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Pneumococcal disease remains an important health priority despite successful implementation of pneumococcal conjugate vaccines (PCVs) in infant immunization programs, mainly due to the emergence of diseases caused by serotypes not included in licensed PCVs. A 15-valent pneumococcal conjugate vaccine (PCV-15) containing the 7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) included in licensed PCV-7 available at study initiation plus 8 additional serotypes (1, 3, 5, 6A, 7F, 19A, 22F, 33F) was developed and evaluated in healthy adults 18–45 years of age. Sixty subjects received one dose of PCV-15 or PCV-7. Injection-site and systemic adverse events (AEs) were collected for 14-days postvaccination and serious AEs were collected for 30-days postvaccination. Safety laboratory tests (hematology, chemistry, and urinalysis) were evaluated prior to vaccination and 14-days postvaccination. Serotype-specific IgG and opsonophagocytic killing activity (OPA) responses to 15 serotypes included in PCV-15 were measured immediately prior to vaccination and 30-days postvaccination. AE incidences were comparable between vaccine groups although numerically higher frequencies of erythema (33.3% versus 13.3%), swelling (50.0% versus 23.3%), and myalgia (63.3% versus 36.7%) were reported among PCV-15 versus PCV-7 recipients. Majority of AEs, irrespective of vaccine received, were transient and of mild-to-moderate intensity. No clinically significant differences were observed when comparing AE duration and severity. No laboratory abnormalities, vaccine-related SAEs or discontinuations from the study due to AEs were reported. IgG concentrations for the shared serotypes substantially increased postvaccination at comparable levels between recipients of PCV-15 and PCV-7. Substantial increases in antibody (IgG and OPA) responses to 8 serotypes unique to PCV-15 were observed in PCV-15 recipients. Slight increases to 2 serotypes unique to PCV-15, serotypes 6A and 19A, were also noted in PCV-7 recipients. PCV-15 displays an acceptable safety profile and induces IgG and OPA responses to all serotypes included in the vaccine.

Natural history studies have correlated serotype-specific anti-capsular polysaccharide (CPS) IgG in newborns with a reduced risk of group B streptococcal disease. A hexavalent CPS-cross-reactive material 197 glycoconjugate vaccine (GBS6) is being developed as a maternal vaccine to prevent invasive group B streptococcus in young infants. In an ongoing phase 2, placebo-controlled trial involving pregnant women, we assessed the safety and immunogenicity of a single dose of various GBS6 formulations and analyzed maternally transferred anti-CPS antibodies. In a parallel seroepidemiologic study that was conducted in the same population, we assessed serotype-specific anti-CPS IgG concentrations that were associated with a reduced risk of invasive disease among newborns through 89 days of age to define putative protective thresholds. Naturally acquired anti-CPS IgG concentrations were associated with a reduced risk of disease among infants in the seroepidemiologic study. IgG thresholds that were determined to be associated with 75 to 95% reductions in the risk of disease were 0.184 to 0.827 μg per milliliter. No GBS6-associated safety signals were observed among the mothers or infants. The incidence of adverse events and of serious adverse events were similar across the trial groups for both mothers and infants; more local reactions were observed in the groups that received GBS6 containing aluminum phosphate. Among the infants, the most common serious adverse events were minor congenital anomalies (umbilical hernia and congenital dermal melanocytosis). GBS6 induced maternal antibody responses to all serotypes, with maternal-to-infant antibody ratios of approximately 0.4 to 1.3, depending on the dose. The percentage of infants with anti-CPS IgG concentrations above 0.184 μg per milliliter varied according to serotype and formulation, with 57 to 97% of the infants having a seroresponse to the most immunogenic formulation. GBS6 elicited anti-CPS antibodies against group B streptococcus in pregnant women that were transferred to infants at levels associated with a reduced risk of invasive group B streptococcal disease. (Funded by Pfizer and the Bill and Melinda Gates Foundation; C1091002 ClinicalTrials.gov number, NCT03765073.).

Shigella remains in the top four pathogens responsible for moderate to severe diarrhoea in children below 5 years of age. The shigella O-specific polysaccharide (O-SP) is a promising vaccine target. We developed a conjugate vaccine prototype incorporating a unique well defined synthetic oligosaccharide hapten, chemically designed for optimal antigenic, conformational, structural, and functional mimicry of the O-SP from Shigella flexneri 2a (SF2a). We aimed to assess the safety, tolerability, and immunogenicity of this original synthetic oligosaccharide-based vaccine candidate, SF2a-TT15, conceived to drive the antibody response towards the key protective determinants of the native lipopolysaccharide antigen, in a first-in-human phase 1 study. We did a first-in-human, dose-escalating, single-blind, observer-masked, randomised, placebo-controlled study at the Clinical Research Center of Tel Aviv Sourasky Medical Center (Israel). Participants were healthy adults aged 18–45 years with low titres of serum SF2a-specific IgG antibodies. 64 eligible participants were assigned to one of two cohorts. 32 participants in each of the two cohorts were randomly assigned via computer-generated algorithm in a stepwise manner to receive the 2 μg (cohort 1) and 10 μg oligosaccharide dose (cohort 2) of the SF2a-TT15 vaccine candidate non-adjuvanted or adjuvanted with aluminium hydroxide (alum) or matching placebos. The vaccine was administered as three single intramuscular injections into the arm, 28 days apart. The primary outcome was the incidence and severity of adverse events, which were assessed in the intention-to-treat safety population analysis including all participants who were randomly assigned and received at least one vaccine or placebo injection. The immunogenicity endpoints were secondary outcomes and were analysed in all participants who were randomly assigned, received all of the assigned injections before the time of the immunogenicity assessment, and provided blood samples for immunological follow-up (per-protocol immunogenicity analysis). The study is registered with ClinicalStudies.gov, NCT02797236 and is completed. Of 203 volunteers initially screened, 64 participants were enrolled between Sept 20, 2016, and Sept 26, 2017. In each of the two cohorts, 12 participants received the adjuvanted vaccine, 12 received the non-adjuvanted vaccine and eight received the matching placebo (four each). The SF2a-TT15 glycoconjugate was well tolerated at both doses. No serious or severe adverse events occurred. Overall, seven (88%) of eight to 12 (100%) of 12 in each group of volunteers had one adverse event or more after receiving the study agents with the majority of adverse events, 300 (98%) of 307, considered mild in intensity. Of the seven adverse events defined as moderate in severity, one (nausea) was suspected to be related to the vaccine candidate. At all post-immunisation days and for both oligosaccharide doses, whether adjuvanted or not, SF2a-TT15 induced significantly higher serum IgG anti-SF2a lipopolysaccharide geometric mean titres (GMTs) as compared with baseline or with the corresponding GMTs in placebo recipients (p<0·01). After one injection, the non-adjuvanted 10 μg oligosaccharide dose induced a 27-times increase in IgG GMT (5080 vs 189) and the non-adjuvanted 2 μg oligosaccharide dose induced a five-times increase (1411 vs 283), compared with baseline. Alum enhanced the specific IgG response at 2 μg oligosaccharide dose after the third injection (GMTs 3200 vs 1176, p=0.045). SF2a-TT15 was safe and well tolerated and induced high titres of anti-SF2a LPS IgG antibodies. These results support further evaluation of this original synthetic oligosaccharide-protein conjugate vaccine candidate for safety, immunogenicity, and protective efficacy in target populations. The European Union Seventh Framework Programme.

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. 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). 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. 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. Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA (MSD).

Pneumococcal disease (PD) prevention remains an unmet medical need in older adults. V116 is an adult-specific, 21-valent pneumococcal conjugate vaccine (PCV) specifically designed to provide protection against pneumococcal serotypes associated with a large proportion of residual invasive pneumococcal disease (IPD). This phase 3 study evaluated the safety, tolerability, and immunogenicity of V116 compared with 23-valent pneumococcal polysaccharide vaccine (PPSV23) in Japanese older adults (NCT05633992). In this phase 3, randomized, double-blind, active comparator-controlled study, 450 vaccine-naïve adults ≥65 years of age were randomized 1:1 to receive a single dose of V116 or PPSV23. Primary immunogenicity objectives were to assess opsonophagocytic activity (OPA) and demonstrate: i) non-inferiority for V116 versus PPSV23 across 12 common serotypes, and cross-reactive serotype 15B in V116, based on geometric mean titers (GMTs) at Day 30; and ii) superiority for nine serotypes unique to V116 based on the proportions of participants exhibiting ≥4 fold rises in serotype-specific OPA responses between baseline and Day 30 (excluding serotype 15C) or based on GMTs at Day 30 (serotype 15C only). The primary safety outcome measured the proportion of participants with adverse events (AEs). V116 was non-inferior compared with PPSV23 for the 12 common serotypes and for the cross-reactive serotype 15B. V116 was superior compared with PPSV23 for the nine unique serotypes (including serotype 15C). The proportion of participants with AEs was comparable between V116 and PPSV23, and there were no vaccine-related serious AEs or deaths. In vaccine-naïve Japanese adults ≥65 years of age, V116 is well tolerated, with a safety profile comparable to PPSV23, and elicits immune responses to all V116 serotypes and the cross-reactive serotype 15B. V116 has the potential to broaden protection against PD in Japan through the inclusion of serotypes responsible for the majority of residual PD in adults. •IPD burden is highest in adults ≥65 years of age; this group accounts for 29 % of Japan's population.•Residual PD remains an unmet medical need, partly caused by non-vaccine-type serotypes.•Serotypes in V116 are responsible for ∼80 % of residual IPD in individuals ≥15 years of age in Japan.•V116 has the potential to broaden protection against residual PD in adults.

•All 3 doses of VAX-24 were well tolerated, with a safety profile similar to PCV20.•All treatment arms resulted in robust increases in OPA GMTs and IgG GMCs.•VAX-24 achieved higher serotype valency and enhanced immune responses versus PCV20. Despite current polysaccharide and conjugate vaccine use, pneumococcal diseases remain prevalent in older adults. VAX-24 is a 24-valent pneumococcal conjugate vaccine (PCV) containing eCRM, a proprietary carrier protein with non-native amino acids (para-azidomethyl-L-phenylalanine) that undergo site-specific conjugation to pneumococcal polysaccharides that have been activated with a small-molecule linker (dibenzocyclooctyne). Site-specific conjugation utilizing click chemistry enables consistent exposure of T-cell epitopes, reduction in carrier protein to pneumococcal polysaccharide ratio, and enhances manufacturing process consistency to improve PCVs by increasing serotype coverage while minimizing carrier suppression. Healthy adults aged 65 or older were randomized in a 1:1:1:1 ratio to receive a single injection of VAX-24 at 1 of 3 dose levels (1.1, 2.2, or a mixed dose of 2.2 or 4.4 mcg) or Prevnar 20® (PCV20) in a phase 2, blinded study. Primary outcome measures were solicited local and systemic events within 7 days post-vaccination, unsolicited adverse events (AEs) within 1 month, and serious AEs, medically attended AEs, or new onset of chronic disease within 6 months of vaccination. Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) were measured pre-vaccination and at 1 month post-vaccination. Of 207 participants enrolled, 200 completed the trial. Safety profiles were comparable across the three VAX-24 doses and PCV20. Robust OPA and IgG immune responses were seen for all 24 serotypes. On average, immune responses to VAX-24 2.2 mcg dose were similar or higher compared to PCV20. In adults ≥ 65 years, VAX-24 had a safety profile similar to PCV20 through six months post-vaccination and induced robust OPA and IgG responses to all 24 serotypes, supporting prior data showing that site-specific conjugation allows for increased serotype coverage with similar or higher immune response vs other PCVs. The outcome of this phase 2 study further supports use of VAX-24 2.2 mcg dose in phase 3 trials. Clinicaltrials.gov: NCT05297578.

In 2010, a Meningococcal group A (MenA) conjugate vaccine (PsA-TT) was WHO prequalified and introduced in preventive campaigns in 1–29 year-olds across the African Meningitis Belt. An extension of the indication to infants and toddlers in the Expanded Programme on Immunization (EPI) was pursued for the protection of new birth cohorts. Between 2008 and 2012, a Phase 2 randomized controlled trial was conducted in Ghana to assess the safety and immunogenicity of different PsA-TT formulations (10 μg, 5 μg or 2.5 μg of MenA polysaccharide) given as one or two doses with EPI vaccines at 14–18 weeks, 9–12 months, and 12–18 months of age (Study A). Between 2012 and 2013, a subsequent Phase 3 randomized controlled trial was conducted in Mali to assess the 10 μg and 5 μg formulations given as one or two doses with EPI vaccines at 9–12 and 15–18 months of age (Study B). Immunogenicity was assessed using a serum bactericidal antibody assay using rabbit complement (rSBA). Non-inferiority of the 5 μg and 2.5 μg PsA-TT formulations to the 10 μg formulation was demonstrated in Study A with ≥93 % seroconversion in MenA rSBA 28 days after each dose. Non-inferiority of the 5 μg to the 10 μg was demonstrated in Study B in terms of seroconversion in MenA rSBA at 28 days (≥97 %) when given as two doses at 9–12 and 15–18 months and as a single dose at 9–12 months. Non-inferiority with respect to most EPI antigens was demonstrated in pairwise comparisons across both studies. Adverse events and serious adverse events reported in either study following vaccinations were similar across vaccine groups. Results of both trials showed that the vaccine was safe and immunogenic when co-administered with the EPI, paving the way for a WHO recommendation for the 5 μg PsA-TT to be included in the EPI as a single dose at 9–18 months of age. PsA-TT-004, registered International Standard Randomized Controlled Trial Number: ISRCTN82484612; PsA-TT-007, International registration number: PACTR201110000328305. •Three MenA vaccine formulations were found to be safe and immunogenic when co-administered with EPI in Ghanaian infants.•Subsequently, 5-& 10-μg formulations were found to be safe and imunogenic when co-administered in 9-18 months Malians.•Both studies led to licensure and recommendation of the 5-μg formulation as a single dose in the EPI in the Meningitis Belt.

This phase 3, randomized, partially double-blind study investigated the safety, tolerability, and immunogenicity of 20-valent pneumococcal conjugate vaccine (PCV20) in healthy toddlers ≥12–<24 months of age who had previously received 2 infant doses of 13-valent PCV (PCV13). Participants were randomized to receive 1 or 2 doses of PCV20 (the second dose was administered 56–70 days after the first dose), or 1 dose of PCV13. The primary pneumococcal immunogenicity endpoint was the percentages of participants with predefined serotype-specific immunoglobulin G (IgG) concentrations (≥0.35 μg/mL) for the 7 additional serotypes 1 month after the last vaccination. Percentages of participants with predefined IgG concentrations for the 13 matched serotypes, IgG geometric mean concentrations, and opsonophagocytic activity (OPA) geometric mean titers were also evaluated for all 20 vaccine serotypes. Safety endpoints included local reactions, systemic events, adverse events, and serious adverse events. Overall, 356 participants were randomized (2-dose PCV20, n = 121; 1-dose PCV20, n = 118; PCV13, n = 117). One month after 1 PCV20 dose, ≥75.9 % of participants had IgG concentrations ≥0.35 μg/mL for all 7 additional serotypes, except serotype 12F (54.6 %). After 2 PCV20 doses, the percentage of participants with IgG concentrations ≥0.35 μg/mL for the 7 additional serotypes was ≥91.2 %. PCV20 elicited IgG and OPA responses for all 20 serotypes including serotype 12F. IgG distributions were well differentiated and substantially higher in PCV20 groups than the PCV13 group for the 7 additional serotypes, and generally similar between all groups for the 13 matched serotypes. In conclusion, a single toddler dose of PCV20 after 2 infant PCV13 doses elicited immune responses expected to help provide protection against the 7 additional serotypes and to provide similar protection against the 13 matched serotypes as PCV13. These data support a transition from PCV13 to PCV20 at the toddler dose. The safety and tolerability profile of PCV20 was similar to PCV13. Trial registration:Clinicaltrials.gov, NCT05408429. •PCV20 safety, tolerability, and immunogenicity in healthy toddlers was investigated.•Participants had previously received 2 infant doses of PCV13.•PCV20 single toddler dose expected to help protect against 7 additional serotypes.•PCV20 expected to provide similar protection as PCV13 against 13 matched serotypes.•The safety/tolerability profile of PCV20 toddler doses was similar to PCV13.

Pneumococcal conjugate vaccines (PCVs) are generally administered in infant schedules with other vaccines. Here, we describe the safety and immunogenicity of routinely recommended pediatric vaccines given with 20-valent-PCV (PCV20). Two phase 3, double-blind, randomized trials evaluated the safety, tolerability, and immunogenicity of PCV20 in infants with concomitant pediatric vaccines. The studies examined a 4-dose series (Study B7471011/NCT04382326; N = 1997) and a 3-dose series (Study B7471012/NCT04546425; N = 1207). Concomitant vaccinations included a combination vaccine (diphtheria, tetanus, acellular pertussis [DTaP] with hepatitis B and poliovirus antigens (DTaP-HBV-IPV) and Haemophilus influenzae type b vaccine [Hib]) in Study B7471011 or combined vaccine (DTaP, hepatitis B, poliovirus, and Hib antigens [DTaP-HBV-IPV/Hib]) in Study B7471012. Measles, mumps, rubella (MMR) and varicella vaccines were given concomitantly with the toddler dose in both studies. Immunogenicity objectives were to demonstrate noninferiority of immune responses to concomitant vaccine antigens for concomitant vaccines given with PCV20 to those given with 13-valent PCV (PCV13). Safety endpoints included systemic events and adverse events (AEs). Noninferiority was met for the primary objectives of percentage of participants with prespecified antibody levels to the DTaP-HBV-IPV and Hib 1 month after the third infant dose (Study B7471011) and 1 month after the toddler dose of DTaP-HBV-IPV/Hib (Study B7471012) in the PCV20 group compared with the PCV13 group. Noninferiority was also met for the geometric mean antibody levels to MMR and varicella vaccines 1 month after the toddler dose in both studies. Systemic event frequencies were similar in the PCV20 and PCV13 groups in both studies, with severity mostly reported as mild or moderate. Frequencies of reported AEs were similar between the PCV20 and PCV13 groups. Immune responses to routine pediatric vaccines given with PCV20 were noninferior to those when given with PCV13. PCV20 may be safely administered with other routine pediatric vaccines. (NCT04382326; NCT04546425). •Two phase 3, double-blind, randomized trials evaluated PCV20 in infants.•The studies included concomitant administration of routine pediatric vaccines.•Immune responses to these concomitant pediatric vaccines were evaluated.•Responses to concomitant vaccines were noninferior with PCV20 to those with PCV13.•PCV20 may be safely administered with other routine pediatric vaccines.

In a phase 3 noninferiority trial, one dose of a new meningococcal vaccine (NmCV-5) elicited immune responses similar to those of MenACWY-D for the four serotypes in common and additional immune responses for serogroup X.