Clinical trial NCT00273325: Immunogenicity of PCV-7 Vaccine in VLBW Infants
Official title: Observational Study of the Immunogenicity of Heptavalent Pneumococcal Conjugate Vaccine in Very-low-birth-weight Infants
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pneumococcal Infections
Streptococcus Pneumoniae
Infant, Newborn
Infant, Low Birth Weight
Infant, Small for Gestational Age
Infant, Premature
Keywords: NICHD Neonatal Research Network
Very Low Birth Weight (VLBW)
Extremely Low Birth Weight (ELBW)
Prematurity
Pneumococcal Vaccines
Vaccines, Conjugate
Immunogenicity
Vaccine Response
Heptavalent pneumococcal conjugate vaccine (PCV-7)
pneumococcal polysaccharide, type 6B
Pneumococcal polysaccharide, type 14
Pneumococcal polysaccharide, type 19F,
Pneumococcal polysaccharide, 23F
Pneumococcal polysaccharide, 18C
Pneumococcal polysaccharide, 4
Pneumococcal polysaccharide, 9V
Lead sponsor: NICHD Neonatal Research Network
Sponsor class: NETWORK
Collaborators: name: National Center for Research Resources (NCRR)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2006-01-09
Enrollment: 368
Sex: ALL
Maximum age (years): 3
Standard ages: CHILD
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Infants \<1,500g birth weight who receive the 3-dose primary series of PCV-7 immunization by 3 months and complete it by 8 months postnatal age

Brief summary: Premature infants are at a high risk for pneumonia. The PCV-7 vaccine effectively prevents the invasive disease from Streptococcus pneumoniae in full-term infants, but was not thoroughly studied in premature infants. This study evaluated the effectiveness and safety of the vaccine given in routine practice to very low birth weight infants, looking at blood antibody levels 4-6 weeks after the final vaccine dose, and adverse events, survival, infections, and neurodevelopmental outcomes at 18-22 months corrected age.

Detailed description: Streptococcus pneumoniae causes an estimated 10-25% of all pneumonias in the United States, and is responsible for an estimated 40,000 deaths per year. Invasive pneumococcal disease has a peak incidence of 235/100,000 among children aged 6-11 months. Pneumococcal meningitis carries a higher risk of death (15%) or neurodevelopmental impairment (12-28%) than Hib or Neisseria meningitides.

Premature infants are at a higher risk for invasive disease with Streptococcus pneumoniae. The heptavalent pneumococcal-CRM197 conjugate vaccine (PCV-7) effectively prevents invasive pneumococcal disease in full-term infants, but was been incompletely studied in premature infants. The American Academy of Pediatrics (AAP) recommends that "prematurely born infants, including infants of low birth weight, should be immunized at the usual chronological age in most cases", but cautions that "some studies suggest a reduced immune response in very low-birth-weight infants (\<1500 g)."

This observational study assessed the effectiveness of the PCV-7 vaccine to generate a sufficient immune response in a safe manner when given to very low birth weight (VLBW) infants in routine pediatric practice. We hypothesized that among VLBW infants, the frequency of estimated minimum protective antibody titers to PCV-7 (\>=0.15 μg/mL) would decrease with decreasing birth weight.

Infants 501-1500g birth weight and \<32 0/7 weeks gestational age were enrolled from nine NICHD Neonatal Research Network centers from 2004 to 2006. Enrollment was stratified by weight group to yield approximately 20 infants per 100g increments from 501-1500g birth weight whose primary PCV-7 series was initiated before 3 months and completed by 8 months after birth. The infants' primary providers gave PCV-7 vaccination at 2, 4, and 6 months after birth. Infants had a single 2-ml blood sample drawn 4-6 weeks following the third dose of PCV-7. Antibodies for each of the seven vaccine serotypes included in PCV-7 were measured by enzyme-linked immunosorbent assay. Children were followed until 18-22 months corrected age to assess survival, infection, and neurodevelopmental outcomes.

Eligibility criteria: Inclusion criteria

* Gestational age \<32 0/7 weeks
* Included in Neonatal Research Network Generic Database
* Family has a telephone at home
* Anticipated availability for blood draw 4-6 weeks following 3rd vaccine dose
* Consent obtained before first dose of PCV-7 is given

Exclusion criteria

* Known immunodeficiency
* HIV exposure
* Parental non-consent
* Primary care pediatrician not willing to participate
* Enrollment in a conflicting trial
* Infant has not received first dose of PCV-7 vaccine by 3 months of age

Primary outcomes:
measure: Serotype 6B pneumococcal capsular polysaccharide antibody >=0.15 μg/ml
timeFrame: 4-6 weeks following the third dose of PCV-7
Secondary outcomes:
measure: Pneumococcal capsular polysaccharide antibody >=0.15 μg/ml for the other six vaccine serotypes
timeFrame: 4-6 weeks following the third dose of PCV-7
measure: Pneumococcal capsular polysaccharide antibodies >=1.0 μg/ml for all seven vaccine serotypes
timeFrame: 4-6 weeks following the third dose of PCV-7
measure: Geometric mean titers of pneumococcal capsular polysaccharide antibody to the seven vaccine serotypes
timeFrame: 4-6 weeks following the third dose of PCV-7
measure: Pneumococcal capsular polysaccharide antibodies >=0.15 μg/ml and >=1.0 μg/ml, and geometric mean titers of antibody, to the seven vaccine serotypes in children completing the primary series, regardless of postnatal age
timeFrame: 4-6 weeks following the third dose of PCV-7
measure: Opsonization of 6B pneumococcal capsular polysaccharide plus 1 low immunogenicity, high prevalence serotype (e.g., 23F) among infants in the lowest quartile of antibody response
timeFrame: 4-6 weeks following the third dose of PCV-7
measure: Effect of possible mediating variables on the achievement of levels of serotype 6B pneumococcal capsular polysaccharide antibody >=0.15 μg/ml
timeFrame: 4-6 weeks following the third dose of PCV-7
measure: Effect of pneumococcal conjugate immunization status (complete & timely v. complete v. incomplete) on outcome (survival, serious infection, neurodevelopmental outcome) at 18-22 months corrected age in infants <=1000g
timeFrame: 18-22 months corrected age
measure: Levels of antibody >=0.15 μg/ml and >=1.0 μg/ml to Hib polyribosylribitol
timeFrame: 4-6 weeks following the third dose of PCV-7
measure: Avidity of antibody to Hib-PRP among infants in the lowest quartile of antibody response,regardless of postnatal or gestational age
timeFrame: 4-6 weeks following the third dose of PCV-7
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Charlotte
country: United States
facility: Wake Forest University
state: North Carolina
city: Durham
country: United States
facility: RTI International
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
Study officials:
affiliation: Duke University
name: Ronald N. Goldberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Barbara J. Stoll, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: RTI International
name: Abhik Das, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Krisa P. Van Meurs, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Waldemar A. Carlo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Miami
name: Shahnaz Duara, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: Carl T. D'Angio, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas, Southwestern Medical Center at Dallas
name: Pablo J. Sanchez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wake Forest University
name: T. Michael O'Shea, MD MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Wayne State University
name: Seetha Shankaran, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: D'Angio CT, Heyne RJ, O'Shea TM, Schelonka RL, Shankaran S, Duara S, Goldberg RN, Stoll BJ, Van Meurs KP, Vohr BR, Das A, Li L, Burton RL, Hastings B, Phelps DL, Sanchez PJ, Carlo WA, Stevenson DK, Higgins RD; NICHD Neonatal Research Network. Heptavalent pneumococcal conjugate vaccine immunogenicity in very-low-birth-weight, premature infants. Pediatr Infect Dis J. 2010 Jul;29(7):600-6. doi: 10.1097/INF.0b013e3181d264a6.
citation: Wynn JL, Li L, Cotten CM, Phelps DL, Shankaran S, Goldberg RN, Carlo WA, Van Meurs K, Das A, Vohr BR, Higgins RD, Stoll BJ, D'Angio CT. Blood stream infection is associated with altered heptavalent pneumococcal conjugate vaccine immune responses in very low birth weight infants. J Perinatol. 2013 Aug;33(8):613-8. doi: 10.1038/jp.2013.5. Epub 2013 Jan 31.
citation: Ang JY, Lua JL, Asmar BI, Shankaran S, Heyne RJ, Schelonka RL, Das A, Li L, Jackson DM, Higgins RD, D'Angio CT; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Nasopharyngeal carriage of Streptococcus pneumoniae in very low-birth-weight infants after administration of heptavalent pneumococcal conjugate vaccine. Arch Pediatr Adolesc Med. 2010 Dec;164(12):1173-5. doi: 10.1001/archpediatrics.2010.233. No abstract available.
citation: D'Angio CT, Murray TE, Li L, Heyne RJ, O'Shea TM, Schelonka RL, Shankaran S, Duara S, Goldberg RN, Stoll BJ, Stevenson DK, Vohr BR, Phelps DL, Carlo WA, Pichichero ME, Das A, Higgins RD; NICHD Neonatal Research Network. Immunogenicity of Haemophilus influenzae type b protein conjugate vaccines in very low birth weight infants. Pediatr Infect Dis J. 2013 Dec;32(12):1400-2. doi: 10.1097/01.inf.0000437263.04493.7c. No abstract available.