Safety and tolerability of 13-valent pneumococcal conjugate vaccine in healthy Chinese adults, children and infants

Abstract

Objective:

Pneumococcal disease is a global problem, including in China. The objective of this study was to provide safety data for single-dose 13-valent pneumococcal conjugate vaccine (PCV13) in Chinese subjects, needed to begin a phase III safety and immunogenicity study in Chinese infants.

Methods:

Healthy Chinese adults (18−55 years), children (3−5 years), and infants (42–98 days) received a single dose of PCV13 in this open-label safety study. Local reactions and systemic events were collected for 7 days via an electronic diary; adverse events were recorded for 1 month after vaccination.

Results:

All 72 (24 per group) screened subjects (58.3% males; mean ± standard deviation [SD] age: 43.3 ± 9.1 years [adults], 4.5 ± 0.7 years [children], and 79.6 ± 15.2 days [infants]) were enrolled, received vaccine, and completed the study. The most frequently reported local reactions per group were pain at the injection site (n = 23 adults [95.8%]), tenderness (n = 18 children [75%]), and swelling (n = 6 infants [25%]), none of which were severe. The mean duration of each local reaction was ⩽2.0 days in infants and ⩽2.4 days in children but in adults was 3.3 days for pain at the injection site and 9 days each for redness and swelling. Systemic events in adults were muscle pain (n = 5), fatigue (n = 3), and headache and joint pain (n = 1 each). One child and seven infants had disturbed sleep (increased or decreased). One adult and one child had mild fever (37.7–38.5°C, as per China Food and Drug Administration guidelines). No subject used antipyretic medication. One adverse event (bronchopneumonia in an infant) was reported, which was serious, severe, and unrelated to vaccination. There were no deaths.

Conclusions:

A single dose of PCV13 was safe and well tolerated in healthy Chinese adults, children, and infants. This study provided the safety data to enable a phase III safety and immunogenicity registration trial in Chinese infants to proceed.

Introduction

Disease caused by Streptococcus pneumoniae is responsible for substantial morbidity and mortality throughout the world, particularly in young children and older adults. The World Health Organization estimated that 476,000 (333,000–529,000) of the estimated 8.8 million deaths worldwide of children <5 years of age in 2008 were caused by pneumococcal infections [World Health Organization, 2012]. In children <5 years of age, there were an estimated 1.7 million cases of invasive pneumococcal disease in China of an estimated 14.5 million cases worldwide in 2000 [O’Brien et al. 2009].

Clinical endpoint trials and postlicensure effectiveness studies have demonstrated the efficacy and effectiveness of pneumococcal conjugate vaccine (PCV), both a 7-valent (PCV7) and an investigational 9-valent (PCV9), in preventing pneumococcal disease [Black et al. 2000; Cutts et al. 2005; Eskola et al. 2001; Griffin et al. 2013; Klugman et al. 2003; Lucero et al. 2009; O’Brien et al. 2003; Pilishvili et al. 2010; Weil-Olivier et al. 2012; Whitney et al. 2003]. To further increase the proportion of disease that could be prevented by vaccination, Pfizer Inc (New York, NY, USA) developed a 13-valent vaccine (PCV13) that was licensed globally based on immunologic comparison with PCV7. PCV13 effectiveness data are now becoming available.

This study of the safety and tolerability of PCV13 represents the initial evaluation of PCV13 in China and is part of the licensing procedure for the vaccine in that country. It provides the safety data needed to begin a phase III safety and immunogenicity study in infants in China.

Methods

Study design

This was an open-label, single-center safety study conducted in accordance with the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP) and the ethical principles that have their origins in the Declaration of Helsinki. Written informed consent was obtained from all subjects, or guardians, before their enrollment. ClinicalTrials.gov identifier: NCT01531322.

Subjects were enrolled into groups sequentially (first adults, then children, then infants) at a satellite site of the Nanjing Center for Disease Prevention and Control; a safety review committee assessed the safety in adults before children were enrolled, and the safety in children before infants were enrolled. At enrollment, before vaccine administration, medical history was taken and a physical examination performed, including temperature.

Additional pneumococcal vaccines (licensed or investigational) were prohibited during the study as were other nonstudy vaccines within 7 days after vaccination and prophylactic antipyretic medications before vaccine administration. Other medications were permitted, including antipyretic medications after vaccination.

At the end of the study, parents/legal guardians of infants were offered three additional doses of the licensed PCV7 for their children to complete the infant pneumococcal vaccination schedule recommended in China.

Participants

Inclusion criteria were Chinese males or females aged 18–55 years (adults), 3–5 years (children), or 42–98 days (infants) who were healthy (or had preexisting stable disease), were not pregnant or breastfeeding, and, if capable of having children, agreed to use reliable birth control throughout the study. Exclusion criteria included previous vaccination with pneumococcal vaccine, anaphylactic reaction to any vaccine or vaccine-related component, or receipt (within 28 days) of any investigational product or medical device; contraindication to vaccination with pneumococcal vaccine or to intramuscular injection; immune deficiency or suppression; major congenital malformation or serious chronic disorder; significant neurologic disorder or history of seizure (including febrile seizure for infants); and other severe acute or chronic medical or psychiatric condition or laboratory abnormality that could increase the risk associated with study participation or interfere with the interpretation of study results.

Vaccines and administration

A single dose of PCV13, supplied as a 0.5-ml suspension in a prefilled syringe, was administered intramuscularly into the deltoid muscle of the arm or anterolateral muscle of the thigh. PCV13 contains polysaccharides from pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F individually conjugated to a nontoxic diphtheria toxin cross-reactive material 197 protein. The vaccine contains 2.2 μg of each polysaccharide except serotype 6B (4.4 μg), with 5.0 mM succinate buffer, 0.85% sodium chloride, 0.02% polysorbate 80, and 0.125 mg aluminum as aluminum phosphate per 0.5-ml dose.

Safety assessment

The subject (or parent/legal guardian/caregiver) monitored and recorded local reactions (pain, redness, swelling and tenderness [infants and children only]), systemic events (adults: fever, vomiting, diarrhea, headache, fatigue, muscle and joint pain; infants and children: fever, decreased appetite, and increased or decreased sleep) and use of antipyretic medications each day for 7 days after vaccination in an electronic diary. Data reported in the electronic diary (e-diary) were transferred electronically to the e-diary vendor, where they were available for review via an internet-based portal. Investigators were able to evaluate e-diary data for completion and compliance, and as part of the ongoing safety review. Events were graded for severity according to CFDA guidelines [China Food and Drug Administration, 2005]. All vaccinated subjects were assessed for safety. Adverse events (AEs) and serious AEs (SAEs) were collected for approximately 1 month and categorized according to the Medical Dictionary for Regulatory Activities (MedDRA).

Statistical methods

The safety population included all subjects who received study vaccine. Regulatory requirements directed a sample size of 20 subjects per group; four more per group were added to allow for potential dropouts. All outcomes were descriptively summarized by group.

Results

All 72 (24 per group) screened subjects were enrolled, received vaccine, and completed the study. There were no screen failures and no withdrawals or discontinuations. All subjects were of Asian origin, 58.3% were males, and the mean ± SD age was 43.3 ± 9.1 years (adults), 4.5 ± 0.7 years (children), and 79.6 ± 15.2 days (infants).

No severe local reactions were reported. The most frequently reported local reaction among adults was pain at the injection site (n = 23 subjects [95.8%]), which was mild or moderate in severity; among children was tenderness insufficient to interfere with limb movement (n = 18 [75%]); and among infants was swelling (n = 6 [25%]), which was mild or moderate in severity (Figure 1). For each local reaction, the mean duration was ⩽2.4 days (range, 1−6 days) in children and ⩽2.0 days (range, 1−4 days) in infants. The mean ± SD duration in adults was 3.3 ± 4.3 days (range, 1−15 days) for pain at the injection site and exceeded 7 days for redness (8.8 ± 5.6 days [range, 1−14 days]) and swelling (9.0 ± 5.7 days [range, 1−14 days]). Two children had a maximum diameter of redness in the range 2.5−5.0 cm. A maximum diameter of swelling in the range 2.5−5.0 cm was experienced by five children and two infants. Three adult subjects reported a maximum diameter of redness and swelling in the range >5−10 cm, and one other in the range 2.5−5.0 cm.

Figure 1.

Percentage of subjects having local reactions within 7 days of PCV13 vaccination. The worst severity is reported for each subject. No severe reactions were reported. For redness and swelling in adults, mild is 2.5−5.0 cm, moderate is >5.0−10.0 cm, and severe is >10.0 cm; in children and infants, mild is 0.5−2.0 cm, moderate is >2.0−7.0 cm, and severe is >7.0 cm. For injection site pain, mild does not interfere with activity, moderate interferes with activity, and severe prevents activity. For tenderness, mild is the presence of tenderness and severe interferes with limb movement.

PCV13, 13-valent pneumococcal conjugate vaccine.

Most systemic events were mild in severity (Table 1). Among adults, the most frequently reported systemic events were muscle pain (n = 5), fatigue (n = 3), and headache and joint pain (n = 1 each). One adult had fever of 38.5°C (categorized as mild [37.7–38.5°C] by the CFDA guidelines [China Food and Drug Administration, 2005]). No adult used antipyretic medication. Among the children, one had increased sleep and one had a body temperature of 37.8°C, categorized as mild fever by the CFDA guidelines [China Food and Drug Administration, 2005], but no child had fever ⩾38.0°C or used antipyretic medication within 7 days of vaccination. Among infants, three subjects each had irritability and increased sleep and four had decreased sleep; no infant had a body temperature ⩾38.0°C or used antipyretic medication within 7 days of vaccination.

Table 1.

Systemic reactions within 7 days of PCV13 vaccination.

	Subjects with events, n (%), greatest reported severity
Event	Adults n = 24	Children n = 24	Infants n = 24
Fever, °C
⩾38.0	1 (4.2)*	0	0
38.0–38.9	1 (4.2)*	0	0
>38.9–40.0	0	0	0
>40.0	0	0	0
Fever grades by CFDA guidelines, °C*
⩾37.7	1 (4.2)*	1 (4.2)*	0
37.7–38.5 (mild)	1 (4.2)*	1 (4.2)*	0
38.6–39.5 (moderate)	0	0	0
39.6–40.5 (serious)	0	0	0
>40.0 (potentially life-threatening)	0	0	0
Vomiting	0	0	0
Diarrhea	0	0	0
Headache†	1 (4.2), mild	NA	NA
Fatigue†	3 (12.5), mild	NA	NA
Muscle pain†	3 (12.5), mild 2 (8.3), moderate	NA	NA
Joint pain†	1 (4.2), mild	NA	NA
Decreased appetite‡	NA	0	0
Irritability‡	NA	0	3 (12.5)
Increased sleep‡	NA	1 (4.2)	3 (12.5)
Decreased sleep‡	NA	0	4 (16.7)
Antipyretic medication	0	0	0
Any systemic event	6 (25.0)	1 (4.2)	7 (29.2)

CFDA, China Food and Drug Administration; NA, not applicable; PCV13, 13-valent pneumococcal conjugate vaccine.

^*Fever of 38.5°C (1 adult) and 37.8°C (1 child), which was considered mild (⩽38.5°C) according to the CFDA [China Food and Drug Administration, 2005].

^†Mild = does not interfere with activity; moderate = some interference with activity; severe = prevents daily routine activity.

^‡Severity not reported.

Only one AE (bronchopneumonia) was reported. It occurred in an infant and was serious (based on hospitalization of the patient) and severe but was not related to the vaccination. There were no deaths.

Discussion

In this safety study in Chinese adults, children, and infants, a single dose of PCV13 was safe and well tolerated. Local reactions were mild to moderate in severity. Only 1 adult and 1 child had fever ⩾37.7°C, but in both cases fever was ⩽38.5°C and therefore considered mild according to the CFDA categories. There was no use of antipyretic medication. Only one AE (a severe SAE of bronchopneumonia) was reported, but it was not related to vaccination. There were no deaths, discontinuations attributed to AEs, or potentially life-threatening events.

Demonstration of the safety of PCV13 in this study enabled the further development of PCV13 in China, a vaccine likely to be more broadly protective than previously licensed PCV7. The most prevalent pneumococcal serotypes among 218 invasive pneumococcal disease strains from 12 hospitals across China, collected from 2005 to 2011, were 19A (22%), 19F (22%), 14 (8%), 3 (7%), and 23F (5%), accounting for 64% of all strains [Zhao et al. 2013]. The estimated coverage by PCV7 (which contains serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) was 41%, compared with the 78% estimated coverage calculated for PCV13 (which contains PCV7 serotypes plus serotypes 1, 3, 5, 6A, 7F, and 19A) [Zhao et al. 2013]. Similarly, the most prevalent pneumococcal serotypes among 471 invasive pneumococcal disease strains from 13 hospitals across China, collected from 2010 to 2011, were 19F (24%), 19A (13%), 3 (10%), 14 (9%), 23F (6%), 15 (5%) and 6A (5%); estimated coverage by PCV7 and PCV13 were 45% and 76%, respectively, overall; 59% and 87% in children; and 42% and 73% in adults [Wang et al. 2013].

In conclusion, in this phase I study of a single dose of PCV13, no safety signal was identified in healthy Chinese adults, children, and infants. This is the first safety study of PCV13 that has proved the safety and tolerability of PCV13 in infants in China, thus enabling a phase III registration trial in China to proceed.