Safety and tolerability of 13-valent pneumococcal conjugate vaccine in the elderly

Abstract

Background

In September 2011 the European Medical Agency authorized the use of 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ≥50 years. The same occurred in the US in December 2011 when the Food and Drug Administration approved the use of PCV13 in the same target age-group with indication for the prevention of invasive pneumococcal diseases and community acquired pneumonia sustained by the serotypes contained in the vaccine. The Liguria Region, in Italy, implemented in 2013 an active and free of charge immunization strategy with PCV13 among adults affected by specific risk conditions and the elderly aged ≥70 years.

Methods

An observational study was performed in order to assess the safety and tolerability of PCV13 among elderly dwelling in the metropolitan area of Genoa, the capital city of Liguria Region. Eligible subjects, who received PCV13 following the public health immunization campaign at the Local Health Unit 3 of Genoa, provided a written informed consent to take part in the study. Eight-hundred-seventy-one subjects were enrolled between October 2013 and May 2014: all were monitored by qualified healthcare personnel for at least 30 min after vaccination at the outpatient clinics, in order to assess any possible sudden reaction. The occurrence of a series of local and systemic solicited reactions and of any unsolicited Adverse Events (AEs) was monitored using a self-administered clinical diary and by regular phone contacts up to 14 and 21 d following immunization, respectively. Moreover, a 6-months follow-up following vaccination was planned in order to monitor Severe Adverse Events (SAEs).

Results

No sudden reaction occurred in vaccinees at the outpatient clinics. Pain (27.4%) was the most frequent reaction reported by subjects at the injection site, while new muscle pain (13.6%), fatigue (10.7%), and headache (9.9%) resulted the most common systemic reactions. Rates of the main reactions reported in this on-field study resulted generally lower than those registered in clinical trials performed in the elderly. The incidence of fever (2.2%) following vaccination was low at values superimposable to that reported in previous studies.

Conclusion

This observational study showed a good safety and tolerability of PCV13 among the elderly in routine clinical practice further confirming the evidence coming from clinical trials in the same age-group.

Keywords: :

• safety
• tolerability
• PCV13
• elderly subjects
• adverse events

Introduction

Streptococcus pneumoniae (Sp) is a leading cause of Invasive Pneumococcal Diseases (IPDs) and Community Acquired Pneumonia (CAP) in the elderly, being a public health issue because of the significant incidence and mortality rates but also due to the associated social and economic costs.^1-3

The clinical burden of Sp disease increases in the presence of some chronic diseases, such as functional or anatomic asplenia, immunodeficiencies, cerebrospinal fluid leak, chronic heart, pulmonary (including asthma), liver, or renal diseases, and in the case of other specific conditions, such as decreased immune function due to immunosuppressive therapy, smoking cigarettes, etc.;⁴moreover, advancing age itself is associated with the relevant clinical impact of Sp in the adult population.^1,4,5

It is acknowledged that novel strategies to reduce the heavy impact of Sp and its related costs in the above mentioned risk-categories are welcome and that vaccination needs to be considered the fundamental tool in this view.^6-8

Sp is classified into a number of serotypes, based on the composition of its outer capsule: there are more than 90 known serotypes whose prevalence varies according to the geographic region, as well as by age.⁹ The current formulation of the available pneumococcal vaccines include pneumococcal serotypes which cause most of the severe diseases sustained by Sp in all geographic regions.¹⁰

Some results from observational studies have demonstrated that the 23-valent polysaccharide vaccine (PPV23; Pneumovax; Sanofi Pasteur MSD, France), available since the ‘80s worldwide, is able to reduce the risk of IPDs in immunocompetent older adults; nevertheless, it has shown significant limits in terms of clinical protection against non bacteremic CAP, in either the general population or in adults with chronic illness.^11-13

In order to remedy these shortcomings, pneumococcal conjugate vaccines, available since 2000 for use in the pediatric setting, faces a new opportunity. In fact, in September 2011, the European Medicines Agency (EMA) adopted a positive opinion recommending authorization for use of the new generation of 13-valent Pneumococcal Conjugate Vaccine (PCV13) among European adults aged 50 years and older;¹⁴ the same occurred in the US where, in December of the same year, Food and Drug Administration (FDA) approved the vaccine for the prevention of IPDs and CAP caused by the PCV13 serotypes.¹⁵ FDA approved PCV13 for the adult indication under the Accelerated Approval pathway, which allows the agency to approve products for serious or life-threatening diseases on the basis of early evidence of a product’s effectiveness that is “reasonably likely to predict clinical benefit.” Approval of PCV13 for adults was based on immunogenicity studies that compared antibody responses to PCV13 with antibody responses to PPV23: data from different clinical studies confirmed a greater anti-pneumococcal functional antibody response for the majority of the PCV13 serotypes, compared with PPSV23 in elderly population.^16-19

These immunogenicity results represent the rationale basis for the recommendation of the vaccine for use in adult population.

The renewed interest in pneumococcal vaccination among adults is certainly based also on the effectiveness results against IPD, CAP, and Sp carriage of the universal immunization programs in infants and children with conjugate vaccines (PCV7-PCV13) in several countries.^20-22

Moreover, the recent results from the Community Acquired Pneumonia Immunization Trial in Adults (CAPITA), a parallel group, double blind, placebo-controlled trial, performed in nearly 85 000 adult persons aged 65 years and older in The Netherlands, have further focused the attention of the scientific community on the great potential benefit of PCV13 for optimizing the prevention of Sp infections among the elderly.^23,24 Indeed, this study confirmed not only the good efficacy of the PCV13 against the 1st episode of vaccine type IPDs (75%, 95%CI:41.4 – 90.8, P = 0.0005), but also the protection against the 1st episode of vaccine type CAP and the 1st episode of non bacteremic pneumonia that resulted 45.6 (95%CI:21.8 – 62.5, P = 0.0006) and 45.0 (95%CI:14.2 – 65.3, P = 0.000 67), respectively.²⁴

However official recommendations for pneumococcal vaccination in adults and the elderly are still heterogeneous between European Countries, even if the use of PCV13 starts to be supported by some scientific society guidelines.^6,7

The Liguria Region, in Italy, implemented in 2013 an active and free of charge immunization strategy with PCV13 among adults affected by specific risk-conditions and the elderly aged ≥ 70 years.²⁵ An observational study was performed in order to monitor in real life the safety and tolerability of PCV13 among the elderly dwelling in the metropolitan area of Genoa, the capital city of the Liguria Region. The results of the tolerability study, together with a preliminary analysis of the ongoing safety follow-up, are outlined below and compared with data of similar clinical trials published in literature. These data were presented at the Ninth World Congress on Vaccines, Immunisation and Immunotherapy (WCVII), held in Genoa, Italy, on 29–30 April 2014.

Methods

Study design

This spontaneous, multicenter, observational study was performed between October 2013 and May 2014, in elderly subjects immunized with PCV13 (Prevenar 13^®, Pfizer/Wyeth, USA) following the public health immunization campaign of the Liguria Region, Italy. In particular, during the first year of the regional program, the vaccine started to be actively recommended, free-of-charge, to individuals born in the years 1938 and 1939. Subjects were recruited and progressively enrolled using the sampling method at 5 outpatient clinics of the Local Health Unit 3 of Genoa, Italy and at the Vaccines and Clinical Trials Unit of the Department of Health Sciences, University of Genoa, Italy (coordinator site). The official partnership between these two institutions is on behalf of the Integrated Group for the Development of Vaccine Sciences (GISVA).

Inclusion and exclusion criteria

All participants were elderly subjects, aged ≥ 70 years, compliant with the procedures foreseen by the study protocol, who have been previously immunized with a single dose of PCV13, with spontaneous access to the outpatient clinics of the Local Health Unit 3 of Genoa, Italy and of the Vaccines and Clinical Trials Unit of the Department of Health Sciences, University of Genoa, Italy. All subjects signed a written informed consent as approval of their participation to the study.

Exclusion criteria at the time of the enrollment included: PPV23 immunization received during the last year, participation or intent to participate in another study and history or any illness/condition that, in the opinion of the physician, might interfere with the aims of the study. Subjects with high-risk medical conditions for IPDs were not excluded, in case they met the inclusion criteria cited above.

Safety and tolerability assessments

All subjects immunized with PCV13 were interviewed by health-care professionals, investigating the inclusion and exclusion criteria for study entry.

In order to monitor the safety and tolerability, subjects were asked to report the occurrence and the intensity of a series of specific solicited local and systemic reactions on a clinical diary up to 7 days after immunization. The incidence of any local and systemic reactions from day 7 to day 14 together with the occurrence of any Adverse Events (AEs) were also recorded in the clinical diary and actively monitored by the clinical staff during the phone contact performed at 21 d following immunization. AEs were recorded in the same clinical diary from immunization up to 21 days after vaccination and, at this time, a follow-up telephone contact was performed.

Local reactions at the site of administration included pain, swelling and redness; the largest diameter of any redness or swelling was measured using a caliper. Redness and swelling were categorized as: absent, if diameter was less than 2.5 cm; mild, if diameter was between 2.5 cm and 5.0 cm; moderate, if diameter was between 5.0 cm and 10.0 cm; and severe, if diameter was >10.0 cm.

If pain at the injection site, or other symptoms, were present, subjects were asked to enter the severity as mild if the symptom was easily tolerated, moderate if there was discomfort sufficient to interfere with usual activity, and severe if the pain was incapacitating.

Systemic reactions were reported as fever (defined as a temperature of ≥38.0 °C), headache, fatigue, myalgia and shivering. Oral temperature was measured using a digital thermometer and the highest daily temperature was recorded.

AEs, including pain at the injection site within 30 min of vaccination, and other unanticipated events were directly monitored by the investigator physicians immediately after immunization.

Any newly diagnosed chronic medical conditions and Serious AEs (SAEs) appeared in the 6 months after vaccination were collected in a second clinical diary to be filled in by the vaccinees, up to 6 months after immunization. Clinical diaries were returned by the subjects to the Department of Health Sciences, University of Genoa, Italy, by regular mail using a stamped envelope. A second phone call was planned 6 months after vaccination.

This observational study was regularly notified to the Ethic Committees of the IRCCS AOU San Martino - IST of Genoa, Italy and of the Local Health Unit 3 of Genoa, Italy. Procedures were conducted in accordance to the ethical principles of the Declaration of Helsinki and Good Clinical Practices. All participants provided written informed consent before study enrollment.

Data analysis

A descriptive analysis of data was performed calculating absolute frequencies and percentages of all the variables collected, after elaboration in an ad hoc e-form.

Results

Up to the end of April 2014, a total of 871 subjects (mean age: 74.3, ± 0.87 SD; male: 548, 62.9%) were regularly enrolled in the study and completed the evaluation of the tolerability assessment.

The main characteristics of the study population is outlined in Table 1.

Table 1. Safety and tolerability of a 13-valent Pneumococcal Conjugate vaccine in the elderly in Liguria Region, Italy: baseline demographic characteristics of the study population

		Elderly immunized with PCV13 % (n/N)
Study sample		n = 871
Gender	male	62.9 (548/871)
	female	37.1 (323/871)
Race	white	98.0 (854/871)
	others	2.0 (17/871)
Mean age in years [SD]		74.3 [± 0.87]
Concomitant seasonal flu vaccination		32.6% (284/871)

With respect to safety and tolerability, no adverse reactions occurred within the 30 minutes following immunization.

The description of the solicited reactions occurring at the injection site and of the systemic reactions is outlined in Tables 2 and 3, respectively.

Table 2. Solicited local reactions in the elderly immunized with PCV13 in Liguria Region, Italy and results from clinical trials in similar target groups

	PCV13 % (n/N) (mean age 74.3 y) (n = 871) – Durando et al	PCV13 % (n/N) naïve (mean age 72.0 y) (n = 431–470) – Schwarz et al^17	PCV13 % (n/N) naïve (mean age 61.7 y) (n = 258–374) – Greenberg et al^18	PCV13 % (n/N) previously vaccinated with PPSV23 (mean age 76.7 y) (n = 463) – Jackson et al^16
Pain	27.4 (239/871)	43.4 (204/470)	69.2	51.7
Swelling	9.4 (82/871)	10.2 (44/431)	10.0	10.4
Redness	9.5 (83/871)	12.3 (53/432)	12.2	10.8
Any local reactionͣ	31.6 (275/871)	46.6 (219/470)	71.4	56.5

ͣ Any local reaction, any pain, any swelling and any redness at the injection site.

Table 3. Solicited systemic reactions in the elderly immunized with PCV13 in Liguria Region, Italy and results from clinical trials in similar target groups

	PCV 13% (n/N) (mean age 74.3 y) (n = 871) – Durando et al	PCV13(%) naive (mean age 72.0 y) (n = 419–456) – Schwarz et al^17	PCV 13 (%) naive (mean age 61.7 y) (n = 258–374) – Greenberg et al^18	PCV13 (%) previously vaccinated with PPSV23 (mean age 76.7 y) (n = 463) – Jackson et al^16
Fever ≥ 38 °C	2.2 (19/871)	3.6 (15/422)	4.2	1.0
Fatigue	10.7 (93/871)	28.5 (130/456)	50.5	34.0
Headache	9.9 (86/871)	24.7 (111/449)	49.7	23.7
Chills	5.6 (49/871)	9.1 (39/429)	19.9	7.9
New muscle pain	13.6 (118/871)	23.4 (105/448)	46.9	36.8
Use of medication to treat fever	0.7 (6/871)	-	8.6	3.0
Use of medication to treat other symptoms	6.2 (54/871)	-	31.3	22.0
Any sistemic eventͣ	21.5 (187/871)	48.5	74.9	60.3

ͣ Any systemic event = any fever ≥ 38 °C, any fatigue, any headache, any chills and any new muscle pain.

At least one local reaction was reported in 275 (31.6%) subjects.

Solicited local reactions resulted generally mild and of short duration in all subjects, and severe intensity was uncommon and observed in <2% of participants. Injection site pain was the most frequent reaction and was reported by 239 (27.4%) individuals; only 5 (2.1%) events were reported as “severe pain” and 42 (17.6%) were indicated as “moderate pain”: these symptoms completely resolved in 3 days following PCV13 immunization.

At least one systemic reaction was reported by 187 (21.5%) individuals.

New muscle pain (118, 13.6%), fatigue (93, 10.7%), and headache (86, 9.9%) were the most common systemic events. Fever and other systemic events, reported in 0.7% and 6.2% respectively, resolved in few days after vaccination and the use of medication for hyperpyrexia and other symptoms resulted not usual treatment.

With respect to the occurrence of unsolicited AEs, the incidence of subjects reporting at least one of these events was low (52, 6.0%): the most frequent category of AEs was influenza like illness, which occurred in 7 subjects (0.8%). The most common individual unsolicited AEs were nasopharyngitis and upper respiratory tract infections (14, 1.6%), joint disorders (10, 1.1%) and others (26, 3.0%).

The safety follow up was planned at six months following immunization and is still on-going.

At the end of August 2014, 347 (39.8%) individuals regularly completed the second diary, and returned it for final analysis to the coordinator center. The preliminary analysis about the safety follow up showed two SAEs. The first occurred in a 76-years-old patient who needed hospitalization in the period 11.11.2013-15.11.2013 due to a lumbar decompression surgery: this SAE was assessed as not related to PCV13 immunization by the investigators. The second was a 75-years-old male participant who developed a CAP, with positive hemoculture (no serotype available), diagnosticated during an hospitalization occurred in Switzerland in the period 25.02.2014–03.03.2014 due to hyperpyrexia (body temperature: 38.8 °C) and transient disorientation. This SAE occurred 29 days after PCV13 vaccination. The subject completely recovered. According to available data this SAE was assessed as possibly related to PCV13 immunization by the investigators.

Discussion

Despite it is well accepted that immunization needs to be considered as the most effective tool for the prevention of Sp and its significant burden among the elderly, official recommendation for pneumococcal vaccination among adults and the elderly are heterogeneous among the Western Countries to date.^6,7 Moreover vaccination coverage rates with PPV23, globally recommended for more than 30 y, are still generally low in Europe.^6,7

Because of the recent availability of the PCV13 for this age-group, and its great potential for possible use in preventive strategies against Sp, the collection of data of its performance on field is of great importance, also in order to provide further evidence supporting its universal recommendation.

To our knowledge, this is the first large observational study that investigated in-depth the tolerability of PCV13 when administered to the elderly in a real life setting. The results from this study confirm the good tolerability profile of PCV13 in the elderly as previously reported during the large clinical developmental plan in the same target group.^16-18

In particular, the rates of solicited reactions up to 14 days following immunization resulted lower than those reported in other similar clinical trials performed in the elderly, both previously immunized with PPV23 and pneumococcal vaccine-naive: this could also be related to the study design and to the method used for data collection (self-administered clinical diary for data collection in the first week following immunization and phone call by health-care professionals at day 21 for data collection in the second week after vaccination). Fever rates, commonly recorded in children after vaccination with PCV13,²⁶ were low (2.2%) among the elderly in our study, and no sudden reaction following immunization, nor deaths occurred during the follow up.

Recently, our research group performed another observational multicenter study among the same target population to evaluate the safety, tolerability and acceptability of a novel intradermal influenza vaccine compared with a intramuscular influenza vaccine in clinical practice.²⁷ Similarly to the present study, the incidence of solicited local reactions following the administration of the intradermal vaccine resulted inferior than that previously reported in phase 3 clinical trials, and a good acceptance profile of the novel influenza vaccine was reported by vaccinees in a real life setting.²⁷

Some limitations of the present study need to be addressed. The first is the lack of a direct comparison of PCV13 with PPV23; moreover, the small sample size of the study prevented the chance to reliably detect an increased incidence of rare AEs. Finally, with respect to the safety profile of PCV13, no conclusive results are available since less than 40% of the vaccinees enrolled in the survey returned the six month safety diary.

Conclusion

The results obtained in this observational study confirmed the good safety and tolerability of PCV13 among the elderly in routine clinical practice. PCV13 could represent an important tool to improve the prevention of pneumococcal disease not only in the pediatric age, but also in older adults.

Abbreviations:
Sp	=	Streptococcus pneumoniae
IPDs	=	Invasive Pneumococcal Diseases
CAP	=	Community Acquired Pneumonia
PPV23	=	23-valent polysaccharide vaccine
EMA	=	European Medical Agency
PCV13	=	13-valent pneumococcal conjugate vaccine
FDA	=	Food and Drug Administration
CAPITA	=	Community Acquired Pneumonia Immunization Trial in Adults
GISVA	=	Integrated Group for the Development of Vaccine Sciences
AEs	=	Adverse events
SAEs	=	Severe adverse events

Disclosure of Potential Conflicts of Interest

P Durando has previously participated at speaker’s bureaus and advisory board meetings sponsored by GSK, Novartis, Pfizer and Sanofi Pasteur and has received research funding as principal investigator or investigator from Crucell Berna, GSK, Novartis, Pfizer, and Sanofi Pasteur.