Cytokine and antibody profiles in 1-year-old children vaccinated with either acellular or whole-cell pertussis vaccine during infancy

Two different types of pertussis vaccines are currently available to protect children against whooping cough, the first-generation whole-cell (Pw) vaccines and the more recent acellular (Pa) vaccines. Both types provide good protection, yet induce different types of immune responses in 6-month-old infants, with a strong Th1 response induced by Pw vaccines compared to a mixed Th1/Th2 response and a delay in non-specific IFN-γ secretions after the administration of Pa vaccines. We show here that at 13 months of age, most Pw- or Pa-vaccinated children display Bordetella pertussis-specific T-cell responses, in addition to significant antibody levels, although a higher Th2/Th1 cytokine ratio remained in Pa recipients compared to Pw recipients. In contrast, the proportion of children with tetanus toxin-specific T-cell responses was lower in Pa than in Pw vaccine recipients, although most children had protective anti-tetanus toxin IgG levels. In addition, the global Th2 bias observed in 6-month-old infants vaccinated with a Pa vaccine was normalized at 13 months.     

Effectiveness of a single dose of acellular pertussis vaccine to prevent pertussis in children primed with pertussis whole cell vaccine

We estimated the protection given by one booster dose of acellular pertussis vaccine (aP) given at 18 months or before school entry to children already primed with whole cell vaccine (wP). Case-control studies were conducted in these two age groups. In children who received or were eligible to receive their 18 months booster, the risk of pertussis was 1.4 and 3.6 times higher for those with 4 and 3 wP, respectively, compared to those with 3 wP + 1 aP. In 5 and 6 yr old children, the risk of pertussis among the subjects with 5 and 4 wP, was 1.4 and 2.1 times higher respectively than in those who received 4 wP + 1 aP. A single dose of aP increased the protection against pertussis and this protection was greater than that obtained with a wP booster.     

Analogous IgG subclass response to pertussis toxin in vaccinated children,healthy or affected by whooping cough

The study of antigen specific IgG subclass distribution during disease, or during any other natural or artificial immunisation, can provide useful information on the kind of the immune response and the expected levels of protection. This is particularly true for diseases, such as pertussis in which the mechanisms underlying specific defence are still not completely understood. An investigation was therefore performed to evaluate the IgG subclass response to pertussis toxin (PT) in sera from 89 healthy vaccinated children and 131 vaccinated or unvaccinated children convalescent after a confirmed B. pertussis symptomatic infection. Antibody titres were expressed in arbitrary ELISA units/ml, and statistical analyses were performed. In unvaccinated convalescent children IgG1 and IgG3 were prevalent whereas in children immunised with two different acellular pertussis (aP) vaccines, both healthy and convalescent, IgG1, IgG2 and IgG4 antibodies were mainly produced. Maintenance of the same anti-PT antibody response pattern in healthy acellular pertussis vaccine recipients and in vaccinated children who later acquire the disease is an interesting result indicative of the priming effect induced by these vaccines in the direction of a relatively higher Th2 cell-polarisation of the immune response.     

The efficacy of whole cell pertussis immunisation: collected data on a vaccine produced in France

The place of whole cell pertussis vaccines in paediatric immunisation schedules is under re-evaluation by public health authorities in many countries, with the expectation that the newly licensed acellular Bordetella pertussis vaccines will induce fewer adverse events while providing equivalent efficacy. In France, for instance, the CSHPF (Conseil supérieur d'hygiène public de France) recently modified its long-standing recommendation that French children only receive whole cell pertussis vaccine. Consequently, an acellular pertussis vaccine may be used for the first booster, at 16-18 months of age, and should be used for the reinforcing dose at 11-13 y of age. French children, nonetheless, continue to receive whole cell pertussis vaccine for the primary series immunisations at 2, 3, and 4 months, as the only whole cell pertussis vaccine available in France (licensed by Aventis Pasteur) has a long-established record of safety and protective efficacy. A review of its unpublished and published clinical results, obtained from studies throughout the world, demonstrates an efficacy of from 84-100% in six different retrospective analyses or outbreak investigations and a protective efficacy of 92% by clinical trial.     

Seroprevalence of IgG antibodies to pertussis toxin in children and adolescents in Estonia

Background and aims

Despite high immunisation coverage and frequent booster doses, the national notification rates of pertussis in Estonia have been increasing. The peak of 97/100,000 was reached in 2010 which is the highest incidence rate since 1962 (210/100,000).We aimed to measure the prevalence of pertussis toxin (PT) IgG type antibodies in subjects of <18 years and to estimate the pertussis infection activity in a recently non-immunised cohort.

Methods

In a cross-sectional serosurvey, all consecutive leftover sera were collected in the Tartu University Hospital during April–August 2012. Anti-PT IgG concentration was measured by commercial ELISA and analysed in yearly cohorts. The antibody concentrations ≥62.5 IU/mL was considered suggestive to pertussis in the last year among 9- to 14-year-olds.

Results

The GMC of the anti-PT-IgG was 7.4 IU/mL (95% CI 6.9–8.0). In the total of 1053 serum samples, the highest proportion of sera with high antibody titres ≥125 IU/mL and ≥62.5 IU/mL were at the ages when pertussis vaccine boosters were given: 7 years 10.9% (95% CI 4.1–22.3) and 2 years 36.9% (95% CI 25.3–49.8), respectively. Approximately half of all sera had undetectable anti-PT IgG levels. The estimated incidence of Bordetella pertussis infection among 9- to 14-year-olds in the year before serum sampling was 6.3% (95% CI 3.3–10.8), which is at least 60 times higher than the officially reported incidence of pertussis disease in respective years.

Conclusions

The serologic method is not suitable for diagnosing pertussis in instances when the last pertussis immunisation was less than one year ago. The relatively high proportion of subjects with undetectable anti-PT IgG levels and the relatively low rate of officially reported pertussis cases suggest that low antibody levels do not necessarily indicate the absence of protection. The estimated incidence rate of pertussis is much higher than officially reported figures, which suggests that asymptomatic/mild B. pertussis infection remains unrecognised and unreported.     

Determination of serum neutralizing antibodies reveals important difference in quality of antibodies against pertussis toxin in children after infection

ObjectivesTo determine neutralizing antibodies to pertussis toxin (PTNAs) in children with suspected pertussis and to compare results of PTNAs and anti-PT IgG antibodies.Methods172 hospitalized children with suspected pertussis were included. Pertussis was confirmed by culture, PCR and/or serology. PTNAs were determined by Chinese hamster ovary (CHO) cell assay.ResultsA correlation between titers of PTNAs and anti-PT IgG levels was noticed in 172 patients (Spearman R = 0.68, P < 0.001). Subjects with same concentrations of anti-PT IgG antibodies could have different titers of PTNAs and the maximum difference observed reached to 1024 times in ELISA-confirmed patients. Moreover, subjects with same titers of PTNAs could have different concentrations of anti-PT IgG antibodies.ConclusionsOur results indicated that in some children high concentrations of anti-PT IgG antibodies do not always mean effective PTNAs induced after infection, stressing the importance of detecting PTNAs after infection and vaccination.Clinical trial registry: Not applicable.     

Immunogenicity and safety of a low-dose diphtheria, tetanus and acellular pertussis combination vaccine with either inactivated or oral polio vaccine as a pre-school booster in UK children

This open, randomised controlled trial studied the immunogenicity and reactogenicity of two combined low-dose diphtheria, tetanus and acellular pertussis vaccines (Td5aP-IPV, REPEVAX, Aventis Pasteur MSD; and Td5aP, COVAXIS, Aventis Pasteur MSD + OPV, GlaxoSmithKline) in comparison with a standard dose diphtheria pre-school booster vaccine (DT2aP-IPV, TETRAVAC, Aventis Pasteur MSD) in a population of 3.5-5-year-old children administered concomitantly with measles, mumps and rubella vaccine (M-M-R II, Aventis Pasteur MSD). A linked sub-study aimed to evaluate the immunogenicity and reactogenicity of Td5aP-IPV in a population of younger children, aged 3-3.5 years. This study demonstrated non-inferiority of seroprotection rates for diphtheria and tetanus for the study vaccines and comparable immunogenicity for pertussis and polio components of the vaccines. Reactogenicity was similar for all three vaccines. The study vaccines containing low-dose diphtheria antigen (Td5aP-IPV and Td5aP + OPV) are immunogenic and have acceptable reactogenicity for use as a pre-school booster vaccine administered concomitantly with MMR.     

Dose-response to acellular pertussis vaccine and comparison with whole cell pertussis vaccine at 15-24 months and 4-6 years of age. Acellular Pertussis Vaccine Study Team.

In a randomized double-blind trial 55 children of 15-24 months and 56 children of 4-6 years of age previously immunized with whole-cell DTP (WC-DTP) received acellular pertussis DTP vaccines containing 12.5 micrograms (AC-12.5) or 25 micrograms (AC-25) each of pertussis toxoid (PT) and filamentous haemagglutinin (FHA) per dose of WC-DTP. No differences in antibody responses or adverse events were noted for children who received AC-25 as compared with AC-12.5. All three groups had significant increases in pertussis agglutinins, but the geometric mean titre (GMT) for 4-6-year-old children who received WC-DTP was higher than the GMT for children who received acellular vaccine. No significant differences were noted in the GMT of antibodies to FHA or PT between children who received WC-DTP and recipients of acellular vaccine. The rates of several adverse reactions were significantly (p less than or equal to 0.05) higher for recipients of WC-DTP, and children given WC-DTP were significantly (p less than or equal to 0.00001) more likely to have received acetaminophen. These acellular vaccines are safe and as immunogenic for FHA and PT as WC-DTP when administered as the fourth or fifth dose to children who received three doses of WC-DTP in infancy. The lower (12.5 micrograms) dose of acellular vaccine was as effective as the higher (25 micrograms) dose in inducing antibodies to FHA and PT in children 15-24 months and 4-6 years of age.     

A single dose of an effective whole cell pertussis vaccine does not significantly increase protection in children primed with a less effective vaccine

We evaluated if a single dose of a protective whole cell pertussis vaccine given before school entry to children primed with a less effective vaccine would increase their protection. A school cohort including 3876 students and a family cohort including 162 children were assessed. Although there was a trend toward increased protection. the better vaccine did not provide a significant improvement. These results suggest that a single dose of an effective vaccine given to children primed with a less effective one does not raise the protection to at level similar to that provided by three doses of the better vaccine.     

Effect of hyperreactivity to endotoxin on the toxicity of pertussis vaccine and pertussis toxin in mice

In mice, greatly enhanced susceptibility to the lethal toxicity of whole-cell pertussis vaccine (PV) was produced by agents known to induce hypersusceptibility to endotoxin (LPS). The decreases in LD50 were 100-fold, 125-fold and 16-fold with galactosamine (GalN), actinomycin D (AcD) and lead acetate (PbAc) respectively and the animals died within 1-2 days. However, these decreases were less than those observed with extracted E. coli LPS, the LD50 of which was reduced approximately 500-fold, 800-fold and 50-fold respectively by these agents. In control mice, without drugs, the main lethal factor in the PV used here seemed to be pertussis toxin (PT), since deaths occurred at 3-5 days after injection, and heating the vaccine at 80 degrees C for 30 min raised the LD50 from 4 to greater than 6 single human doses (SHD) per mouse. In GalN and PbAc-treated mice, the toxicity of PV can be explained by its LPS content in view of the failure of heating at 80 degrees C to reduce toxicity. However, in AcD-treated mice, the 80 degrees C heated vaccine was threefold less toxic than the unheated material, suggesting a contribution of PT to vaccine toxicity in these animals. Indeed the toxicity of PT was increased by AcD. The possible bearing of these observations on children who appear to show serious adverse reactions to PV is discussed. Two acellular vaccines were devoid of lethal toxicity in either normal mice or in mice treated with any of the three drugs.     

Differences in avidity of IgG antibodies to pertussis toxin after acellular pertussis booster vaccination and natural infection

Background

Pertussis toxin (PT) is a specific virulence factor of Bordetella pertussis and it is included in all acellular pertussis vaccines (aP). Although immunity after infection seems to persist longer than that after vaccination, the exact mechanism(s) is not known. Primary aim of this study was to develop an ELISA method for measuring avidity index (AI) of IgG-anti-PT antibodies and to compare antibody responses after booster vaccination and infection. Secondary aim was to evaluate if the AI-ELISA has potential in the serodiagnosis of pertussis.

Material

Serum samples from a total of 409 subjects were included in the study. Paired sera were taken from 97 adolescents who received booster vaccine ten years ago (dTpa-004) and from 80 young adults who received a second booster dose ten years after the previous booster vaccine (dTpa-040). Thirty-two paired sera from culture-confirmed pertussis patients, 161 single sera from serologically diagnosed patients and 39 single sera from healthy controls were included. AI of IgG-anti-PT antibodies were determined with newly developed ELISA using diethylamine (DEA) as a bond breaking agent. The IgG-anti-PT antibodies were measured by standardized ELISA.

Results

A significant increase was found in antibody concentrations and AI between PRE and one month POST vaccination ten years ago [GMC for antibody: 7.9 IU/ml vs. 98.3 IU/ml (p = 0.0001); for AI: 40.4% vs. 56.1% (p = 0.0001)]. Similar result was observed after the second booster dose [GMC for antibody: 9.2 IU/ml vs. 92.4 IU/ml (p = 0.0001); for AI: 36.1% vs. 59.5% (p = 0.0001)] and between the first and second sera of culture-confirmed patients [GMC for antibody: 6.9 IU/ml vs. 285.1 IU/ml (p = 0.0001); for AI: 40.5% vs. 68.4% (p = 0.0001)]. Healthy controls showed lower levels of both antibodies and AI.

Conclusions

Our results suggest that there may be difference in quality and quantity of antibodies to PT after vaccination and after infection. Furthermore, AI could be a help for vaccine studies.     

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.     

Sequence variation in pertussis S1 subunit toxin and pertussis genes in Bordetella pertussis strains used for the whole-cell pertussis vaccine produced in Poland since 1960: efficiency of the DTwP vaccine-induced immunity against currently circulating B. pertussis isolates

The present study indicates that the appearance of the B. pertussis harbouring prn2 gene allele variant (not found among clinical isolates before 1990s) may have been induced by long-term vaccination in Poland with DTP-composed vaccine strains presenting exclusively prn1. However, ptxS1A allele of pertussis toxin subunit S1 encoding gene, predominant in the currently isolated B. pertussis strains, has been found in vaccine strains used for whole-cell pertussis component (wP) production of DTP vaccine in 1960-1978. This outrules the possibility that the appearance of ptxSIA allele might be related to vaccine pressure driven by non-ptxS1A vaccine strains used for long-term immunization with wP. Intranasal challenge animal model testing the efficiency of the clearance of B. pertussis strains harbouring different ptxS1/prn allele gene combinations revealed that currently produced DTwP vaccine may not contain adequate B. pertussis vaccine strains, since isolates with gene variants different from those observed in vaccine strains were eliminated from the lungs of the immunized animals with lower efficiency.     

Phase I clinical trial of an acellular pertussis vaccine composed of genetically detoxified pertussis toxin combined with FHA and 69 kDa.

An acellular pertussis vaccine composed of genetically detoxified pertussis toxin (PT-9K/129G), filamentous haemagglutinin (FHA) and pertactin (69 kDa protein) was evaluated in adult volunteers, in double blind, versus placebo. No fever was reported in either group. Mild local reactions were reported after injection of both vaccine and placebo. After the first dose a marked increase in antibodies to PT, FHA and 69 kDa protein was seen in vaccinated subjects with the exception of one who responded well to PT and FHA but did not show a humoral response to the 69 kDa protein. All vaccinees acquired cellular immunity against the three antigens. No significant variation was observed in the humoral or cellular responses after the second dose.     

Increase in the incidence of pertussis and quality of whole-cell pertussis component of the DTP vaccine produced in Poland. Part I. Potency of DTP vaccine

This study aimed to identify and to evaluate the level of potency fluctuations of the pertussis component of Polish-produced DTP vaccine lots produced within 1972-2001 due to the changes having occurred in production and potency testing procedures. The study confirms that higher potency values were obtained for vaccine lots produced since 80-ties, e.g. after changes of: references lots (1975), vaccine strains (1978) and source of animals used in Kendrick tests (1979). Additionally, the comparisons performed revealed a down trend in potency levels within 1992-1999 correlating to the lowering of the number of IOU/dose.     

School-age children and adolescents suspected of having been to be infected with pertussis in Japan

Many countries including Japan have adapted acellular pertussis vaccines combined with diphtheria and tetanus toxoids (DTaP). DTaP vaccine coverage is approximately >90%, but pertussis re-emergence has been observed since 2000 in Japan. In the present study, anti-pertussis antibodies were investigated among school-age children and adolescents from 2013 to 2015. The positive rate of anti-pertussis toxin (PT) antibodies was higher among children aged 12–13 years (60.0%. 95%CI; 56.0–63.9%) in 2014 and 18–19 years (73.0%. 95%CI; 61.4–82.6%) in 2013, compared with 6–7 years (47.1%. 95%CI; 40.7–53.6%). The mean PT antibody titer was higher among children aged 12–13 years (23.8 EU/ml. 95%CI; 21.9–25.8) in 2014 and 18–19 years (29.3 EU/ml. 95%CI; 23.0–35.6) in 2013, compared with 6–7 years (18.3 EU/ml. 95%CI; 15.5–21.2). Distributions of pertussis antibodies and mean titers at their same grade of school-age were similar from 2013 to 2015. Although school-age children were immunized with 4 doses of DTaP, the data suggested the decay of vaccine-acquired immunity and possibility of asymptomatic infection in school age, indicating the additional DTaP vaccination before the entry of elementary school, preventing household contact.     

Differences of humoral and cellular immune response to an acellular pertussis booster in adolescents with a whole cell or acellular primary vaccination

To study the pertussis-specific immune response of adolescents with different prevaccination schedules, we measured the humoral and cell-mediated immunity (CMI) to pertussis antigens before and after a five-component Tdap booster vaccination in 78 adolescents, who had previously received either five doses of a two-component acellular pertussis vaccine (aP; last dose age 4-6 years), four doses of aP (last dose age 18-24 months), or four doses of whole cell pertussis vaccine (wcP; last dose age 18-24 months). The proportion of participants with a twofold rise in titre was 79% against pertussis toxin (PT), 94% against filamentous hemagglutinin (FHA), and 99% against pertactin (PRN) without significant differences between the three groups. However, participants with primary wcP vaccination showed higher postvaccination titres to pertussis toxin (geometric mean titre, GMT 50.3EU/ml) than those with either four (GMT 17.1EU/ml) or five (GMT 16.4EU/ml) previous aP doses. CMI indices to PT, FHA, PRN and fimbriae (FIM) increased after vaccination and were similar between groups. The current adolescent Tdap booster immunization induced good humoral and cellular immune response to pertussis. The higher antibody titres to pertussis toxin may indicate a more effective priming of B cell memory after primary whole-cell vaccination.     

Adverse reactions after injection of adsorbed diphtheria-pertussis-tetanus (DPT) vaccine are not due only to pertussis organisms or pertussis components in the vaccine.

Reactions to adsorbed diphtheria-pertussis-tetanus (DPT) vaccine have mostly been attributed to the pertussis organisms or pertussis components in the vaccine. Nevertheless reactions may also be due to other factors such as sensitization induced by aluminium adjuvants and impurities present in crude toxoids that cannot be removed by purification of toxoids after formalinization. Aluminium compounds such as aluminium phosphate and aluminium hydroxide are the most commonly used adjuvants with vaccines for human use. Due to the increasing concern about the toxicity of aluminium, other adjuvants like calcium phosphate may be evaluated as an alternative to aluminium adjuvants. To minimize reactions after immunization with DPT vaccine due to impurities in the toxoids, the use of toxoided purified toxins is suggested.