi Pasteur (Grant/Research Support) Erik Lamberth, MD, Pfizer (Employee) Allison Thompson, MD, Pfizer (Employee) Jelena Drozd, MS, Pfizer (Employee) James Trammel, MS, Pfizer (Employee) Yahong Peng, PhD, Pfizer (Employee, Shareholder) Peter Giardina, PhD, Pfizer (Employee) Kathrin U. Jansen, PhD, Pfizer (Employee, Shareholder) William C. Gruber, MD, Pfizer (Employee, Shareholder) Daniel Scott, MD, Pfizer (Employee, Shareholder) Wendy Watson, MD, Pfizer (Employee, Shareholder)

While widespread use of pneumococcal conjugate vaccines (PCVs) has reduced disease burden, expanding serotype coverage remains an unmet need in disease prevention. The 20-valent PCV (PCV20) contains capsular polysaccharide conjugates from serotypes included in the 13-valent PCV (PCV13; Prevnar 13®) as well as 7 additional serotypes. In a phase 2 study of PCV20 in adults 60–64 years of age, robust immune responses were observed at 1 month after vaccination; antibody persistence up to 12 months after vaccination from that study is described herein. In this randomized, active-controlled, double-blind study (ClinicalTrials.gov NCT03313037), adults aged 60–64 years received a single PCV20 dose followed 1 month later by saline placebo or PCV13 followed 1 month later by 23-valent pneumococcal polysaccharide vaccine (PPSV23), which provided benchmarks for all PCV20 serotypes. Immunogenicity was assessed at baseline and at 1 and 12 months after vaccination as serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) and immunoglobulin G (IgG) geometric mean concentrations (GMCs). OPA and IgG geometric mean fold rises (GMFRs) from baseline to 12 months after vaccination were assessed. In the PCV20 group, OPA GMTs (n=185–200 at Month 12) for all PCV20 serotypes increased substantially from baseline to 1 month after vaccination and then declined by Month 12 but remained elevated above baseline. OPA GMFRs from baseline to Month 12 after PCV20 vaccination were 1.9–15.0 for the serotypes in common with PCV13 and 5.6–15.6 for the 7 additional serotypes. Similar results were observed for IgG concentrations, with GMFRs of 2.4–9.4 for the PCV13 serotypes and 3.0–15.5 for the 7 additional serotypes. At Month 12, 11 months after PPSV23 vaccination (n=162–195), OPA GMFRs were 5.3–11.5 for the 7 additional serotypes; IgG GMFRs were 5.0–10.4. Benchmarking to PCV13 serotypes in the control group was not appropriate as these subjects received both PCV13 and PPSV23, which overlap in polysaccharide composition for 12 serotypes. Immune responses induced by PCV20 persisted at 12 months after vaccination in adults 60–64 years of age, further supporting the potential of PCV20 to expand serotype protection against adult pneumococcal disease. Mariano Young Jr., MD, Pfizer Inc (Employee, Shareholder) Daniel Scott, MD, Pfizer (Employee, Shareholder) Michael W. Pride, PhD, Pfizer (Employee, Shareholder) Ingrid L. Scully, PhD, Pfizer Inc (Employee, Shareholder) John Ginis, BS, Pfizer Inc (Employee, Shareholder) Yahong Peng, PhD, Pfizer (Employee, Shareholder) Kathrin U. Jansen, PhD, Pfizer (Employee, Shareholder) William C. Gruber, MD, Pfizer (Employee, Shareholder) Wendy Watson, MD, Pfizer (Employee, Shareholder)

Abstract Background Because of the number and variability of serotypes causing pneumococcal disease among different geographic regions, age groups, and environmental backgrounds, expanding serotype coverage with pneumococcal conjugate vaccines (PCVs) is a continued unmet need. Methods This phase 1, randomized, double-blind study included healthy Japanese adults aged 18–49 years residing in the United States. Subjects were randomized 1:1:1 to receive a single dose of a 20-valent PCV (containing 13-valent PCV [PCV13] serotypes plus 8, 10A, 11A, 12F, 15B, 22F, 33F), a novel pneumococcal polysaccharide conjugate vaccine with extended coverage, or PCV13 (control). Safety was the primary endpoint and included reactogenicity events occurring ≤ 14 days after vaccination, adverse events (AEs) ≤ 1 month after vaccination, and serious AEs (SAEs) ≤ 6 months after vaccination. The secondary endpoint was pneumococcal serotype-specific immunogenicity as determined by opsonophagocytic activity (OPA) titers on sera collected before and 1 month after vaccination. Results Overall, 35 subjects received PCV20 and 35 subjects received PCV13. One subject withdrew before the 1-month follow-up. Local reactions and systemic events across groups were generally mild or moderate (Figure 1). Two vaccine-related AEs occurred (injection site erythema and swelling in the PCV20 group); no severe AEs, SAEs, or safety-related withdrawals were reported. OPA geometric mean titers increased for all 20 serotypes in the PCV20 group and all 13 serotypes in the PCV13 group 1 month after vaccination; corresponding OPA geometric mean fold rises from baseline to 1 month after vaccination are reported (Figure 2; Figure 3). Figure 1 Figure 2 Figure 3 Conclusion PCV20 was well tolerated and induced serotype-specific functional OPA immune responses that are anticipated to be associated with protection in Japanese adults. ClinicalTrials.gov: NCT03642847. Funding: Pfizer Inc. Disclosures David Fitz-Patrick, MD, Pfizer Inc (Grant/Research Support) Mariano Young Jr., MD, Pfizer Inc (Employee, Shareholder) Daniel Scott, MD, Pfizer (Employee, Shareholder) Ingrid L. Scully, PhD, Pfizer Inc (Employee, Shareholder) Gary Baugher, PharmD, Pfizer Inc (Employee, Shareholder) Yahong Peng, PhD, Pfizer (Employee, Shareholder) Kathrin U. Jansen, PhD, Pfizer (Employee, Shareholder) William C. Gruber, MD, Pfizer (Employee, Shareholder) Wendy Watson, MD, Pfizer (Employee, Shareholder)