A randomized clinical trial to identify the optimal antigen and MF59(®) adjuvant dose of a monovalent A/H1N1 pandemic influenza vaccine in healthy adult and elderly subjects

Background

Vaccines against pandemic A/H1N1 influenza are required to protect the entire population. This dose range study aimed to identify priming antigen and adjuvant doses resulting in optimal levels of antibody-mediated protection after primary and one-year booster immunizations.

Methods

This randomised trial enrolled 410 healthy adult (18–60 years) and 251 healthy elderly (>60 years) participants. Subjects received vaccine containing either 3.75 μg or 7.5 μg antigen, adjuvanted with half the standard dose, or a standard dose of MF59^® (Novartis Vaccines) adjuvant, respectively. An additional adult cohort received non-adjuvanted vaccine containing 15 μg antigen. Two doses of investigational vaccine were administered three weeks apart, followed by a single booster dose of adjuvanted seasonal influenza vaccine one year after priming. Immunogenicity was assessed by haemagglutination inhibition and microneutralization assays pre- and post-immunization, the safety profile of each vaccine was also evaluated.

Results

All of the vaccine formulations investigated were highly immunogenic and well tolerated in both adult and elderly subjects. The 7.5 μg formulation induced the highest antibody titres after primary and booster immunizations, and resulted in better long-term antibody persistence, in both age groups. Assessment according to European licensure criteria for influenza vaccines concluded that single adjuvanted priming doses containing 3.75 μg and 7.5 μg antigen were optimal for the adult and elderly populations, respectively.

Conclusions

These data demonstrate that one priming dose of MF59-adjuvanted A/H1N1 vaccine provided healthy adult (3.75 μg or 7.5 μg formulations) and healthy elderly (7.5 μg formulation) individuals with adequate levels of seroprotection. Booster administration after two priming doses of either vaccine formulation resulted in the rapid development of seroprotective antibody titres.

Trial registration

www.clinicaltrials.gov (NCT00971906).     

Long-term persistence of anti-HBs after vaccination with a recombinant DNA yeast-derived hepatitis B vaccine: 8-year results

The aim of this study was to evaluate the persistence of antibodies 7 years after hepatitis B booster administration in healthy adult volunteers who were vaccinated in 1987. In October 1986, 188 seronegative, healthy adult volunteers (117 men and 71 women) were vaccinated with a 20 μg dose recombinant DNA yeast-derived hepatitis B vaccine. Mean age of the study group was 23.3 years (±0.28). Immunisation was carried out according to a 0-1-2 month vaccination schedule, with a boosterdose at 12 months. Of the 159 subjects who received the full vaccination course, 63 (40%) had a blood sample taken 8 years after the first vaccination. Of these 63 subjects, five were excluded from teh analysis due to an irregular vaccination schedule and four subjects did not complete the accompanying questionnaire on possible booster administration. So, 54 subjects remained available for further analysis. Fourteen individuals had received an additional booster of hepatitis B vaccine sometime between 1989 and 1994. The geometric mean titre (GMT) at month 13 for these 14 individuals was 1494 mIU ml⁻¹, compared with 3103 mIU ml⁻¹ for those who did not receive an interim booster. Forty subjects, who received no additional booster dose besides that of month 12, met the inclusion criteria of the follow-up study. Of these, all subjects except one were seropositive for anti-HBs at month 96 (GMT: 215.9 mIU ml⁻¹). All subjects were still anti-HBc negative at that time. Distribution of individual antibody titres revealed that overall 92.5% of subjects retained protective antibody levels (10 mIU ml⁻¹); 72.5% of vaccinees retained high levels of anti-HBs (100 mIU ml⁻¹) as compared to 99.2 and 97.0% at month 13, respectively. A positive correlation was found between the subjects' titres at month 13 and month 96. A 0-1-2 dose vaccination course with a booster dose administered at month 12, induces a protective immune response which lasts at least until 7 years after the full vaccination course of the subjects. A positive correlation was found between the anti-HBs antibody titres at month 13 and month 96.     

Immunological impact of an additional early measles vaccine in Gambian children: responses to a boost at 3 years

Background

Measles vaccine in early infancy followed by a dose at 9 months of age protects against measles and enhances child survival through non-specific effects. Little is known of immune responses in the short or long term after booster doses.

Methods

Infants were randomized to receive measles vaccine at 9 months of age (group 1) or 4 and 9 months of age (group 2). Both groups received a boost at 36 months of age. T-cell effector and memory responses using IFN-γ ELIspot and cytokine assays and antibody titres using a haemagglutination-inhibition assay were compared at various times.

Results

Vaccination at 4 months of age elicited antibody and CD4 T-cell mediated immune responses .Two weeks after vaccination at 9 months of age group 2 had much higher antibody titres than group1 infants; cell-mediated effector responses were similar. At 36 months of age group 2 antibody titres exceeded protective levels but were 4-fold lower than group 1; effector and cytokine responses were similar. Re-vaccination resulted in similar rapid and high antibody titres in both groups (median 512); cellular immunity changed little. At 48 months of age group 2 antibody concentrations remained well above protective levels though 2-fold lower than group 1; T-cell memory was readily detectable and similar in both groups.

Conclusions

An additional early measles vaccine given to children at 4 months of age induced a predominant CD4 T-cell response at 9 months and rapid development of high antibody concentrations after booster doses. However, antibody decayed faster in these children than in the group given primary vaccination at 9 months of age. Cellular responses after 9 months were generally insignificantly different.     

A one-year study of trivalent influenza vaccines in primed and unprimed volunteers: immunogenicity, clinical reactions and protection

Three hundred volunteers were divided into two age groups, 14-30 years and 31-60 years. Each participant was immunized intramuscularly with a subunit, whole virus or absorbed whole virus vaccine, containing A/Bangkok/1/79 (H3N2), A/Brazil/11/78 (H1N1) and B/Singapore/222/79 influenza virus. Serum haemagglutination-inhibition (HI) antibody response, protection, and reactogenicity were studied after one and two doses of the vaccines. Primary immunization induced much higher percentages of HI antibody titres greater than or equal to 100 against all three vaccine viruses and much higher geometric mean titres (GMT) in volunteers with pre-immunization titres greater than or equal to 18 as compared to those with pre-immunization titres less than 18. Secondary immunization did not result in an increase of GMTs or antibody titres greater than or equal to 100 in volunteers with pre-immunization titres less than 18. On the whole, the response to the subunit vaccine was similar to that to the other two vaccines. To influenza B/Singapore/222/79 virus the response was lowest after administration of the whole virus vaccine in the age group 31-60 years. Over 50% of the HI titres greater than or equal to 100 found after immunization in the different vaccine and age groups were still present after one year. Serologically established infections during the winter months following immunization amounted to 15% in the subunit vaccine group, 6% in the whole virus vaccine group, and 10% in the adsorbed whole virus vaccine group. Local and systemic reactions to all three vaccines were mild in nature. Local reactions after primary immunization were much less frequent following administration of the subunit vaccine as compared to the other two vaccines, especially in the younger age group. In comparison to primary immunization, after booster immunization the incidence of local reactions was higher for the subunit vaccine and lower for the adsorbed whole virus vaccine. In the age group 14-30 years the incidence of local reactions after primary as well as booster immunization was much greater in females than in males, especially when the adsorbed whole virus vaccine was used.     

Antibody kinetics among 8–10 years old respondents to hepatitis B vaccination in a low endemic country and the effect of a booster dose given 5 or 10 years later

Few data are available concerning the persistence of anti-HBs and the effect of booster doses given several years post-vaccination against hepatitis B during preadolescence. The objective of this open-labelled clinical trial was to evaluate the persistence of antibodies after vaccination with three paediatric doses of Engerix-B at the age of 8–10 years and the effect of a booster dose given 5 (Group Y5) or 10 (Group Y10) years later. Anti-HBs were measured before and one month post-primary vaccination, then 5 and 10 years later, before the booster dose, as well as one month and 1 year post-booster. The anamnestic response was defined as a ≥fourfold increase of anti-HBs post-booster (≥10 IU/L) when compared to pre-booster. Ten years post-primary vaccination, 559 of the 652 initially randomized subjects (86%) were eligible for analysis. Group Y5, 5 years post-booster results: 99% of subjects had detectable levels of antibodies and 96% a titer ≥10 IU/L. The anti-HBs GMTs decreased from 114,489 IU/L one month post-booster to 3354 IU/L 5 years later. Group Y10 results: 10 years post-primary vaccination 96% of subjects had a detectable level of anti-HBs and 85% were above the threshold of 10 IU/L. The GMTs one month post-booster were 31,030 IU/L. The challenge with a booster demonstrated an anamnestic response in 99% of subjects in group Y5 and 100% of subjects in group Y10. All subjects were anti-HBc negative. The booster doses were well tolerated. The excellent anamnestic response observed after the booster dose demonstrates the persistence of immunity in virtually all young adults vaccinated at the age of 8–10 with three paediatric doses of Engerix-B.     

Immunogenicity of low doses of recombinant hepatitis B vaccine in young males

A trial of low doses (1.25 and 0.625 micrograms) of recombinant hepatitis B vaccine in 110 males aged 17-19 years is reported. Follow-up was extended to one year and further data are reported for participants from earlier trials of 10, 5 and 2.5 microgram doses for comparison. Seroconversion rates after the booster dose were 94% at 1.25 micrograms and 89% at 0.625 micrograms, compared to 100% at higher doses. Geometric mean titres (GMT) of antibody to hepatitis B surface antigen (anti-HBs) were significantly lower with the 0.625 microgram dose than with 1.25 micrograms at all times, reaching a GMT of 42.6 IU l-1 and 152.9 l-1, respectively, after the booster dose. GMT values at 12 months were 513.9, 510.0, 320.7, 46.5 and 13.3 IU l-1 in the 10, 5, 2.5, 1.25 and 0.625 microgram dose groups, respectively. Increases in GMT after the booster dose were parallelled in all groups. GMT decreased by approximately equal to 65% between 7 and 12 months in the three lowest dose groups, significantly less than the fall of 80% at 5 and 10 micrograms. However, to secure variability among vaccinees, the minimum effective dose for young adults should be greater than 5 micrograms per dose.     

A one-year study of trivalent influenza vaccines in primed and unprimed volunteers: immunogenicity, clinical reactions and protection.

Three hundred volunteers were divided into two age groups, 14-30 years and 31-60 years. Each participant was immunized intramuscularly with a subunit, whole virus or absorbed whole virus vaccine, containing A/Bangkok/1/79 (H3N2), A/Brazil/11/78 (H1N1) and B/Singapore/222/79 influenza virus. Serum haemagglutination-inhibition (HI) antibody response, protection, and reactogenicity were studied after one and two doses of the vaccines. Primary immunization induced much higher percentages of HI antibody titres greater than or equal to 100 against all three vaccine viruses and much higher geometric mean titres (GMT) in volunteers with pre-immunization titres greater than or equal to 18 as compared to those with pre-immunization titres less than 18. Secondary immunization did not result in an increase of GMTs or antibody titres greater than or equal to 100 in volunteers with pre-immunization titres less than 18. On the whole, the response to the subunit vaccine was similar to that to the other two vaccines. To influenza B/Singapore/222/79 virus the response was lowest after administration of the whole virus vaccine in the age group 31-60 years. Over 50% of the HI titres greater than or equal to 100 found after immunization in the different vaccine and age groups were still present after one year. Serologically established infections during the winter months following immunization amounted to 15% in the subunit vaccine group, 6% in the whole virus vaccine group, and 10% in the adsorbed whole virus vaccine group. Local and systemic reactions to all three vaccines were mild in nature. Local reactions after primary immunization were much less frequent following administration of the subunit vaccine as compared to the other two vaccines, especially in the younger age group. In comparison to primary immunization, after booster immunization the incidence of local reactions was higher for the subunit vaccine and lower for the adsorbed whole virus vaccine. In the age group 14-30 years the incidence of local reactions after primary as well as booster immunization was much greater in females than in males, especially when the adsorbed whole virus vaccine was used.     

国产和法国产风疹疫苗的免疫效果及安全性

通过对国产和法国产两种风疹疫苗在４岁儿童和１７岁学生中接种观察表明，血凝抑制（ＨＩ）抗体，阳转率均为１００．０％。４岁儿童免疫后１个月的抗体几何平均滴度倒数（ＧＭＲＴ）分别为１５６．８．１６０．５：１７岁学生免疫后１个月抗体ＧＭＲＴ分别为１６８．９．１６４．７，两种疫苗在两个年龄组中免疫后抗体ＧＭＲＴ的差异无显著的统计学意义。通过对两种疫苗在４岁儿童免疫后１年的观察，抗体阳性率均为１００．０％，ＧＭＲＴ分别为１２３．７和１１５．６。与免疫后１个月相比，ＨＩ抗体ＧＭＲＴ的差异无显著的统计学意义；两种疫苗在免疫后１年抗体ＧＭＲＴ的差异也无显著的统计学意义。另外，在接种两种疫苗后未发现不良反应。     

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。     

Antibody titres after primary and booster vaccination of infants and young children with a virosomal hepatitis A vaccine (Epaxal)

To evaluate the immunogenicity and tolerability of Epaxal in infants and children, 30 infants (aged 6-7 months) and 30 children (aged 5-7 years) received a single intramuscular dose of the aluminium-free virosomal hepatitis A virus (HAV) vaccine Epaxal and a booster dose after 12 months. Anti-HAV antibody titres were measured at baseline (before injection), at 1 and 12 months after primary vaccination, and 1 month after the booster vaccination. Sixteen evaluable infants had maternal anti-HAV antibodies at baseline. Complete seroprotection (titre >/= 20 mIU/ml) was achieved by all infants and children at Month 1 and at Month 12. Additionally, all subjects showed a strong antibody response to booster vaccination. In infants without maternal anti-HAV antibodies, the response was four-fold higher than in those with maternal anti-HAV antibodies. Both doses of Epaxal were well tolerated. These preliminary data suggest that Epaxal is an effective hepatitis A vaccine for children and infants from 6 months of age.     

Elucidating the difference in the kinetics of antibody titres of infants in Belgium and Vietnam

Serological results obtained in a single laboratory from twin-studies on maternal immunisation, in Vietnam and Belgium offer the opportunity to compare antibody kinetics in infants before and after infant vaccination in the presence of vaccine-induced maternal antibodies. Nonlinear mixed-effects models (NLMMs) making use of a hypothesised dynamic evolution that captures the change in antibody titres over time, were employed to model anti-PT and anti-Prn antibody dynamics. Our proposed modelling approach provided useful insight into understanding the differences in the infants’ antibody kinetics in both countries since NLMMs offer the possibility of pooling all data in one analysis and incorporate relevant covariates of interest.In both controlled cohort studies, pregnant women were vaccinated with a tetanus, diphtheria, acellular pertussis (Tdap) vaccine (Boostrix®, Belgium; Adacel®, Vietnam), and children were followed before and after primary vaccination, and before and after booster vaccination (Infanrix hexa®). From our models, both anti-PRN and anti-PT antibody titres at birth of Vietnamese infants were significantly lower than those of Belgian infants born to vaccinated women groups. Even though the antibody titres in the cord at birth of Belgian infants were also higher than those of Vietnamese infants born to the control women groups, the difference was not significant. The significant difference between infants born to vaccinated women in the two countries was likely due to the use of different vaccine brands in pregnant women and the different vaccination histories of women in these two countries.Our analyses also suggested that the blunting effect was present during the primary immunisation but went away afterward for anti-PT data. In contrast, for anti-PRN antibodies, the blunting effect persisted after the primary vaccination and possibly went away after the booster dose. Countries should be aware of the regional situation in view of recommending maternal immunization.     

Booster vaccination with a fractional dose of an oral cholera vaccine induces comparable vaccine-specific antibody avidity as a full dose: A randomised clinical trial

Antibody avidity is an important measure of the quality of vaccine-induced immune responses. Murine and human studies suggest that antibody avidity may be augmented by limiting access to antigen. The primary objective of this study was to evaluate in primed Swedish adults if booster vaccination with fractional doses (1/5th and 1/25th) of a model oral vaccine, the cholera vaccine Dukoral®, results in higher avidity antibody responses compared to boosting with a full vaccine dose. We also evaluated if fractional booster vaccination elicited similar magnitudes of antibody response compared to a full dose, and if the previously observed increase in antibody avidity after booster vaccination 1–2 years later occurred when boosting after a shorter interval.To this end, a randomised, open-label, exploratory Phase-II trial was performed. Swedish adults (n = 44), primed with two full doses of Dukoral®, were randomised into three groups and given a booster dose at either full (n = 14), 1/5th (n = 17) or 1/25th (n = 13) dose four months later. Antibody responses to cholera toxin B-subunit (CTB) were measured in serum and mucosal antibody in lymphocyte secretions (ALS).We found that the 1/5th and 1/25th booster doses had similar abilities as the full dose to induce significantly higher avidity anti-CTB antibody responses in both ALS and serum samples, as compared to after priming vaccination. There was a non-significant trend to lower magnitudes of ALS and serum IgA responses after the 1/5th compared to the full booster dose, and responses after the 1/25th dose were significantly lower.Our findings suggest fractional booster doses of Dukoral® four months after priming result in anti-toxoid mucosal antibody responses with increased antibody avidity compared to after priming vaccinations.ISRCTN registry identifier 11806026.     

Antibody persistence and safety and immunogenicity of a second booster dose nine years after a first booster vaccination with a reduced antigen diphtheria-tetanus-acellular pertussis vaccine (Tdap) in adults

BackgroundOver the last decades, pertussis showed periodic increases in its incidence among adults, despite being a vaccine-preventable disease.MethodsThis phase III, multicenter, extension study (NCT00489970) was conducted in adults from the United States, followed at Year (Y) 5 and Y9 post-vaccination with a dose of reduced-antigen-content tetanus-diphtheria-acellular pertussis vaccine containing either 3 (Tdap-B group) or 5 pertussis components (Tdap-A group). Willing participants in Tdap groups and newly-recruited participants (Control group) received one Tdap-B dose at Y9. Antibody persistence (at Y5 and Y9) and safety of Tdap-B at Y9 were assessed. Non-inferiority of immune response elicited by 2 Tdap doses was evaluated at Y9: (i) versus one Tdap-B dose for diphtheria and tetanus in terms of seroprotection rates; (ii) for all antigens in terms of booster response rates (Tdap-B and Tdap-A groups versus Control group); and (iii) for pertussis antigens in terms of geometric mean concentrations (GMCs) versus a 3-dose series of a combined diphtheria-tetanus-acellular pertussis vaccine (DTPa) administered during infancy.Results1257 participants were enrolled at Y5 and 809 participants were vaccinated at Y9. Seroprotection rates in both Tdap groups were ≥98.4% and ≥98.0% (Y5) and ≥98.3% and ≥98.1% (Y9) for diphtheria and tetanus, respectively. For pertussis antigens, antibody concentrations above assay cut-offs were observed for ≥76.6% (Y5) and ≥84.9% (Y9) of participants in Tdap groups. At Y9, one month post-Tdap vaccination, comparable seroprotection/seropositivity rates and antibody GMCs were observed among groups. Non-inferiority of immune responses in both Tdap groups was demonstrated when compared to the Control group for diphtheria and tetanus and to a 3-dose DTPa series for pertussis antigens. Non-inferiority criteria in terms of booster response were not met for all antigens. No safety concerns were raised.ConclusionA second dose of Tdap-B administered in adults, 9 years after initial Tdap vaccination, is immunogenic and well-tolerated.     

Booster response to recombinant yeast-derived hepatitis B vaccine in vaccinees whose anti-HBs responses were initially elicited by a plasma-derived vaccine.

One hundred and eight primary school students who had been vaccinated with three doses of a plasma-derived hepatitis B vaccine were randomly divided into two groups, to receive a booster dose of either the same vaccine or of a recombinant yeast-derived vaccine. The pre-booster anti-hepatitis B surface antigen (HBs) geometric mean titres (GMT) were similar in both groups (281.8 mIU ml-1 versus 295.1 mIU ml-1, p greater than 0.5). One month after booster vaccination, all the vaccinees in both groups had a marked elevation in their anti-HBs titres, the anti-HBs GMT in group 1 and group 2 being 19,952.6 and 51,286.1 mIU ml-1 (p less than 0.05), respectively. In conclusion, the recombinant yeast-derived hepatitis B vaccine was able to elicit an excellent booster response in vaccinees who had originally received a plasma-derived vaccine.     

Persistence of bactericidal antibodies following primary and booster MenACWY-TT vaccination of toddlers: A review of clinical studies

The long-term persistence of antibody responses following primary vaccination with quadrivalent conjugate vaccines targeting meningococcal serogroups A, C, W, and Y (MenACWY) and the duration of protection following a booster dose have not been fully elucidated, particularly in children who received primary dosing as toddlers. This review summarizes the findings of one phase 3 and three phase 2 open-label, randomized clinical studies that assessed the long-term antibody persistence of MenACWY conjugated to tetanus toxoid as a carrier protein (MenACWY-TT) in toddlers. Following primary vaccination, antibody responses persisted for approximately 2–3 years and then decreased up to 5 years after vaccination. Geometric mean titers remained elevated for all serogroups up to 5 years after primary vaccination. In children who received a booster dose of MenACWY-TT at 4–5 years after primary dosing as toddlers, antibody responses were documented in >99% of subjects across all serogroups, with minimal decreases in antibody persistence from 2–6 years after booster vaccination. The persistence of meningococcal serogroup C (MenC) antibody responses was similar between MenACWY-TT and MenC vaccine recipients after primary and booster dosing. Together, these findings indicate that antibody responses to primary MenACWY-TT vaccination persist for 2–3 years. Additionally, these findings indicate that in subjects who receive primary MenACWY-TT vaccination as toddlers, the antibody response to booster MenACWY-TT vaccination lasts for up to 6 years and suggest that immune memory is afforded at least into early adolescence, which is an age group at increased risk of invasive meningococcal disease.     

Comparison of the immune response of four different dosages of a yeast-recombinant hepatitis B vaccine in Singapore children: a four-year follow-up study.

The immunogenicity of four different dosages of yeast-derived hepatitis B vaccine (Merck, Sharp & Dohme: 0.6 micrograms, 1.25 micrograms, 2.5 micrograms and 5.0 micrograms), administered at 0, 1 and 6 months (0-1-6 schedule) intramuscularly, was evaluated in 122 seronegative healthy children 1-12 years of age. Three months after the first dose, 83.9-100% of the vaccinees seroconverted. Peak geometric mean titres (GMT) of between 1088 mlU/ml and 1699 mlU/ml were attained 3 months after completion of the vaccination schedule. After 24 months, anti-HBs (antibody to hepatitis B surface antigen) was detected in 93.1-100% of the vaccinees, but the GMT dropped to between 214.3 mlU/ml and 303.5 mlU/ml. After 48 months, 88.8-100% of the vaccinees continued to possess anti-HBs and 70.3-87% had titres above 10 mlU/ml. As expected, the GMT declined further to between 72.6 mlU/ml and 118.8 mlU/ml. There were no significant differences in seroconversion rates and GMT among the different dosage groups. All the vaccinees remained asymptomatic and free from hepatitis B virus infection. The study showed that reduced dosages of the vaccine (0.6 micrograms, 1.25 micrograms and 2.5 micrograms) were as immunogenic as the standard dose (5 micrograms); the 2.5-micrograms dose was recommended for the national childhood immunization programme in Singapore. No booster is necessary for at least four years after vaccination.     

An observational study of antibody responses to a primary or subsequent pertussis booster vaccination in Australian healthcare workers

Adult pertussis vaccination is increasingly recommended to control pertussis in the community. However, there is little data on the duration and kinetics of immunity to pertussis boosters in adults. We compared IgG responses to vaccination with a tetanus, low-dose diphtheria, low-dose acellular pertussis (Tdap) booster at 1 week, 1 month and 1 year post-vaccination in whole-cell (wP)-primed Australian paediatric healthcare workers who had received an adult Tdap booster 5–12 years previously, to those who received their first Tdap booster.Tdap vaccination was well tolerated in both groups. Previously boosted adults had significantly higher pre-vaccination IgG concentrations for all vaccine-antigens, and more were seropositive for pertussis toxin (PT)-specific IgG (≥ 5 IU/mL) (69.5%; 95% confidence interval (CI) 59.5–79.5) than adults in the naïve group (45.2%; 95% CI 32.8-57.5). Tdap vaccination significantly increased IgG responses 1 month post-vaccination in both groups. This increase was more rapid in previously boosted than in naïve adults, with geometric mean fold-increases in PT-IgG at 1 week post vaccination of 3.6 (95% CI 2.9–4.3) and 2.6 (95% CI 2.2–3.2), respectively. Antibody waning between 1 month and 1 year post-vaccination was similar between groups for IgG specific to PT and filamentous haemagglutinin (FHA), but was faster for IgG against pertactin (PRN) in the naïve group (GMC ratio 0.36; 95% CI 0.31–0.42) than the previously boosted group (GMC ratio 0.45; 95% CI 0.39–0.50). At baseline, all but one adult had protective IgG titres against tetanus toxin (TT) (≥ 0.1 IU/mL), and 75.6% in the previously boosted and 61.3% in the naïve group had protective IgG titres against diphtheria toxoid (DT) of ≥ 0.1 IU/mL.This study shows that pertussis immune memory is maintained up to 12 years after Tdap vaccination in wP-primed Australian adults. There was no evidence that pertussis immune responses waned faster after a booster dose. These findings support current recommendations of repeating Tdap booster vaccination in paediatric healthcare workers at least every 10 years. Clinical trials registry: ACTRN12615001262594.     

Immunological priming induced by a two-dose series of H5N1 influenza antigen, administered alone or in combination with two different formulations of AS03 adjuvant in adults: results of a randomised single heterologous booster dose study at 15 months

One influenza pandemic preparedness strategy involves priming a population with a pre-pandemic subtype-specific vaccine and boosting the immunological response at the time of the pandemic with a strain-matched vaccine. In the current study, adults (n = 469) randomised 15 months previously to receive an A/Indonesia/5/2005 (H5N1) influenza vaccine (3.75 μg haemagglutinin antigen [HA]) administered alone or in combination with an oil-in-water emulsion based Adjuvant System containing 11.86 mg (AS03_A) or 5.93 mg (AS03_B) tocopherol per dose, received one booster dose of A/turkey/Turkey/1/2005 (H5N1) vaccine (3.75 μg HA) with or without AS03_A. An anamnestic antibody response that met US regulatory acceptance criteria was observed 15 months after priming. Although superior immunogenicity of AS03-adjuvanted compared to unadjuvanted priming was not demonstrated, higher antibody titres which persisted longer were seen when both priming and boosting regimens were adjuvanted. This may affect duration of response or heterologous immunity. The booster vaccines had a clinically acceptable safety/reactogenicity profile after adjuvanted or unadjuvanted priming. This study has been registered at www.clinicaltrials.govNCT00771615.     

Antibody persistence and the effect of a booster dose given 5, 10 or 15 years after vaccinating preadolescents with a recombinant hepatitis B vaccine

The persistence of antibody obtained post-vaccination of preadolescents with three doses of Engerix-B and the effect of a booster administered 5, 10 or 15 years later were monitored in 663 vaccinees. Five, 10 and 15 years post-vaccination >94% of subjects had detectable antibodies and 88.2%, 86.4% and 76.7% had a titre ≥10 IU/L; GMTs were 269 IU/L, 169 IU/L and 51 IU/L, respectively; 99.1–100% vaccinees reached a titre ≥10 IU/l post-booster. GMTs were 118012 IU/L, 32477 IU/L, and 13946 IU/L when the booster was administered 5, 10 or 15 years post-vaccination, respectively. We conclude that vaccination induces immunity in the great majority of vaccinees for at least 15 years. The response to a booster dose suggests persistence of immune memory in almost all vaccinees. Although a booster dose increases substantially anti-HBs titres, the clinical relevance of such an increase remains unknown. These results do not support the need of a booster for at least 15 years when vaccinating preadolescents with Engerix-B.     

Duration of the immune response in subjects inoculated with antimeningococcal A and C vaccines kept in storage at -20 degrees C and at 4 degrees C: influence of pre-vaccination titres on the vaccinal response.

The antibody titres in 250 subjects, aged 5 to 22 years, who were vaccinated with a mannitol-lyophilized antimeningococcal A + C vaccine, stable only when stored at -20 degrees C, were followed for two years. As measured by indirect haemagglutination (IHA) and indirect immunofluorescence (IF) techniques, titres for both A and C Neisseria meningitidis antibodies remained high. Two years after vaccination titres of antibodies against type A showed fourfold increase over the initial titres in from 46% to 100% of groups of subjects and against type C in from 42% to 80%. For 130 subjects vaccinated with a new lactose-lyophilized antimeningcoccal A + C vaccine (presumed stable at 4 degrees C) antibody titres were measured up to 16 months after inoculation with this vaccine stored at -20 degrees C and also after storage for several periods at 4 degrees C. Antibody titres in all these subjects had fallen to their initial titres by 16 months. The importance of evaluating the results on subjects showing low initial titres (less than or equal to 1/8 as measured by IHA) is discussed, as inclusion of high initial titres influences the extent of the response.