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A pneumococcal conjugate vaccine (PCV) specifically focused on serotypes associated with adult residual disease burden is urgently needed. We aimed to assess V116, an investigational 21-valent PCV, that contains pneumococcal polysaccharides (PnPs), which account for 74-94% of invasive pneumococcal disease in adults aged 65 years or older.We did a phase 1/2, randomised, double-blind, active comparator-controlled, multicentre, non-inferiority and superiority trial. The phase 1 study was done at two clinical sites in the USA, and the phase 2 study was done in 18 clinical sites in the USA. Eligible participants were healthy adults with or without chronic medical conditions assessed as stable, aged 18-49 years in the phase 1 trial and aged 50 years or older in the phase 2 trial. Participants were excluded if they had a history of invasive pneumococcal disease or other culture-positive pneumococcal disease within the past 3 years, known hypersensitivity to a vaccine component, known or suspected impairment of immunological function, were pregnant or were breastfeeding, or had previously received any pneumococcal vaccine. Participants had to abstain from sexual activity or use protocol approved contraception. All participants were centrally randomly assigned to a vaccine group using an interactive response technology system. Participants and investigators were masked to group assignment. In phase 1, participants were randomly assigned (1:1:1) to receive a single dose of V116-1 (2 μg per pneumococcal polysaccharide [PnP] per 0·5 mL) or V116-2 (4 μg per PnP per 1·0 mL) or the 23-valent unconjugated PnP vaccine, PPSV23 (25 μg per PnP per 0·5 mL). In phase 2, participants were randomly assigned (1:1) to receive one dose of V116 (4 μg per PnP per 1·0 mL) or PPSV23 (25 μg per PnP per 0·5 mL), stratified by age. Safety analyses included all randomly assigned participants who received study vaccine; immunogenicity analyses were per protocol. For both phases, the primary safety outcome was the proportion of participants with solicited injection-site adverse events and solicited systemic adverse events up to day 5 after vaccination and the proportion of participants with vaccine-related serious adverse events to 6 months after vaccination. In phase 2, primary immunogenicity outcomes were to test non-inferiority of V116 compared with PPSV23 as measured by serotype-specific opsonophagocytic antibody geometric mean titres (OPA-GMT) ratios for the serotypes common to the two vaccines at 30 days after vaccination (using a 0·33 margin) and to test superiority of V116 compared with PPSV23 as measured by serotype-specific OPA-GMT ratios for the serotypes unique to V116 at 30 days after vaccination (using a 1·0 margin). This trial is registered with Clinicaltrials.gov, NCT04168190.Between Dec 6 and 26, 2019, 92 volunteers were screened and 90 (98%) enrolled for phase 1 (59 [66%] women; 31 [34%] men); 30 participants were assigned to each group and received study vaccine. 30 (100%) participants in the V116-1 group, 29 (97%) in the V116-2 group, and 30 (100%) participants in the PPSV23 group were included in the per-protocol immunogenicity evaluation. From Sept 23, 2020, to Jan 12, 2021, 527 volunteers were screened, and 510 (97%) participants were enrolled in the phase 2 trial. 508 participants (99%; 254 [100%] of 254 participants randomly assigned to the V116 group and 254 [99%] of 256 randomly assigned to PPSV23 group) received study vaccine (281 [55%] women; 227 [45%] men). 252 (99%) of 254 of participants in the V116 group and 254 (99%) of 256 participants in the PPSV23 group were included in the primary immunogenicity analyses. There were no vaccine-related serious adverse events or vaccine-related deaths in either study phase. In both phases, the most common solicited injection site adverse event was injection site pain (phase 1 22 [73%] participants in V116-1 group, 23 [77%] participants in V116-2 group, and 17 [57%] participants in the PPSV23 group; phase 2 118 [46%] of 254 participants in the V116 group and 96 [38%] of 254 in the PPSV23 group]. The most common solicited systemic adverse events in phase 1 was fatigue (eight [27%] participants in the V116-1 group, eight [27%] participants in the V116-2 group, and five [17%] participants in PPSV23 group) and myalgia (eight [27%] participants in the V116-1 group, nine (30%) participants in the V116-2 group, and four (13%) participants in the PPSV23 group]. In phase 2, the most frequently reported solicited systemic adverse event was fatigue (49 [19%] participants in V116 group, and 31 [12%] participants in PPSV23 group). In both phases, most of the solicited adverse events in all vaccine groups were mild and of short duration (≤3 days). V116 met non-inferiority criteria compared with PPSV23 for the 12 shared serotypes and met superiority criteria compared to PPSV23 for the nine unique serotypes.V116 was well tolerated with a safety profile generally similar to PPSV23; consistent with licensed pneumococcal conjugate vaccines. Functional OPA antibodies were induced to all V116 vaccine serotypes. The vaccine was non-inferior to PPSV23 for the 12 serotypes common to both vaccines and superior to PPSV23 for the nine unique serotypes in V116. Our findings support the development of V116 for prevention of pneumococcal disease in adults.Merck SharpDohme, subsidiary of MerckCo, Rahway, NJ, USA.

Background V116, an investigational 21-valent PCV, contains the following pneumococcal polysaccharides (PnPs): 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, 16F, 17F, 19A, 20, 22F, 23A, 23B, 24F, 31, 33F, 35B, and a de-O-acetylated 15B (deOAc15B). This phase 1 study evaluated the safety, tolerability, and immunogenicity of V116 in pneumococcal vaccine-naive adults compared with the 23-valent polysaccharide pneumococcal vaccine (PPSV23). Methods Adults (n=90) 18–49 years were randomized 1:1:1 to receive a single dose of V116-1 (2 μg dose/each PnPS, V116-2 (4 μg dose/PnPS) or PPSV23. Adverse events (AEs) were collected following vaccination. Pneumococcal serotype-specific opsonophagocytic activity (OPA) was measured prior to and 30 days postvaccination (Day 30). Results There were no serious AEs, deaths, or discontinuations due to AEs. Immune responses at Day 30 in the V116-1 and V116-2 groups were generally comparable to PPSV23 for the common serotypes and higher than PPSV23 for the unique serotypes. At Day 30, the OPA GMTs were higher in the V116-2 group compared with the V116-1 group for all serotypes except 9N. The OPA geometric mean titre ratio (95% CI) (V116-2/PPSV23) ranged from 0.89 (0.58, 3.51) to 2.40 (1.24, 4.62) for all common serotypes and 2.80 (1.64, 4.79) to 58.07 (25.10, 134.33) for all unique serotypes; the lower bound of the 95% CI for the OPA GMT ratio (V116-2/PPSV23) was >0.5 for all common serotypes and >1.0 for all unique serotypes. Conclusions These safety and immunogenicity data support the continued development of V116 for the prevention of pneumococcal disease in adults.

In clinical trials, the three-drug regimen of ruzasvir (RZR) 60 mg, uprifosbuvir (UPR) 450 mg and grazoprevir 100 mg, with or without ribavirin, has demonstrated promising efficacy and excellent tolerability across a wide range of hepatitis C virus (HCV)-infected individuals. The present study assessed the efficacy and safety of the two-drug combination of RZR 60 mg plus UPR 450 mg administered for 12 weeks in participants with HCV genotype (GT) 1-6 infection. In this open-label clinical trial, treatment-naive or -experienced and cirrhotic or noncirrhotic participants with chronic HCV GT1-6 infection received RZR 60 mg plus UPR 450 mg orally once daily for 12 weeks (NCT02759315/protocol PN035). The primary efficacy endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). One hundred and sixty participants were enrolled. SVR12 rates were 96% (52 of 54) in participants with GT1a infection; 100% (15 of 15) in those with GT1b infection; 97% (28 of 29) in those with GT2 infection; 77% (30 of 39) in those with GT3 infection; 90% (18 of 20) in those with GT4 infection; and 67% (2 of 3) in those with GT6 infection. Drug-related adverse events (AEs) reported by >5% of participants were fatigue (n = 10, 6.3%) and diarrhoea (n = 9, 5.6%). Five participants reported a total of 11 serious AEs, none considered drug-related. One participant experienced on-treatment alanine aminotransferase/aspartate aminotransferase elevations that resolved without intervention. Data from the present study indicate that the combination of RZR 60 mg plus UPR 450 mg once daily for 12 weeks was well tolerated overall but was effective only for certain genotypes.

BACKGROUND: New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3.METHODS: Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720.FINDINGS: 241 participants were randomised between Feb 18, 2015, and March 16, 2015. 240 participants completed 8 weeks of treatment and reached follow-up 12 weeks after the end of treatment. Of the four regimens, grazoprevir plus ruzasvir plus uprifosbuvir 450 mg had the most consistently high SVR12 (>90%) for participants infected with genotype 1 (21 [91%] of 23), genotype 2 (15 [94%] of 16), and genotype 3 (20 [91%] of 22). In particular, among those with genotype 2 infection, the grazoprevir plus ruzasvir plus uprifosbuvir 450 mg regimen had a higher SVR12 (15 [94%] of 16) than the grazoprevir plus ruzasvir plus uprifosbuvir 300 mg regimen (ten [71%] of 14), grazoprevir plus elbasvir plus uprifosbuvir 300 mg regimen (11 [69%] of 16), or grazoprevir plus elbasvir plus uprifosbuvir 450 mg regimen (nine [60%] of 15). Overall, the most common adverse events were headache (55 [23%] of 240), fatigue (47 [20%] of 240), and nausea (32 [13%] of 240). Two (INTERPRETATION: These results support further evaluation of the three-drug direct-acting antiviral agent regimen of grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV-infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV-HIV co-infection.FUNDING: Merck & Co, Inc.

Background There is a need for hepatitis C virus (HCV) therapies with excellent efficacy across genotypes and in diverse populations. Part A of the C-CREST-1 and C-CREST-2 trials led to the selection of a three-drug regimen of grazoprevir (MK-5172; an HCV NS3/4A protease inhibitor; 100 mg/day) plus ruzasvir (MK-8408; an NS5A inhibitor; 60 mg/day) plus uprifosbuvir (MK-3682; an HCV NS5B polymerase inhibitor; 450 mg/day). Part B of the studies tested this combination as a single formulation in different treatment durations in a broader population. Methods Part B of these randomised, phase 2, open-label clinical trials enrolled individuals from 15 countries who were chronically infected with HCV genotypes 1–6 (HCV RNA ≥10 000 IU/mL) with or without compensated cirrhosis. Those with genotype 1, genotype 2, genotype 4, or genotype 6 were treatment-naive; those with genotype 3 could be treatment-naive or treatment-experienced with pegylated interferon and ribavirin. Randomisation occurred centrally using an interactive voice response system and integrated web response system. Participants were randomly assigned to receive treatment for 8, 12, or 16 weeks with a fixed-dose combination of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin. The primary endpoint was the proportion of participants achieving sustained virological response 12 weeks after the end of all study therapy (SVR12), defined as HCV RNA less than the lower limit of quantification (either target detected unquantifiable or target not detected [

Abstract 1394 Background Herpes zoster incidence is higher in patients undergoing chemotherapy for hematologic malignancy [HM] (25-100 cases/1000 person-years) than in the general population (≂f3-5 cases/1000 person-years) and the general older adult population (7-12 cases/1000 person-years). The licensed live-attenuated zoster vaccine was heat-treated [ZVHT] and assessed in adults with HM. Methods Randomized, double-blind, placebo-controlled, multicenter Phase I study of 4 ZVHT doses (≂f30 days apart) in adults ≥18 years with HM. Eighty subjects were enrolled, of whom 61 received ZVHT and 19 placebo (Pbo). Blood was collected at baseline and ≂f28 days after each dose to measure (1) VZV antibody concentrations by glycoprotein enzyme-linked immunosorbent assay (gpELISA), and (2) varicella zoster virus (VZV) T-cell responses by interferon-gamma enzyme-linked immunospot (IFN-γ ELISPOT) assay. All vaccinated patients were evaluated for adverse events (AEs) through day 28 postdose 4. The primary hypothesis was that 4 doses of ZVHT would elicit a statistically significant VZV-specific immune response (lower bound of 90% CI on geometric mean fold rise [GMFR] >1.0) in adults with HM. Results Injection-site adverse events (AEs) occurred in 31.1% of the ZVHT group and 10.5% of the Pbo group. Of overall vaccine-related systemic AEs (ZVHT: 18.0%, Pbo: 15.8%), only nausea was reported by >10% in either group (ZVHT: 0.0%, Pbo: 10.5%). There were 2 reported vaccine-related serious AEs in the ZVHT group (vomiting, 2 days postdose 1; peripheral neuropathy, 6 days postdose 2). Four AEs resulting in death were reported in the ZVHT group (coronary arteriosclerosis, 24 days postdose 1; malignant neoplasm, 18 days postdose 2; leukemia, 10 days postdose 2; neutropenic sepsis, 48 days postdose 2), all deemed not vaccine-related by the investigator. Two subjects discontinued due to vaccine-related AEs (peripheral neuropathy, ZVHT 6 days postdose 2; nausea and vomiting, Pbo 2 days postdose 1). No ZVHT recipient had a rash that was PCR positive for the vaccine strain of VZV. At baseline, the VZV-specific gpELISA GMT was 205 (90% CI: 158, 267) and the IFN-γ ELISPOT GMC was 11 (90% CI: 7, 18). Both measures increased Postdose 4: gpELISA GMT was 262 (90% CI: 204, 336); IFN-γ ELISPOT GMC was 24 (90% CI: 14, 41). The primary hypothesis was met, as Postdose 4 immune responses were significantly higher than baseline for both gpELISA (GMFR=1.3 [90% CI: 1.1, 1.5], p=0.003) and IFN-γ ELISPOT (GMFR= 2.2 [90% CI: 1.4, 3.5], p=0.004). Conclusion In the HM population, ZVHT had an acceptable safety profile and elicited statistically significant VZV-specific antibody and functional T-cell responses at 28 days Postdose 4. Disclosures: Camacho: Merck: Research Funding. Off Label Use: This clinical research study examined the safety and immunogenicity of a heat-treated version of the licensed live-attenuated zoster vaccine (Zostavax) assessed in adults with hematologic malignancy. Betts:Merck: Research Funding. Wertheim:Merck: Research Funding. Zhao:Merck: Employment. Fernsler:Merck: Employment. Manoff:Merck: Employment. Annunziato:Merck: Employment.