1. Abstract Introduction Material and Methods Results Conclusions
SAFETY AND INMUNOGENICITY OF A NEW HEPTAVALENT PNEUMOCOCCAL CONJUGATE VACCINE IN HEALTHY ADULTS. PHASE I.
1. Center for Biomolecular Chemistry. Havana. Cuba National Center for Toxicology. Havana. Cuba Finlay Institute. Havana. Cuba.
Authors: Paredes-Moreno B1, González- García N1, Pérez-Rodríguez S2, Mirabal M3, Rivero-Vázquez I2, González- Delgado CA2, Tamayo-Rodríguez M2, Díaz-Machado A2, Rubino -Moreno J2, Oliveros-Oliveros R2, Martínez-Pérez M2, Martín-Trujillo A2, García-Rivera D1, Rodríguez-Noda LM1, Pérez- Baños A1, Soroa-Millán Y1, Rodríguez-Estrada Y1, Álvarez -García MA1, Iglesias-Machado A1, Santana-Mederos D1, Valdés Balbín Y1, Vérez-Bencomo V1.
Abstract
A phase I, parallel, controlled and double blind clinical trial was designed to assess the security in healthy adults of a new conjugate vaccine containing the seven serotypes of S. pneumoniae more frequently associated with infection in Latina-American. This vaccine (PCV7-TT) has been designed in Cuba, and 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.
Forty subjects were randomized to two groups to receive a dose of PCV7-TT (n=20) or Polysaccharide Vaccine PNEUMO 23 ® (n=20). Each subject was followed for 3 hours after the vaccination for immediate adverse events. During the next 30 days they 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.
A dose of PCV7-TT in healthy adults did not report the occurrence of serious adverse events related to the administration of the studied vaccine. The vaccine proved to be as secure as a control vaccine capsular polysaccharide 23-valent. The results of the evaluation of antibody concentration and opsonophagocytic titer demonstrated the ability of the vaccine VCN7-TT activated an immune response against the seven vaccinated serotype. This was the first clinical trial with this vaccine, and the results open the way to clinical trial in infants and children.
Introduction
Based on the recommendations made by WHO on the Target Product Profile and Advanced Market Commitment for pneumococcal conjugate vaccines and surveillance reports SIREVA , a new pneumococcal conjugate vaccine candidate (PCV7-TT) was developed in Cuba. The TPP recognizes that a combination of a limited number of serotypes (1, 5, 6A/6B, 14, 19F, and 23F) accounts for at least 60% of disease both globally and in every region of the world, and a vaccine with this coverage would be expected to have a considerable public health impact and be favorably assessed by cost effectiveness analyses [1, 2]. This new candidate contains the serotypes 1, 5, 6B, 14, 18C, 19F and 23F, all conjugated to tetanus toxoid.
In the present study, we investigated the safety of PCV7-TT during a randomized Phase I clinical trial in healthy adults, using PNEUMO23® as control vaccine.
Material and Methods
A Phase I, controlled, randomized, parallel and double-blind clinical trial was designed to assess the safety and the preliminary immunogenicity of PCV7-TT in healthy adults. The protocol was reviewed by the Ethics Committee of National Center for Toxicology. It was conducted in accordance with the code of Ethic of the World Medical Association for experiments in human beings [3].
Forty healthy young, men between years old, resident in Havana, who had not received prior pneumococcal vaccination, were enrolled in the study once gave written informed consent for their study participation.
The subjects were randomized to receive a single intramuscular dose in their right arm of either PNEUMO23® (n=20) or PCV7-TT (n=20).
PCV7-TT (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.
PNEUMO23® vaccine (Manufacturer: Sanofi Pasteur) was used as a control.
The primary outcome of this study was safety but immunogenicity was also explored.
Post-vaccination, subjects 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 subjects 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 subjects was recorded during 30 days.
Serotype specific OPA and ELISA were performed at the Immunology Department in Center for Biomolecular Chemistry, following the WHO recommended protocol [4, 5].
Statistics: Random list was generated using R program and randomization 1:1 was used to assign 20 subject to the group PCV7-TT and 20 subjects to the group PNEUMO23® . 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.
Results
A total of 79 subjects were evaluated for inclusion and 40 were included. They were randomized in two groups: 20 subjects received one dose of PCV7-TT and 20 received one dose of PNEUMO23® as control vaccine. Demographic characteristic of the two groups were comparable for ethnicity and age. Subjects were followed-up during 30 days after vaccination. Data from all included subjects were analyzed for safety and immunogenicity outcomes. One voluntary loss was reported in PCV7-TT group.
94 adverse events were reported during the trial, 47% of these events were reported in PNEUMO23® group and 53% in PCV7-TT group. 56 adverse events were related with vaccination, 50% in each group.
Local adverse events were reported in the 80% of subject immunized with PCV7-TT and 75% for PNEUMO23®. Local pain was the most frequent event, 75% for PNEUMO23® and 70% for PCV7-TT. Also, induration was reported in 10% of subjects immunized with PCV7-TT and 5% for PNEUMO23® . Only three systemic adverse events were reported: headache, drowsiness and discomfort. 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. 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 [6].
After vaccination with one dose of PCV7-TT , more than 50% of subjects attained OPA titer over 1:8. These are the first results of immunogenicity in humans being immunized with PCV7-TT.
Table 1. Adverse events in subjects vaccinated with PCV7-TT or PNEUMO23® .
Adverse events
PCV7-TT
PNEUMO 23® n %
Local
Local pain 14 70 15 75
Local temperature increase 5 25 4 20
Redness
Induration 2 10 1
Local Inflammation
Local Hypersensibility
Systemic
Discomfort
Headache
Drowsiness
Figure 1. % of Subjects with OPA titer ≥1:8 pre and post-vaccination.
PCV7-TT was as safe as control vaccine PNEUMO23® in healthy adults. These are the first clinical results of PCV7-TT in humans beings and they pave the way toward next clinical trials in children and infants. See posters P-183, P-197
Conclusions
References
[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] WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Available from: [accessed 22 March 2013]
[4] Target Product Profile (TPP) for the Advance Market Commitment. (AMC) for pneumococcal conjugate vaccines (Part 1). Geneva: World Health Organization Available from:
[5] Training manual for Enzyme linked immunosorbent assay for the quantitation of Streptococcus pneumoniae serotype specific IgG (Pn PS ELISA). (007sp Version). Available from:
[6] Scott DA et al. Vaccine 2007;25:
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.