Impact of routine vaccination with a conjugate Haemophilus influenzae type b vaccine

Based on a unique nationwide registration of vaccinated children, we studied the impact of routine Hib vaccination with special emphasis on vaccine uptake and adherence, vaccine effectiveness with respect to Hib meningitis, and indirect effects with respect to Hib meningitis among the unvaccinated children. Uptake and adherence was generally satisfactory. We estimated >97% effectiveness for all three doses of vaccine and observed herd-immunity in unvaccinated children comparable to a vaccine effectiveness of 94% 3.5 years into the programme. In conclusion, nationwide routine Hib vaccination is highly effective in protecting against Hib meningitis, and rapid achievement of herd immunity is possible with catch-up vaccination of older children.     

Vaccine effectiveness of tetanus toxoid,reduced diphtheria toxoid,and acellular pertussis vaccine during a pertussis outbreak in Maine

BackgroundMultiple school-associated pertussis outbreaks were reported in Maine from 2010 to 2011. These outbreaks were associated with an overall increase in pertussis cases statewide. Waning of protection in students recently vaccinated with tetanus, diphtheria, and acellular pertussis (Tdap) has been implicated in the increase in reported rates of pertussis nationally.MethodsWe conducted a retrospective cohort study to evaluate Tdap vaccine effectiveness (VE) among students aged 11–19 years in two schools reporting outbreaks in 2011. All pertussis cases reported from August through November, 2011 at the two schools were included. Vaccination history was verified using provider information, state vaccine registry data, and parental verification. Attack rates (AR) were calculated. VE and duration of protection was calculated as VE = 1 − (AR_vaccinated/AR_unvaccinated) × 100% using a log binomial regression model.ResultsOf 416 students enrolled, 314 were included in the analyses. Twenty-nine cases collectively in Schools A and B. Tdap coverage was 65% at School A and 42% at School B before the start of the outbreak. Among students enrolled in the study, attack rates were 11.9% and 7.7% at Schools A and B, respectively. Overall VE was 68.5% (95% confidence interval (CI) 37.7–86.2). VE was 70.4% (95% CI 17.5–89.4) for School A and 65.2% (95% CI −19.2 to 89.9) for School B. VE <2 years versus ≥2 years from outbreak onset was not significantly different.ConclusionsTdap was moderately effective in preventing disease among vaccinated students. Vaccine coverage of 65% or less was suboptimal and might contribute to outbreaks. Waning VE was not demonstrated. Increased vaccination coverage rates as well as further evaluation of the role of acellular vaccine on VE is needed.     

Impact and cost-effectiveness of a second tetanus toxoid,reduced diphtheria toxoid,and acellular pertussis (Tdap) vaccine dose to prevent pertussis in the United States

IntroductionThe United States experienced a substantial increase in reported pertussis cases over the last decade. Since 2005, persons 11 years and older have been routinely recommended to receive a single dose of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine. The objective of this analysis was to evaluate the potential impact and cost-effectiveness of recommending a second dose of Tdap.MethodsA static cohort model was used to calculate the epidemiologic and economic impact of adding a second dose of Tdap at age 16 or 21 years. Projected costs and outcomes were examined from a societal perspective over a 20-year period. Quality-adjusted Life Years (QALY) saved were calculated.ResultsUsing baseline pertussis incidence from the National Notifiable Diseases Surveillance System, Tdap revaccination at either age 16 or 21 years would reduce outpatient visits by 433 (5%) and 285 (4%), and hospitalization cases by 7 (7%) and 5 (5%), respectively. The costs per QALY saved with a second dose of Tdap were approximately US $19.7 million (16 years) and $26.2 million (21 years). In sensitivity analyses, incidence most influenced the model; as incidence increased, the costs per QALY decreased. To a lesser degree, initial vaccine effectiveness and waning of effectiveness also affected cost outcomes. Multivariate sensitivity analyses showed that under a set of optimistic assumptions, the cost per QALY saved would be approximately $163,361 (16 years) and $204,556 (21 years).ConclusionA second dose of Tdap resulted in a slight decrease in the number of cases and other outcomes, and that trend is more apparent when revaccinating at age 16 years than at age 21 years. Both revaccination strategies had high dollar per QALY saved even under optimistic assumptions in a multivariate sensitivity analysis.     

Immune responses in children after vaccination with a typhoid Vi-tetanus toxoid conjugate vaccine in Bangladesh

A cluster-randomized trial of Vi-TT was conducted in Dhaka, Bangladesh, using JE vaccine as the control. A subset of 1,500 children were randomly selected on 2:1 basis (Vi-TT vs JE) to assess immune response. Blood was collected before vaccination, and on days 28, 545 and 730 post-vaccination and plasma anti-Vi-IgG response was measured. A robust, persistent antibody response was induced after single dose of Vi-TT, even after 2 years of vaccination. While there is no accepted serological antibody threshold of protection, analyzing the antibodies of children who received Vi-TT provides evidence that may later be useful in predicting population protection.     

FDA approval of expanded age indication for a tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine

On July 8, 2011, the Food and Drug Administration (FDA) approved an expanded age indication for the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) Boostrix (GlaxoSmithKline Biologicals, Rixensart, Belgium). Originally, Boostrix was licensed in 2005 for persons aged 10 through 18 years, but in 2008, FDA approved an expanded age indication for Boostrix to include persons aged 19 through 64 years. FDA has now expanded the age indication to include persons aged 65 years and older. Boostrix is now licensed for use in persons aged 10 years and older as a single-dose booster vaccination. This notice summarizes the indications for use of Boostrix. Recommendations of the Advisory Committee on Immunization Practices (ACIP) for Tdap vaccines have been published previously. Publication of revised Tdap recommendations within the next year is anticipated.     

Immune responses in adults to revaccination with a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine 10 years after a previous dose

Background

Although decennial adult boosters of tetanus and diphtheria toxoids are recommended in Canada and the United States, a second dose of pertussis vaccine during adulthood is not currently recommended.

Methods

This open-label, multicenter study compared the safety and immunogenicity of a first dose of an adult formulation of tetanus, diphtheria, and acelluar pertussis vaccine (Tdap) with a repeat dose of Tdap in adults who had received Tdap 10 years previously.

Results

A total of 769 participants ranging in age from 20 to 72 years took part in this study; 92.3% of naïve and 92.7% of repeat-dose participants had at least one solicited adverse event. Injection-site pain (84.4% and 87.8%), erythema (29.7% and 23.1%), and swelling (23.3% and 20.5%), and myalgia (53.5% and 60.1%), headache (37.6% and 40.6%), malaise (29.0% and 29.4%), and fever (4.9% and 4.2%) were the most common solicited adverse events reported in the naïve and repeat-dose groups, respectively. Postvaccination antibody levels ≥0.1 IU/mL were achieved by 99.7% of the naïve-group participants and all of the repeat-dose participants for tetanus and 96.1% of the naïve group and 98.5% of the repeat-dose group for diphtheria, both meeting the predefined noninferiority criteria. For pertussis antibodies, anti-PT (89.2 EU/mL vs. 116 EU/mL) was higher in the repeat-dose group, anti-FHA (249 vs. 214) and anti-PRN (216 vs. 266) were similar, and anti-FIM (1015 vs. 779) was higher in the naïve group. Noninferiority criteria were met for all antigens except for anti-FIM.

Conclusion

A repeat dose of Tdap vaccine 10 years after the first dose was well tolerated and immunogenic in adults (ClinicalTrials.gov identifier: NCT00712959).     

Adverse reactions and antibody response to an acellular pertussis toxoid vaccine in adult volunteers

A monovalent pertussis toxoid vaccine (JNIH-7, Biken, Japan) was evaluated for reactogenicity and immunogenicity in 20 healthy adults (phase 1 study). Fever of greater than or equal to 38 degrees C was recorded in 2/20; local reactions started in 2/20 on day 1 (early onset) and in 3/20 on day 7 (late onset). All 15/15 subjects tested showed a significant antibody response to pertussis toxin by neutralization or enzyme-linked immunosorbent assay. Significantly elevated antibodies were still detected in 12/13 subjects 32 months after the single subcutaneous dose of vaccine.     

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.     

Immunogenicity and reactogenicity of a single dose of a diphtheria--tetanus--acellular pertussis component vaccine (DTaP) compared to a diphtheria--tetanus toxoid (Td) and a diphtheria toxoid vaccine (d) in adults

We compared immunogenicity and reactogenicity of a single dose of DTaP vaccine (containing tetanus and diphtheria toxoids and four acellular pertussis antigens) with conventional Td- or d-vaccines in 180 German adults. Antibody values against diphtheria and tetanus toxin and against the pertussis antigens fimbriae (FIM), filamentous hemagglutinin (FHA) and pertussis toxin (PT) were measured in pre- and post-immunization sera. Reactogenicity was determined by a patient diary card. Pre-immunization antibody values against diphtheria toxin were low in all three vaccine groups. After immunization, > or = 80% of the vaccinees in all three groups were fully protected (> or = 0.1 IU/ml), but geometric mean values were significantly higher in DTaP recipients compared to Td or d recipients (1.65 vs. 0.44 and 0.48, respectively; both P < 0.05). Pre-immunization antibody values against tetanus toxin were high in all three groups, and after immunization 100% of the vaccinees were protected (> or = 0.1 IU/ml). Furthermore, substantial antibody responses against pertussis antigens were elicited in DTaP recipients with geometric mean rises of 22.5, 4.1 and 7.5 for antibodies against FHA, fimbriae and PT, respectively. All three vaccines were well tolerated. Frequency and severity of local reactions were similar between DTaP and Td recipients and even less common in d recipients. Since DTaP did provide a significant boost of anti-pertussis antibodies and a significantly higher anti-diphtheria response than conventional Td vaccine without an increase of side effects, it might be an appropriate candidate for use in adults.     

High levels of antibody in adults three years after vaccination with a reduced antigen content diphtheria-tetanus-acellular pertussis vaccine

There is increasing interest in prevention of pertussis in adults by vaccination, but little is known about the duration of the antibody response to pertussis, diphtheria or tetanus in reduced antigen content vaccines formulated for adult use. Follow-up of a clinical trial including 550 adults comparing responses to reduced antigen content diphtheria-tetanus-acellular pertussis (dTpa) vaccine, or a licensed Td vaccine, provided the opportunity to evaluate this. Blood samples were collected at 0, 1, 12, 24 and 36 months following vaccination; of the original cohort of 550, 387 subjects (dTpa group N=310, Td+pa group N=77) were tested at month 36. Following a decrease in antibody levels against all vaccine antigens between one and 24 months following vaccination, levels stabilized during the third year, remaining higher at 36 months than pre-vaccination for all vaccine antigens. In particular, more than 90% of subjects remained seropositive for pertussis toxin and pertactin antibodies at 36 months after vaccination, suggesting ongoing protection against pertussis. Adult-formulated dTpa vaccines could replace Td for routine booster vaccination of older individuals.     

High levels of antibody in adults three years after vaccination with a reduced antigen content diphtheria-tetanus-acellular pertussis vaccine

There is increasing interest in prevention of pertussis in adults by vaccination, but little is known about the duration of the antibody response to pertussis, diphtheria or tetanus in reduced antigen content vaccines formulated for adult use. Follow-up of a clinical trial including 550 adults comparing responses to reduced antigen content diphtheria-tetanus-acellular pertussis (dTpa) vaccine, or a licensed Td vaccine, provided the opportunity to evaluate this. Blood samples were collected at 0, 1, 12, 24 and 36 months following vaccination; of the original cohort of 550, 387 subjects (dTpa group N = 310, Td + pa group N = 77) were tested at month 36. Following a decrease in antibody levels against all vaccine antigens between one and 24 months following vaccination, levels stabilized during the third year, remaining higher at 36 months than pre-vaccination for all vaccine antigens. In particular, more than 90% of subjects remained seropositive for pertussis toxin and pertactin antibodies at 36 months after vaccination, suggesting ongoing protection against pertussis. Adult-formulated dTpa vaccines could replace Td for routine booster vaccination of older individuals.     

Effects of pertussis vaccination on transmission: vaccine efficacy for infectiousness

We estimated the effect of pertussis vaccination on reducing transmission from vaccinated breakthrough cases from a comprehensive follow-up of a community of 30,000 residents in Niakhar, Senegal. Using a wide spectrum of case definitions, vaccine efficacy was estimated as 1 - the ratio of secondary attack rates (SAR) in all households with cases during the calendar year 1993, a pertussis epidemic year. Vaccine efficacy for infectiousness (VEi) was 85% (95% confidence interval (CI), 46-95%) for children vaccinated with three doses of a whole-cell (WC; 94%) or an acellullar (6%) pertussis vaccine, with pertussis defined as a cough >/=21 days with paroxysms confirmed by culture, serology, or contact with a culture-confirmed person. It was high for all case definitions. Partial vaccination reduced infectiousness. Pertussis vaccination is highly effective in reducing transmission from vaccinated breakthrough cases.     

Impact of maternally derived pertussis antibody titers on infant whole-cell pertussis vaccine response in a low income setting

BackgroundMaternal vaccines against pertussis are not yet recommended in the developing world. Besides unclear burden estimates, another concern is that transplacental transfer of maternal pertussis antibodies could result in attenuation of the immune response to whole cell pertussis (DTwP) primary vaccination series in infants. This study was taken up to determine whether higher levels of maternal pertussis antibodies attenuate immune response of infants to DTwP vaccination series given at 6–10–14 weeks of age.MethodologyA total of 261 pregnant women and their infants from four low-income settlements in Karachi, Pakistan were enrolled in this study. The study endpoints were infant antibody titers for Pertussis toxin (PTx), Filamentous hemagglutinin antigen (FHA), Pertactin (PRN) and Fimbriae type 2/3 (FIM) – from birth through 18 weeks of age. Cord blood or pre-vaccine pertussis antibody titers indicate the concentration of maternal antibodies transferred to infants. Linear regression models were used to determine the association between higher maternal antibody titers and infant immune response to DTwP vaccine. Geometric Mean Ratio (GMR) was calculated as the ratio of infant antibody titers at specified time points against the maternal antibody titers at the time of delivery.ResultsAt eighteen weeks of age, the adjusted β regression coefficient for PTx was 0.06 (95% CI: -0.49-0.61), FHA 0.02 (95% CI: -0.26 -0.29), PRN 0.02 (95%CI -0.38- 0.43), and FIM 0.17 (95%CI: -0.21-0.54). Among infants who received at least two doses of DTwP vaccine, higher maternal antibody titers did not have any attenuating effect on infant post-immunization antibody titers against all four pertussis antigens.ConclusionMaternal pertussis antibodies did not attenuate infant’s immune response to pertussis antigens in DTwP primary vaccine given at 6–10–14 weeks of age.     

Economic impact of implementing decennial tetanus toxoid,reduced diphtheria toxoid and acellular pertussis (Tdap) vaccination in adults in the United States

BackgroundIn the United States, persons ≥11 years are recommended to receive one dose of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine, followed by decennial tetanus- and diphtheria-toxoid (Td) boosters. Many providers use Tdap instead of Td. We evaluated epidemiologic and economic impacts of replacing Td boosters with Tdap.MethodsWe used a static cohort model to examine replacing Td with Tdap over the lifetime of 4,386,854 adults ≥21 years. Because pertussis is underdiagnosed and true incidence is unknown, we varied incidence from 2.5 cases/100,000 person-years to 500 cases/100,000 person-years. We calculated vaccine and medical costs from claims data. We estimated cost per case prevented and per quality-adjusted life year (QALY) saved; sensitivity analyses were conducted on vaccine effectiveness (VE), protection duration, vaccine cost, disease duration, hospitalization rates, productivity loss and missed work. We did not include programmatic advantages resulting from use of a single tetanus-toxoid containing vaccine.ResultsAt lowest incidence estimates, administering Tdap resulted in high costs per averted case ($111,540) and QALY saved ($8,972,848). As incidence increased, cases averted increased and cost per QALY saved decreased rapidly. With incidence estimates of 250 cases/100,000 person-years, cost per averted case and QALY saved were $984 and $81,678 respectively; at 500 cases/100,000 person-years, these values were $427 and $35,474. In multivariate sensitivity analyses, assuming 250 cases/100,000 person-years, estimated cost per QALY saved ranged from $971 (most favorable) to $217,370 (least favorable).ConclusionsOur findings suggest that replacing Td with Tdap for the decennial booster would result in high cost per QALY saved based on reported cases. However, programmatic considerations were not accounted for, and if pertussis incidence, which is incompletely measured, is assumed to be higher than reported through national surveillance, substituting Tdap for Td may lead to moderate decreases in pertussis cases and cost per QALY.     

Epidemiology of pertussis in a country with high vaccination coverage

Introduction

Pertussis has been a preventable disease in Catalonia since 1965, but the annual number of cases remains high. The aim of this study was to analyze the epidemiology of pertussis in Catalonia and its implications for control purposes.

Methods

An epidemiological study was carried out in Catalonia between 2004 and 2008. Pertussis cases reported to the Department of Health were collected and disease reports were filled out with the case information. Incidence rates, rate ratios (RR) and their 95% confidence intervals (CI) were calculated.

Results

963 cases were reported: 555 (57.6%) were confirmed and 408 (42.4%) were suspected cases. The reported incidence rate was 2.01 × 10⁻⁵ person years in 2004 and 4.34 in 2008. The biggest increase in cases between 2004 and 2008 was observed in the ≥35 years age group (RR: 6.98; 95%CI: 2.11-36.36). 303 (31.5%) patients were hospitalized, of whom 93.7% were aged <1 year. Clinical differences were observed in paroxysmal cough (83.8% in suspected and 76.4% in confirmed cases, p = 0.005), posttussive vomiting (47.1% and 36.1%, respectively, p = 0.001), apnoea (13.7% and 21.3%, respectively, p = 0.003) and fever (20.1% and 12.4%, respectively, p = 0.001).

Conclusion

Pertussis incidence rates increased during the study period, with the greatest increase occurring in the ≥35 years age group. A booster dose of vaccine in young people could reduce the circulation of B. pertussis in adolescents and adults and indirectly reduce the incidence in children.     

Reactogenicity and immunogenicity of tetanus toxoid,reduced diphtheria toxoid,and acellular pertussis vaccine (Tdap) in pregnant and nonpregnant women

ObjectiveTetanus toxoid, reduced diphtheria toxoid, and acellular pertusiss (Tdap) vaccine is recommended during each pregnancy, regardless of prior receipt. Data on reactogenicity and immunogenicity, particularly after repeated Tdap, are limited. We compared local injection-site and systemic reactions and serologic response following Tdap in (1) pregnant and nonpregnant women and (2) pregnant women by self-reported prior Tdap receipt.Study designPregnant women (gestational age 20–34 weeks) and nonpregnant women receiving Tdap were enrolled in this observational study. Injection-site and systemic reactions were assessed for one week post-vaccination. Pertussis toxin, filamentous hemagglutinin, pertactin, fimbriae, tetanus and diphtheria specific IgG antibody titers were determined by standardized enzyme-linked immunosorbent assay at baseline and 28 days post-vaccination. Reactogenicity and serologic responses were compared by pregnancy status, and within pregnant women by self-reported prior Tdap receipt.Results374 pregnant and 225 nonpregnant women were vaccinated. Severe local or systemic reactions or “any” fever were uncommon (≤3% for both groups). Moderate/severe injection-site pain was significantly higher in pregnant (17.9%) versus nonpregnant (11.1%) women, but did not prompt a healthcare visit. Proportions of other moderate/severe or any severe reactions were not significantly higher in pregnant compared to nonpregnant women. Moderate/severe (including pain) and severe reactions were not significantly higher in pregnant women receiving repeat versus first-time Tdap. Antibody titers increased from baseline to post-vaccination for all vaccine antigens in pregnant and nonpregnant women; post-vaccination titers against pertussis toxin and filamentous hemagglutinin were significantly higher in nonpregnant versus pregnant women (p < 0.01).ConclusionTdap was well-tolerated in pregnant and nonpregnant women. Pregnant women were more likely to report moderate/severe pain at the Tdap injection-site compared with nonpregnant women, but did not necessitate medical visits. Prior Tdap receipt did not increase occurrence of moderate/severe local or systemic reactions in pregnant women. Serologic responses to all vaccine antigens were robust.Clinical Trial Registration@ClinicalTrials.gov. NCT02209623.https://clinicaltrials.gov/ct2/show/NCT02209623.     

The contagious nature of a vaccine scare: How the introduction of HPV vaccination lifted and eroded MMR vaccination in Denmark

BackgroundHuman papillomavirus (HPV) vaccine coverage was high in Denmark until it plunged following negative media coverage. We examined whether the decline in HPV vaccination undermined uptake of another adolescent vaccine, measles, mumps and rubella (MMR).MethodsThe Danish national health register provided data on uptake of MMR vaccine dose 2 (at age 13) for children born from 1991 to 2003 (n = 827,716). The primary exposure variable comprised three time periods: before HPV vaccine introduction, during high HPV vaccine coverage, and after the drop in HPV vaccine coverage. To examine the effect of HPV vaccination on MMR2 uptake, we estimated MMR2 uptake by age 13 using logistic regression, controlling for gender, birth month, birth year, and maternal education.FindingsMMR2 vaccination coverage was high for both girls and boys (86% and 85%) in 2009. Following the introduction of HPV vaccine for girls in 2009, MMR2 coverage increased for girls even as it decreased for boys (gender gap 4·6 percentage points, 95% CI 4·3 to 4·8). Coverage with MMR2 for girls continued to be high over the following four years, and almost all girls (91%) who received MMR2 vaccination also received HPV1 vaccination within the same week. When negative media coverage led to a decline in HPV vaccination, MMR2 uptake for girls also declined. By 2015, MMR2 coverage for girls and boys had become similar again (80% and 79%). Families with the highest level of maternal education showed the strongest decline in MMR2 coverage for girls.InterpretationConcomitant vaccine provision can increase overall vaccine uptake. However, reduced demand for one vaccine may reduce concomitant vaccination and undermine resiliency of a country’s vaccination program.FundingDrs. Gørtz and Ejrnæs appreciate generous funding from the Novo Nordisk Foundation (grant no. NNF17OC0026542) and from the Danish National Research Foundation through its grant (DNRF-134) to the Center for Economic Behavior and Inequality (CEBI) at the University of Copenhagen.     

Impact of systematic vaccination with the antimeningococcal C conjugated vaccine in a health area in Andalusia

BACKGROUND: A retrospective longitudinal study of population incidence was made to assess the effectiveness of meningococcal serogroup C conjugate vaccine, after its mass introduction in children in the geographic area of a health district, measuring its population impact, and we have studied the state of the meningococcal disease. METHODS: Vaccine coverage in children born between 1991 and 2001, and rates of incidence in declared cases of meningococcal disease in seven epidemiological seasons (1997/98 to 2003/04) were calculated. The impact of vaccination against serogroup C meningitis was assessed comparing the average annual rates of previous and later seasons to the vaccination campaigns in population younger and older than 10, using the Fisher exact test. RESULTS: In all the study period, 109 cases of meningococcal disease were declared, of which 50 were of serogroup C meningococcal disease. Starting from 2000/2001 season the incidence of serogroup C disease decreased in the population below 10. In this age group, the annual average rate of post-vaccine seasons decreases in respect to pre-vaccine (from 8.2 to 2.0 per 100,000 inhabitants) showing a statistically significant difference. In the population above 10 years, this incidence reduction was not observed. In the study period, no case of vaccine failure was declared. CONCLUSIONS: The absence of vaccine failure and the impact observed on the incidence of serogroup C meningococcal disease in children under 10 suggests the effectiveness of this new conjugate vaccine, together with suitable vaccination conditions (vaccination schedule, high catch-up, etc.) which are developing in our health district.