Immunogenicity and reactogenicity of a combined adsorbed tetanus toxoid, low dose diphtheria toxoid, five component acellular pertussis and inactivated polio vaccine in six-year-old children

BACKGROUND: The objective of this study was to assess the immunogenicity and reactogenicity of the combined adsorbed tetanus toxoid, low dose diphtheria toxoid, 5-component acellular pertussis and inactivated polio vaccine (TdcP-IPV) as compared with a pediatric dose diphtheria formulation, combined with adsorbed tetanus toxoid and 3-component acellular pertussis (DTacP), in 6-year-old children who were immunized with 4 doses of diphtheria-tetanus-whole cell cellular pertussis (DTwcP) plus oral polio vaccine (OPV) before 2 years of age, according to the local Spanish vaccination calendar. METHODS: One hundred ninety-four healthy 6-year-old children were randomized to receive 1 dose of TdcP-IPV or 1 dose of DTacP and OPV. RESULTS: One month postvaccination, antidiphtheria and antitetanus titers were > or =0.1 IU/mL in 100% of patients in both study groups. TdcP-IPV reached 100% seroprotection rates against polio types 1, 2 and 3. In OPV recipients, these rates were 100, 100 and 96.8%, respectively. Seropositivity rates for pertussis toxin, filamentous hemagglutinin, pertactin and fimbrial components of the TdcP-IPV vaccine were 97.9, 89.6, 90.6 and 100%. The incidence of local and systemic reactions was 50.5 and 39.2% in the TdcP-IPV group and 59.4 and 38.5% in the DTacP plus OPV group, and no serious adverse events were reported. CONCLUSIONS: TdcP-IPV vaccine was shown to be immunogenic and safe when given as a booster in children 6 years of age who were primed with 4 doses of DTwcP and OPV.     

Safety and immunogenicity of pneumococcal conjugate vaccine in combination with diphtheria,tetanus toxoid,pertussis and Haemophilus influenzae type b conjugate vaccine

BACKGROUND: Pneumococcal polysaccharide/protein conjugate vaccines (PnCV) are immunogenic and effective in infancy. However, an addition to the nine currently recommended vaccine injections during the first year of life of African children may be a deterrent to participation in a PnCV program. Thus we have evaluated the safety and immunogenicity of a 9-valent PnCV (Wyeth Lederle Pediatrics and Vaccines) mixed with diphtheria, tetanus toxoid, cell pertussis and type b (TETRAMUNE). METHODS: Healthy Gambian infants were randomized at the age of 2 months to receive three doses 1 month apart of either (1) placebo reconstituted in TETRAMUNE in the right thigh (control) or (2) PnCV in the left thigh and TETRAMUNE in the right thigh (separate) or (3) PnCV reconstituted in TETRAMUNE as a single injection in the right thigh (combined). The vaccines were given together with routine Expanded Program on Immunization vaccines. Adverse reactions were recorded after vaccination, and antibody concentrations were measured by enzyme-linked immunosorbent assays. RESULTS: Local induration and tenderness were observed more commonly at the site of injection of TETRAMUNE than at the site of injection with PnCV after each dose of vaccination. Swelling at the site of injection was encountered more frequently at the site of administration of TETRAMUNE than at the site of administration PnCV ( P< 0.00001 for Doses 1 and 2 and P< 0.0009 for Dose 3). Swelling at the site of administration of TETRAMUNE mixed with PnCV was comparable with that observed for TETRAMUNE alone. Although most mothers reported that the babies "felt hot" 24 h after each injection, febrile reactions (temperature, >or=38 degrees C) were infrequent and resolved with antipyretics. Geometric mean titer for anti-polyribosylribitol phosphate antibody was 11.6 microg/ml [95% confidence limits (95% CI), 9.2, 14.6] in the control group and comparable with 13.3 microg/ml (95% CI 11.0, 16.0) in the combined group and significantly higher at 17.9 microg/ml (95% CI 14.7, 21.9; P= 0.01) in the separate group. Geometric mean concentrations of serotype-specific pneumococcal antibodies were higher in the combined group than the separate group for all nine serotypes. Antibody responses to diphtheria and pertussis antigens were similar in all groups. Anti-tetanus toxoid antibody concentrations were lowest in the combined group (6.66 IU/ml, 95% CI 5.77, 7.68 in the control group; 5.15 IU/ml, 95% CI 4.39, 6.03 in the combined group; P= 0.02). However, all vaccinees achieved protective antibody values. CONCLUSION: The combination of TETRAMUNE and PnCV is safe and immunogenic.     

An evaluation of the safety and immunogenicity of a five-component acellular pertussis, diphtheria, and tetanus toxoid vaccine (DTaP) when combined with a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine (PRP-T) in Taiwanese infants

OBJECTIVE: Immunologic interference particular to the Haemophilus influenzae type b (Hib) response has been observed with previous acellular pertussis-Hib combination vaccines. To test this hypothesis a clinical trial to assess the safety and immunogenicity of a five-component (pertussis toxoid [PT], filamentous hemagglutinin [FHA], pertactin [PRN], and fimbriae 2 and 3 [FIM]), pertussis vaccine combined with diphtheria and tetanus toxoids (DTaP) when given simultaneously with a lyophilized Hib-tetanus toxoid conjugate vaccine (PRP-T) in infants at 2, 4, 6, and 18 months of age was conducted. The study compared two methods of administration: both vaccines combined in a single syringe and administered as a single injection, or both vaccines administered concurrently but at separate sites of injection. METHODS: Healthy 2-month-old infants were enrolled at the National Taiwan University Hospital. DTaP, PRP-T, and oral poliomyelitis vaccine (OPV) were given at 2, 4, 6, and 18 months. Reaction information was collected by telephone 2 days after each vaccination. Serum was collected at 2, 6, 7, 18, and 19 months of age. RESULTS: One hundred thirty-five healthy infants were enrolled in Taiwan, of which 127 (94%) completed the 18-month booster: 68 received the combined vaccine and 67 the separate vaccines. All vaccines were well tolerated. No differences in rates of local and systemic reactions were seen between the two methods of administration. No serious adverse events were reported. Serologic responses were comparable between the groups. Pertussis responses (enzyme-liked immunoabsorbant assay units [EU]/mL) at 7 months were, for combined versus separate, PT (131 vs 105), FHA (116 vs 116), PRN (100 vs 77), and FIM (922 vs 702). At 19 months, pertussis results were, for combined versus separate, PT (216 vs 182), FHA (203 vs 200), PRN (263 vs 197), and FIM (892 vs 732). Only the 7-month PT response in the combined group was significantly higher (combined 131 EU/mL vs separate 105 EU/mL). After the third dose (age 6 months), all subjects achieved serologic serum antibody levels indicative of protection against Hib, diphtheria, tetanus, and poliovirus types 1, 2, and 3. In fact, 96% of children had anti-PRP levels indicative of protection (>/=0.15 microgram/mL) against Hib after only two doses. At 7 months, anti-PRP geometric mean titer values were 11.8 micrograms/mL in the combined group compared with 13.0 micrograms/mL in the separate group. The anti-PRP geometric mean titers after the 18-month booster were 58.5 micrograms/mL in the combined group versus 55.3 micrograms/mL in the separate group. CONCLUSION: The five-component DTaP vaccine may be combined with PRP-T vaccine without clinically significant immunologic interaction when given in a 2-, 4-, 6-, and 18-month schedule.     

吸附无细胞百白破灭活脊髓灰质炎和b型流感嗜血杆菌（结合）联合疫苗的安全性和免疫原性的meta分析

目的评价吸附无细胞百白破灭活脊髓灰质炎和b型流感嗜血杆菌(结合)(DTaP-IPV/Hib)五联疫苗与吸附无细胞百白破联合(DTaP)疫苗、b型流感嗜血杆菌结合疫苗(Hib)疫苗、灭活脊髓灰质炎(IPV)疫苗的免疫原性和安全性。方法检索国内外发表的有关DTaP-IPV/Hib联合疫苗与DTaP、Hib、IPV疫苗的随机对照试验(RCTs)文献,采用meta分析方法,利用RevMan 5.0软件评价DTaP-IPV/Hib联合疫苗的安全性和免疫原性。结果最终纳入6篇英文RCTs。DTaP-IPV/Hib五联疫苗对百日咳类毒素(PT)产生较高的血清保护性抗体水平(RR=0.26,95%CI:0.14~0.48)。抗百日咳抗体WMD=21.11,95%CI:9.36~32.86,抗1型脊髓灰质炎抗体WMD=59.15,95%CI:2.81~115.48和抗3型脊髓灰质炎抗体WMD=169.82,95%CI:75.33~264.30的抗体滴度水平在DTaP-IPV/Hib联合疫苗中均高于单种疫苗。但是抗b型流感嗜血杆菌荚膜多糖抗体的水平WMD=-3.58,95%CI:-5.52~-1.64在DTaP-IPV/Hib五联疫苗较低。安全性分析结果显示:红肿(RR=0.82,95%CI:0.72~0.93)和触痛(RR=0.45,95%CI:0.30~0.65),在五联疫苗中发生率较低,但是肿胀发生率较高。结论DTaP-IPV/Hib五联疫苗在基础免疫中的免疫原性与安全性与对照疫苗具有可比性。     

Safety and immunogenicity of Haemophilus influenzae type b-tetanus toxoid conjugate, presented in a dual-chamber syringe with diphtheria-tetanus-pertussis and inactivated poliomyelitis combination vaccine

The safety and immunogenicity of combining two established vaccines, polyribosyl ribitol phosphate conjugated to tetanus toxoid (PRP-T) (ActHIB, Pasteur Mérieux Connaught, Lyon, France) and diphtheria-tetanus-whole cell pertussis and inactivated poliovirus vaccine (DTP-IPV) (Tetracoq, Pasteur Mérieux Connaught, Lyon, France) were evaluated using a new dual-chamber syringe delivery system. Results were compared with those obtained when the two combination vaccines were either administered separately (two sites) or reconstituted manually and injected at a single site. A total of 487 2-month-old infants were enrolled in this study by 61 paediatricians in France. Infants were randomised to receive three immunisations of PRP-T and DTP-IPV at 2, 3 and 4 months of age, given either with the dual-chamber syringe (n = 213), as separate injections (n = 215), or as a single manually reconstituted injection (n = 59). Blood samples were taken prior to the first immunisation and 4 weeks after the third immunisation for the measurement of antibody titres. Infants were monitored by the parents for 3 days after each immunisation to detect local and systemic reactions. Local and systemic reactions occurring the 3 days following immunisation were as expected for the combination vaccines used. Safety of the vaccination using the dual-chamber syringe was as good as, if not slightly better than, that for the two vaccines administered separately. After the first immunisation, pain and unusual crying were significantly more frequent in infants who received two injections, compared to those who were immunised with the dual-chamber syringe. Serological responses were good for all antigens in the three groups and there was no evidence for any immunological interference. Almost all subjects in each group achieved levels of antibodies considered to be protective for all antigens. There were no clinically relevant differences in antibody response between any of the groups. The dual-chamber and separate injection methods of vaccination were equivalent according to a pre-defined criterion (percentage of infants with anti-PRP antibody titres ≥1.0 μg/ml). Conclusion Results from this study suggest that the two vaccines, PRP-T and DTP-IPV, may be safely and effectively administered in infants using the new dual-chamber syringe. This presentation provides an innovative strategy to combine different vaccines that are not yet available as a single formulation. Received: 20 December 1997 / Accepted: 5 January 1998     

Adverse effects and sero-responses to an acellular pertussis/diphtheria/tetanus vaccine when combined with Haemophilus influenzae type b vaccine in an accelerated schedule

Acellular pertussis vaccines provide protection against pertussis with few adverse effects. Differences in the reactogenicity and immunogenicity of available pertussis vaccines may be influenced by the immunisation schedule employed. We assessed responses to an acellular pertussis, diphtheria, tetanus vaccine mixed with Haemophilus influenzae type b (Hib) vaccine, (PRP-T) given at age 2, 3 and 4 months. Parents kept a symptom diary for 3 days after each immunisation. Antibodies to diphtheria, tetanus, pertussis toxin and filamentous haemagglutinin were measured by enzyme immunoassay at 2 and 5 months. Results were compared with historical controls who received a combination whole-cell pertussis, diphtheria, tetanus/PRP-T vaccine in the same schedule. A total of 262 infants were recruited, of whom 251 were fully evaluated after three doses of vaccine. Systemic and most local reactions were less frequent following the acellular combination. Fever ≥38°C was reported after only 0.6% of doses. Redness or swelling ≥2.5 cm were unusual after the first two doses (2–5%), but rates rose to 13% after the third dose. Antibody responses to diphtheria and tetanus toxoids were lower, while those to pertussis antigens were higher, more uniform and less attenuated by pre-immunisation antibody than in infants who received the whole-cell combination. All infants achieved protective antibody titres of at least 0.1 IU/ml for diphtheria and 0.01 IU/ml for tetanus. Conclusion The acellular combination vaccine was immunogenic for diphtheria, tetanus and pertussis components and was associated with low rates of fever following immunisation. Received: 9 June 1998 / Accepted: 2 November 1998     

Additional recommendations for use of tetanus toxoid, reduced-content diphtheria toxoid, and acellular pertussis vaccine (Tdap)

The American Academy of Pediatrics and the Centers for Disease Control and Prevention are amending previous recommendations and making additional recommendations for the use of tetanus toxoid, reduced-content diphtheria toxoid, and acellular pertussis vaccine (Tdap). Review of the results from clinical trials and other studies has revealed no excess reactogenicity when Tdap is given within a short interval after other tetanus- or diphtheria-containing toxoid products, and accrual of postmarketing adverse-events reports reveals an excellent safety record for Tdap. Thus, the recommendation for caution regarding Tdap use within any interval after a tetanus- or diphtheria-containing toxoid product is removed. Tdap should be given when it is indicated and when no contraindication exists. In further efforts to protect people who are susceptible to pertussis, the American Academy of Pediatrics and Centers for Disease Control and Prevention recommend a single dose of Tdap for children 7 through 10 years of age who were underimmunized with diphtheria-tetanus-acellular pertussis (DTaP). Also, the age for recommendation for Tdap is extended to those aged 65 years and older who have or are likely to have contact with an infant younger than 12 months (eg, health care personnel, grandparents, and other caregivers).     

Tetravalent diphtheria, tetanus, pertussis and inactivated poliomyelitis vaccine

Two hundred forty-nine infants were immunized after being randomly allocated to the classical Tetracoq vaccine or to inactivated poliomyelitis vaccines prepared on monkey kidney cells or on Vero-type continuous cell lines either mixed with DPT or placed in a 2-compartment syringe separating (by-pass) the polio vaccine from the DPT. The 3 preparations were well tolerated and led to a good immune response: the first after 3 injections, the second and third after the second injection.     

Adverse effects of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine in 6- to 7-year-old children

Although the safety profile of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines in adolescents and adults has been documented, few data have reported about their adverse events in children. Healthy 6- to 7-year-old children who were immunized with Tdap vaccine were evaluated for adverse events on Days 1, 2, 4, and 7 postimmunization. Information of sex, body mass index (BMI), and previous diphtheria-pertussis-tetanus (DPT) immunization history was obtained and evaluated for the association with the adverse events. A total of 243 6- to 7-year-old children were immunized with Tdap. Among the 243 children immunized, remarkable adverse events included redness more than or equal to 10?mm in 47 (19%) children, induration more than or equal to 10?mm in 57 (23%), tenderness in 130 (53%), and fever in 12 (5%). Redness and induration resolved in 7 days and fever resolved on Day 4. The adverse events were not associated with gender, BMI above the mean value, or the type of fourth DPT immunization. Adverse events after Tdap vaccination were mild and dissolved within 7 days in 6- to 7-year-old children.     

Prevention of pertussis among adolescents: recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine

The purpose of this statement is to provide the rationale and recommendations for adolescent use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines. Despite universal immunization of children with multiple doses of pediatric diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine, pertussis remains endemic with a steady increase in the number of reported cases. Two peaks in the incidence of pertussis occur in pediatric patients: infants younger than 6 months of age who are inadequately protected by the current immunization schedule and adolescents 11 through 18 years of age whose vaccine-induced immunity has waned. Significant medical and public health resources are being consumed in postexposure management of adolescent cases, contacts, and outbreaks with little beneficial effect on individuals or the epidemiology of disease. Two Tdap products were licensed in 2005 for use in people 10 through 18 years of age (Boostrix) and 11 through 64 years of age (Adacel). The American Academy of Pediatrics recommends the following: 1. Adolescents 11 to 18 years of age should receive a single dose of Tdap instead of tetanus and diphtheria toxoids (Td) vaccine for booster immunization. The preferred age for Tdap immunization is 11 to 12 years. 2. Adolescents 11 to 18 years of age who have received Td but not Tdap are encouraged to receive a single dose of Tdap. An interval of at least 5 years between Td and Tdap is suggested to reduce the risk of local and systemic reactions; however, intervals of less than 5 years can be used, particularly in settings of increased risk of acquiring pertussis, having complicated disease, or transmitting infection to vulnerable contacts. Data support acceptable safety with an interval as short as approximately 2 years. 3. Tdap and tetravalent meningococcal conjugate vaccine (MCV4 [Menactra]) should be administered during the same visit if both vaccines are indicated. If this is not feasible, MCV4 and Tdap can be administered using either sequence. When not administered simultaneously, the American Academy of Pediatrics suggests a minimum interval of 1 month between vaccines. The rationale for this strategy is to provide direct protection of immunized adolescents. With implementation of vaccine recommendations, indirect benefitalso is likely to extend to unimmunized peers and other age groups. The strategy of universal Tdap immunization at 11 to 12 years of age is cost-effective.     

Safety and immunogenicity of acellular pertussis vaccine, combined with diphtheria and tetanus as the Japanese commercial Takeda vaccine, compared with the Takeda acellular pertussis component combined with Lederle's diphtheria and tetanus toxoids in two-, four- and six-month-old infants.

A double blind, randomized, controlled trial compared the safety and immunogenicity of an acellular pertussis vaccine formulated at Lederle using the Takeda acellular pertussis component combined with Lederle diphtheria and tetanus toxoids vaccines (APDT), with the commercially available Japanese Takeda vaccine (APDT-T/J) as a three-dose series to 2-, 4-, and 6-month-old children. Sera were analyzed for antibody to pertussis antigens: lymphocytosis-promoting factor; filamentous hemagglutinin; 69-kDa outer membrane protein; pertussis agglutinogens; neutralizing antibodies to LPF; and to diphtheria and tetanus toxoids. Information concerning local reactions and systemic events were collected daily for 10 days postimmunization. The overall reaction rate was low for both groups. There were no reactions that contraindicated subsequent vaccine and no serious adverse events. For local reactions statistically significant differences between the groups were seen only for a greater incidence of induration in the APDT group at 2 months (12% vs. 0%, P < 0.01), and at 4 months (8% vs. 0%, P = 0.4) compared to the APDT-T/J group. Of the few systemic reactions the only statistically significant difference between the vaccine groups was a greater incidence of fretfulness in the APDT group after the initial immunization (12% vs. 2%, P = 0.05). There were no statistically significant differences in the immune response between the two vaccines at the 7-month visit. We conclude that APDT is equivalent to the commercially available Takeda vaccine (APDT-T/J).     

Economic evaluation of use of diphtheria, tetanus, and acellular pertussis vaccine or diphtheria, tetanus, and whole-cell pertussis vaccine in the United States, 1997

OBJECTIVE: To compare the economic costs and benefits associated with using either diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) or diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTwP) in the United States in 1997. DESIGN: Standard cost-benefit analysis, from both the societal and health care system perspectives, was performed for each combination vaccine as well as for the pertussis components singly. SETTING: A simulated cohort of 4.1 million children from birth to age 15 years. MAIN OUTCOME MEASURES: Net costs (savings) and benefit-cost ratios (BCRs) RESULTS: Without a vaccination program, diphtheria, tetanus, and pertussis disease caused more than 3 million cases and more than 28,000 deaths, at a cost of $23.6 billion. From the societal perspective, net savings because of the use of DTaP and DTwP were $22.510 million and $22.623 million, respectively. The net savings from the acellular pertussis component and the whole-cell pertussis component only were $4.362 million and $4.474 million, respectively. Benefit-cost ratios for DTaP from a societal and health care system perspective were 27:1 and 9:1, respectively. Sensitivity analyses of key variables did not result in appreciable changes in results. CONCLUSIONS: Compared with no program, vaccination with DTaP or DTwP resulted in substantial savings, regardless of the perspective taken and for all sensitivity analyses conducted. Compared with DTwP, use of DTaP generated a small cost increase that might be offset by the value of other factors, such as increased confidence in pertussis vaccination resulting from reduced adverse events. Arch Pediatr Adolesc Med. 2000;154:797-803     

Reduced immunogenicity of diphtheria and tetanus toxoids when combined with pertussis toxoid

The effect of pertussis toxoid on the immunogenicity of diphtheria and tetanus toxoids (DT) was studied during a double blind efficacy trial of an acellular pertussis vaccine. Infants received DT with or without pertussis toxoid at 3, 5 and 12 months of age. Geometric mean concentrations were higher in the DT than in the DT-pertussis toxoid group 1 month (diphtheria toxoid 4.76 versus 3.58 IU/mL, P = 0.009; tetanus toxoid 4.42 versus 2.66 IU/mL, P < 0.0001) and 2 years after the third injection (diphtheria toxoid 0.15 versus 0.10 IU/mL, P < 0.0001; tetanus toxoid 0.38 versus 0.18 IU/mL, P < 0.0001). Pertussis toxoid causes a small but significant reduction of the immunogenicity of diphtheria toxoid and tetanus toxoid.     

Adult formulation of a five component acellular pertussis vaccine combined with diphtheria and tetanus toxoids and inactivated poliovirus vaccine is safe and immunogenic in adolescents and adults

BACKGROUND: Pertussis is increasingly recognized as an important cause of cough illness in adolescents and adults. PURPOSE: To evaluate the safety and antibody response to a single dose of an adult formulation of a five component (pertussis toxoid, filamentous hemagglutinin, pertactin, fimbriae 2 and 3) acellular pertussis vaccine (aP) combined with diphtheria and tetanus toxoids (TdaP) and inactivated poliovirus vaccine (TdaP-IPV) in adolescents and adults and to assess the response to a second dose of the acellular pertussis vaccine in a subset of the adults. POPULATION AND SETTING: The study addressed 1207 healthy participants (736 adults and 466 adolescents) recruited in five Canadian communities. STUDY DESIGN: In a randomized, observer-blind, controlled clinical trial, adult participants received Td followed at a separate visit by aP, TdaP followed by IPV or TdaP-IPV; adolescents received Td-IPV followed at a separate visit by aP or TdaP-IPV. A subgroup of adults was given a booster of aP 1 month after TdaP. OUTCOME MEASURES: Antibody titers measured before and 1 month after each immunization; adverse events enumerated at 24 h, 72 h and 8 to 10 days. RESULTS: The aP vaccine given by itself was associated with adverse events less frequently than were Td, Td-IPV, TdaP or TdaP-IPV vaccines, but reaction rates did not differ significantly among the latter products. The antibody response against Bordetella pertussis antigens was vigorous in all groups, although adults given the TdaP-IPV vaccine had lower antibody titers against filamentous hemagglutinin, pertactin, diphtheria and tetanus antibodies than those given TdaP vaccine. Similarly adolescents given TdaP-IPV had lower antibody titers against pertussis toxin, filamentous hemagglutinin, fimbriae and agglutinins than those given Td-IPV and aP alone. A second dose of acellular pertussis vaccine was not associated with increased adverse events in adults but elicited increased antibody titers over that achieved by a single dose only against pertussis toxin. CONCLUSIONS: This adult formulation five component aP vaccine given as TdaP-IPV is safe and immunogenic in adolescents and adults and is a candidate vaccine for adolescent and adult immunization programs.     

Extensive swelling reaction associated with diphtheria and tetanus toxoids and acellular pertussis vaccine

Although extensive swelling reactions in the injected limb after the administration of diphtheria-tetanus toxoid-acellular pertussis vaccine have been reported previously, to our knowledge, computerized tomography images of this entity have not been published. A 4-year-old boy with extensive swelling after vaccination with diphtheria-tetanus toxoid-acellular pertussis vaccine is presented.