Summary Background The Finnish Invasive Pneumococcal disease (FinIP) vaccine trial was designed to assess the effectiveness of a pneumococcal vaccine containing ten serotype-specific polysaccharides ...conjugated to Haemophilus influenzae protein D, tetanus toxoid, and diphtheria toxoid as the carrier proteins (PHiD-CV10) against invasive pneumococcal disease. Methods In this cluster-randomised, double-blind trial, children aged younger than 19 months received PHiD-CV10 in 52 clusters or hepatitis vaccines as control in 26 clusters. Infants aged younger than 7 months at the first vaccination received either a 3+1 or a 2+1 vaccination schedule, children aged 7–11 months received a 2+1 schedule, and those 12–18 months of age received a two-dose schedule. The primary and secondary objectives were to assess vaccine effectiveness against culture-confirmed invasive pneumococcal disease due to any of the ten vaccine serotypes for the 3+1 and 2+1 schedules, respectively, in children who received at least one PHiD-CV10 dose before 7 months of age. Masked follow-up of pneumococcal disease lasted from the first vaccination (from February, 2009, to October, 2010) to January 31, 2012. Invasive disease data were retrieved from data accumulated in the national infectious diseases register. This trial and the nested acute otitis media trial are registered with ClinicalTrials.gov , numbers NCT00861380 and NCT00839254 , respectively. Findings 47 366 children were enrolled from February, 2009, to October, 2010. 30 527 participants were assessed for the primary objective. 13 culture-confirmed vaccine-type cases of invasive pneumococcal disease were detected: none in the PHiD-CV10 3+1 group, one in the PHiD-CV10 2+1 group, and 12 in the control groups. The estimates for vaccine effectiveness were 100% (95% CI 83–100) for PHiD-CV10 3+1 and 92% (58–100) for PHiD-CV10 2+1 groups. Two cases of any culture-confirmed invasive disease irrespective of serotype were detected in combined PHiD-CV10 infant cohorts compared with 14 in the corresponding control cohorts (vaccine effectiveness 93%, 75–99). In catch-up cohorts, seven cases of invasive disease were reported, all in the control group: two cases in the children enrolled at 7–11 months of age; and five cases in children enrolled at 12–18 months of age (vaccine effectiveness 100%, 79–100). Non-fatal serious adverse events suspected to be vaccine-related were reported via routine post-immunisation safety surveillance in 18 children. Interpretation This nationwide trial showed high PHiD-CV10 effectiveness against invasive pneumococcal disease when given in different schedules. For the first time, effectiveness of a 2+1 schedule in infants was confirmed in a clinical trial. Funding GlaxoSmithKline Biologicals SA and National Institute for Health and Welfare, Finland.
The relationship between pneumococcal conjugate vaccine-induced antibody responses and protection against community-acquired pneumonia (CAP) and acute otitis media (AOM) is unclear. This study ...assessed the impact of the ten-valent pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on these end points. The primary objective was to demonstrate vaccine efficacy (VE) in a per-protocol analysis against likely bacterial CAP (B-CAP: radiologically confirmed CAP with alveolar consolidation/pleural effusion on chest X-ray, or non-alveolar infiltrates and C-reactive protein ≥ 40 µg/ml); other protocol-specified outcomes were also assessed.
This phase III double-blind randomized controlled study was conducted between 28 June 2007 and 28 July 2011 in Argentine, Panamanian, and Colombian populations with good access to health care. Approximately 24,000 infants received PHiD-CV or hepatitis control vaccine (hepatitis B for primary vaccination, hepatitis A at booster) at 2, 4, 6, and 15-18 mo of age. Interim analysis of the primary end point was planned when 535 first B-CAP episodes, occurring ≥2 wk after dose 3, were identified in the per-protocol cohort. After a mean follow-up of 23 mo (PHiD-CV, n = 10,295; control, n = 10,201), per-protocol VE was 22.0% (95% CI: 7.7, 34.2; one-sided p = 0.002) against B-CAP (conclusive for primary objective) and 25.7% (95% CI: 8.4%, 39.6%) against World Health Organization-defined consolidated CAP. Intent-to-treat VE was 18.2% (95% CI: 5.5%, 29.1%) against B-CAP and 23.4% (95% CI: 8.8%, 35.7%) against consolidated CAP. End-of-study per-protocol analyses were performed after a mean follow-up of 28-30 mo for CAP and invasive pneumococcal disease (IPD) (PHiD-CV, n = 10,211; control, n = 10,140) and AOM (n = 3,010 and 2,979, respectively). Per-protocol VE was 16.1% (95% CI: -1.1%, 30.4%; one-sided p = 0.032) against clinically confirmed AOM, 67.1% (95% CI: 17.0%, 86.9%) against vaccine serotype clinically confirmed AOM, 100% (95% CI: 74.3%, 100%) against vaccine serotype IPD, and 65.0% (95% CI: 11.1%, 86.2%) against any IPD. Results were consistent between intent-to-treat and per-protocol analyses. Serious adverse events were reported for 21.5% (95% CI: 20.7%, 22.2%) and 22.6% (95% CI: 21.9%, 23.4%) of PHiD-CV and control recipients, respectively. There were 19 deaths (n = 11,798; 0.16%) in the PHiD-CV group and 26 deaths (n = 11,799; 0.22%) in the control group. A significant study limitation was the lower than expected number of captured AOM cases.
Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice.
www.ClinicalTrials.gov NCT00466947.
In the nation-wide double-blind cluster-randomised Finnish Invasive Pneumococcal disease trial (FinIP, ClinicalTrials.gov NCT00861380, NCT00839254), we assessed the indirect impact of the 10-valent ...pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against five pneumococcal disease syndromes.
Children 6 weeks to 18 months received PHiD-CV10 in 48 clusters or hepatitis B/A-vaccine as control in 24 clusters according to infant 3+1/2+1 or catch-up schedules in years 2009-2011. Outcome data were collected from national health registers and included laboratory-confirmed and clinically suspected invasive pneumococcal disease (IPD), hospital-diagnosed pneumonia, tympanostomy tube placements (TTP) and outpatient antimicrobial prescriptions. Incidence rates in the unvaccinated population in years 2010-2015 were compared between PHiD-CV10 and control clusters in age groups <5 and ≥5 years (5-7 years for TTP and outpatient antimicrobial prescriptions), and in infants <3 months. PHiD-CV10 was introduced into the Finnish National Vaccination Programme (PCV-NVP) for 3-month-old infants without catch-up in 9/2010.
From 2/2009 to 10/2010, 45398 children were enrolled. Vaccination coverage varied from 29 to 61% in PHiD-CV10 clusters. We detected no clear differences in the incidence rates between the unvaccinated cohorts of the treatment arms, except in single years. For example, the rates of vaccine-type IPD, non-laboratory-confirmed IPD and empyema were lower in PHiD-CV10 clusters compared to control clusters in 2012, 2015 and 2011, respectively, in the age-group ≥5 years.
This is the first report from a clinical trial evaluating the indirect impact of a PCV against clinical outcomes in an unvaccinated population. We did not observe consistent indirect effects in the PHiD-CV10 clusters compared to the control clusters. We consider that the sub-optimal trial vaccination coverage did not allow the development of detectable indirect effects and that the supervening PCV-NVP significantly diminished the differences in PHiD-CV10 vaccination coverage between the treatment arms.
Human papillomavirus (HPV) infection is associated with the risk of developing certain cancers, including cancers of the cervix, vulva, vagina, penis, anus, rectum, and oropharynx. In 2016, the ...bivalent HPV-16/18 vaccine was included in the Korea National Immunization Program. This vaccine protects against HPV types 16 and 18 and other oncogenic HPV types predominant in cervical and anal cancers. This post-marketing surveillance (PMS) study assessed the safety of the HPV-16/18 vaccine in Korea. The study was conducted in males and females aged between 9 and 25 years, from 2017 to 2021. Safety was measured in terms of frequency and intensity of adverse events (AEs), adverse drug reactions (ADRs), and serious adverse events (SAEs) after each vaccine dose. The safety analysis included all participants who were vaccinated as per prescribing information and who completed a 30-day follow-up after at least one dose. Data were collected using individual case report forms. The total safety cohort included 662 participants. A total of 220 AEs were reported in 144 subjects (21.75%), and there were 158 ADRs in 111 subjects (16.77%), with the most common being injection site pain in all cases. No SAEs or serious ADRs were reported. Most AEs were reported after the first dose and were injection site reactions with mild intensity that recovered. No individuals required hospitalization or an emergency department visit. Safety results showed that the HPV-16/18 vaccine was generally well tolerated in the Korean population, and no safety concerns were identified.
ClinicalTrials.gov Identifier: NCT03671369.
What is the context?
Infection with human papillomavirus (HPV) is linked to the development of certain cancers.
More specifically, HPV types 16 and 18 are predominant in cervical and anal cancers.
In 2016, the HPV-16/18 vaccine was included in the National Immunization Program of Korea.
What is new?
The objective of this study was to evaluate the safety of the HPV-16/18 vaccine following its introduction in Korea.
The study was conducted from 2017 to 2021 in young Korean men and women between 9 and 25 years of age.
The study analyzed 662 participants, of whom:
∘ 144 reported 220 adverse events
∘ 111 reported 158 adverse drug reactions
∘ None reported serious adverse events
The safety of the vaccine was measured after each dose as the number and intensity of:
∘ Adverse events, which are side-effects or unwanted reactions that might be associated with the use of the vaccine
∘ Adverse drug reactions, which are side-effects or unwanted reactions associated with the use of the vaccine
∘ Serious adverse events, which are reactions resulting in death, disability, are life-threatening, or require hospitalization (or prolongation of it).
Most adverse events occurred following the first dose, were mild in intensity, and the participants recovered after a few days. Injection site pain was the most common adverse event following vaccination.
What is the impact?
The study showed that the HPV-16/18 vaccine is safe and generally well tolerated in Korean participants.
Summary Background Although fever is part of the normal inflammatory process after immunisation, prophylactic antipyretic drugs are sometimes recommended to allay concerns of high fever and febrile ...convulsion. We assessed the effect of prophylactic administration of paracetamol at vaccination on infant febrile reaction rates and vaccine responses. Methods In two consecutive (primary and booster) randomised, controlled, open-label vaccination studies, 459 healthy infants were enrolled from ten centres in the Czech Republic. Infants were randomly assigned with a computer-generated randomisation list to receive three prophylactic paracetamol doses every 6–8 h in the first 24 h (n=226) or no prophylactic paracetamol (n=233) after each vaccination with a ten-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) co-administered with the hexavalent diphtheria-tetanus-3-component acellular pertussis-hepatitis B-inactivated poliovirus types 1, 2, and 3- H influenzae type b (DTPa-HBV-IPV/Hib) and oral human rotavirus vaccines. The primary objective in both studies was the reduction in febrile reactions of 38·0°C or greater in the total vaccinated cohort. The second objective was assessment of immunogenicity in the according-to-protocol cohort. These studies are registered with ClinicalTrials.gov , numbers NCT00370318 and NCT00496015. Findings Fever greater than 39·5°C was uncommon in both groups (after primary: one of 226 participants <1% in prophylactic paracetamol group vs three of 233 1% in no prophylactic paracetamol group; after booster: three of 178 2% vs two of 172 1%). The percentage of children with temperature of 38°C or greater after at least one dose was significantly lower in the prophylactic paracetamol group (94/226 42% after primary vaccination and 64/178 36% after booster vaccination) than in the no prophylactic paracetamol group (154/233 66% after primary vaccination and 100/172 58% after booster vaccination). Antibody geometric mean concentrations (GMCs) were significantly lower in the prophylactic paracetamol group than in the no prophylactic paracetamol group after primary vaccination for all ten pneumococcal vaccine serotypes, protein D, antipolyribosyl-ribitol phosphate, antidiphtheria, antitetanus, and antipertactin. After boosting, lower antibody GMCs persisted in the prophylactic paracetamol group for antitetanus, protein D, and all pneumococcal serotypes apart from 19F. Interpretation Although febrile reactions significantly decreased, prophylactic administration of antipyretic drugs at the time of vaccination should not be routinely recommended since antibody responses to several vaccine antigens were reduced. Funding GlaxoSmithKline Biologicals (Belgium).
Highlights • First safety study of six novel pneumococcal protein-containing vaccine formulations. • Formulations contained dPly alone or dPly and PhtD, alone or with 10 PS-conjugates. • All ...formulations used as two- or three-dose series in healthy adults were well-tolerated. • All formulations were immunogenic for protein antigens. • PS-conjugate-containing formulations were also immunogenic for the PS-conjugates.
Introduction: Protein D-containing vaccines may decrease acute otitis media (AOM) burden and nasopharyngeal carriage of non-typeable Haemophilus influenzae (NTHi). Protein D-containing pneumococcal ...conjugate vaccine PHiD-CV (Synflorix, GSK Vaccines) elicits robust immune responses against protein D. However, the phase III Clinical Otitis Media and PneumoniA Study (COMPAS), assessing PHiD-CV efficacy against various pneumococcal diseases, was not powered to demonstrate efficacy against NTHi; only trends of protective efficacy against NTHi AOM in children were shown.
Areas covered: This review aims to consider all evidence available to date from pre-clinical and clinical phase III studies together with further evidence emerging from post-marketing studies since PHiD-CV has been introduced into routine clinical practice worldwide, to better describe the clinical utility of protein D in preventing AOM due to NTHi and its impact on NTHi nasopharyngeal carriage.
Expert commentary: Protein D is an effective carrier protein in conjugate vaccines and evidence gathered from pre-clinical, clinical and observational studies suggest that it also elicits immune response that can help to reduce the burden of AOM due to NTHi. There remains a need to develop improved vaccines for prevention of NTHi disease, which could be achieved by combining protein D with other antigens.
Highlights • Pneumococcal protein antigens could provide serotype-independent protection. • Two PHiD-CV/dPly/PhtD vaccine formulations were assessed in healthy infants. • Both protein-based vaccines ...elicited immune responses to pneumococcal proteins. • The vaccines had no impact on pneumococcal nasopharyngeal carriage prevalence. • Future evaluations will assess their impact against pneumococcal disease endpoints.
Summary Background Antimicrobial drugs are frequently prescribed to children for respiratory tract infections such as otitis, tonsillitis, sinusitis, and pneumonia. We assessed the effect of the ...ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; GlaxoSmithKline) on antimicrobial purchases. Methods In this nationwide phase 3–4 cluster-randomised, double-blind trial, children younger than 19 months were randomly assigned to receive PHiD-CV10 in 52 of 78 clusters or hepatitis B or A vaccine as control in 26 clusters according to three plus one or two plus one schedules (infants younger than 7 months) or catch-up schedules (children aged 7–18 months). The main objective for the antimicrobial treatment outcome was to assess vaccine effectiveness against outpatient prescriptions of antimicrobial drugs recommended by national treatment guidelines for acute otitis media in Finland in children who received at least one dose of study vaccine before 7 months of age. Masked follow-up lasted from the date of first vaccination (from Feb 18, 2009, through Oct 5, 2010) to Dec 31, 2011. We obtained data on all purchased antimicrobial prescriptions through the benefits register of the Social Insurance Institution of Finland. This and the nested acute otitis media trial are registered at ClinicalTrials.gov , numbers NCT00861380 and NCT00839254. Findings More than 47 000 children were enrolled. In 30 527 infants younger than 7 months at enrolment, 98 436 outpatient antimicrobial purchases were reported with incidence of 1·69 per person-year in the control clusters. Analysis of the main objective included 91% of all antimicrobial purchases: 31 982 in the control and 57 964 in the PHiD-CV10 clusters. Vaccine effectiveness was 8% (95% CI 1–14) and the incidence rate difference 0·12 per person-year corresponding to the number needed to vaccinate of five (95% CI 3–67) to prevent one purchase during the 2 year follow-up for combined PHiD-CV10 three plus one and two plus one infant schedules. The vaccine effectiveness was identical for the two infant schedules. In the catch-up schedules, the vaccine effectiveness was 3% (95% CI −4 to 10). Interpretation Despite low relative rate reductions the absolute rate reductions were substantial because of the high incidence of the outcome. This reduction would lead to over 12 000 fewer antimicrobial purchases per year in children younger than 24 months in Finland (birth cohort of 60 000 children). Funding GlaxoSmithKline Biologicals SA and National Institute for Health and Welfare (THL), Finland.
As a stepping stone toward evaluation in infants, the safety and immunogenicity of an investigational 12-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine ...(12vPHiD-CV) was assessed in toddlers. 12vPHiD-CV contains CRM
197
-conjugated capsular polysaccharides of serotypes 6A and 19A in addition to capsular polysaccharides of the 10 serotypes in PHiD-CV. In this phase I, double-blind, multicenter study (NCT01485406) conducted in Germany, 61 healthy toddlers aged 12-23 months previously primed with three PHiD-CV doses were randomized (1:1) to receive one dose of 12vPHiD-CV or PHiD-CV. Safety and reactogenicity of 12vPHiD-CV were assessed in terms of occurrence of grade 3 vaccination-related solicited and unsolicited adverse events (AEs) and vaccination-related serious AEs. Immune responses were evaluated 1 month post-vaccination. Grade 3 solicited local AEs (all considered vaccination-related) were reported for two (6.5%, redness) and three (9.7%, swelling) toddlers in the 12vPHiD-CV group and one (3.4%, swelling) in the PHiD-CV group. Grade 3 vaccination-related solicited general AEs were only reported in the PHiD-CV group. No grade 3 unsolicited or serious AEs were reported. For PHiD-CV serotypes, 100% of toddlers in both groups had antibody concentrations ≥0.2 µg/mL 1 month post-vaccination, and antibody geometric mean concentrations increased from pre-boosting. For serotypes 6A and 19A, antibody responses tended to be higher in the 12vPHiD-CV than the PHiD-CV group. A single dose of 12vPHiD-CV administered in toddlers was well tolerated and no safety concerns were identified. Immune responses were comparable to those induced by PHiD-CV when administered in toddlers previously primed with three doses of PHiD-CV.
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