Safety, tolerability, and immunogenicity of an adult pneumococcal conjugate vaccine, V116 (STRIDE-3): a randomised, double-blind, active comparator controlled, international phase 3 trial.

BACKGROUND: The same pneumococcal conjugate vaccines (PCVs) have been used in adults and children in many settings. Differences in the epidemiology of pneumococcal disease between populations necessitates an adult-specific PCV. We aimed to assess the safety, tolerability, and immunogenicity of V116, an investigational 21-valent PCV designed for adults. METHODS: This randomised, double-blind, active comparator controlled, international phase 3 trial enrolled adults with or without stable chronic medical conditions at 112 clinical sites in 11 countries or territories. Random assignment was performed using a central electronic interactive response technology system. Cohort 1 (≥50 years) was stratified by age (50-64, 65-74, 75-84, and ≥85 years) and randomised 1:1 to receive one intramuscular dose of V116, or the active comparator, PCV20. Cohort 2 (18-49 years) was randomised 2:1 to receive one intramuscular dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured before (day 1) and after vaccination (day 30). Four primary immunogenicity outcomes were assessed per-protocol. First, in cohort 1, non-inferiority of V116 to PCV20 was tested using serotype-specific OPA geometric mean titres (GMT) ratios for serotypes common to both vaccines; the lower bound of the 95% CI had to be greater than 0·5 for non-inferiority. Second, superiority of V116 to PCV20 was tested for OPA GMT ratios for the serotypes unique to V116; the lower bound of the 95% CI had to be greater than 2·0 for superiority. Third, superiority of V116 to PCV20 was evaluated by the proportions of participants with a four-fold or greater rise from day 1 to day 30 for serotypes unique to V116; the lower bound of the 95% CI of the differences in proportions (V116 - PCV20) had to be greater than 10% for superiority. Finally, in cohort 2, immunobridging was assessed for all 21 serotypes in V116 for adults aged 18-49 years to 50-64 years; the lower bound of the 95% CI for the OPA GMTs had to be greater than 0·5 for non-inferiority. The safety analysis included all randomly assigned participants who received study vaccine. The primary safety outcome was the proportion of participants with solicited injection site and solicited systemic adverse events until day 5 and vaccine-related serious adverse events up to 6 months after vaccination. This trial is registered at ClinicalTrials.gov (NCT05425732). FINDINGS: Between July 13, and Nov 22, 2022, 2754 individuals were screened and 2663 participants were randomly assigned. 2656 individuals were vaccinated (1179 in V116 cohort 1; 1177 in PCV20 cohort 1; 200 in V116 cohort 2; and 100 in PCV20 cohort 2). V116 met non-inferiority criteria compared with PCV20 for the ten serotypes common to both vaccines at day 30 in cohort 1 (p<0·0001 for each common serotype). V116 met superiority criteria compared with PCV20 in cohort 1 for ten of the 11 serotypes unique to V116 at day 30 (OPA GMT ratio: p<0·0001 for all unique serotypes except 15C, which was p=0·41; four-fold or greater rise in OPA from day 1-30: p<0·0001 for all serotypes except 15C, which was p=0·67). Immune responses in V116 participants aged 18-49 years were non-inferior compared with V116 participants aged 50-64 years for all V116 serotypes (p<0·0001 for all V116 serotypes). In cohort 1, 685 (58·2%) of participants in V116, and 778 (66·2%) of participants in PCV20 reported one or more adverse event. In cohort 2, 164 (82·0%) participants in V116 and 79 participants (79·0%) in PCV20 reported one or more adverse event. Six deaths were reported, all in cohort 1, none of which were considered vaccine-related (in V116: one due to sepsis, one due to cerebrovascular accident, one due to myocardial infarction, and one due to hepatic cirrhosis and hepatic encephalopathy; in PCV20: one due to cardiac arrest and one due to abdominal abscess). There were no vaccine-related serious adverse events. INTERPRETATION: V116 was non-inferior to PCV20 for the ten serotypes common to both vaccines and superior to PCV20 for all serotypes unique to V116, except for 15C. Immune responses successfully immunobridged between younger and older adults for all serotypes in V116. V116 was generally well tolerated with safety profile similar to PCV20. FUNDING: Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA (MSD).

Immunogenicity of Current and Next-Generation Pneumococcal Conjugate Vaccines in Children: Current Challenges and Upcoming Opportunities.

Global use of pneumococcal conjugate vaccines (PCVs) with increasingly broader serotype coverage has helped to reduce the burden of pneumococcal disease in children and adults. In clinical studies comparing PCVs, higher-valency PCVs have met noninferiority criteria (based on immunoglobulin G geometric mean concentrations and response rates) for most shared serotypes. A numeric trend of declining immunogenicity against shared serotypes with higher-valency PCVs has also been observed; however, the clinical relevance is uncertain, warranting additional research to evaluate the effectiveness of new vaccines. Novel conjugation processes, carriers, adjuvants, and vaccine platforms are approaches that could help maintain or improve immunogenicity and subsequent vaccine effectiveness while achieving broader protection with increasing valency in pneumococcal vaccines.

Anal dysplasia and anal cancer screening practices among liver transplant centers in the United States: Results of an online survey.

BACKGROUND: Solid organ transplant recipients are at an increased risk for anogenital Human Papillomavirus (HPV)-related disease, including anal high-grade squamous intraepithelial lesions (HSIL) and anal squamous cell cancer (ASCC). Guidelines for ASCC screening in transplant recipients are limited. Our aim was to understand current practice of ASCC screening in adult liver transplant (LT) candidates and recipients at transplant centers across the United States. METHODS: We surveyed medical directors of 113 LT centers across the United States which had publicly available contact information. The survey evaluated center perceptions on cancer and HPV disease risk in transplant populations, ASCC screening, barriers and facilitators for ASCC screening and HPV vaccination practices. RESULTS: We received 26/113 (23%) responses, of which 24 were complete and included in the analysis. Eleven of 24 (46%) centers reported screening for ASCC and 3/24 (12.5%) centers reported having formal guidelines. Centers who perform ASCC screening were more likely to perform transplants in people living with HIV and were more aware of the burden of HPV disease in transplant populations. All respondents believed that additional data on the impact of screening on ASCC incidence would support screening decisions. Increased access to specialists for screening/high-resolution anoscopy was also perceived as a facilitator. Only 7/24 (29%) centers regularly evaluated HPV vaccination status of their patients. CONCLUSION: This national survey of LT centers reveals non-standardized ASCC screening practices, and identified data, educational and resource needs to improve prevention of ASCC in this population.

PCV15, a pneumococcal conjugate vaccine, for the prevention of invasive pneumococcal disease in infants and children.

INTRODUCTION: Streptococcus pneumoniae is a causative agent of pneumonia and acute otitis media (AOM), as well as invasive diseases such as meningitis and bacteremia. PCV15 (V114) is a new 15-valent pneumococcal conjugate vaccine (PCV) approved for use in individuals ≥6 weeks of age for the prevention of pneumonia, AOM, and invasive pneumococcal disease. AREAS COVERED: This review summarizes the V114 Phase 3 development program leading to approval in infants and children, including pivotal studies, interchangeability and catch-up vaccination studies, and studies in at-risk populations. An integrated safety summary is presented in addition to immunogenicity and concomitant use of V114 with other routine pediatric vaccines. EXPERT OPINION: Across the development program, V114 demonstrated a safety profile that is comparable to PCV13 in infants and children. Immunogenicity of V114 is comparable to PCV13 for all shared serotypes except serotype 3, where V114 demonstrated superior immunogenicity. Higher immune responses were demonstrated for V114 serotypes 22F and 33F. Results of the ongoing study to evaluate V114 efficacy against vaccine-type pneumococcal AOM and anticipated real-world evidence studies will support assessment of vaccine effectiveness and impact, with an additional question of whether higher serotype 3 immunogenicity translates to better protection against serotype 3 pneumococcal disease.

A phase I study of intra-anal artesunate (suppositories) to treat anal high-grade squamous intraepithelial lesions.

BACKGROUND: Ablation or surgical excision is the typical treatment of anal high-grade squamous intraepithelial lesions (HSIL). Recurrences are common due to the persistence of underlying human papillomavirus (HPV) infection. Additional well-tolerated and effective non-surgical options for HPV-associated anal disease are needed. METHODS: This 3+3 dose escalation Phase I clinical trial evaluated the safety and tolerability of artesunate suppositories in the treatment of patients with biopsy-proven HSIL. RESULTS: The maximal tolerated dose was 400 mg, administered in 3 cycles. All adverse events associated with the use 200- and 400-mg artesunate suppositories were Grade 1. At the 600-mg dose, patients experienced clinically significant nausea. CONCLUSION: Artesunate suppositories are a safe treatment option for anal HSIL.

An indirect treatment comparison (ITC) and matching-adjusted indirect comparison (MAIC) between a 15-valent (V114) and a 20-valent (PCV20) pneumococcal conjugate vaccine among healthy infants.

OBJECTIVES: Immunogenicity between 15-valent V114 (PCV15) and 20-valent PCV20 pneumococcal conjugate vaccines in healthy infants is compared in an indirect treatment comparison and matching-adjusted indirect comparison. Hypotheses: immunogenicity of V114 is non-inferior to PCV20 for all PCV13 serotypes, and superior to PCV20 for serotype 3 based on lower bound margins. METHODS: Two phase 3 pivotal studies on 3 + 1 pediatric vaccination schedule at age 2, 4, 6, and 12-15 months compared V114 (N = 858) to PCV13 (N = 856) and PCV20 (N = 1001) to PCV13 (N = 987). Infant's age and race in V114 study were matched to those in PCV20 study. Primary endpoints were serotype-specific Immunoglobulin G (IgG) response rate difference (RRD) 30 days post-dose (PD)3; IgG geometric mean concentration (GMC) ratios 30 days PD3 and PD4. RESULTS: V114 was non-inferior (marginRRD>-10%-point; marginGMCratio >0.5) to PCV20 (p-value <0.001) for all endpoints. V114 was superior (marginRRD >0%-point; marginGMCratio >1.2) to PCV20 (p-value <0.001) for serotype 3: RRD was 34.5% (95%CI 27.9%-41.1%) PD3, and IgG GMC ratios were 2.39 (95%CI 2.12-2.68) PD3 and 2.15 (95%CI 1.90-2.41) PD4. CONCLUSION: Immune response to V114 administered in a 3 + 1 schedule in healthy infants was considered non-inferior to PCV20 for all 13 PCV13 serotypes and superior for serotype 3 PD3 and PD4. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers NCT03893448, NCT04382326.

The 15-valent pneumococcal conjugate vaccine V114 induces cross-reactive antibodies against pneumococcal serotype 6C.

Pneumococcal serogroups consist of structurally related serotypes, and serotype-specific antibodies can cross-react against other serotypes within the same serogroup. Cross-reactivity of vaccine-induced serotype 6A antibodies, and, to a lesser extent, serotype 6B antibodies, to serotype 6C has been demonstrated following receipt of the 13-valent pneumococcal conjugate vaccine (PCV13), which contains serotypes 6A and 6B. V114 is a 15-valent PCV containing the 13 PCV13 serotypes plus two additional serotypes, 22F and 33F. This study assessed cross-reactivity to serotype 6C in recipients of V114 and PCV13 as well as specificity of opsonophagocytic activity (OPA) responses in serogroup 6. Following receipt of V114 or PCV13, the observed OPA geometric mean titers to serotypes 6A, 6B, and 6C were comparable across both vaccination groups (post-single dose in adults ≥50 years of age [n = 250] and from pre- to post-dose 4 in pediatric participants 12-15 months of age [n = 150]). Based on OPA inhibition studies, V114 induced cross-reactive antibodies to serotype 6C in adult and pediatric populations that were specific and comparable to those induced by PCV13. Based on experience with PCV13, V114 may also provide comparable protection against pneumococcal disease caused by serotype 6C; however, this will have to be evaluated in real-world studies.

Safety and Immunogenicity of V114 in Preterm Infants: A Pooled Analysis of Four Phase Three Studies.

BACKGROUND: Risk of invasive pneumococcal disease is 3-fold higher in preterm versus full-term infants. V114 is a 15-valent pneumococcal conjugate vaccine (PCV) containing the 13 serotypes in PCV13 plus 2 unique serotypes, 22F and 33F. A pooled subgroup analysis was performed in preterm infants (<37 weeks gestational age) enrolled in 4 pediatric phase 3 studies evaluating the safety and immunogenicity of different 4-dose regimens of V114 or PCV13. METHODS: Healthy preterm infants were randomized 1:1 to receive V114/PCV13 in the 4 studies. Safety was evaluated as the proportion of participants with adverse events (AEs) following receipt of PCV. Serotype-specific antipneumococcal immunoglobulin G (IgG) geometric mean concentrations, IgG response rates and opsonophagocytic activity geometric mean titers were measured at 30 days postdose 3, pretoddler dose and 30 days postdose 4. RESULTS: V114 and PCV13 were administered to 174 and 180 participants, respectively. Mean gestational age was 35.4 weeks (range: 27 - <37 weeks). Proportions of participants with AEs were comparable between vaccination groups; most AEs experienced were of short duration (≤3 days) and mild-to-moderate intensity. V114-elicited IgG geometric mean concentrations, IgG response rates and opsonophagocytic activity geometric mean titers were generally comparable to PCV13 for the 13 shared serotypes and higher for serotypes 22F and 33F at 30 days postdose 3 and postdose 4. CONCLUSIONS: In preterm infants, V114 was well tolerated and induced comparable immune responses to PCV13 for the 13 shared serotypes and higher immune responses to serotypes 22F and 33F. Results support the use of V114 in preterm infants.

A Phase 3, Randomized, Double-Blind, Comparator-Controlled Study to Evaluate Safety, Tolerability, and Immunogenicity of V114, a 15-Valent Pneumococcal Conjugate Vaccine, in Allogeneic Hematopoietic Cell Transplant Recipients (PNEU-STEM).

BACKGROUND: Individuals who receive allogeneic hematopoietic cell transplant (allo-HCT) are immunocompromised and at high risk of pneumococcal infections, especially in the months following transplant. This study evaluated the safety and immunogenicity of V114 (VAXNEUVANCE; Merck, Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA), a 15-valent pneumococcal conjugate vaccine (PCV), when given to allo-HCT recipients. METHODS: Participants received 3 doses of V114 or PCV13 (Prevnar 13; Wyeth LLC) in 1-month intervals starting 3-6 months after allo-HCT. Twelve months after HCT, participants received either PNEUMOVAX 23 or a fourth dose of PCV (if they experienced chronic graft vs host disease). Safety was evaluated as the proportion of participants with adverse events (AEs). Immunogenicity was evaluated by measuring serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) for all V114 serotypes in each vaccination group. RESULTS: A total of 274 participants were enrolled and vaccinated in the study. The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at day 90. CONCLUSIONS: V114 was well tolerated in allo-HCT recipients, with a generally comparable safety profile to PCV13. V114 induced comparable immune responses to PCV13 for the 13 shared serotypes, and was higher for V114 serotypes 22F and 33F. Study results support the use of V114 in allo-HCT recipients. Clinical Trials Registration. clinicaltrials.gov (NCT03565900) and European Union at EudraCT 2018-000066-11.

Phase 3 trial to evaluate the safety, tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, followed by 23-valent pneumococcal polysaccharide vaccine 6 months later, in at-risk adults 18-49 years of age (PNEU-DAY): A subgroup analysis by baseline risk factors.

Immunocompetent adults with certain medical and behavioral factors are at increased risk of pneumococcal disease. In some countries, sequential vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for at-risk adults. This subgroup analysis from a phase 3 study evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 6 months later by PPSV23, in immunocompetent adults 18-49 years of age with pre-defined risk factors for pneumococcal disease. Safety and immunogenicity post-vaccination were analyzed by type and baseline number of risk factors for pneumococcal disease (1 and ≥2 risk factors). This analysis included 1,131 participants randomized 3:1 to receive either V114 or PCV13, followed by PPSV23. The majority (73.1%) of participants had at least one risk factor. Safety and tolerability profiles of V114 and PCV13 were similar across risk factor groups. V114 administered either alone or sequentially with PPSV23 6 months later was immunogenic for all 15 serotypes, including those not contained in PCV13, regardless of the number of baseline risk factors. V114 has the potential to broaden serotype coverage for at-risk adults.

Comment on Chandler et al. 23-Valent Pneumococcal Polysaccharide Vaccination Does Not Prevent Community-Acquired Pneumonia Hospitalizations Due to Vaccine-Type Streptococcus pneumoniae. Microorganisms 2022, 10, 560.

The 23-valent pneumococcal polysaccharide vaccine (PPSV23) targets 23 common serotypes and is recommended for use in adults in various countries to protect against pneumococcal infection. Test-negative design (TND) studies aim to include cases and controls from the same healthcare facilities; however, design choices or limitations associated with conducting real-world research can affect the study results. Here, we highlight how some methodological limitations may have affected results and conclusions of a published study described by Chandler et al.

Predictors of in-hospital mortality in a cohort of people living with HIV (PLHIV) admitted to an academic medical intensive care unit from 2009 to 2014: A retrospective cohort study.

Outcomes for critically ill people living with human immunodeficiency virus (PLHIV) have changed with the use of antiretroviral therapy (ART). To identify these outcomes and correlates of mortality in a contemporary critically ill cohort in an urban academic medical center in Baltimore, a city with a high burden of HIV, we conducted a retrospective cohort study of individuals admitted to a medical intensive care unit (MICU) at a tertiary care center between 2009 and 2014. PLHIV who were at least 18 years of age with an index MICU admission of ≥24 hours during the 5-year study period were included in this analysis. Data were obtained for participants from the time of MICU admission until hospital discharge and up to 180 days after MICU admission. Logistic regression was used to identify independent predictors of hospital mortality. Between June 2009 and June 2014, 318 PLHIV admitted to the MICU met inclusion criteria. Eighty-six percent of the patients were non-Hispanic Blacks. Poorly controlled HIV was very common with 70.2% of patients having a CD4 cell count <200 cells/mm3 within 3 months prior to admission and only 34% of patients having an undetectable HIV viral load. Hospital mortality for the cohort was 17%. In a univariate model, mortality did not differ by demographic variables, CD4 cell count, HIV viral load, or ART use. Regression analysis adjusted by relevant covariates revealed that MICU patients admitted from the hospital ward were 6.4 times more likely to die in hospital than those admitted from emergency department. Other positive predictors were a diagnosis of end-stage liver disease, cardiac arrest, ventilator-dependent respiratory failure, vasopressor requirement, non-Hodgkin lymphoma, and symptomatic cytomegalovirus disease. In conclusion, in this critically ill cohort with HIV infection, most predictors of mortality were not directly related to HIV and were similar to those for the general population.

Immunogenicity, Safety, and Tolerability of V114, a 15-Valent Pneumococcal Conjugate Vaccine, in Immunocompetent Adults Aged 18-49 Years With or Without Risk Factors for Pneumococcal Disease: A Randomized Phase 3 Trial (PNEU-DAY).

BACKGROUND: Adults with certain medical and behavioral factors are at increased risk for pneumococcal disease (PD). Sequential vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for at-risk adults in some countries. METHODS: This phase 3 trial evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 6 months later by PPSV23, in immunocompetent adults aged 18-49 years with or without predefined risk factors for PD (NCT03547167). Overall, 1515 participants were randomized 3:1 to receive either V114 or PCV13, followed by PPSV23. RESULTS: Most common solicited adverse events (AEs) following administration of V114 or PCV13 as well as PPSV23 were injection-site pain and fatigue. The proportion of participants with AEs was comparable in both groups. V114 and PCV13 were immunogenic based on opsonophagocytic activity (OPA) geometric mean titers (GMTs) 30 days postvaccination for all serotypes contained in each respective vaccine. OPA GMTs to the 2 unique serotypes in V114 were robust in the V114 group. PPSV23 was immunogenic for all 15 serotypes contained in V114 in both vaccination groups, including 22F and 33F. CONCLUSIONS: V114 administered alone or sequentially with PPSV23 is well tolerated and immunogenic for all 15 serotypes, including those not contained in PCV13, in immunocompetent adults aged 18-49 years with or without certain medical or behavioral risk factors for PD. CLINICAL TRIALS REGISTRATION: NCT03547167 and EudraCT 2017-004915-38.

Lot-to-lot consistency, safety, tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, in healthy adults aged ≥50 years: A randomized phase 3 trial (PNEU-TRUE).

BACKGROUND: Older adults are at risk of pneumococcal disease and associated morbidity and mortality. This phase 3 study (V114-020) assessed lot-to-lot consistency across safety and immunogenicity outcomes for V114, a 15-valent pneumococcal conjugate vaccine (PCV), in healthy adults aged ≥ 50 years. METHODS: Adults were randomized in a 3:3:3:1 ratio to receive a single dose of one of three lots of V114 or 13-valent PCV (PCV13), stratified by age (50-64 years, 65-74 years, and ≥ 75 years). Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were evaluated at baseline (Day 1) and 30 days post-vaccination. Non-serious and serious adverse events (AEs) were evaluated post-vaccination through 14 days and Month 6, respectively. RESULTS: Of 2340 participants enrolled, 2282 (97.5%) completed the study. Proportions of participants experiencing ≥ 1 AE were 81.0%, 77.4%, and 78.0% for V114 lots 1, 2, and 3, respectively. Comparison of V114 combined lots with PCV13 showed that proportions of participants experiencing AEs, solicited AEs, and serious AEs were comparable for both vaccines, with the exception of injection-site pain (more frequently reported with V114). OPA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) at 30 days post-vaccination were comparable across V114 lots, and all lots met predefined equivalence criteria for all 15 vaccine serotypes (lower and upper limits of the 95% confidence intervals of serotype-specific OPA GMT ratios for all possible pairwise comparisons across the three lots were within the equivalence margin of 0.5-2.0). Serotype-specific OPA GMTs and IgG GMCs were comparable in the V114 combined lots and PCV13 groups for the 13 shared serotypes and higher in the V114 group for serotypes unique to V114 (22F and 33F). CONCLUSIONS: V114 is well tolerated with a consistent safety profile and immune response across manufacturing lots. CLINICAL TRIALS REGISTRATION: NCT03950856 (www.clinicaltrials.gov); 2018-004266-33 (EudraCT).

Safety and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, in adults living with HIV.

OBJECTIVES: To evaluate safety and immunogenicity of V114 [15-valent pneumococcal conjugate vaccine (PCV) containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F], followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) 8 weeks later, in adults living with HIV. DESIGN: In this phase 3 study (V114-018; NCT03480802), pneumococcal vaccine-naive adults with HIV (CD4+ cell count ≥50 cells/µl, plasma HIV RNA <50 000 copies/ml, receiving antiretroviral therapy) were randomized 1 : 1 to receive one dose of V114 or licensed 13-valent PCV (PCV13) on day 1; participants received PPSV23 at week 8. METHODS: Adverse events and serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were evaluated after each vaccination. RESULTS: Of 302 participants enrolled, 292 (96.7%) completed the study. Proportions of participants experiencing at least one adverse event were 73.0 and 62.7% in the V114 and PCV13 groups following PCV and 60.7 and 71.6% following PPSV23. Most solicited adverse events were of mild or moderate severity and short duration. OPA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) were generally comparable between groups for shared serotypes at day 30 and maintained at week 12. OPA and IgG responses for additional serotypes in V114 (22F, 33F) were higher following V114 than PCV13 at day 30 but comparable at week 12, 30 days post-PPSV23. CONCLUSION: In pneumococcal vaccine-naive adults living with HIV, V114 was well tolerated and induced immune responses for all 15 pneumococcal serotypes. V114 can be followed by PPSV23 8 weeks later to broaden serotype coverage.

A phase 3 trial of safety, tolerability, and immunogenicity of V114, 15-valent pneumococcal conjugate vaccine, compared with 13-valent pneumococcal conjugate vaccine in adults 50 years of age and older (PNEU-AGE).

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have greatly reduced the incidence of pneumococcal disease, yet unmet medical need remains due to increased disease caused by non-vaccine serotypes (STs). V114 (VAXNEUVANCETM, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA) is a 15-valent PCV containing 13 serotypes in licensed PCV13 and 2 additional serotypes (22F, 33F) which significantly contribute to pneumococcal disease burden. This phase 3 trial compared safety, tolerability, and immunogenicity of V114 to PCV13 in adults ≥50 years of age. METHODS: Adults were randomized 1:1 to receive a single dose of V114 or PCV13; randomization was stratified by age (50-64 years, 65-74 years, and ≥75 years). Adverse events (AEs) were collected following vaccination. Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were measured prior to and 30 days after vaccination (Day 30). Primary objectives included assessing noninferiority of V114 to PCV13 for the 13 shared serotypes and superiority of V114 to PCV13 for the two unique serotypes. Superiority of V114 to PCV13 for shared serotype 3 was assessed as a secondary objective. RESULTS: Overall, 1,202 participants were vaccinated (V114 N = 602, PCV13 N = 600). The most commonly reported AEs across both groups were injection-site pain, fatigue, and myalgia. V114 met noninferiority criteria compared to PCV13 for the 13 shared serotypes (using a 2-fold non-inferiority margin for the ratio of OPA geometric mean titers [GMTs] [V114/PCV13] at Day 30) and met superiority for the 2 unique serotypes (using a 2-fold super-superiority margin for the ratio of OPA GMTs [V114/PCV13] at Day 30 and a 0.10 super-superiority margin for the difference in proportions of participants with ≥4-fold rise from prevaccination to Day 30). V114 met superiority criteria compared to PCV13 for serotype 3 (based on a super-superiority margin of 1.2 for the ratio of the OPA GMTs [V114/PCV13] and a superiority margin of 0 for the difference in proportions of participants with ≥4-fold rise). [NCT03950622, EudraCT#2018-004316-22, Japic-CTI#194845].

Safety, tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, administered concomitantly with influenza vaccine in healthy adults aged ≥50 years: a randomized phase 3 trial (PNEU-FLU).

Streptococcus pneumoniae and influenza viruses are associated with significant morbidity and mortality in older adults. Concomitant vaccination against these agents reduces hospitalization and mortality rates. This phase 3 trial evaluated safety, tolerability, and immunogenicity of concomitant and non-concomitant administration of V114, a 15-valent pneumococcal conjugate vaccine containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F, 19A, 22F, 23F, 33F, and quadrivalent inactivated influenza vaccine (QIV), in healthy adults aged ≥50 years. Participants (N = 1,200) were randomized 1:1 to receive either V114 administered concomitantly with QIV (concomitant group) or QIV plus placebo (non-concomitant group) on Day 1, followed by placebo (concomitant group) or V114 (non-concomitant group) 30 days later. Randomization was stratified by age and history of pneumococcal polysaccharide vaccine receipt. Overall, 426 (71.0%) and 438 (73.5%) participants in the concomitant and non-concomitant groups experienced solicited injection-site adverse events (AEs); 278 (46.3%) and 300 (50.3%) reported solicited systemic AEs. Most solicited AEs were mild or moderate in severity and of short duration. Non-inferiority for pneumococcal- and influenza-specific antibody responses (lower bound 95% confidence interval of opsonophagocytic activity [OPA] and hemagglutination inhibition geometric mean titers [GMTs] ratios ≥0.5) was demonstrated for concomitant versus non-concomitant administration for all 15 pneumococcal serotypes and all four influenza strains. Consistent with previous studies, a trend was observed toward lower pneumococcal OPA GMTs in the concomitant versus the non-concomitant group. V114 administered concomitantly with QIV is generally well tolerated and immunologically non-inferior to non-concomitant administration, supporting coadministration of both vaccines.

The pipeline of new molecules and regimens against drug-resistant tuberculosis.

The clinical development and regulatory approval of bedaquiline, delamanid and pretomanid over the last decade brought about significant progress in the management of drug-resistant tuberculosis, providing all-oral regimens with favorable safety profiles. The Nix-TB and ZeNix trials of a bedaquiline - pretomanid - linezolid regimen demonstrated for the first time that certain forms of drug-resistant tuberculosis can be cured in the majority of patients within 6 months. Ongoing Phase 3 studies containing these drugs may further advance optimized regimen compositions. Investigational drugs in clinical development that target clinically validated mechanisms, such as second generation oxazolidinones (sutezolid, delpazolid, TBI-223) and diarylquinolines (TBAJ-876 and TBAJ-587) promise improved potency and/or safety compared to the first-in-class drugs. Compounds with novel targets involved in diverse bacterial functions such as cell wall synthesis (DrpE1, MmpL3), electron transport, DNA synthesis (GyrB), cholesterol metabolism and transcriptional regulation of ethionamide bioactivation pathways have advanced to early clinical studies with the potential to enhance antibacterial activity when added to new or established anti-TB drug regimens. Clinical validation of preclinical in vitro and animal model predictions of new anti-TB regimens may further improve the translational value of these models to identify optimal anti-TB therapies.