Safety,tolerability, and immunogenicity of V114 pneumococcal vaccine compared with PCV13 in a 2+1 regimen in healthy infants: A phase III study (PNEU-PED-EU-2)

BackgroundThis phase III study evaluated safety, tolerability, and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine) in healthy infants. V114 contains all 13 serotypes in PCV13 and additional serotypes 22F and 33F.MethodsHealthy infants were randomized to two primary doses and one toddler dose (2+1 regimen) of V114 or PCV13 at 3, 5, and 12 months of age; diphtheria, tetanus, pertussis (DTaP), inactivated poliovirus (IPV), Haemophilus influenzae type b (Hib), hepatitis B (HepB) vaccine was administered concomitantly. Adverse events (AEs) were collected on Days 1–14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-primary series, immediately prior to toddler dose, and 30 days post-toddler dose. Primary objectives included non-inferiority of V114 to PCV13 for 13 shared serotypes and superiority of V114 to PCV13 for serotypes 22F and 33F.Results1191 healthy infants were randomized to V114 (n = 595) or PCV13 (n = 596). Proportions of participants with solicited AEs and serious AEs were comparable between groups. V114 met non-inferiority criteria for 13 shared serotypes, based on difference in proportions with serotype-specific IgG ≥0.35 μg/mL (lower bound of two-sided 95% confidence interval [CI] >−10.0) and IgG geometric mean concentration (GMC) ratios (lower bound of two-sided 95% CI >0.5) at 30 days post-toddler dose. V114 met superiority criteria for serotypes 22F and 33F, based on response rates (lower bound of two-sided 95% CI >10.0) and IgG GMC ratios (lower bound of two-sided 95% CI >2.0) at 30 days post-toddler dose.Antibody responses to DTaP-IPV-Hib-HepB met non-inferiority criteria, based on antigen-specific response rates.ConclusionA two-dose primary series plus toddler dose of V114 was well-tolerated in healthy infants. Compared with PCV13, V114 provided non-inferior immune responses to 13 shared serotypes and superior immune responses to additional serotypes 22F and 33F.     

Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine in Japanese healthy infants: A phase III study (V114-033)

BackgroundThis phase III study evaluated safety, tolerability, and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine) in Japanese infants. V114 contains all 13 serotypes in PCV13 plus additional serotypes 22F and 33F.MethodsHealthy Japanese infants were randomized to receive three primary doses of V114 or PCV13 (dose 1 at 2–6 months of age; doses 2 and 3 ≥ 27 days after prior dose), plus a toddler dose at 12–15 months of age. Adverse events (AEs) were collected on Days 1–14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-dose 3, pre-dose 4, and 30 days post-dose 4. Primary objectives included non-inferiority of V114 to PCV13 for the 13 shared serotypes based on serotype-specific IgG response rates (IgG ≥ 0.35 μg/mL) and geometric mean concentration (GMC) ratios, and for serotypes 22F and 33F based on IgG response rates and compared with the lowest response of any serotype in the PCV13 group, at 30 days post-dose 3.ResultsOverall, 694 infants were randomized to V114 (n = 347) or PCV13 (n = 347). Proportions of participants with solicited and serious AEs were comparable between vaccination groups. V114 met non-inferiority criteria for all 13 shared serotypes, based on difference in proportion of responders (lower bound of two-sided 95 % confidence interval [CI] > −10.0) and IgG GMC ratios (V114/PCV13, lower bound of two-sided 95 % CI > 0.5) at 30 days post-dose 3. The non-inferiority criterion based on IgG response rates was met for serotype 22F, but narrowly missed for serotype 33F (90.9 %, lower bound of two-sided 95 % CI −10.6).ConclusionIn Japanese infants, a four-dose series of V114 was generally well tolerated. Compared with PCV13, V114 provided non-inferior immune responses to the 13 shared serotypes and higher immune responses to serotype 22F and 33F post-primary series.Trial registration: ClinicalTrials.gov: NCT04384107; EudraCT 2019-003644-68.     

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)

BackgroundOlder 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.MethodsAdults 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.ResultsOf 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).ConclusionsV114 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).     

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)

BackgroundPneumococcal 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 (VAXNEUVANCE^TM, 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.MethodsAdults 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.ResultsOverall, 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,followed by sequential PPSV23 vaccination in healthy adults aged ≥50 years: A randomized phase III trial (PNEU-PATH)

BackgroundStreptococcus pneumoniae causes pneumococcal disease, and older adults are at an increased risk. Sequential vaccination of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for broad protection against pneumococcal disease in some countries.MethodsThis phase III 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 12 months later by PPSV23, in healthy adults aged ≥50 years (NCT03480763). A total of 652 participants were randomized 1:1 to receive either V114 or PCV13, followed by PPSV23.ResultsThe most common solicited adverse events (AEs) following PCV vaccination included injection-site pain and fatigue. Higher proportions of participants with these events were observed in the V114 group following PCV; however, these differences were not clinically significant. Following PPSV23 vaccination, the most common solicited AEs were injection-site pain and injection-site swelling; the proportions of participants with these events were comparable between both groups. Incidence of serious AEs was low in both groups following PCV and PPSV23, and none were related to study vaccines. No deaths occurred during the study. Serum opsonophagocytic activity geometric mean titers and immunoglobulin G geometric mean concentrations were comparable between both groups for all 15 serotypes in V114 following PPSV23. Immune responses elicited by V114 persisted for at least 12 months. Immune responses at 30 days and 12 months post-vaccination with PCV were comparable between both groups for the 13 shared serotypes and higher in the V114 group for the V114-unique serotypes (22F and 33F).ConclusionAdministration of V114 followed by PPSV23 was well tolerated and induced comparable antibody levels to PCV13 followed by PPSV23 in healthy adults aged ≥50 years.     

Immunogenicity of PCV24, an expanded pneumococcal conjugate vaccine,in adult monkeys and protection in mice

Invasive pneumococcal disease (IPD) is responsible for serious illnesses such as bacteremia, sepsis, meningitis, and pneumonia in young children, older adults, and persons with immunocompromising conditions and often leads to death. Although the most recent pneumococcal conjugate vaccines (PCVs) have been designed to target serotypes identified as the primary causative agents of IPD, the epidemiological landscape continues to change stressing the need to develop new PCVs. We have developed an investigational 24-valent PCV (PCV24) including serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F all conjugated to CRM197 and evaluated this vaccine in adult monkeys. PCV24 was shown to be immunogenic and induced functional antibody for all vaccine serotypes. Of the serotypes common to PCV13 and V114 (PCV15), PCV24 had a similar immunogenic response with the exceptions of 23F which had higher IgG GMCs for PCV13 and V114, and 7F which had higher GMCs for PCV13. Functional antibody responses were similar for the serotypes in common between PCV24, PCV13 and V114 vaccines, with the exception of serotype 7F which was greater for PCV13. Overall, this study shows that PCV24 provided similar immunogenicity as the lower valent vaccines in adult monkeys with no apparent serotype interference. In addition, PCV24 also provided protection against pneumococcal infection in a mouse challenge model.     

Immunogenicity and safety of 7-valent pneumococcal conjugate vaccine (PCV7) in children aged 2–5 years in China

BackgroundThe widespread use of pneumococcal conjugate vaccines (PCVs) has significantly decreased pneumococcal disease worldwide. However, China has not adopted PCVs in their national immunization schedules and had only approved these vaccines for children aged 2–15 months by 2020.MethodsIn an open-label trial, enrolled healthy children aged 2–5 years old were randomized 1:1 and divided into a 7-valent pneumococcal conjugate vaccine (PCV7) group and a Haemophilus influenzae type b conjugate vaccine (Hib) group. Children in the PCV7 group received a single dose of PCV7, and the Hib group received a single dose of Hib vaccine. Blood samples were collected before and 6 months after vaccination. Immunogenicity and safety of PCV7 were assessed at prespecified time points.ResultsSix months after a single dose of PCV7, children in the PCV7 group for all 7 serotypes, IgG mean concentrations (GMCs) and opsonophagocytic geometric mean titres (GMTs) were significantly higher (P < .001) than at baseline, and the proportion of IgG ≥ 0.35 µg/mL ranged from 90.0% to 100%. Although the antibody level increased with age, preexisting antibodies did not induce hyporesponsiveness to PCV7. In the Hib group, the antibody levels were not significantly different or had changed slightly at 6 months. PCV7 was well tolerated in all age groups, and no serious adverse events (AEs) emerged during this study.ConclusionsA single dose of PCV7 was immunogenic and safe for Chinese children aged 2–5 years, and the preexisting antibodies against the PCV7 serotypes did not change the response to vaccination. The findings supported the effectiveness of PCV7 in this age group. PCVs with broader serotype coverage are expected to expand pneumococcal disease protection.     

A phase 3, randomized,double-blind study to evaluate the immunogenicity and safety of 3 lots of 20-valent pneumococcal conjugate vaccine in pneumococcal vaccine-naive adults 18 through 49 years of age

IntroductionIntroduction of pneumococcal conjugate vaccines (PCVs), including the 13-valent PCV (PCV13), has considerably reduced pneumococcal disease burden. However, additional serotypes not in PCV13 continue to present a substantial disease burden. The 20-valent PCV (PCV20) was developed to expand protection against pneumococcal disease beyond PCV13. As part of the phase 3 clinical development program, the current study assessed consistency of immune responses across 3 lots of PCV20 and described the safety profile of PCV20.MethodsThis phase 3, randomized, multicenter, double-blind study of pneumococcal vaccine-naive adults 18–49 years of age randomized 1710 participants in a 2:2:2:1 ratio to receive 1 of 3 lots of PCV20 or PCV13. Immunogenicity was assessed through serotype-specific opsonophagocytic activity (OPA) titers before and approximately 1 month (28–42 days) after vaccination. Reported local reactions within 10 days, systemic events within 7 days, adverse events (AEs) within 30 days, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) within 6 months after vaccination were evaluated.ResultsEquivalence in immune responses (OPA geometric mean titers) for all 20 vaccine serotypes was demonstrated across the 3 PCV20 lots. Robust responses, assessed by OPA geometric mean fold rises, percentage of participants achieving ≥4-fold rises, and percentage of participants with OPA titers ≥lower limit of quantitation, were observed after PCV20. Reported rates of local reactions, systemic events, and AEs were similar between the pooled PCV20 lots and PCV13; most events were mild or moderate. Reported rates of SAEs and NDCMCs were low and similar between the PCV20 and PCV13 groups.ConclusionsThree different lots of PCV20 demonstrated robust and consistent immunogenicity. The safety and tolerability of PCV20 was acceptable and similar to that of PCV13. (Clinicaltrials.gov: NCT03828617).     

A trial to evaluate the safety and immunogenicity of a 20-valent pneumococcal conjugate vaccine in populations of adults ≥65 years of age with different prior pneumococcal vaccination

IntroductionA 20-valent pneumococcal conjugate vaccine, PCV20, was developed to expand protection against vaccine-preventable pneumococcal disease. PCV20 contains the components of the 13-valent pneumococcal conjugate vaccine, PCV13, and includes capsular polysaccharide conjugates for 7 additional serotypes. Thus, PCV20 may cover those additional serotypes in individuals previously vaccinated with PCV13 or provide benefits of immunization with a conjugate vaccine to individuals previously immunized with a pneumococcal polysaccharide vaccine. This study described the safety and immunogenicity of PCV20 in adults ≥65 years of age with prior pneumococcal vaccination.MethodsThis phase 3, multicenter, randomized, open-label study was conducted in the United States and Sweden. Adults ≥65 years of age were enrolled into 1 of 3 cohorts based on their prior pneumococcal vaccination history (23-valent pneumococcal polysaccharide vaccine [PPSV23], PCV13, or both PCV13 and PPSV23). Participants were randomized 2:1 within their cohort to receive a single dose of PCV20 or PCV13 in those with prior PPSV23 only, and PCV20 or PPSV23 in those with prior PCV13 only; all participants with prior PCV13 and PPSV23 received PCV20. Safety was assessed by prompted local reactions within 10 days, systemic events within 7 days, adverse events (AEs) within 1 month, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) within 6 months after vaccination. Immune responses 1 month after PCV20 were assessed.ResultsThe percentages of participants reporting local reactions, systemic events, and AEs after PCV20 administration were similar across cohorts and comparable with the PCV13 and PPSV23 control groups. SAE and NDCMC rates were low in all groups. Robust immune responses, including opsonophagocytic antibody responses, to the 20 vaccine serotypes were observed 1 month after PCV20 regardless of prior pneumococcal vaccination.ConclusionsPCV20 was well tolerated and immunogenic in adults ≥65 years of age previously vaccinated with different pneumococcal vaccine regimens.Clinicaltrials.gov NCT03835975.     

Distribution of serotypes causing invasive pneumococcal disease in older adults from high-income countries and impact of pediatric and adult vaccination policies

BackgroundNeither indirect protection through use of 13-valent and 10-valent pneumococcal conjugate vaccines (PCV13 and PCV10) in pediatric National Immunization Programs (NIPs) nor direct vaccination with the 23-valent polysaccharide vaccine have eliminated vaccine serotype invasive pneumococcal disease (IPD) in older adults. Vaccinating older adults with higher-valency PCV15 and PCV20 could address remaining IPD due to pediatric PCV serotypes plus additional IPD due to serotypes included in these vaccines.MethodsWe collected serotype-specific IPD data in older adults (≥65 years in most countries), from national or regional surveillance systems or hospital networks of 33 high-income countries. Data were from official government websites, online databases, surveillance system reports, published literature, and personal communication with in-country investigators. Average percentages of IPD serotypes were calculated.ResultsAmong 52,905 cases of IPD with a serotype identified, PCV13 serotypes accounted for 33.7% of IPD (55.8% and 30.6% for countries with PCV10 and PCV13 in the pediatric NIP), most commonly serotypes 3 (14.9%) and 19A (7.0%). PCV15 and PCV20 would cover an additional 10.4% and 32.9% of older adult IPD beyond PCV13 serotypes (PCV10 countries: 7.7% and 23.3%; PCV13 countries: 10.6% and 34.6%). The most common of these additional serotypes were 8 (9.9%), 22F (7.9%), 12F (4.6%), and 11A (3.3%). PPSV23 policies for older adults were not correlated with lower IPD percentages due to PPSV23 serotypes.ConclusionsVaccinating older adults with higher-valency PCVs, especially PCV20, could substantially reduce the remaining IPD burden in high-income countries, regardless of current PCV use in pediatric NIPs and adult PPSV23 policies.     

Randomized trial to evaluate the safety,tolerability, and immunogenicity of a booster (third dose) of BNT162b2 COVID-19 vaccine coadministered with 20-valent pneumococcal conjugate vaccine in adults ≥65 years old

BackgroundOlder adults are at increased risk of adverse outcomes from pneumococcal disease and COVID-19. Vaccination is an established strategy for preventing both illnesses. This study evaluated the safety and immunogenicity of coadministration of the 20-valent pneumococcal conjugate vaccine (PCV20) and a booster (third dose) of BNT162b2 COVID-19 vaccine.MethodsThis phase 3, randomized, double-blind, multicentre study included 570 participants aged ≥65 years randomized 1:1:1 to PCV20 and BNT162b2 coadministered, or PCV20 or BNT162b2 only (administered with saline for blinding). Primary safety endpoints included local reactions, systemic events, adverse events (AEs) and serious AEs (SAEs). Secondary objectives were immunogenicity of PCV20 and BNT162b2 when administered together or separately.ResultsCoadministration of PCV20 and BNT162b2 was well tolerated. Local reactions and systemic events were generally mild-moderate; injection-site pain and fatigue were the most frequent local and systemic events, respectively. AE and SAE rates were low and similar across groups. No AEs led to discontinuation; no SAEs were considered vaccination-related. Robust immune responses were observed, with opsonophagocytic activity geometric mean fold rises (GMFRs; from baseline to 1 month) of 2.5–24.5 and 2.3–30.6 across PCV20 serotypes in Coadministration and PCV20-only groups, respectively. GMFRs for full-length S-binding IgG of 35.5 and 39.0, and for neutralizing titres against SARS-CoV-2-wild type virus of 58.8 and 65.4, were observed in the Coadministration and BNT162b2-only groups, respectively.ConclusionsSafety and immunogenicity of coadministered PCV20 and BNT162b2 were similar to those of PCV20 or BNT162b2 administered alone, suggesting that the 2 vaccines may be coadministered.Trial Registration: ClinicalTrials.gov, NCT04887948.     

Non-immunization associated with increased risk of sudden unexpected death in infancy: A national case–control study

ObjectiveIn the context of vaccine scepticism, our study aimed to analyse the association between immunization status and the occurrence of sudden unexpected death in infancy (SUDI).Study design: A multi-centre case–control study was conducted between May 2015 and June 2017 with data from the French national SUDI registry (OMIN) for 35 French regional SUDI centres. Cases were infants under age 1 year who died from SUDI and who were registered in OMIN. Controls, matched to cases by age and sex at a 2:1 ratio, were infants admitted to Nantes University Hospital. All immunization data for diphtheria (D), tetanus (T), acellular pertussis (aP), inactivated poliovirus (IPV), Haemophilus influenzae b (Hib), hepatitis B (HB) and 13-valent pneumococcal conjugate vaccine (PCV13) were collected by a physician. Cases and controls were considered immunized if at least one dose of vaccine was administered.ResultsA total of 91 cases and 182 controls were included. The median age was 131 days (interquartile range 98–200.0) and the sex ratio (M/F) was about 1.1. For all vaccines combined (D-T-aP-IPV-Hib and PCV13), 22 % of SUDI cases versus 12 % of controls were non-immunized, which was significantly associated with SUDI after adjustment for potential adjustment factors (adjusted odds ratio 2.01 [95 % confidence interval 1.01–3.98, p = 0,047]).ConclusionsNon-immunization for D-T-aP-IPV-Hib-HB and PCV13 was associated with increased risk of SUDI. This result can be used to inform the general public and health professionals about this risk of SUDI in case of vaccine hesitancy.     

Kinetics of pneumococcal antibodies among HIV-exposed,uninfected infants in Botswana

BackgroundStreptococcus pneumoniae is a leading cause of severe infections among children. Despite vaccination, HIV-exposed, uninfected (HEU) children have a higher incidence of invasive pneumococcal disease than HIV-unexposed, uninfected (HUU) children. We sought to compare the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV-13) in HEU and HUU infants.MethodsWe conducted a prospective cohort study of 134 mother-infant dyads in Botswana. Infants received PCV-13 doses at 2, 3, and 4 months through routine clinical care. We measured IgG antibodies specific to vaccine serotypes in sera collected from infants at 0, 5, and 12 months of age. We calculated the proportion of infants with protective IgG levels (≥0.35 µg/mL) to specific pneumococcal serotypes.ResultsAt birth, fewer than half of infants had protective IgG levels to serotypes 1 (38%), 3 (46%), 4 (33%), 5 (23%), 6B (40%), 7F (44%), 9 V (44%), and 23F (46%). Compared to HUU infants (n = 97), HEU infants (n = 37) had lower antibody concentrations at birth to serotypes 5 (p = 0.046) and 19A (p = 0.008) after adjustment for maternal age and infant birth weight. More than 80% of HEU and HUU infants developed protective antibody levels to each of the 13 vaccine serotypes following PCV-13 vaccination. Median concentrations of antibodies to pneumococcal serotypes declined by 55–93% between 5 and 12 months of age, with fewer than half of infants having protective antibody levels to serotypes 1 (47%), 3 (28%), 9 V (44%), 18C (24%), and 23F (49%) at 12 months of age.ConclusionsBoth HEU and HUU infants developed protective antibody responses to PCV-13 administered in a 3 + 0 schedule. However, antibody concentrations to many pneumococcal serotypes waned substantially by 12 months of age, suggesting that a PCV-13 booster dose in the second year of life may be needed to maintain protective pneumococcal antibody levels in older infants and young children.     

Preclinical evaluation of an investigational 21-valent pneumococcal conjugate vaccine,V116, in adult-rhesus monkey,rabbit, and mouse models

Despite the widespread effectiveness of pneumococcal conjugate vaccines on the overall incidence of invasive pneumococcal disease, the global epidemiological landscape continues to be transformed by residual disease from non-vaccine serotypes, thus highlighting the need for vaccines with expanded disease coverage. To address these needs, we have developed V116, an investigational 21-valent non-adjuvanted pneumococcal conjugate vaccine (PCV), containing 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) individually conjugated to the nontoxic diphtheria toxoid CRM197 carrier protein. Preclinical studies evaluated the immunogenicity of V116 in adult monkeys, rabbits, and mice. Following one dose, V116 was found to be immunogenic in preclinical animal species and induced functional antibodies for all serotypes included in the vaccine, in addition to cross-reactive functional antibodies to serotypes 6C and 15B. In these preclinical animal studies, the increased valency of V116 did not result in serotype-specific antibody suppression when compared to lower valent vaccines V114 or PCV13. In addition, when compared with naïve controls, splenocytes from V116 to immunized animals demonstrated significant induction of CRM197-specific T cells in both IFN-γ and IL-4 ELISPOT assays, as well as Th1 and Th2 cytokine induction through in vitro stimulation assays, thus suggesting the ability of V116 to engage T cell dependent immune response pathways to aid in development of memory B cells. V116 also demonstrated significant protection in mice from intratracheal challenge with serotype 24F, a novel serotype not contained in any currently licensed vaccine.     

Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV15) in healthy infants

BackgroundPediatric use of pneumococcal conjugate vaccines (PCV) has been associated with significant decrease in disease burden. However, disease caused by non-vaccine serotypes has increased. Safety and immunogenicity of 15-valent PCV (PCV15) containing serotypes included in 13-valent PCV (PCV13) plus serotypes 22F and 33F were evaluated in infants (NCT01215188).MethodsInfants received adjuvanted PCV15, nonadjuvanted PCV15, or PCV13 at 2, 4, 6, and 12–15 months of age. Safety was monitored for 14 days after each dose. Serotype-specific IgG geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured at postdose-3, predose-4, and postdose-4.ResultsSafety profiles were comparable across vaccination groups. At postdose-3, both PCV15 formulations were non-inferior to PCV13 for 10 of 13 shared serotypes but failed non-inferiority for 3 serotypes (6A, 6B, and 19A) based on proportion of subjects achieving IgG GMC ≥0.35 µg/mL. Adjuvanted PCV15 and nonadjuvanted PCV15 were non-inferior to PCV13 for 11 and 8 shared serotypes, respectively, based on postdose 3 comparisons of GMC ratios. PCV15 induced higher antibodies to serotypes 3, 22F, and 33F than PCV13.ConclusionsPCV15 displayed acceptable safety profile and induced IgG and OPA to all 15 vaccine serotypes at levels comparable to PCV13 for 10 of 13 shared serotypes.Study identification: V114-003.CLINICALTRIALS.GOV identifier: NCT01215188.     

A phase 3, multicenter,randomized, double-blind,active-comparator-controlled study to evaluate the safety,tolerability, and immunogenicity of a 4-dose regimen of V114, a 15-valent pneumococcal conjugate vaccine,in healthy infants (PNEU-PED)

BackgroundPneumococcal disease (PD) remains a major health concern with considerable morbidity and mortality in children. Currently licensed pneumococcal conjugate vaccines (PCVs) confer protection against PD caused by most vaccine serotypes, but non-vaccine serotypes contribute to residual disease. V114 is a 15-valent PCV containing all 13 serotypes in Prevnar 13? (PCV13) and additional serotypes 22F and 33F. This pivotal phase 3 study compared safety and immunogenicity of V114 and PCV13.Methods1720 healthy infants were randomized 1:1 to receive a 4-dose regimen of V114 or PCV13 concomitantly with other routine pediatric vaccines. Safety was evaluated after each dose as proportion of participants with adverse events (AEs). Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured at 1-month post-dose 3 (PD3), pre-dose 4, and 1-month post-dose 4 (PD4). IgG response rates, geometric mean concentrations (GMCs), and opsonophagocytic activity (OPA) were compared between vaccination groups.ResultsThe proportion, maximum intensity, and duration of injection-site, systemic, and serious AEs were generally comparable between V114 and PCV13 groups. In comparison to PCV13, V114 met non-inferiority criteria for all 15 serotypes based on IgG response rates at PD3. V114 met non-inferiority criteria by IgG GMCs for all serotypes at PD3 and PD4, except for serotype 6A at PD3. V114-induced antibodies had bactericidal activity as assessed by OPA. Further, V114 met superiority criteria for shared serotype 3 and unique serotypes 22F and 33F compared to PCV13 by serotype-specific IgG GMCs at both PD3 and PD4. Immunogenicity of concomitantly administered routine pediatric vaccines was comparable in V114 and PCV13 groups.ConclusionsIn healthy infants, V114 displays acceptable safety and tolerability profiles and generates comparable immune responses to PCV13. V114 also met superiority criteria for serotypes 3, 22F, and 33F. These results support use of V114 for prevention of PD as part of routine infant vaccination schedules.Trial registration: ClinicalTrials.gov: NCT03893448; EudraCT: 2018-004109-21.     

Serotype distribution of Streptococcus pneumoniae isolated from children hospitalized in Beijing children’s hospital (2013–2019)

BackgroundStreptococcus pneumoniae can cause many infectious diseases among children, and relevant vaccines have not been scheduled into the National Immunization Program in China. The serotype distribution of Streptococcus pneumoniae is essential information used to evaluate the value of pneumococcal vaccines and formulate immunization strategies.MethodsStreptococcus pneumoniae isolates, identified as the disease pathogens, were collected from children hospitalized in Beijing Children’s Hospital from 2013 to 2019. The serotype was detected by the Quellung reaction.ResultsA total of 903 isolates of Streptococcus pneumoniae were collected, among which 809 were from non-invasive infections and 94 were from invasive infections. The non-invasive isolates were mainly isolated from respiratory secretions (49.4%) and bronchoalveolar lavage fluid (38.9%), while invasive isolates were from venous blood (5.4%), cerebrospinal fluid (2.8%) and pleural effusion (2.8%). The leading serotypes were 19F (36.0%), 19A (13.6%), 23F (9.4%), 14 (8.9%), 6A (6.9%), and 6B (5.3%). The overall coverage rates of 10-, 13-, 15-, 20-valent pneumococcal conjugate vaccines (PCV10, PCV13, PCV15, PCV20) and 23-valent pneumococcal polysaccharide vaccine (PPV23) as well as Pneumosil (a 10-valent pneumococcal conjugate vaccine) were 61.6%, 83.2%, 83.4%, 88.0%, 82.4% and 81.6%, respectively. The coverage rates of PCV13, PCV15 and PPV23 in isolates from invasive infections were significantly higher than those from non-invasive infections. The coverage rates of Pneumosil, either on the whole or among different age groups or different infections, were significantly higher than those of PCV10.ConclusionsSerotypes 19F, 19A, 23F, 14, 6A and 6B were the most common types among the isolates. As for pneumococcal vaccines available now, the coverage rate of PCV13 was high, especially in isolates from invasive infections. The promotion of PCV13 or further high valent vaccines might be of greater benefit in preventing pneumococcal infections than other pneumococcal vaccines in children.     

Safety and immunogenicity of sequential administration of PCV13 followed by PPSV23 in pneumococcal vaccine-naïve adults aged ≥ 65 years: Comparison of booster effects based on intervals of 0.5 and 1.0 year

ObjectiveAn open-label study was conducted to compare the safety and immunogenicity of a sequential administration of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) between an interval of 0.5 (0.5-y) and 1 year (1.0-y) in adults aged ≥ 65 years.MethodsPneumococcal vaccine-naïve adults aged ≥ 65 years (n = 129) received a sequential administration with an interval of 0.5-y or 1.0-y or received a single administration of PPSV23 (single PPSV23). We evaluated the immunogenicity before and 1 month after each vaccination and at 0.5-y intervals for 2 years. The primary endpoint was the increase in geometric mean fold rises (GMFRs) of immunoglobulin G (IgG) or opsonophagocytic activity (OPA) for eight common serotypes one month after one dose of PPSV23. The secondary endpoint was the safety profile for one dose of PPSV23.ResultsOne month after administration of PPSV23, the GMFRs of IgG considerably increased for five of eight serotypes in the 1.0-y interval group, whereas the GMFRs of IgG considerably increased for two serotypes in the 0.5-y interval group. Furthermore, GMFRs of OPA markedly increased for all eight serotypes in the 1.0-y interval group, while GMFRs of OPA markedly increased for four serotypes in the 0.5-y interval group. At 2 years after initial vaccination, GMFRs of IgG or OPA were higher for all serotypes, except for serotype 3, than those in the single PPSV23 group irrespective of intervals. No significant difference was found in the frequencies of local reactions of all grades between the two intervals.ConclusionsThe 1.0-y interval provided better booster effects induced by PPSV23 than those of the 0.5-y interval in a sequential administration in pneumococcal vaccine-naïve adults aged ≥ 65 years. No difference was found in the safety profile between both intervals.     

Impact of tetanus-diphtheria-acellular pertussis immunization during pregnancy on subsequent infant immunization seroresponses: follow-up from a large randomized placebo-controlled trial

BackgroundPertussis immunization during pregnancy results in high pertussis antibody concentrations in young infants but may interfere with infant immune responses to post-natal immunization.MethodsThis phase IV, multi-country, open-label study assessed the immunogenicity and safety of infant primary vaccination with DTaP-HepB-IPV/Hib and 13-valent pneumococcal conjugate vaccine (PCV13). Enrolled infants (6–14 weeks old) were born to mothers who were randomized to receive reduced-antigen-content diphtheria-tetanus-three-component acellular pertussis vaccine (Tdap group) or placebo (control group) during pregnancy (27^0/7–36^6/7 weeks’ gestation) with crossover immunization postpartum. All infants received 2 or 3 DTaP-HepB-IPV/Hib and PCV13 doses according to national schedules. Immunogenicity was assessed in infants pre- and 1 month post-primary vaccination. The primary objective was to assess seroprotection/vaccine response rates for DTaP-HepB-IPV/Hib antigens 1 month post-primary vaccination.Results601 infants (Tdap group: 296; control group: 305) were vaccinated. One month post-priming, seroprotection rates were 100% (diphtheria; tetanus), ≥98.5% (hepatitis B), ≥95.9% (polio) and ≥94.5% (Hib) in both groups. Vaccine response rates for pertussis antigens were significantly lower in infants whose mothers received pregnancy Tdap (37.5–77.1%) versus placebo (90.0–99.2%). Solicited and unsolicited adverse event rates were similar between groups. Serious adverse events occurred in 2.4% (Tdap group) and 5.6% (control group) of infants, none were vaccination-related.ConclusionsPertussis antibodies transferred during pregnancy may decrease the risk of pertussis infection in the first months of life but interfere with the infant’s ability to produce pertussis antibodies, the clinical significance of which remains unknown. Safety and reactogenicity results were consistent with previous experience.Clinical Trial Registration: ClinicalTrials.gov: NCT02422264.     

Long-term impact of pneumococcal conjugate vaccines for children on adult pneumococcal pneumonia in Japan: Two multicenter observational studies from 2011 to 2020

BackgroundPediatric pneumococcal conjugate vaccines (PCVs) introduction has directly and indirectly reduced pneumococcal pneumonia and invasive disease caused by PCV-covered serotypes among children and adults globally. In Japan, both PCV7 and PCV13 were introduced into the national immunization program (NIP) for children in 2013. However, the long-term impact of PCV use in children on adult pneumococcal pneumonia in Japan remains unclear.MethodsWe assessed serotypes isolated from adult pneumococcal pneumonia patients (in- and outpatients) in two multicenter observational studies in Japan: 2011–2014 and 2016–2020. The latter study period was divided into two periods to evaluate changes after PCV introduction in children. The Quellung reaction was used to determine serotypes. We evaluated trends of individual and vaccine-covered serotypes over three periods and assessed the difference in changes by patient group before and after the introduction of pediatric PCVs.ResultsA total of 650 patients were enrolled: 224, 322, and 104 in 2011–2014, 2016–2017, and 2018–2020, respectively. The median age was 73 years; 59.7% (388/650) were male; 86.9% (565/650) had comorbidities; and 10.2% (66/650) were nursing-home residents. The proportion of PCV13 serotypes decreased from 52.7% in 2011–2014 to 30.4% in 2016–2017 (p <0.001) after PCV13 introduction for children. However, PCV13, PCV15, and PCV20 serotypes still accounted for 38.5, 43.3, and 59.6% of total pneumococcal pneumonia in 2018–2020, respectively. Decline of PCV13 serotypes was more marked in patients aged ≥65 (-23.5%; p <0.001) than those aged <65 (-12.3%; p = 0.104) from 2011–2014 to 2016–2020. The proportion of PPSV23 non-PCV13 serotypes didn’t change over time.ConclusionsThe proportion of adult pneumococcal pneumonia caused by PCV13 serotypes in Japan declined after pediatric PCVs introduction into NIP, possibly due to indirect effects of pediatric PCVs. However, use of new PCVs in Japanese adults may potentially prevent additional pneumococcal pneumonia cases. Now, pneumococcal vaccination strategy for older adults requires discussion.