Respiratory Syncytial Virus (RSV) causes lower respiratory tract infections that can be severe and sometimes fatal. The risk for severe RSV infection is highest in infants and older adults. A safe and effective RSV vaccine for older adults represents a serious unmet medical need due to higher morbidity and mortality in this age group. In this randomized, partially double-blind, placebo-controlled, phase 1 dose-escalation study, we evaluated the safety, tolerability and immunogenicity of an investigational messenger ribonucleic acid (mRNA) vaccine encoding the RSV fusion protein (F) stabilized in the prefusion conformation. The study was conducted in healthy younger adults (ages ≥18 and ≤49 years) and healthy older adults (ages ≥60 and ≤79 years). Participants received mRNA-1777 (V171) or placebo as a single intramuscular dose. For each dose level, three sentinel participants were administered open-label mRNA-1777 (V171). Seventy-two younger adults were randomized and administered 25, 100, or 200 µg mRNA-1777 (V171) or placebo, and 107 older adults were randomized and administered 25, 100, 200 or 300 µg mRNA-1777 (V171) or placebo. Primary objectives were safety and tolerability and secondary objectives included humoral and cell-mediated immunogenicity. All dose levels of mRNA-1777 (V171) were generally well tolerated and no serious adverse events related to the vaccine were reported. Immunization with mRNA-1777 (V171) elicited a humoral immune response as measured by increases in RSV neutralizing antibody titers, serum antibody titers to RSV prefusion F protein, D25 competing antibody titers to RSV prefusion F protein, and cell-mediated immune responses to RSV-F peptides.

Neutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.e., seasonal variation) are necessary. Five decades of clinical trial literature were leveraged to build a model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinical endpoints. The MBMA was validated by backward translation to animal challenge experiments and forward translation to predict results of a recent RSV mAb trial. MBMA predictions were evaluated against a human trial of 70 participants who received either placebo or one of four dose-levels of MK-1654 and were challenged with RSV [NCT04086472]. The MBMA was used to perform clinical trial simulations and predict efficacy of MK-1654 in the infant target population. The MBMA established a quantitative relationship between RSV SNA and clinical endpoints. This relationship was quantitatively consistent with animal model challenge experiments and results of a recently published clinical trial. Additionally, SNA elicited by increasing doses of MK-1654 in humans reduced RSV symptomatic infection rates with a quantitative relationship that approximated the MBMA. The MBMA indicated a high probability that a single dose of ≥ 75 mg of MK-1654 will result in prophylactic efficacy (> 75% for 5 months) in infants. An MBMA approach can predict efficacy of neutralizing antibodies against RSV and potentially other respiratory pathogens.

New dengue vaccines are needed to prevent this globally expanding vector-borne disease. The V180 vaccine candidate consists of four recombinant, soluble, dengue virus envelope glycoproteins and has been previously evaluated in two clinical trials for safety and immunogenicity in Flavivirus-naive participants (NCT01477580 and NCT01477580). Here, we report on a randomized, placebo-controlled, double-blind study of the safety and immunogenicity of the V180 vaccine in subjects who have previously received the live attenuated tetravalent vaccine (LATV) developed by the National Institute of Allergy and Infectious Diseases (protocol #V180-002 [CIR-301]). The study was designed to evaluate whether this recombinant subunit vaccine could boost the neutralizing antibody responses induced by dengue LATV. Twenty participants who had previously received one or two doses of dengue LATV were randomized and received a single dose of V180 nonadjuvanted (N = 8), V180 adjuvanted with Alhydrogel™ (aluminum hydroxide gel, Brenntag Biosector, Frederikssund, Denmark) (N = 8), or placebo (N = 4). Immunogenicity was measured using a plaque reduction neutralization test at days 1, 15, 28, and 180 after vaccination. In addition, vaccine safety (solicited and unsolicited adverse events) was assessed using a vaccination report card for 28 days following vaccination, and serious adverse events were captured from the time of informed consent through the final study visit at 6 months after vaccination. The results of the study demonstrate that the V180 vaccine is generally well tolerated and immunogenic in these dengue-seropositive volunteers.

Vaccines against COVID-19 are needed to overcome challenges associated with mitigating the global pandemic. We report the safety and immunogenicity of V590, a live recombinant vesicular stomatitis virus-based COVID-19 vaccine candidate. In this placebo-controlled, double-blind, three-part phase 1 study, healthy adults were randomised to receive a single intramuscular dose of vaccine or placebo. In Part 1, younger (18–54 years) and, in Part 2, older (≥55 years) adults seronegative for SARS-CoV-2 nucleocapsid received one of four V590 dose levels (5.00 × 10⁵; 2.40 × 10⁶; 1.15 × 10⁷; or 5.55 × 10⁷ plaque-forming units [pfu]) or placebo. In Part 3, a single V590 dose level (5.55 × 10⁷ pfu) or placebo was administered to younger SARS-CoV-2 seropositive adults. Primary endpoints included adverse events (AEs) and for Parts 1 and 2 anti-SARS-CoV-2 serum neutralising antibody responses measured by 50% plaque reduction neutralisation (PRNT50) assay at Day 28. Registration NCT04569786 [P001-02]. 232 participants were randomised and 219 completed the study. In seronegative participants, anti-SARS-CoV-2 spike-specific antibody responses to V590 were low and comparable to placebo across the lower dose levels. At the highest dose level (5.55 × 10⁷ pfu), anti-SARS-CoV-2 spike-specific PRNT50 was 2.3-fold higher than placebo. The most frequently reported AEs were injection-site pain (38.4%), headache (15.1%) and fatigue (13.4%). V590 was generally well-tolerated. However, Day 28 anti-SARS-Cov-2 spike-specific antibody responses in seronegative participants following a single intramuscular administration of V590 were not sufficient to warrant continued development. The study was funded by Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

We report on the safety and immunogenicity of V591, a measles vector-based SARS-CoV-2 vaccine candidate. In this multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial, healthy adults with no history of COVID-19 disease were assigned to intramuscular injection of V591 or placebo (4:1 ratio). In part 1, younger adults (18-55 years) received V591 median tissue culture infectious dose (TCID₅₀)-levels of 1×10⁵ or 1×10⁶ or placebo, 56 days apart. In part 2, younger and older (>55 years) adults received a single dose of one of four (10⁴/10⁵/10⁶/10⁷) or one of two (10⁵/10⁶) V591 TCID₅₀ levels, respectively, or placebo. Primary outcome: safety/tolerability. Secondary outcome: humoral immunogenicity. ClinicalTrials.gov: NCT04498247. From August–December 2020, 444 participants were screened and 263 randomised (210 V591; 53 placebo); 262 received at least one and 10 received two doses of V591 or placebo. Adverse events were experienced by 140/209 (67.0%) V591 dose-group participants and 37/53 (69.8%) placebo-group participants following injection 1; most frequent were fatigue (57 [27.3%] vs 20 [37.7%]), headache (57 [27.3%] vs 19 [35.8%]), myalgia (35 [16.7%] vs 10 [18.9%]), and injection-site pain (35 [16.7%] vs 4 [7.5%]). No deaths nor vaccine-related serious adverse events occurred. At Day 29, no anti-SARS-CoV-2 spike serum neutralising antibody and IgG-responses were identified in placebo or the three lower V591 dose-groups; responses were detected with V591 1×10⁷ TCID₅₀, although titres were lower than convalescent serum. V591 was generally well tolerated, but immunogenicity was insufficient to warrant continued development. Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

In clinical trials, the degree of glucose lowering with sitagliptin has been correlated with the magnitude of dipeptidyl peptidase-4 (DPP-4) inhibition over 24 h. Previous studies evaluating sitagliptin doses ranging from 25 to 200 mg/day demonstrated that the daily dose of 100 mg provided maximal glucose-lowering efficacy for this compound in patients with type 2 diabetes. However, sitagliptin 200 mg once daily provided numerically greater percent plasma DPP-4 inhibition compared with 100 mg once daily. The purpose of this study was to evaluate whether sitagliptin 200 mg once daily provides greater improvement in glycemic efficacy as assessed by weighted mean glucose (WMG) over 24 h relative to sitagliptin 100 mg once daily and to relate the percent DPP-4 inhibition achieved with these doses to any between-treatment differences in glycemic efficacy. In a double-blind crossover study, patients with type 2 diabetes (fasting plasma glucose [FPG] 130-250 mg/dL) were randomized to one of six treatment sequences over three treatment periods (placebo, sitagliptin 100 mg once daily, or sitagliptin 200 mg once daily). Each of the treatment periods was 7 days in duration, with 28-day washout periods between treatments. After each treatment period, patients underwent blood sampling at various time points over 24 h to determine 24-h WMG. Plasma DPP-4 activity was assessed at trough, 24 h following dosing on day 7; percent DPP-4 inhibition was corrected for sample assay dilution. The 103 randomized patients had a baseline mean FPG of 172 mg/dL. Following a planned interim analysis, the study was stopped because the 24-h WMG values were not different between the sitagliptin doses. Furthermore, a significant carryover effect across periods was observed for FPG; thus, efficacy results from period 1 are presented herein. The 24-h WMG values were significantly (p < 0.01) lower with sitagliptin relative to placebo, but the difference between sitagliptin doses was not significant (p = 0.365). Corrected percent plasma DPP-4 inhibition at trough was not significantly (p = 0.791) different with sitagliptin 200 mg (LS mean [95% CI] 96.9% [90.0, 100.0]) compared with sitagliptin 100 mg (95.6% [88.4, 100.0]). The early termination and the carryover effect described above are limitations to this study. Across sitagliptin doses in this study, the similarity of the 24-h WMG concentrations and the similarity of the corrected DPP-4 inhibition values support prior findings that the maximal glucose-lowering efficacy of sitagliptin is achieved with once-daily dosing of 100 mg. Clinicaltrials.gov: NCT00541229.