Pneumococcal Conjugate Vaccines and Otitis Media: An Appraisal of the Clinical Trials

Table 1

PCV clinical trials with otitis media as an endpoint [2–4, 9, 10, 12, 15].

	NCKP [3, 15]	FinOM [2]	FinOM [9]	Native American Trial [10, 12]	POET [4]
Study vaccine	PCV7-CRM	PCV7-CRM	PCV7-OMPC	PCV7-CRM	PCV11-PD
Period	1995–1998	1995–1999	1995–1999	1997–2000	2000–2004
No. of children	37,868	1662	1666	8045	4907
No. in vaccine and control	18, 926 vaccine,; 18, 942 control	831 vaccine,; 831 control	835 vaccine,; 831 control	4142 vaccine,; 3903 control	2455 vaccine,; 2452 control
Enrollment	Healthy 2-month-old infants	Healthy 2-month-old infants	Healthy 2-month-old infants	Healthy infants aged; 6 weeks to 24 months*	Healthy infants aged; 6 weeks to 5 months
Study period	Children aged 2 months to 3.5 years	Children aged 2 months to 4-5 years	Children aged 2 months to 2 years	Children aged 6 weeks to; 24 months	Children aged 6 weeks to; 24–27 months
Incidence PCPY, control group	2.0–2.6 visits	—	—	—	—
	—	1.24 episodes	1.24 episodes	1.4 episodes	0.12 episodes
Vaccination schedule	2, 4, 6, and 12–15 months	2, 4, 6, and 12 months	2, 4, 6, and 12 months^†	2, 4, 6, and 12–15 months	3, 4, 5, and 12–15 months
Design	Prospective, individually; randomized (1:1),; double-blind, controlled	Prospective, individually randomized (1:1), double-blind, controlled	Prospective, individually randomized (1:1), double-blind, controlled	Prospective, community randomized, double-blind, controlled	Prospective, individually randomized (1:1), double-blind, controlled
Control vaccine	Meningococcal serogroup C conjugate	Hepatitis B virus	Hepatitis B virus	Meningococcal serogroup C conjugate	Hepatitis A virus
Primary otitis media endpoint	Number of episodes of or visits for otitis media	Number of episodes of AOM due to vaccine pneumococcal serotypes	All episodes of culture-confirmed pneumococcal AOM caused by vaccine serotypes	Clinically diagnosed episodes of otitis media, including AOM	First episode of AOM due to vaccine pneumococcal serotypes
Otitis media definition	Obtained from computerized records using diagnoses registered by emergency and pediatric physicians in the NCKP populations	Visibly abnormal tympanic membrane (color, position, or mobility) suggesting middle-ear effusion plus at least one sign of acute infection^‡	Visibly abnormal tympanic membrane (color, position, or mobility) suggesting middle-ear effusion plus at least one sign of acute infection^‡	Otitis media visits, as documented by the patients’ treating physicians, were recorded	Abnormal tympanic membrane (redness, bulging, or loss of light reflex) or presence of MEF (simple or pneumatic otoscopy or microscopy), plus two predefined clinical symptoms within 14 days preceding the clinical diagnosis^§
Myringotomy criteria	Not routinely obtained	All children presenting with AOM	All children presenting with respiratory infection or symptoms suggesting AOM if AOM was diagnosed at the visit	Not performed	Pediatricians decided whether to refer children with AOM clinical features to an ENT specialist for confirmation and myringotomy
Source of MEF	Cultures of spontaneously ruptured tympanic membranes	MEF sample from myringotomy with aspiration for bacterial culture and pneumococcal serotyping	MEF sample from myringotomy with aspiration for bacterial culture and pneumococcal serotyping	Samples obtained from spontaneously draining otitis media episodes for bacterial culture and serotyping	MEF sample from myringotomy with aspiration for bacterial culture and pneumococcal serotyping

*The primary efficacy cohort included children aged 6 weeks to less than 7 months at enrollment who received the full vaccine schedule.
^†187 children in the vaccine group received a 23-valent pneumococcal polysaccharide vaccine at the fourth (booster) dose, instead of PCV7-OMPC.
^‡Fever, earache, irritability, diarrhea, vomiting, acute otorrhea (not caused by otitis externa), and other symptoms of respiratory infection.
^§Ear pain, ear discharge, fever, irritability, hearing loss, vomiting, diarrhea, lethargy, or anorexia.
ENT: ear, nose, and throat.
PCV7-CRM: pneumococcal conjugate vaccine candidate targeting serotypes, 4, 6B, 9V, 14, 18C, 19F, and 23F, each individually conjugated to cross-reactive material (CRM197), the nontoxic diphtheria toxin analogue; PCV7-OMPC: pneumococcal conjugate vaccine candidate targeting serotypes, 4, 6B, 9V, 14, 18C, 19F, and 23F, each individually conjugated to a meningococcal outer-membrane protein complex; PCV11-PD: pneumococcal conjugate vaccine candidate targeting serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F, each conjugated to a cell-surface protein of H. influenzae.