Immunity to diphtheria and tetanus in England and Wales

The immunity profile of the English and Welsh population to diphtheria and tetanus has been determined by measuring diphtheria and tetanus antitoxin levels for 3088 and 3142 sera, respectively. Time-resolved fluorimetric immunoassay - DELFIA was used to measure diphtheria antitoxin levels and an in-house, indirect ELISA to measure tetanus antitoxin levels. More than 80% of those aged between 2 and 20-24 years had protective diphtheria antitoxin levels of 0.01 IU/ml, or greater, and more than 80% of those aged between 4 and 35-39 years had protective tetanus antitoxin levels of 0.1 IU/ml, or greater. Only 29% and 53% of those aged 60 and over were protected against diphtheria and tetanus. Two increases of diphtheria antitoxin levels greater than 0.1 IU/ml and tetanus antitoxin levels greater than 1.0 IU/ml were apparent, starting at 4 and 14 years of age, which correspond with the policy of giving a diphtheria and tetanus toxoid booster on school entry and a tetanus plus low-dose diphtheria toxoid (recently introduced) booster to school leavers. This is the first comprehensive study of diphtheria and tetanus immunity in the English and Welsh population and shows that the accelerated schedule of immunisation, introduced in 1990, has effectively primed immunological memory against both these antigens and that boosting at school entry and at school leaving is effective in increasing levels of immunity.     

Humoral immunity 10 years after booster immunization with an adolescent and adult formulation combined tetanus, diphtheria, and 5-component acellular pertussis vaccine

Persistence of antibodies after a single dose of Tdap vaccine (tetanus, diphtheria, and 5-component acellular pertussis vaccine) was evaluated in a follow-up study of adolescents (N=324) and adults (N=644) who had received Tdap in earlier clinical trials. Outcome measures were seroprotection (tetanus and diphtheria) or seropositivity (pertussis) and geometric mean concentrations. Humoral immune responses to all antigens were robust 1 month after initial immunization, decreased at subsequent measurements, but continued to exceed pre-immunization levels 1, 3, 5, and 10 years later. Protective levels of diphtheria and tetanus antitoxin persisted in 99.3% of adolescents 10 years after a booster dose of Tdap. Seropositivity to 1 or more pertussis antigens also persisted in most adolescents for 10 years. Although tetanus antitoxin responses were similar in adults to those observed in adolescents, diphtheria antitoxin titers were lower, reflecting the fact that a smaller proportion of adults had received diphtheria toxoid in the previous 10 years compared to adolescents. These data will contribute to the selection of the optimal interval for repeat doses of Tdap.     

Booster response to the tetanus and diphtheria toxoid carriers of 11-valent pneumococcal conjugate vaccine in adults and toddlers.

We measured the tetanus and diphtheria antitoxin responses after administration of one dose of a mixed carrier (tetanus and diphtheria toxoids) 11-valent pneumococcal conjugate vaccine (PncDT) in 20 Finnish adults (mean age 26.1 years) and 20 Finnish (mean age 23.2 months) and 23 Israeli (mean age 18.5 months) toddlers. The vaccinees had previously been immunised with multiple doses of vaccines containing diphtheria and tetanus toxoids. A double-antigen ELISA was used to measure the antitoxin concentrations. PncDT induced significant booster responses in both adults and toddlers to the tetanus and the diphtheria carrier proteins. Thus, the effect on the tetanus and diphtheria immunity of multivalent conjugate vaccines containing tetanus and diphtheria toxoids as carriers needs to be evaluated before such vaccines are routinely implemented.     

International collaborative studies on potency assays of diphtheria and tetanus toxoids

Collaborative studies showed that relative potency assays for a particular type of diphtheria toxoid (adsorbed) and for tetanus toxoid (plain and adsorbed) gave very similar results, whether the assays were carried out by toxin challenge or by antitoxin titration after immunization of experimental animals with graded doses of toxoid. The same numerical results were obtained with a scoring system as with a system based on survivals only. Although skin tests were used on a very limited scale in these studies, it seems likely that they could replace lethal tests for the diphtheria challenge assays.     

The effect of reconstitution of an Haemophilus influenzae type b-tentanus toxoid conjugate (PRP-T) vaccine on the immune responses to a diphtheria-tetanus-whole cell pertussis (DTwP) vaccine: a five-year follow-up.

Controversial results have been obtained from previous studies on the combined administration of Haemophilus influenzae type b-tetanus toxoid conjugate (PRP-T) and diphtheria-tetanus-whole-cell pertussis (DTwP) combination vaccines, with regard to possible reciprocal interference between the constituent antigens. To document the priming effect and possible long-term immunogenic interference of PRP-T and DTwP combination vaccines, a randomized, double-blind, controlled study was conducted in Belgium. A total of 168 healthy infants received, at 3, 4 and 5 months of age, DTwP vaccine mixed just prior to injection either with PRP-T vaccine (group A, DTwP//PRP-T, N = 85) or with placebo (group B, DTwP//Placebo, N = 83). At the age of 14 months, children of both groups were randomized to receive either a dose of DTwP//PRP-T vaccine (subgroups A1 and B1) or a dose of Hib polysaccharide (PRP) vaccine (subgroups A2 and B2). Those children in subgroups A1 and B1 had an additional serum sample taken at the age of 5 years (at the time of a DT booster). The immune response to Hib polysaccharide at the age of 4, 5 and 6 months confirmed the excellent immunogenicity profile of PRP-T in infants. In addition, the vigorous anamnestic response (i.e. a 20-fold increase of GMT) to a booster dose of the plain capsular polysaccharide (PRP) reflected the efficient Hib-priming induced by the combined DTwP//PRP-T vaccine. Reconstitution of PRP-T with DTwP did not affect the immune response to diphtheria toxoid or pertussis agglutinins. Nevertheless, at almost any time point during the five-year follow-up, the tetanus antitoxin GMT values were significantly lower in the DTwP//PRP-T group (A and A1) than in the DTwP//Placebo group (B and B1). Despite the suppressive effect on GMT values, intergroup differences in rates of seroprotection were never significant, except after doses 2 and 3 for which there were lower percentages of children in group A with antitoxin titers > 0.05 IU/mL and > 1.0 IU/mL. In the group primed with the combined DTwP//PRP-T vaccine, (1) a DT booster dose at the age of 5 years provoked a 150-fold increase in tetanus antitoxin GMT, (2) a high tetanus antitoxin GMT value was attained (GMT = 19.3 IU/mL) and (3) all children in this group had tetanus antitoxin titers > 1.0 IU/mL, so it may be concluded that all these children will still be protected against tetanus until at least the age of the next recommended booster dose (i.e. the age of 15 years). No differences in the occurrence of adverse events were observed between the groups who received the DTwP//PRP-T vaccine or the DTwP//Placebo vaccine, both vaccines being associated with events customarily attributable to DTwP (data not shown). Our results indicate (1) that the combination vaccine, DTwP//PRP-T, represents a safe and effective alternative for the existing uncombined vaccines and (2) that the long-term effect of interference between the components of future combination vaccines should be studied with subsequent booster doses, followed by the evaluation of persistence of antibodies over several years.     

Tetanus and diphtheria antitoxin levels following a hospital-based adult immunization program.

A hospital-based program to immunize adults against tetanus unless specific contraindications to immunization are present has been in effect at Parkland Memorial Hospital since 1959. Adsorbed tetanus toxoid was used from 1959 to 1970, and was replaced at that time by adult type adsorbed combined tetanus/diphtheria toxoid. In the present survey, the titers of diphtheria and tetanus antitoxins were determined in sera from 97 adults admitted to the Medical Service. Titers of diphtheria antitoxin less than 0.0125 units per ml were found in only seven patients and less than 0.0125 units per ml of tetanus antitoxin in only 17 patients. This high prevalence of immunity especially to tetanus appears to reflect our practice of routine immunization of adults. Although the recommended frequency of tetanus boosters has recently been reduced for adults who have completed a full primary immunization series, susceptibility to diphtheria or tetanus or both is not uncommon among adults in the US. Unless contraindications are present, we therefore urge routine immunization of all adults seeking medical care and of all hospital personnel as a means of diminishing the risk of diphtheria and tetanus in those adult populations with a significant incidence of susceptibility to these diseases.     

Immunogenicity of a combined diphtheria-tetanus-acellular pertussis vaccine in adults

Two clinical studies were undertaken to evaluate the immunogenicity of an adult-type dTpa booster vaccine (Boostrix by GlaxoSmithKline Biologicals). Blood samples taken prior to vaccination showed that 24.4 and 13.0% of subjects were seronegative for diphtheria and tetanus antibodies, respectively. Moreover, about one-third of the vaccinees had no detectable levels of antibodies to pertussis toxoid (PT) or pertactin (PRN). One month post-vaccination, more than 93% of all individuals, regardless of age or type of vaccine received, had seroprotective antibody levels for diphtheria and tetanus (> or = 0.1IU/ml). In those individuals vaccinated with the adult-type dTpa vaccine (Boostrix), more than 98% were found to be seropositive for antibodies to all three pertussis antigens (PT, filamentous haemogluttin (FHA), and PRN). These data suggest that immunity to diphtheria, tetanus and pertussis (DTP) in adults wanes and that booster vaccination with an adult-type combined dTpa vaccine would boost the serological response to diphtheria antitoxin, tetanus antitoxin and antibodies to Bordetella pertussis PT, FHA and PRN.     

The primary serological response to a single dose of adsorbed tetanus toxoid, high concentration type

Single-dose immunization against tetanus was studied in 511 previously non-immunized residents of rural villages in Upper Volta. Males and females were equally represented and a wide age range was covered. A single dose of adsorbed tetanus toxoid containing 17.5 Lf units of toxoid and 3.86 mg of aluminium phosphate per 0.5 ml dose was used. Blood samples were taken 7 days, 2 months, and 12 months after immunization, and serum antitoxin titres were determined by neutralization titrations in mice. Adverse reactions were negligible. Only 2 participants gave evidence of prior immunization by developing detectable antitoxin titres after 7 days; they were eliminated from the study. After 12 months, 59% of the participants had antitoxin titres of ≥0.01 IU/ml, a titre usually considered protective. The mean titre and the proportion of those protected decreased substantially with increasing age; overall, females gave somewhat greater serological responses than males. Mean titre increased by 25% between 2 months and 1 year after immunization; the increase was greater in females than in males. In children under 6 years of age, 100% of females and 82% of males had protective titres after 1 year.     

Immunogenicity of a low-dose diphtheria,tetanus and acellular pertussis combination vaccine with either inactivated or oral polio vaccine compared to standard-dose diphtheria,tetanus, acellular pertussis when used as a pre-school booster in UK children: A 5-year follow-up of a randomised controlled study

This serological follow up study assessed the kinetics of antibody response in children who previously participated in a single centre, open-label, randomised controlled trial of low-dose compared to standard-dose diphtheria booster preschool vaccinations in the United Kingdom (UK). Children had previously been randomised to receive one of three combination vaccines: either a combined adsorbed tetanus, low-dose diphtheria, 5-component acellular pertussis and inactivated polio vaccine (IPV) (Tdap–IPV, Repevax^®; Sanofi Pasteur MSD); a combined adsorbed tetanus, low-dose diphtheria and 5-component acellular pertussis vaccine (Tdap, Covaxis^®; Sanofi Pasteur MSD) given concomitantly with oral polio vaccine (OPV); or a combined adsorbed standard-dose diphtheria, tetanus, 2-component acellular pertussis and IPV (DTap–IPV, Tetravac^®; Sanofi Pasteur MSD). Blood samples for the follow-up study were taken at 1, 3 and 5 years after participation in the original trial (median, 5.07 years of age at year 1), and antibody persistence to each vaccine antigen measured against defined serological thresholds of protection.All participants had evidence of immunity to diphtheria with antitoxin concentrations greater than 0.01 IU/mL five years after booster vaccination and 75%, 67% and 79% of children who received Tdap–IPV, Tdap + OPV and DTap–IPV, respectively, had protective antitoxin levels greater than 0.1 IU/mL. Long lasting protective immune responses to tetanus and polio antigens were also observed in all groups, though polio responses were lower in the sera of those who received OPV.Low-dose diphtheria vaccines provided comparable protection to the standard-dose vaccine and are suitable for use for pre-school booster vaccination.     

Safety and immunogenicity of single dose of tetanus–diphtheria (Td) vaccine among non/partially immune children against diphtheria and/or tetanus,Hyderabad, India, 2007

In Hyderabad, India, diphtheria is common among children aged 5–19 years. On account of low coverage of diphtheria vaccine boosters recommended under the universal immunization programme, a large proportion of children were susceptible/partially immune against diphtheria and/or tetanus. We evaluated immunogenicity and safety of single dose of indigenously developed tetanus–diphtheria (Td) vaccine (diphtheria–toxoid ≤5 Lf) among 483 school children from Hyderabad aged 7–17 years and susceptible/partially immune against diphtheria and/or tetanus. Serological testing 6 weeks after vaccination indicated that vaccine was highly immunogenic with >96% sero-protected against both antigens. The immune response observed indicated a booster response to previously acquired immunity. Administration of additional dose of Td vaccine to the older school children and replacing the tetanus toxoid vaccine with Td in the school health programme would considerably reduce diphtheria burden in Hyderabad.     

Update on adult immunizations

The past few years have seen numerous additions and modifications to the current immunization schedules. Starting with the 2010 to 2011 influenza season, the Centers for Disease Control and Prevention have recommended universal annual influenza vaccination for all persons without a contraindication who are 6 months of age and older, including healthy persons aged 19 to 49 years. Hepatitis B vaccination is now recommended for all susceptible diabetics ≤60 years of age. One dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine, adsorbed, is recommended to replace one tetanus and diphtheria toxoids adsorbed (adult) vaccination for all adults, including those 65 years of age or older, who are anticipating contact with infants and unvaccinated pregnant women (preferably during the second or third trimester). All adult vaccines remain underused. This article will summarize the most recent changes in the adult immunization recommendations of the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention.     

Durability of immunity to diphtheria, tetanus and poliomyelitis after a three dose immunization schedule completed in the first eight months of life

Blood samples were obtained from school entrants whose primary immunization schedule had consisted of three doses of DT or DTP vaccine and three doses of OPV all given before the age of 8 months. The sera were separated and assayed for diphtheria antitoxin, tetanus antitoxin and antibodies to the three serotypes of poliovirus. The results of the assays showed that the abbreviated three dose schedule induced satisfactory immunity to all five infections until school entry and that a reinforcing dose at 18 months was unnecessary.     

Vaccination of infants with a four-dose and a three-dose vaccination schedule

Swedish infants were vaccinated with diphtheria, tetanus and pertussis toxoids, inactivated poliovirus vaccine and a Haemophilus influenzae type b - tetanus toxoid conjugate vaccine at 2, 4, 6 and 15 months (US vaccination program, 'US arm', n=118) or at 3, 5 and 12 months of age (Swedish vaccination program, 'Swedish arm', n=103). The antigen amounts in the diphtheria and tetanus vaccines were higher in the Swedish than in the US arm while the amounts in the other vaccines were the same in both arms. There were no serious side effects. Local reactions increased with the numbers of doses but did not differ significantly between the groups. Serum was obtained at 2, 7, 15 and 16 months in the US arm and at 3, 6, 12 and 13 months of age in the Swedish arm. A fifth serum was obtained in both groups at 4 yr of age. For vaccines with the same antigen amount the following was observed: a. three doses at 2, 4 and 6 months were more immunogenic than two doses at 3 and 5 months; b. the third dose in the Swedish arm was more immunogenic than the third dose in the US arm; c. the fourth dose in the US arm induced higher antibodies than the third dose in the Swedish arm (except for pertussis toxin antibodies that were similar in both groups) and the differences tended to remain at the age of 4 yr. Children in the Swedish arm received a higher diphtheria toxoid dose (25 Lf) than in the US arm (15 Lf) which led to higher diphtheria toxin antibodies in the Swedish arm at comparable ages. Children in the Swedish arm received a higher tetanus toxoid dose (7 Lf) than in the US arm (6 Lf). Tetanus antibodies were similar at comparable ages. In conclusion, the immunogenicity of vaccines in infancy can be improved by increasing the number of doses, by prolonging the intervals between doses and by increasing the antigen amount in the vaccine.     

Recombinant cholera toxin B subunit (rCTB) as a mucosal adjuvant enhances induction of diphtheria and tetanus antitoxin antibodies in mice by intranasal administration with diphtheria-pertussis-tetanus (DPT) combination vaccine

Recombinant cholera toxin B subunit (rCTB) which is produced by Bacillus brevis carrying pNU212-CTB acts as a mucosal adjuvant capable of enhancing host immune responses specific to unrelated, mucosally co-administered vaccine antigens. When mice were administered intranasally with diphtheria-pertussis-tetanus (DPT) combination vaccine consisting of diphtheria toxoid (DTd), tetanus toxoid (TTd), pertussis toxoid (PTd), and formalin-treated filamentous hemagglutinin (fFHA), the presence of rCTB elevated constantly high values of DTd- and TTd-specific serum ELISA IgG antibody titres, and protective levels of diphtheria and tetanus toxin-neutralizing antibodies but the absence of rCTB did not. Moreover, the addition of rCTB protected all mice against tetanic symptoms and deaths. DPT combination vaccine raised high levels of serum anti-PT IgG antibody titres regardless of rCTB and protected mice from Bordetella pertussis challenge. These results suggest that co-administration of rCTB as an adjuvant is necessary for induction of diphtheria and tetanus antitoxin antibodies on the occasion of intranasal administration of DPT combination vaccine.     

Immunogenicity of IRIV- versus alum-adjuvanted diphtheria and tetanus toxoid vaccines in influenza primed mice

The immunogenicity and protectivity of two different toxoid vaccines were compared in mice. In one formulation, toxoids (diphtheria or tetanus) were adsorbed to alumoxid, whereas in the other formulation the toxoids were crosslinked to immunopotentiating reconstituted influenza virosomes (IRIVs). A preimmunization with influenza antigens is necessary for a good anti-toxoid antibody response when the IRIV formulation was administered. After two immunizations with the IRIV- or alum-based vaccines, the IRIV-based formulation induced a higher humoral immune response than toxoids adsorbed to alum. Using an in vitro test, diphtheria toxin neutralizing antibodies were tested. Di-IRIV induced a significantly (p = 0.002) higher titer of diphtheria toxin neutralizing antibodies than Di-alum. Tetanus challenge experiments showed, that the IRIV-based tetanus vaccine induced a threefold higher titer of protective antibodies than the tetanus toxoid adsorbed to alum. Therefore, the IRIV-based formulations appeared to be superior to the alum-based vaccines in terms of immunogenicity and protectivity.     

Controlled trial of Haemophilus influenzae type B diphtheria toxoid conjugate combined with diphtheria, tetanus and pertussis vaccines, in 18-month-old children, including comparison of arm versus thigh injection.

A randomized, controlled comparison was made in 175 healthy 18-month-old children given either diphtheria and tetanus toxoids and pertussis vaccine, adsorbed (DTP) and haemophilus b diphtheria toxoid conjugate vaccine (PRP/D) concurrently at separate sites (66 children) or a new vaccine combining these products (109 children). Rates of local or systemic adverse effects postimmunization and antibody responses to each component did not differ significantly between groups. DTP-containing vaccines were better tolerated when given in the thigh than in the arm. The combination DTP-PRP/D vaccine performed satisfactorily at 18 months of age, avoiding the inconvenience of two injections.     

Immune response to a diphtheria and tetanus toxoid administration in a three-dose diphtheria tetanus whole-cell pertussis/enhanced inactivated poliovirus vaccination schedule: a 7-year follow up

The immune response to diphtheria and tetanus toxoid components of a combined diphtheria tetanus whole-cell pertussis/enhanced inactivated poliovirus (DTwP/eIPV) vaccine, administered in a three-dose schedule to infants at 2, 3 and 10 months of age and followed by a booster at the age of 8 years, was compared with the immune profile of a group of children at the same ages given the customary DTwP vaccine schedule at 2, 4, 6, and 12 months of age and a booster at the age of 8. Diphtheria- and tetanus-antitoxin titers were measured in parallel enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA). After the reinforcing dose given at 10 months of age, diphtheria antitoxin concentrations of 0.01 IU/ml were found in 100% of infants in the study group, 91.7% of whom reached a titer of 0.1 IU/ml and a geometric mean titer (GMT) of 0.40 and 0.93 IU/ml in ELISA and RIA, respectively. At 3 and 6 years of age, diphtheria antitoxin values of 0.01 IU/ml were detected in 100 and 94% of children with GMT of 0.043 and 0.024 IU/ml, respectively. Seropositivity and GMT values indicative of protection were measured by both ELISA and RIA after the booster at the age of 8 years. Similar results were found in the control group, although the GMT tended to be higher. A good correlation between results obtained by ELISA vs. RIA was evident throughout. Priming at 2 and 3 months with diphtheria and tetanus antitoxin, as a component of a DTwP program, and reinforcing 6 months later induced an immune response indicative of protection against the diseases, which persisted up to the age of the booster recommended at school entry.     

临沂市健康人群白喉和破伤风抗体水平调查

目的为有计划地进行人群抗体水平监测,了解人群免疫状况,为制定免疫对策、评价免疫效果提供依据。方法采用分层随机抽样的方法,2001、2003、2004年调查了临沂市10个县(区)0~39岁847人的白喉和破伤风抗体水平。结果白喉和破伤风抗体总阳性率分别为77.80%和74.03%,阳性率均是0~4岁组最高,20~39岁组最低;山区县低于平原县和市区。白喉和破伤风抗体几何平均浓度分别为0.0997U/ml和0.0674U/ml,均是8~10岁组最高,20~39岁组最低。结论临沂市白喉和破伤风疫苗基础免疫的效果可靠,但随着年龄的增长,免疫力衰退而重新成为易感者,故应及时对成人加强百日咳、白喉的免疫,并在新生儿破伤风高危县区对育龄期妇女开展破伤风疫苗免疫。     

Immunity against diphtheria among children and adults in Izmir, Turkey

The aim of this study was to evaluate diphtheria immunity in a sample of the Turkish population having high childhood immunization coverage, including a booster dose of diphtheria toxoid at 12-15 years of age. A total of 599 persons aged 1-70 years were selected with cluster sampling. The information on socio-demographic characteristics, vaccination status and diphtheria history was gathered for each participant. Diphtheria antitoxin levels were measured qualitatively by using micro-enzyme immune assay. Of studied population, 72.3% had fully protective antitoxin levels (≥0.1 IU/ml). The rate of protection was 92.5% in the children aged 0-2 years, 93.2% in the primary school children aged 7-9 years, and 86.0% in the adolescents aged 15-19 years. After 20 years of age, diphtheria protection rates showed a significant age-related decrease, reaching minimum in the 30-39 age group, in which 47.3% of these subjects had fully protective antitoxin levels. The diphtheria antitoxin geometric mean titer (GMT) was highest in the 0-2 year age group (1.18 IU/ml). In the adolescents aged 15-19 years, diphtheria antitoxin GMT was 0.71 IU/ml. Then, geometric mean titer decreased with increasing age, and reached the minimum level in the 40-59 years age group (0.18 IU/ml). The protection rate among females was significantly lower than males (67.1% vs. 80.9%). The difference was apparent in the 20-29 and the 30-39 years age group: 80% of the males and 46.2% of the females in the 20-29 years age group, and 60% of males and 44.1% of females in the 30-39 years age group were fully protected against diphtheria (p < 0.0001). These results suggest that in Izmir, Turkey, full serological protection against diphtheria is only detectable in <50% of the young adult population, even though childhood immunization coverage is relatively high. Potentially, there is still risk of diphtheria outbreaks among the adults in our country. Therefore, a revaccination of adults with reduced doses of diphtheria toxoid should be considered to sustain diphtheria immunity.     

百白破混合制剂免疫持久性研究

70~80年代末,在观察基地比较吸附DPT间隔1月、2月接种2针和未吸附DPT接种3针、2针的免疫效果和免疫持久性,经血清学效果测定表明,四组儿童基免后能产生良好的白喉、破伤风抗体应答,而接种非吸附DPT儿童的百日咳抗体产生较差。加免后,三种抗体明显上升,白喉抗体至少可持续8年,破伤风抗体可维持5年左右,而百日咳抗体仅能维持3年左右。另对吸附DPT间隔2月接种2针与未吸附DPT接种3针比较,基免后白喉、破伤风、百日咳三种抗体均以吸附DPT效果较好,加免后则无显著差异。