1. Conclusions. Abstract Introduction Material and Methods Results
PHASE I CLINICAL TRIAL IN CHILDREN WITH A CUBAN PNEUMOCOCCAL CONJUGATE VACCINE.
Authors: Puga-Gómez R1, Dotres-Martínez C.P1, Broño C.R2, Ruiz C.R2, Ricardo Y1, Paredes-Moreno B3, González-García N3, Rosell-León S3, García-Cristia Y1, del Valle-Rodríguez R.A1, Echemendía-Marín V3, Lam-Hernández J.L1, Orta-Pino T2, Betancourt-Pérez B2, Mesa-Herrera ME1, Rodríguez-Concepción A2, Duany-Álvarez D1, Santana-Mederos D, Valdés-Balbín Y3, Vérez-Bencomo V3.
1. Pediatric Hospital “Juan Manuel Márquez”. Havana. Cuba Primary Health System from Marianao. Havana. Cuba Center for Biomolecular Chemistry. Havana. Cuba.
Abstract
A new conjugate vaccine containing the seven serotypes of S. pneumoniae more frequently associated with infection in Latina-American have been designed in Cuba. The candidate vaccine (PCV7-TT) contains 2µg of each capsular polysaccharide 1, 5, 14, 18C, 19F and 23F and 4µg of 6B, conjugated to tetanus toxoid (TT) and aluminum phosphate as adjuvant. The safety of the vaccine in healthy adults was showed during Then, the Cuban National Regulatory Authority recommended assessing the safety in children around 5 years old, previous to clinical trials in infants.
A phase I, parallel, controlled and double blind clinical trial was designed to assess the safety of PCV-7 in fifteen 4-5 years old children. The protocol was reviewed by the Ethics Committee of “Juan Manuel Márquez” Pediatric Hospital. Children were randomized to received one dose of PCV7-TT (n=10) or Synflorix (n=5). Each child was followed for 3 hours after the vaccination for immediate adverse events. During the next 30 days the child’s parents recorded any adverse events in a diary, and they received medical visits at 7, 21 and 30 days after immunization. Blood samples were obtained before and 30 days after vaccination for immunological evaluation.
No serious adverse events were reported using PCV7-TT. The adverse events reported were comparable between both vaccines, and local pain was the most frequent. PCV7-TT shows a good safety profile. Once demonstrate the general safety profile of PCV7-TT in children, we started Phase I clinical trials in infant during last semester 2013.
Introduction
The safety of this PCV7-TT vaccine was demonstrated in healthy young adults during phase I clinical trial a year ago (See Poster P-192).
In the present study, we investigated the safety of PCV7-TT during a randomized Phase I clinical trial in children 4-5 years old, using Synflorix as control vaccine.
Cuba has been developing a new heptavalent conjugate vaccine (PCV7-TT) during the last 8 years, containing the seven most prevalent serotypes in children below 6 years: 1, 5, 6B,14, 18C, 19F and 23F, accounting for ~70% of isolated serotypes in the Americas and others regions [1, 2]. PCV7-TT contains 2µg of serotypes 1, 5, 14, 18C, 19F and 23F and 4µg of 6B, each conjugated to tetanus toxoid (TT) and aluminum phosphate is used as adjuvant.
[1] Johnson HL et al. PLoS Med 2010;7:1-13
[2] Castañeda E et al. Pediatr Infect Dis J 2009;28:e265-70
[3] Scott DA et al. Vaccine 2007;25:
[4] Bryant KA et al. Pediatrics 2010;125:866-7
A phase I, parallel, controlled, randomized (ratio 1:2) and double blind clinical trial was designed to assess the safety and the preliminary immunogenicity of PCV7-TT in 4-5 years old children. The protocol was reviewed by the Ethics Committee of Children Universitary Hospital “Juan Manuel Márquez”. It was conducted in accordance with the code of Ethic of the World Medical Association for experiments in human beings [3].
Fifteen healthy children 4-5 years old resident in Havana, who had not received prior pneumococcal vaccination, were enrolled in the study once their parents gave written informed consent for their study participation. They were recruited by their doctors in the Primary Health Attention after full information about the study. The children were randomized to receive a single intramuscular dose in their right arm of either Synflorix (n=5) or PCV7-TT (n=10).
PCV7-TT (Batch Neu-13.02, Manufacturer: Center for Bimolecular Chemistry, Cuba) contains 2mg of serotypes 1, 5, 14, 18C, 19F, 23F and 4 mg of serotype 6B, each conjugated to TT.
Synflorix vaccine (Batch ASPNA305AA, Manufacturer: GSK) was used as a control.
The primary outcome of this study was safety but immunogenicity was also explored.
Post-vaccination, children were followed for 30 days to assess adverse events. Serum was obtained before and 30 days after vaccination for assessment of immunogenicity. Each subject was closely followed for 3 hours post-vaccination for immediate adverse effects. During the next 30 days the child’s parents recorded any adverse events in a diary, and they received medical visits at 1, 2, 3, 7, 21 and 30 days after immunization.
Local injection-site adverse events (local pain, tenderness, redness, induration, swelling, local temperature increase, functional impotence, abscess or necrosis) and systemic symptoms (fever, anaphylactic shock, drowsiness, nausea, vomits and headache) were recorded during the first 7 days after vaccination. Any other events occurring with the child was recorded by the parents during 30 days.
Statistics: Random list was generated using R program and randomization 1:2 was used to assign 10 subject to the group PCV7-TT and 5 subjects to the group Synflorix. Subjects were included in the safety analysis if they received the required dose and all evaluations visits were made. All researchers and participants were blinded until the end of the study. A non-parametric test (Fisher’s Exact Test for Count Data) was used to compare incidence for each adverse event and percentages of occurrence for adverse events were calculated in both groups.
Material and Methods
Conclusions.
PCV7-TT was as safe as control vaccine Synflorix in children aged 4-5 years. These are the first clinical results of PCV7-TT in children and they pave the way toward next clinical trials in children and infants
Results
Immunogenicity of PCV7-TT was also evaluated. Despite the small sample of this study, the immunological results are considered very promising as the majority of children had OPA titer lower than 1:8 and became over 1:8 after vaccination for each serotype in PCV7-TT. Detailed results are showed in Poster 183.
A total of 26 subjects were evaluated for inclusion and 15 were included. They were randomized in two groups: 10 subjects received one dose of PCV7-TT and 5 received one dose of Synflorix as control vaccine. Demographic characteristic of the two groups were comparable for gender, ethnicity and age. Subjects were followed-up during 30 days after vaccination. Data from all included subjects were analyzed for safety and immunogenicity outcomes. No losses or exclusions were reported.
Local adverse events were reported in the 70% of subject immunized with PCV7-TT and 60% for Synflorix. Local pain was the most frequent event, 40% for Synflorix and 70% for PCV7-TT. Also, induration was reported in 40% of children immunized with Synflorix and 30% for PCV7-TT. Only two systemic adverse events were reported: fever and vomits, and only the fever were common for both vaccines (one subject for each group). Vomits were reported for one subject immunized with Synflorix. In all cases, the local and systemic events appear and disappear during the first 72 hours after vaccination.
No local or systemic event was reported as severe. No statistical difference (p≥0.05) was found between groups for incidence of local and systemic adverse events.
Three unexpected adverse events were reported in the subjects immunized with Synflorix, while 15 unexpected events were reported for PCV7-TT during the 30 days after vaccination. One subject immunized with PCV7-TT reported 8 of the 15 unexpected events, which appeared between 7 to 21 days after vaccination. No serious adverse events were reported using PCV7-TT.
In general, both vaccines were well tolerated, and local pain was the more frequent adverse event for PCV7-TT. The safety profile showed by PCV7-TT is similar to other currently PCV as PCV13, with local reactions as main adverse events in adults and infants [3, 4].
Adverse Events
PCV7-TT
N=10
Synflorix
N=5 n %
Expected Local Events
Local pain 7 70 2 40
Redness 1 10
Induration 3 30
Local temperature increase 20
Local Inflammation
Expected Systemic Events
Fever
Vomits
Acknowledgements
We would like thanks to World Health Organization and Pan-American Health Organization, mainly Jose Luis Di-Fabio and Ana María Henao, for the permanent support to this project.