Vaccination of adults 65 years of age and older with tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Boostrix®): Results of two randomized trials

doi:10.1016/j.vaccine.2011.12.055

Vaccine

Volume 30, Issue 9, 21 February 2012, Pages 1721-1728

https://doi.org/10.1016/j.vaccine.2011.12.055 Get rights and content

Abstract

Background

Pertussis can cause significant morbidity in elderly patients, who can also transmit this disease to infants and young children. There is little data available on the use of acellular pertussis vaccines in recipients ≥65 years of age.

Methods

Two studies examined the safety and immunogenicity of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine (Boostrix^®) in healthy ≥65 year olds. In Study A subjects received single doses of Tdap and seasonal influenza vaccine either co-administered or given one month apart. In Study B subjects received either Tdap or tetanus-diphtheria (Td) vaccine. Antibodies were measured before and one month after vaccination. Reactogenicity and safety were actively assessed using diary cards.

Results

A total of 1104 subjects 65 years of age and older received a Tdap vaccination in the two studies. In study A, no differences in immune responses to Tdap or influenza vaccine were observed between co-administered or sequentially administered vaccines. In study B, Tdap was non-inferior to Td with respect to diphtheria and tetanus seroprotection, and anti-pertussis GMCs were non-inferior to those observed in infants following a 3-dose diphtheria, tetanus and acellular pertussis (DTaP) primary vaccination series, in whom efficacy against pertussis was demonstrated. Reports of adverse events were similar between Tdap and Td groups.

Conclusions

Tdap was found to be immunogenic in subjects ≥65 years, with a safety profile comparable to US-licensed Td vaccine. Tdap and influenza vaccine may be co-administered without compromise of either the reactogenicity or immunogenicity profiles of the two vaccines.

Highlights

► Pertussis can cause significant morbidity in elderly patients. ► Tdap vaccine (Boostrix^®) is immunogenic in subjects ≥65 years. ► The safety profile of Tdap is comparable to that of the US-licensed Td vaccine.

Introduction

In 2009, a total of 16,858 cases of pertussis were reported in the United States [1]. This observation continues a trend for increase in pertussis incidence in the US: the overall incidence of pertussis increased from 3.62/100,000 in 2007 to 5.48/100,000 in 2009 [1], [2]. The incidence of pertussis increased in all age groups from 1999 through 2006, with the greatest rate of increase observed in adults ≥65 years of age. There were 258 confirmed pertussis cases in adults ≥65 years of age in 2008 [2]. However, under-reporting of pertussis is widely acknowledged [3], especially in older patients who may not present with classic symptoms such as inspiratory “whoop”. It is estimated that in the US up to 22,000 cases of pertussis a year may occur in the elderly [2], [4]. Serological studies in the US, Australia and the Netherlands suggest pertussis outbreaks in aged care facilities and in older adults [5], [6], [7].

Although unvaccinated infants are at the highest risk for hospitalization and complications associated with pertussis, hospitalizations and deaths due to pertussis increase with age in adults. US adults aged ≥65 years with pertussis report experiencing paroxysmal cough (86%), whoop (33%), apnoea (32%) and post-tussive vomiting (27%) [4]. The frequency of hospitalizations and pneumonia is higher in this age group than in younger adults (12% vs. 3% and 8% vs. 3%, respectively) [4]. The elderly may have severe consequences (including death) induced by severe coughing paroxysms or cough syncope [8]. Between 1990 and 2004, 5 pertussis-associated deaths were reported in persons aged 49–82 years of age; it is considered that pertussis-related deaths are probably under-reported [4].

Adults, including parents and grandparents whose immunity has waned, are susceptible to pertussis disease and may transmit pertussis infection to vulnerable infants and young children [9], [10], [11]. Therefore, pertussis booster vaccination has the two-fold objective of preventing pertussis in the vaccinated individual, and decreasing the exposure of persons at increased risk for complications (i.e., infants) from pertussis [12]. The latter objective is often referred to as “cocooning”.

There are no standalone pertussis vaccines licensed for use in the US. Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines were approved in the United States in 2005 and recommended for booster vaccination of adolescents and adults 11–64 years of age, replacing the next scheduled dose of tetanus-diphtheria (Td) vaccine [13]. Tdap vaccination was also recommended for adults up to age 64 years who have close contact with infants <2 months of age, for health care workers, and women in the immediate post-partum period [13], [14]. Tdap vaccination for adults ≥65 years of age was not recommended at that time due to a lack of safety and immunogenicity data of Tdap use in this age group.

Here we report the results of two clinical trials that examined the safety and immunogenicity of a Tdap vaccine (Boostrix^®, GlaxoSmithKline [GSK] Biologicals, Rixensart) in US adults ≥65 years of age. One study (Study A) evaluated the co-administration of Tdap with trivalent inactivated influenza vaccine. The primary analysis population for this study was adults aged 19–64 years. The study also included an exploratory analysis cohort of subjects ≥65 years of age. Results for the primary population have been reported previously [15]. The second study (Study B) was designed to evaluate the immunogenicity and safety of Tdap compared to licensed Td vaccine in ≥65 year olds. This study also compared the immune responses to the pertussis components of the Tdap vaccine to those observed in an infant population after receiving a 3 dose primary vaccination series with paediatric diphtheria toxoid, tetanus toxoid, and acellular pertussis vaccine (DTaP) as a means of assessing the efficacy of Tdap in ≥65 year olds.

Section snippets

Methods

Study A was a Phase III randomized, open-label study conducted in 12 centres in the United States between October 2006 and February 2007 (NCT106323). The purpose of the study was to demonstrate the immunogenicity and safety of Tdap co-administered with influenza vaccine (Fluarix^®, GlaxoSmithKline Biologicals, Rixensart) in adults 19–64 years of age [15]. An additional cohort of adults ≥65 years of age was included for exploratory analysis of vaccine immunogenicity and safety in this age group.

Results

A total of 217 subjects (112 in the Tdap + Flu group and 105 in the Flu→Tdap group) received Tdap vaccination in Study A (four subjects in the Flu→Tdap group withdrew prior to receiving Tdap vaccination; Fig. S1, on-line supplement). There were 887 subjects who received Tdap vaccination in Study B (Fig. S1, on-line supplement). No subject withdrew from either study due to an adverse event. The treatment groups in each study were similar with respect to demographic features of enrolled subjects (

Discussion

Data from two clinical trials show the immunogenicity and tolerability of Tdap in individuals ≥65 years of age. Tdap vaccine was shown to be immunogenic in this age group, with robust increases in antibodies for all vaccine antigens following vaccination. The percentages of Tdap recipients with seroprotective levels of anti-D and anti-T antibodies one month after vaccination were non-inferior to those observed following receipt of Td vaccine. Consistent with results of earlier studies [22], [24]

Acknowledgements

The authors thank Mark Blatter, Daniel Brune, Mariananda Kumar, Randle Middleton, Matthew P. Finneran, Steven Geller, Robert Jeanfreau, Steven Kaster, Andrew Lewin, Isaac Marcadis, Richard Mills, Anthony Puopolo, Leah M. Schmidt, William Seger and the other investigators and study staff, as well as the subjects who participated in each study. The authors thank Drs Joanne Wolter and Julia Donnelly for assistance in preparation of the manuscript. All authors are employees of GSK. The

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Cited by (55)

Cost of illness due to pertussis in adults ≥50 years of age in the United Kingdom
2023, Vaccine
Pertussis is an endemic respiratory tract infection caused by Bordetella pertussis that may affect all individuals from infants to older adults. Pertussis incidence in adults is often underreported and in various countries, including the United Kingdom (UK), there are evidence gaps on pertussis-associated economic burden in the older adult population. We aimed to quantify the economic burden of pertussis in adults aged ≥50 years in the UK.
A cost-of-illness study was conducted to estimate the cost of pertussis from a societal perspective. We utilized a sum diagnosis cost approach in which costs related to infection with pertussis were included. Medical, patient, and indirect costs were calculated individually and combined to calculate total costs. A framework was developed to assess costs for consecutive age groups from 50–54 years of age to ≥85 years of age. Sensitivity and scenario analyses were used to assess analysis uncertainty.
The base-case analysis estimated the total annual economic burden of pertussis to be approximately £238 million (M). This comprised approximately £159 M in indirect costs, £66 M in medical costs, and £13 M in patient costs. Costs for the age group 55–59 years had the highest impact on the economic burden, with approximately £79 M in total annual costs. Visits to general practitioners and nurses were the largest contributors to medical costs (∼£37 M) followed by inpatient visits (∼£21 M). Transportation costs (∼£10 M) were the major patient costs. Productivity loss (∼£71 M) and leisure time loss (∼£72 M) had comparable contributions to annual indirect costs. Sensitivity and scenario analyses suggested that incidence rates, indirect costs, and underreporting estimates had the highest impact on outcomes.
Total cost of pertussis in the UK among adults ≥50 years of age is substantial and highest for adults 55–59 years of age. Indirect costs were the main contributors to the economic burden.
Safety and immunogenicity of SIIPL Tdap, a new tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine, in healthy subjects 4–65 years of age: A Phase II/III randomized, observer-blinded, active controlled, multicenter clinical study in Germany
2023, Vaccine
This study assessed the safety and immunogenicity of a new booster vaccine against tetanus, diphtheria, and pertussis manufactured by Serum Institute of India Pvt. Ltd (SIIPL Tdap).
The Phase II/III trial was randomized (2:1), observer blinded and active controlled. Healthy subjects aged 4–65 years received a single dose of either SIIPL Tdap or comparator Tdap vaccine (Boostrix®, GlaxoSmithKline, Belgium), and were followed-up for 30 days. Blood samples for safety and immunogenicity assessments were collected pre-vaccination and on day 30 post-vaccination. The study assessed safety and reactogenicity of SIIPL Tdap compared to the comparator Tdap as well as the co-primary immunogenicity outcomes: (i) seroprotection rates against diphtheria toxoid (DT) and tetanus toxoid (TT) and (ii) the booster response rates against pertussis toxoid (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) 30 days post-vaccination in all study subjects. A margin of −10 % was used for non-inferiority testing. Secondary outcomes included the booster response rates against DT and TT, seropositivity rates against pertussis antigens, and antibody geometric mean concentrations (GMCs) for all vaccine components.
At Day 30 post-vaccination, SIIPL Tdap was assessed as non-inferior to the comparator Tdap in terms of: i) seroprotection rates against DT (94.4 % vs. 94.9 %) and TT (99.9 % vs. 100 %) and ii) pertussis booster response rates (93.8 % vs. 88.4 % anti-PT, 89.7 % vs. 90.9 % anti-FHA and 86.3 % vs. 84.4 % anti-PRN), for SIIPL Tdap versus comparator Tdap, respectively. GMCs for anti-PT and anti-PRN were higher in subjects vaccinated with SIIPL Tdap compared to comparator Tdap. All other secondary outcomes were comparable. The overall frequency of local and systemic solicited AEs was comparable; no treatment related SAEs were reported.
Booster vaccination with SIIPL Tdap was non-inferior to comparator Tdap with respect to the immunogenicity of the vaccine components and was equally well tolerated.
EudraCT number: 2019-002706-46.
The aging immune system: Dysregulation, compensatory mechanisms, and prospects for intervention
2021, Handbook of the Biology of Aging
Despite its dynamic organization and self-renewal capacity, with large numbers of its cellular components continually turning over and being replaced, the immune system in older people is different from that of the young. Much but not all of this is reflected in different distributions of cells of the adaptive immune system, with innate immunity showing less marked age effects. In humans, most available data pertain to peripheral blood with relatively little known about differences in other organs. Differences at the level of hematopoiesis contribute to these age effects, as does thymic involution in the case of T cells. The main drivers of the changes in adaptive immunity are pathogen exposure throughout life with the accumulation of T and B cells imbuing memory to previously encountered agents or maintaining immunosurveillance against persistent agents, and the reciprocal decrease of naïve cells which have not been exposed to their cognate antigens. True “senescence” in the pathological sense is hard to determine in human immunity, and may only occur very late in life when clonal exhaustion and attrition contribute to failing memory immune responses or contraction of the naïve cell repertoire results in the lack of appropriate receptors to respond to certain neoantigens.
Immune response and allergies to vaccines
2020, Revista Medica Clinica Las Condes
Las vacunas son altamente efectivas en prevenir enfermedades infecciosas a través del desarrollo en el individuo de una respuesta inmune protectora, sin desarrollar la enfermedad. Los distintos tipos de vacunas producen diferentes tipos de respuestas inmunes y variadas estrategias se han desarrollado para mejorar esta respuesta. El sistema inmune sufre cambios con la edad y esta inmunosenecencia altera la capacidad de responder frente a ellas. Por otro lado, si bien el sistema inmune puede reconocer elementos presentes en las vacunas y montar respuestas de hipersensibilidad ante ellos, las alergias a las vacunas son raras, teniendo que distinguirlas adecuadamente de otro tipo de reacciones. En caso que un paciente presente una reacción compatible con alergia, es importante conocer todos los componentes de la vacuna para realizar un estudio adecuado.
Vaccines are highly effective in preventing infectious diseases through the development in the individual a protective immune response, without developing the disease. Different types of vaccines produce different types of immune responses, and varied strategies have been developed to improve this response. The immune system undergoes changes with age, and this inmunosenescence alters the ability to respond to them. On the other hand, although the immune system can recognize elements present in vaccines and establish hypersensitivity responses to them, vaccine allergies are rare, having to properly distinguish them from other types of reactions. In the event that a patient has an allergy-compatible reaction, it is important to know all the components of the vaccine to conduct a proper study.
Safety review of tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccines (Tdap) in adults aged ≥65 years, Vaccine Adverse Event reporting System (VAERS), United States, September 2010–December 2018
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Citation Excerpt :
In 2012, the Advisory Committee on Immunization Practices (ACIP) recommended Boostrix in persons aged ≥65 years, when feasible, but use of either available Tdap was acceptable [3,4]. Pre-licensure studies of Boostrix among adults ≥65 years found that local reactions were the most commonly observed adverse events (AEs) [2,5]. In a safety review of Tdap in the Vaccine Adverse Event Reporting System (VAERS) during 2005–2010 (before these vaccines were recommended for individuals ≥65 years of age), Moro and colleagues described safety findings consistent with those in pre-licensure studies [6].
The Advisory Committee on Immunization Practices (ACIP) recommends vaccination with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in persons ≥65 years of age. To date, few studies have assessed the safety of Tdap in this population. We aimed to summarize reports submitted to the Vaccine Adverse Event Reporting System (VAERS) following receipt of Tdap in this age group.
We searched for and analyzed U.S. VAERS reports of Tdap among individuals ≥65 years of age submitted from September 1, 2010 through December 31, 2018. We classified reports according to concurrent vaccination, seriousness, and outcome (death, non-death) and determined the frequency of reported adverse events (AEs). For serious reports, we reviewed available medical records. Data mining analyses were undertaken to detect disproportionality in reporting.
VAERS received a total of 1,798 reports following Tdap, of which 104 (6%) were serious. The most common AEs were injection site erythema (26%; n = 468), injection site pain (19%; n = 335), injection site swelling (18%; n = 329), and erythema (18%; n = 321). We identified seven deaths; none were attributed to Tdap. Among serious non-death reports, nervous system disorders (35.1%; n = 34) and infections and infestations (n = 18.6%; n = 18) were most commonly reported. Data mining did not identify any vaccine-AE combination reported more frequently than expected.
We did not identify any new safety concern over nearly a decade of recommended Tdap use among adults ≥65 years of age. Findings from this post-marketing review are consistent with prior post-marketing observations and pre-licensure studies.
Alterations in responses to vaccines in older people
2019, Revue des Maladies Respiratoires
Le vieillissement croissant de la population impose de prévenir les infections sévères et fréquentes sur ce terrain par des vaccins. Cependant, l’immunosénescence altère l’intensité et la qualité des réponses vaccinales, limitant ainsi l'efficacité des recommandations vaccinales dirigées après 65 ans contre la grippe, le pneumocoque, la coqueluche mais également le tétanos ou le zona. Ces vaccins élaborés, sauf le zona, pour les jeunes enfants sont peu adaptés au sujet âgé. Mieux comprendre les mécanismes de l’immunosénescence et les raisons de ces limitations devrait permettre d’améliorer dans le futur l’efficacité de ces réponses vaccinales. L’immunosénescence, aggravée par les co-morbidités, varie avec l’âge, devient patente après 60–65 ans et profonde après 85 ans. Toutes les étapes des réponses vaccinales sont touchées par l’immunosénescence, depuis l’immunité innée nécessaire à l’activation de ces réponses jusqu’à l’induction de réponses anticorps protecteurs et de la mémoire immunitaire. Néanmoins, la capacité de développer de nouvelles réponses en primo-vaccination est plus touchée que la capacité de réponse aux rappels, toutefois également altérée. La revue détaille les altérations des réponses vaccinales et l’efficacité des vaccins sur ce terrain et analyse les quelques pistes actuellement poursuivies pour tenter d’améliorer le degré de protection conféré aux sujets âgés par ces vaccins.
The aging population raises a number of public health issues including a need to address the severity and frequency of infections observed in older people. Vaccines play an important role in prevention. However, immunosenescence alters the intensity and quality of vaccine responses, thus limiting the impact of recommendations directed after 65 years for vaccination against flu, pneumococci, pertussis, tetanus and zoster. Immunosenescence, aggravated by co-morbidities, varies with age, becoming apparent after 60–65 years and more profound after 85 years. All stages of vaccine responses are affected by immunosenescence, from the innate immunity required to activate these responses to the induction of protective antibody responses and immune memory. Nevertheless, the capacity to develop new responses to primary vaccination is more affected than the ability to respond to recalls, although this is also impaired. Responses to vaccines are differentially altered depending on vaccine and age. Influenza vaccines are modestly immunogenic and several meta-analyses agree an estimate for efficacy of about 50% against virologically-proven flu and 40% against flu-related deaths. The anti-pneumococcal 23-valent non-conjugated vaccine does not induce memory while the 13-valent conjugated one does, but their efficacy are likely to be similar between 70 to 52% before 75 years. A sequential vaccination program with the 13-valent primo-vaccination followed by the 23-valent, recommended in immune-suppressed patients, is currently being studied in France. The waning of immunity to pertussis makes recalls necessary in the elderly who develop good antibody responses. Several research avenues are currently being pursued to try improve the degree of protection conferred by these vaccines in elderly.

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^☆: These clinical trials are registered at www.clinicaltrials.gov: NCT106323 and NCT00835237.

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Vaccination of adults 65 years of age and older with tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Boostrix®): Results of two randomized trials☆

Abstract

Background

Methods

Results

Conclusions

Highlights

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgements

J Infect

Vaccine

J Biol Stand

J Pediatr

Vaccine

Vaccine

Vaccine

Summary of notifiable diseases – United States

The epidemiology of pertussis: a comparison of the epidemiology of the disease pertussis with the epidemiology of Bordetella pertussis infection

Pediatrics

A “new age” in pertussis prevention new opportunities through adult vaccination

Am J Prev Med

Pertussis outbreaks in aged-care facilities

N S W Public Health Bull

Antibody responses to Bordetella pertussis antigens and clinical correlations in elderly community residents

Clin Infect Dis

A pertussis outbreak associated with social isolation among elderly nuns in a convent

Clin Infect Dis

Vaccination of adults 65 years of age and older with tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Boostrix^®): Results of two randomized trials☆