Neurological and immunological adverse events after pneumococcal conjugate vaccine in children using national immunization programme registry data.

BACKGROUND: Despite the general consensus on the safety of pneumococcal conjugate vaccine (PCV), safety concerns unveiled during post-licensure surveillance need to be addressed. We investigated whether there is a transient increased risk following a three-dose series of pneumococcal conjugate vaccine (PCV) administered at 2, 4 and 6 months of age. METHODS: This was a population-based cohort study using the Korea immunization registry data linked to nationwide administrative claims data. Self-controlled risk interval analysis was conducted for PCV recipients who had an outcome of interest within pre-defined risk and control intervals between 2018 and 2022. The outcomes were anaphylaxis, asthma, encephalopathy, febrile seizure, Kawasaki disease and thrombocytopenia. We used conditional Poisson regression model to estimate the incidence rate ratios (IRRs) and 95% confidence intervals (CIs) comparing the outcomes in the risk and control intervals. RESULTS: Of 1 114 096 PCV recipients, 8661 had outcomes either in the risk or control intervals. Their mean age at Dose 1 was 10.0 weeks, 58.3% were boys, and 85.3% received 13-valent PCV. PCV was not associated with an increased risk of any outcomes except for febrile seizure. There were 408 (56.0%) cases of febrile seizure in the risk interval, corresponding to an IRR of 1.27 (95% CI 1.10-1.47). CONCLUSIONS: It is reassuring to note that there was no increased risk of the potential safety concerns following PCV administration. Despite the transient increased risk of febrile seizure, absolute numbers of cases were small. Febrile seizure is generally self-limiting with a good prognosis, and should not discourage parents or caregivers from vaccinating their children.

Cardiovascular, Neurological, and Immunological Adverse Events and the 23-Valent Pneumococcal Polysaccharide Vaccine.

Importance: Despite widespread immunization with the 23-valent pneumococcal polysaccharide vaccine (PPSV23), safety concerns remain owing to a lack of statistical power and largely outdated evidence. Objective: To evaluate the association between cardiovascular, neurological, and immunological adverse events and PPSV23 vaccination in older adults. Design, Setting, and Participants: This population-based cohort study using a self-controlled risk interval design used a large linked database created by linking the Korea Immunization Registry Information System and the National Health Information Database (2018 to 2021). Participants included patients aged 65 years or older with a history of PPSV23 vaccination and incident cardiovascular, neurological, or immunological events during the risk and control intervals. Data were analyzed from November 2022 to April 2023. Exposure: 23-valent pneumococcal polysaccharide vaccine. Main Outcomes and Measures: The occurrence of 1 among 6 cardiovascular events (myocardial infarction, atrial fibrillation, cardiomyopathy, heart failure, hypotension, and myocarditis or pericarditis), 2 neurological events (Bell palsy and Guillain-Barré syndrome), and 3 immunological events (sepsis, thrombocytopenia, and anaphylaxis) during the risk and control periods. The risk and control intervals were defined as 1 to 28 and 57 to 112 days after PPSV23 vaccination, respectively. Conditional Poisson regression was used to estimate the incidence rate ratio (IRR) with a 95% CI. Results: Altogether, 4355 of the 1 802 739 individuals who received PPSV23 vaccination and experienced at least 1 outcome event were included (mean [SD] age, 72.4 [8.2] years; 2272 male participants [52.1%]). For cardiovascular events, there were no significant associations for myocardial infarction (IRR, 0.96; 95% CI, 0.81-1.15), heart failure (IRR, 0.85; 95% CI, 0.70-1.04), and stroke (IRR, 0.92; 95% CI, 0.84-1.02). Similarly, no increased risks were observed for neurological and immunological outcomes: Bell palsy (IRR, 0.95; 95% CI, 0.72-1.26), Guillain-Barré syndrome (IRR, 0.27; 95% CI, 0.06-1.17), sepsis (IRR, 0.99; 95% CI, 0.74-1.32), and thrombocytopenia (IRR, 1.18; 95% CI, 0.60-2.35). Conclusions and Relevance: In this self-controlled risk interval study, there was no appreciable increase in risk for most cardiovascular, neurological, or immunological adverse events following PPSV23. The updated safety profile of PPSV23 provides supportive evidence for the establishment of immunization strategies for older adults.

A phase 3 randomized trial of the safety and immunogenicity of 20-valent pneumococcal conjugate vaccine in adults ≥ 60 years of age in Japan, South Korea, and Taiwan.

BACKGROUND: Pneumococcal infections are associated with high disease burden in older individuals in Japan, South Korea, and Taiwan. The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to extend protection beyond earlier pneumococcal vaccines. METHODS: This phase 3 randomized, double-blind study investigated the safety and immunogenicity of PCV20 in participants ≥ 60 years of age from Japan, South Korea, and Taiwan. Participants were randomized to receive PCV20 or 13-valent pneumococcal conjugate vaccine (PCV13). One month after vaccination, PCV20 recipients received a saline injection and PCV13 recipients received 23-valent polysaccharide vaccine (PPSV23). Primary immunogenicity objectives were to demonstrate noninferiority of PCV20 to PCV13 (13 matched serotypes) or PPSV23 (7 additional serotypes) for serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) 1 month after vaccination with PCV20, PCV13, or PPSV23. Noninferiority for each serotype was declared if the lower bound of the 2-sided 95% CI for OPA geometric mean ratio (GMR) was > 0.5. Safety endpoints included local reactions, systemic events, adverse events (AEs), and serious AEs. RESULTS: Overall, 1421‬ participants were vaccinated (median age [range]: 65 [60-85] years). PCV20 was noninferior to PCV13 for all 13 matched serotypes and to PPSV23 for 6 of 7 additional serotypes. Although statistical noninferiority was missed for serotype 8 (lower bound of the 2-sided 95% CI for OPA GMR = 0.5, thus not meeting the statistical noninferiority criterion of > 0.5), secondary immunogenicity endpoints for serotype 8 were supportive of a robust immune response. The incidence of AEs and the frequency and severity of local reactions and systemic events were generally similar after PCV20 and PCV13. No safety concerns were identified. CONCLUSION: PCV20 generated robust immune responses to all vaccine serotypes in older adults in Japan, South Korea, and Taiwan. The safety and tolerability profile was similar to PCV13. PCV20 is expected to help protect against all 20 vaccine serotypes. NCT04875533.

Non-protective immunity after standard pneumococcal vaccination series identified as a potential contributing risk factor for refractory otolaryngologic conditions in children.

OBJECTIVE: To examine the relationship between conferred immunity after standard pneumococcal series and refractory otolaryngologic infections in pediatric patients using post-vaccination antibody titers, and to identify contributory underlying conditions revealed when vaccination/re-vaccination fails to confer protective immunity. STUDY DESIGN: IRB-reviewed and "exempt" retrospective case series with chart review using the Epic® Electronic Medical Record system from 2013 to 2021. SETTING: Dedicated tertiary referral children's hospital. METHODS: Pneumococcal antibody titer results were assessed for children ages 0 to 21 years and: (1) at least 1 of 7 otolaryngologic disease diagnoses and (2) having received the 4-dose schedule of pneumococcal conjugate vaccine (PCV 7 or 13). RESULTS: A total of 241 subjects met inclusion criteria with 356 laboratory tests. Recurrent acute otitis media, chronic rhinitis, and chronic otitis media with effusion were the 3 most frequent diagnoses. At presentation, only 27.0% of subjects had titers conferring immunity from their prior vaccinations with PCV. About 85 subjects had been subsequently revaccinated with Pneumococcal Polysaccharide Vaccine (PPSV), and antibody responses conferring immunity reached 91.8%. Seven subjects never developed adequate responses; 5 of these had recurrent acute otitis media as the primary otolaryngologic diagnosis. Secondary "revealed" diagnoses included Juvenile Rheumatoid Arthritis (n = 1), unresolved specific antibody deficiency (n = 2), and Hypogammaglobulinemia (n = 1). CONCLUSION: In pediatric patients with recurrent infectious otolaryngologic disease refractory to traditional medical and surgical therapy, inadequate responses to pneumococcal vaccination may be revealed. This correlation represents a potential pathway for diagnosis and therapy.

Immune thrombocytopenic purpura and Guillain-Barré syndrome after 23-valent pneumococcal polysaccharide vaccination in Japan: The vaccine effectiveness, networking, and universal safety (VENUS) study.

BACKGROUND: To address the lack of an active vaccine safety surveillance system in Japan, the Vaccine Effectiveness, Networking, and Universal Safety (VENUS) study was initiated in 2021 as a pilot system using existing health insurance claims data and vaccination records. METHODS: This study evaluated the value of the VENUS study by assessing the incidence of immune thrombocytopenic purpura (ITP) and Guillain-Barré syndrome (GBS) following vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPSV23) using a self-controlled case series (SCCS) design. RESULTS: Incidence rate ratios for ITP during 28-day and 42-day risk periods were 0.89 (95% confidence interval [CI], 0.12-6.4), and 0.58 (95% CI, 0.081-4.2), respectively. Neither was statistically significant. Incidence rate ratios could not be estimated for GBS due to the limited sample size. CONCLUSION: The VENUS study can provide valuable insights to facilitate the establishment of an advanced vaccine monitoring system in Japan.

Safety and immunogenicity of a multivalent pneumococcal conjugate vaccine given with 13-valent pneumococcal conjugate vaccine in healthy infants: A phase 2 randomized trial.

Use of pneumococcal conjugate vaccines (PCVs) has led to substantial reductions in the global burden of pediatric pneumococcal disease. Expansion of serotype coverage has been achieved by increasing PCV valency, but this may carry the potential risk of antibody interference. A complementary 7-valent PCV (cPCV7) including polysaccharide conjugates from 7 non-13-valent (PCV13) serotypes was developed to potentially complement PCV13-mediated protection and expand serotype coverage. This study evaluated cPCV7 and PCV13 coadministered in separate limbs or separated in time in infants. This phase 2, multicenter, open-label study included 512 infants randomized 1:1:1 to receive cPCV7 coadministered with PCV13 at ages 2, 4, 6, and 12 months (cPCV7 Coadministered); cPCV7 given at ages 3, 5, 7, and 13 months, 3‒5 weeks after PCV13 (cPCV7 Separated); or PCV13 at ages 2, 4, 6, and 12 months followed by a single supplemental dose of cPCV7 at 13 months (PCV13 Control). Safety evaluations included local reactions, systemic events, and adverse events. Serotype-specific immunoglobulin G concentrations and opsonophagocytic activity titers were assessed. The safety profile of cPCV7 was similar to that of PCV13. cPCV7 was well-tolerated in infants when coadministered with or given separately from PCV13. Robust and functional immune responses for all cPCV7 serotypes were observed in both cPCV7 groups. No immunologic interference was observed for either the cPCV7 or PCV13 serotypes with coadministration. A single cPCV7 dose induced immune responses in toddlers. These findings support potential coadministration of a complementary PCV to supplement protection provided by existing PCVs.Trial registration: ClinicalTrials.gov, NCT03550313.

Reports of Injection Site Necrosis After 23-Valent Pneumococcal Vaccine Use.

This case series uses postmarketing data to evaluate the incidence of injection site necrosis after 23-valent pneumococcal vaccine use in the global market.

20­Valent Pneumococcal Conjugate Vaccine: Pediatric First Approval.

20­valent pneumococcal conjugate vaccine (PCV20; Prevnar 20®; Apexxnar®) is a pneumococcal conjugate vaccine (PCV) developed by Pfizer for active immunization for the prevention of pneumococcal infections. PCV20 has a similar structure and formulation to Pfizer's 13-valent PCV (PCV13; Prevnar 13®; Prevenar 13®), with the addition of polysaccharides to target seven further Streptococcus pneumoniae serotypes (8, 10A, 11A, 12F, 15B, 22F and 33F). PCV20 has been approved for active immunization for the prevention of pneumonia and invasive disease caused by S. pneumoniae in adults since June 2021 in the USA and since February 2022 in the EU. Following further evaluation of its safety, immunogenicity, and effectiveness in pediatric populations, in April 2023 PCV20 received its first pediatric approval, in the USA, for active immunization for the prevention of invasive pneumococcal disease (IPD) caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F in individuals 6 weeks to 17 years of age and for the prevention of otitis media caused by S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F in individuals 6 weeks to 5 years of age. This article summarizes the milestones in the development of PCV20 leading to this first pediatric approval for active immunization for the prevention of IPD and otitis media caused by S. pneumoniae.

Dynamics of invasive pneumococcal disease in infants < 2 years old following PCV7/13 implementation using two infant and a booster dose schedule: evidence for indirect protection of young infants, Israel, 2004 to 2019.

BackgroundPneumococcal conjugated vaccine (PCV)7 and PCV13 programmes started in Israel from July 2009 and November 2010 respectively, with a 2+1 schedule (one dose at 2 months old, one at 4 months old, and a booster dose at 12 months old). Thereafter, invasive pneumococcal disease (IPD) rates substantially declined in children. Uptake of all three doses in < 2-year-olds since 2012 is > 90%. For still incompletely vaccinated infants (≤ 12 months old), how well the PCV 2+1 programme shields from IPD is not fully resolved.AimTo assess the adequacy of protection conferred by the 2+1 schedule PCV vaccination programme, particularly among incompletely-vaccinated infants.MethodsThis was a population-based, prospective, nationwide active IPD surveillance study in Israel, 2004-2019, in children < 24 months old. We estimated annual incidence rates (IR) of overall IPD, IPD caused by PCV13 serotypes (VT13), and non-PCV13 serotypes (NVT13). Annual IPD IRs were stratified by age: < 4 months (receiving ≤ 1 dose), 4-6 months (immediately post dose 2), 7-12 months (a few months post dose 2), and 13-23 months (post dose 3). Late-PCV (2004-2008) to pre-PCV13 (2016-2019) mean annual IR ratios (IRRs) were calculated.Results2,569 IPD episodes were recorded. VT13 decreased > 90% in all age groups, while NVT13 seemed to increase. All-IPD rates declined in all age groups by 56-70%. The 2+1 schedule impact on 7-12-month-old infants (pre-booster) was similar to that on 13-23-month-old children (post booster), with PCV13 IPD reductions of 97% and 98%, respectively.ConclusionsIndirect (herd) protection of infants, including < 4 month-olds with ≤ 1 PCV dose, was achieved by the 2+1 PCV schedule programme which thus seems adequate.

Comprehensive review of safety in Experimental Human Pneumococcal Challenge.

INTRODUCTION: Experimental Human Pneumococcal Challenge (EHPC) involves the controlled exposure of adults to a specific antibiotic-sensitive Streptococcus pneumoniae serotype, to induce nasopharyngeal colonisation for the purpose of vaccine research. The aims are to review comprehensively the safety profile of EHPC, explore the association between pneumococcal colonisation and frequency of safety review and describe the medical intervention required to undertake such studies. METHODS: A single-centre review of all EHPC studies performed 2011-2021. All recorded serious adverse events (SAE) in eligible studies are reported. An unblinded meta-analysis of collated anonymised individual patient data from eligible EHPC studies was undertaken to assess the association between experimental pneumococcal colonisation and the frequency of safety events following inoculation. RESULTS: In 1416 individuals (median age 21, IQR 20-25), 1663 experimental pneumococcal inoculations were performed. No pneumococcal-related SAE have occurred. 214 safety review events were identified with 182 (12.85%) participants presenting with symptoms potentially in keeping with pneumococcal infection, predominantly in pneumococcal colonised individuals (colonised = 96/658, non-colonised = 86/1005, OR 1.81 (95% CI 1.28-2.56, P = <0.001). The majority were mild (pneumococcal group = 72.7% [120/165 reported symptoms], non-pneumococcal = 86.7% [124/143 reported symptoms]). 1.6% (23/1416) required antibiotics for safety. DISCUSSION: No SAEs were identified directly relating to pneumococcal inoculation. Safety review for symptoms was infrequent but occurred more in experimentally colonised participants. Most symptoms were mild and resolved with conservative management. A small minority required antibiotics, notably those serotype 3 inoculated. CONCLUSION: Outpatient human pneumococcal challenge can be conducted safely with appropriate levels of safety monitoring procedures in place.

A Phase III, multicenter, randomized, double-blind, active comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of V114 compared with PCV13 in healthy infants (PNEU-PED-EU-1).

BACKGROUND: V114 (15-valent pneumococcal conjugate vaccine [PCV]) contains all serotypes in 13-valent PCV (PCV13) and additional serotypes 22F and 33F. This study evaluated safety and immunogenicity of V114 compared with PCV13 in healthy infants, and concomitant administration with DTPa-HBV-IPV/Hib and rotavirus RV1 vaccines. METHODS: V114 and PCV13 were administered in a 2+1 schedule at 2, 4, and 11-15 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-primary series (PPS), immediately prior to a toddler dose, and 30 days post-toddler dose (PTD). Primary objectives included non-inferiority of V114 to PCV13 for 13 shared serotypes and superiority of V114 to PCV13 for the two additional serotypes. RESULTS: 1184 healthy infants 42-90 days of age were randomized 1:1 to V114 (n = 591) or PCV13 (n = 593). Proportions of participants with solicited AEs and serious AEs were comparable between vaccination groups. V114 met pre-specified non-inferiority criteria for all 13 shared serotypes, based on the difference in proportions of participants with serotype-specific IgG concentrations ≥0.35 µg/mL (response rate; 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), and pre-specified superiority criteria for serotypes 22F and 33F (lower bound of two-sided 95% CI >10.0 for response rates and >2.0 for GMC ratios). Antibody responses to DTPa-HBV-IPV/Hib and RV1 vaccines met pre-specified non-inferiority criteria, based on antigen-specific response rates to DTPa-HBV-IPV/Hib and anti-rotavirus IgA geometric mean titers. CONCLUSIONS: After a 2+1 schedule, V114 elicited non-inferior immune responses to 13 shared serotypes and superior responses to the two additional serotypes compared with PCV13, with comparable safety profile. These results support the routine use of V114 in infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04031846; EudraCT: 2018-003787-31.

Impact of the COVID-19 pandemic on a clinical trial of pneumococcal vaccine scheduling (PVS) in rural Gambia.

The COVID-19 pandemic represents an unprecedented challenge for clinical research. The Pneumococcal Vaccine Schedules (PVS) study is a non-inferiority, interventional trial in which infants resident in 68 geographic clusters are randomised to two different schedules for pneumococcal vaccination. From September 2019 onwards, all infants resident in the study area became eligible for trial enrolment at all Expanded Programme on Immunisation (EPI) clinics in the study area. Surveillance for clinical endpoints is conducted at all 11 health facilities in the study area. PVS is conducted as a collaboration between the Medical Research Council Unit The Gambia (MRCG) at LSHTM and the Gambian Ministry of Health (MoH). The COVID-19 pandemic caused many disruptions to PVS. MRCG instructed interventional studies that participant enrolment be suspended on 26 March 2020, and a public health emergency was declared in The Gambia on 28 March 2020. Enrolment in PVS restarted on 1 July 2020 and was suspended again on 5 August 2020 after The Gambia experienced a sharp increase in COVID-19 cases in late July 2020 and restarted again on 1 September 2020. During periods of suspended enrolment of infants at EPI clinics, PVS continued safety surveillance at health facilities, albeit with disruptions. During the periods of suspended enrolment, infants who had been enrolled before 26 March 2020 continued to receive the PCV schedule to which they had been randomly allocated based on their village of residence, whereas all other infants received the standard PCV schedule. Throughout 2020 and 2021, the trial faced numerous technical and operational challenges: disruption to MoH delivery of EPI services and clinical care at health facilities; episodes of staff illness and isolation; disruption of MRCG transport, procurement, communications and human resource management; and also a range of ethical, regulatory, sponsorship, trial monitoring and financial challenges. In April 2021, a formal review concluded that the pandemic had not compromised the scientific validity of PVS and that the trial should continue as per protocol. The continuing challenges that COVID-19 poses to PVS, and other clinical trials will persist for some time.

A phase 3 study of safety and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, followed by 23-valent pneumococcal polysaccharide vaccine, in children with HIV.

OBJECTIVES: To evaluate the safety and immunogenicity of V114 [15-valent pneumococcal conjugate vaccine (PCV) containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9 V, 14, 18C, 19A, 19F, 22F, 23F, 33F], followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) 8 weeks later, in children with HIV. DESIGN: This phase 3 study (NCT03921424) randomized participants 6-17 years of age with HIV (CD4 + T-cell count ≥200 cells/µl, plasma HIV RNA <50 000 copies/ml) to receive V114 or 13-valent PCV (PCV13) in a double-blind manner on Day 1, followed by PPSV23 at Week 8. METHODS: Adverse events (AEs), pneumococcal serotype-specific immunoglobulin G (IgG), and opsonophagocytic activity (OPA) were evaluated 30 days after each vaccination. RESULTS: The proportion of participants experiencing at least one AE post-PCV was 78.8% in the V114 group ( n  = 203) and 69.6% in the PCV13 group ( n  = 204); respective proportions post-PPSV23 were 75.4% ( n  = 203) and 77.2% ( n  = 202). There were no vaccine-related serious AEs. IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) were generally comparable between V114 and PCV13 for shared serotypes at Day 30, and were higher for V114 compared with PCV13 for the additional V114 serotypes 22F and 33F. Approximately 30 days after PPSV23, IgG GMCs and OPA GMTs were generally comparable between the V114 and PCV13 groups for all 15 serotypes in V114. CONCLUSIONS: In children with HIV, a sequential administration of V114 followed 8 weeks later with PPSV23 is well tolerated and induces immune responses for all 15 pneumococcal serotypes included in V114.

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.

Association of pneumococcal vaccination with cardiovascular diseases in older adults: The vaccine effectiveness, networking, and universal safety (VENUS) study.

The protective effect of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) against cardiovascular disease has been investigated in the United States and Europe; however, its effect has not been fully established. This study aimed to investigate the protective effect of PPSV23 on cardiovascular events in adults aged ≥ 65 years. This population-based nested case-control study was conducted using the claims data and vaccine records between April 2015 and March 2020 from the Vaccine Effectiveness, Networking, and Universal Safety (VENUS) Study. PPSV23 vaccination was identified using vaccination records in each municipality. The primary outcome was acute myocardial infarction (AMI) or stroke. The adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for PPSV23 vaccination were calculated using conditional logistic regression. Among 383,781 individuals aged ≥ 65 years, 5,356 and 25,730 individuals with AMI or stroke were matched with 26,753 and 128,397 event-free controls, respectively. Individuals who were PPSV23 vaccinated, compared with the unvaccinated individuals, had significantly lower odds of AMI or stroke events (aOR, 0.70 [95% CI, 0.62-0.80] and aOR, 0.81 [95% CI, 0.77-0.86], respectively). More recent PPSV23 vaccination was associated with lower odds ratios (AMI, aOR 0.55 [95% CI, 0.42-0.72] for 1-180 days and aOR 1.11 [95% CI, 0.84-1.47] for 720 days or longer; stroke, aOR 0.83 [95% CI, 0.74-0.93] for 1-180 days and aOR 0.90 [95% CI, 0.78-1.03] for 720 days or longer). Among Japanese older adults, individuals who were PPSV23 vaccinated, compared with unvaccinated individuals, had significantly lower odds of AMI or stroke events.

Immunogenicity and safety of a 10-valent pneumococcal conjugate vaccine administered as a 2 + 1 schedule to healthy infants in The Gambia: a single-centre, double-blind, active-controlled, randomised, phase 3 trial.

BACKGROUND: Three pneumococcal conjugate vaccines (PCVs) are currently licensed and WHO prequalified for supply by UN agencies. Here, we aimed to investigate the safety and immunogenicity of SIIPL-PCV compared with PHiD-CV and PCV13, when administered to infants according to a 2 + 1 schedule. METHODS: This single-centre, double-blind, active-controlled, randomised, phase 3 trial was done in Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine clinical trial facilities within two government health centres in the western region of The Gambia. Healthy, PCV-naive infants aged 6-8 weeks were enrolled if they weighed at least 3·5 kg and had no clinically significant health complaints, as determined by history and clinical examination. Eligible infants were randomly assigned (1:1:1) to receive either SIIPL-PCV, PHiD-CV, or PCV13 using permuted blocks of variable size. Parents and the trial staff assessing all study outcomes were masked to vaccine group. The first PCV vaccine was given with other routine Expanded Programme on Immunization vaccines when infants were aged 6-8 weeks (visit 1). At visit 2, routine vaccines alone (without a PCV) were administered. At visit 3, the second dose of the PCV was administered alongside other routine vaccines. At visit 4, a blood sample was collected. Visits 1-4 took place at intervals of 4 weeks. The booster PCV was administered at age 9-18 months (visit 5), with final follow-up 4 weeks after the booster (visit 6). The primary immunogenicity outcome compared the serotype-specific IgG geometric mean concentrations (GMCs) generated by SIIPL-PCV with those generated by PHiD-CV and PCV13, 4 weeks after the booster. We used descriptive 95% CIs without adjustment for multiplicity. Immunogenicity analyses were done in the per protocol population (defined as all children who received all the assigned study vaccines, who had an immunogenicity measurement available, and who had no protocol deviations that might interfere with the immunogenicity assessment). This trial was registered with the Pan African Clinical Trials Registry, PACTR201907754270299, and ClinicalTrials.gov, NCT03896477. FINDINGS: Between July 18 and Nov 14, 2019, 745 infants were assessed for study eligibility. Of these, 85 infants (11%) were ineligible and 660 (89%) were enrolled and randomly assigned to receive SIIPL-PCV (n=220), PHiD-CV (n=220), or PCV13 (n=220). 602 infants (91%) were included in the per protocol immunogenicity population. The median age at vaccination was 46 days (range 42-56). 342 infants (52%) were female and 318 (48%) were male. Post-booster serotype-specific IgG GMCs generated by SIIPL-PCV ranged from 1·54 µg/mL (95% CI 1·38-1·73) for serotype 5 to 12·46 µg/mL (11·07-14·01) for serotype 6B. Post-booster GMCs against shared serotypes generated by PHiD-CV ranged from 0·80 µg/mL (0·72-0·88) for serotype 5 to 17·31 µg/mL (14·83-20·20) for serotype 19F. Post-booster GMCs generated by PCV13 ranged from 2·04 µg/mL (1·86-2·24) for serotype 5 to 15·54 µg/mL (13·71-17·60) for serotype 6B. Post-booster IgG GMCs generated by SIIPL-PCV were higher than those generated by PHiD-CV for seven of the eight shared serotypes (1, 5, 6B, 7F, 9V, 14, and 23F). The GMC generated by serotype 19F was higher after PHiD-CV. The SIIPL-PCV to PHiD-CV GMC ratios for shared serotypes ranged from 0·64 (95% CI 0·52-0·79) for serotype 19F to 2·91 (2·47-3·44) for serotype 1. The serotype 1 GMC generated by SIIPL-PCV was higher than that generated by PCV13, whereas serotype 5, 6A, 19A, and 19F GMCs were higher after PCV13. The SIIPL-PCV to PCV13 GMC ratios ranged from 0·72 (0·60-0·87) for serotype 19A to 1·44 (1·23-1·69) for serotype 1. INTERPRETATION: SIIPL-PCV was safe and immunogenic when given to infants in The Gambia according to a 2 + 1 schedule. This PCV is expected to provide similar protection against invasive and mucosal pneumococcal disease to the protection provided by PCV13 and PHiD-CV, for which effectiveness data are available. Generating post-implementation data on the impact of SIIPL-PCV on pneumococcal disease endpoints remains important. FUNDING: Bill & Melinda Gates Foundation.

Safety and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, in children with SCD: a V114-023 (PNEU-SICKLE) study.

Sickle cell disease (SCD) is an inherited red blood cell disease that results in a multitude of medical complications, including an increased risk of invasive disease caused by encapsulated bacteria, such as Streptococcus pneumoniae. Pneumococcal vaccines have contributed to a significant reduction in pneumococcal disease (PD) in children and adults, including those with SCD. This phase 3 study evaluated the safety and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine (PCV), in children with SCD. A total of 103 children aged 5 to 17 years with SCD were randomized and received a single dose of V114 or Prevnar 13 (PCV13). Safety was evaluated as the proportion of participants with adverse events (AEs). Serotype-specific immunoglobulin G (IgG) levels and opsonophagocytic activity (OPA) were measured immediately before vaccination and 30 days after vaccination. Overall, the rates of injection-site and systemic AEs reported after vaccination were similar between the vaccination groups. Up to 6 months after vaccination, serious AEs were those expected for patients with SCD, and none were assessed to be vaccine related. IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) for the 13 shared serotypes were generally comparable between recipients of V114 and PCV13. Additionally, V114 induced immune responses to serotypes 22F and 33F, which are not included in PCV13. The safety and tolerability profiles of V114 were consistent with those reported for PCV13. Immune responses following vaccination with V114 were generally comparable to PCV13 for the shared serotypes and higher for unique serotypes 22F and 33F. These results support the use of V114 in children with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03731182.

The safety of pneumococcal vaccines at the time of sequential schedule: data from surveillance of adverse events following 13-valent conjugated pneumococcal and 23-valent polysaccharidic pneumococcal vaccines in newborns and the elderly, in Puglia (Italy), 2013-2020.

Background: Nowadays, two types of anti-pneumococcal vaccine are available: pneumococcal 13-valent conjugate vaccine (PCV13), first licensed in the United States (US) in 2013, and pneumococcal 23-valent polysaccaridic vaccine (PPSV23), first licensed in the US in 1999. These vaccines are recommended in Italy for the immunization of newborns and of the elderly, using a combined sequential schedule for the latter. This report aims to describe the PCV13- and PPSV23-related AEFIs notified in Puglia in 2013-2020, in order to design these products' safety profile in a real-life scenario, three years after the official recommendation about the sequential schedule for people over 60 years of age. Methods: This is a retrospective observational study. Data were gathered from the list of AEFIs notified following PCV13 and PPSV23 administration in Puglia in 2013-2020. The number of administered vaccine doses was obtained from the regional immunization database. AEFIs were classified according to WHO's algorithm, and causality assessment was carried out in case of serious AEFIs. Results: From January 2013 to December 2020, 764,183 doses of PCV13 and 40,382 doses of PPSV23 were administered in Puglia. In the same period, 71 PCV13 AEFIs (Reporting Rate: 9.29 x100,000 doses) and 5 PPSV23 AEFIs (Reporting Rate: 12.4 x100,000 doses) were reported. The overall male/female ratio in AEFIs was 0.85. The majority of AEFIs occurred in subjects aged less than 2 (64/76, 84.2%), while 10 out of 76 (13.2%) occurred in patients aged 60 or older. 22 AEFIs were classified as serious and for 12 (54.5%) causality assessment showed a consistent relationship with immunization. The most commonly reported symptoms were fever (Reporting Rate: 4.72 x100,000 doses) and neurological symptoms (Reporting Rate: 3.23 x100,000 doses). Only one death was notified, classified as non-vaccine-related. Conclusions: The benefit of pneumococcal vaccination appears to be greater than the risk of AEFIs for both PCV13 and PPSV23. In fact, AEFIs occur in less than 0.1‰ of patients and the majority of AEFIs are mild and self-limiting.

Pneumococcal vaccine schedules (PVS) study: a cluster-randomised, non-inferiority trial of an alternative versus standard schedule for pneumococcal conjugate vaccination-statistical analysis plan.

RATIONALE: The effectiveness of universal immunisation with pneumococcal conjugate vaccine (PCV) has been evident in many countries. However, the global impact of PCV is limited by its cost, which has prevented its introduction in several countries. Reducing the cost of PCV programmes may facilitate vaccine introduction in some countries and improve the sustainability of PCV in EPIs in low-income countries when they transition away from subsidised vaccine supply. METHODS AND DESIGN: PVS is a real-world field trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. the alternative '1+1' schedule) compared to the standard schedule of three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. the standard '3+0' schedule). Delivery of the interventions began in late 2019 in 68 geographic clusters and will continue for 4 years. The primary endpoint is the prevalence of nasopharyngeal vaccine-type pneumococcal carriage in children aged 2-260 weeks with clinical pneumonia in year 4. Secondary endpoints are the prevalence of vaccine-type pneumococcal carriage among all ages in year 4 and the incidence of radiological pneumonia in children enrolled to receive the interventions. Additional disease and carriage endpoints are included. PURPOSE: This statistical analysis plan (SAP) describes the cohorts and populations, and follow-up criteria, to be used in different analyses. The SAP defines the endpoints and describes how adherence to the interventions will be presented. We describe how analyses will account for the effect of clustering and stratified randomisation. The SAP defines the approach to non-inferiority and other analyses. Defining the SAP early in the trial will avoid bias in analyses that may arise from prior knowledge of trial findings.

Kawasaki Disease Following the 13-valent Pneumococcal Conjugate Vaccine and Rotavirus Vaccines.

BACKGROUND: Temporal associations between Kawasaki disease (KD) and childhood vaccines have been reported. Limited data on KD following 13-valent pneumococcal conjugate (PCV13) and rotavirus vaccines are available. METHODS: We conducted a self-controlled risk interval study using Vaccine Safety Datalink electronic health record data to investigate the risk of KD following PCV13 and rotavirus vaccines in children <2 years of age who were born from 2006 to 2017. All hospitalized KD cases identified by International Classification of Diseases diagnosis codes that fell within predefined risk (days 1-28 postvaccination) and control (days 29-56 for doses 1 and 2, and days 43-70 for doses 3 and 4) intervals were confirmed by manual chart review. RESULTS: During the study period, 655 cases of KD were identified by International Classification of Diseases codes. Of these, 97 chart-confirmed cases were within risk or control intervals. In analyses, the age-adjusted relative risk for KD following any dose of PCV13 was 0.75 (95% confidence interval, 0.47-1.21). Similarly, the age-adjusted relative risk for KD following any dose of rotavirus vaccine was 0.66 (95% CI, 0.40-1.09). Overall, there was no evidence of an elevated risk of KD following PCV13 or rotavirus vaccines by dose. In addition, no statistically significant temporal clustering of KD cases was identified during days 1 to 70 postvaccination. CONCLUSIONS: PCV13 and rotavirus vaccination were not associated with an increased risk of KD in children <2 years of age. Our findings provide additional evidence for the overall safety of PCV13 and rotavirus vaccines.