Immunogenicity of PCV-7 Vaccine in VLBW Infants (PCV-7)

Observational Study of the Immunogenicity of Heptavalent Pneumococcal Conjugate Vaccine in Very-low-birth-weight Infants

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.

Study Overview

• Status: Completed
• Conditions: Pneumococcal Infections; Streptococcus Pneumoniae; Infant, Small for Gestational Age; Infant, Premature; Infant, Low Birth Weight; Infant, Newborn

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.

• Study Type: Observational
• Enrollment (Actual): 368

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Charlotte, North Carolina, United States, 27157
      • Wake Forest University
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Durham, North Carolina, United States, 27705
      • RTI International
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center at Dallas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 months (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• 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

Description

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

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Serotype 6B pneumococcal capsular polysaccharide antibody >=0.15 μg/ml	4-6 weeks following the third dose of PCV-7

Secondary Outcome Measures

Outcome Measure	Time Frame
Pneumococcal capsular polysaccharide antibody >=0.15 μg/ml for the other six vaccine serotypes	4-6 weeks following the third dose of PCV-7
Pneumococcal capsular polysaccharide antibodies >=1.0 μg/ml for all seven vaccine serotypes	4-6 weeks following the third dose of PCV-7
Geometric mean titers of pneumococcal capsular polysaccharide antibody to the seven vaccine serotypes	4-6 weeks following the third dose of PCV-7
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	4-6 weeks following the third dose of PCV-7
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	4-6 weeks following the third dose of PCV-7
Effect of possible mediating variables on the achievement of levels of serotype 6B pneumococcal capsular polysaccharide antibody >=0.15 μg/ml	4-6 weeks following the third dose of PCV-7
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	18-22 months corrected age
Levels of antibody >=0.15 μg/ml and >=1.0 μg/ml to Hib polyribosylribitol	4-6 weeks following the third dose of PCV-7
Avidity of antibody to Hib-PRP among infants in the lowest quartile of antibody response,regardless of postnatal or gestational age	4-6 weeks following the third dose of PCV-7

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Center for Research Resources (NCRR)
• Investigators: Principal Investigator: Shahnaz Duara, MD, University of Miami; Principal Investigator: Carl T. D'Angio, MD, University of Rochester

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Helpful Links

• NICHD Neonatal Research Network

Study record dates

Study Major Dates

• Study Start: July 1, 2004
• Primary Completion (Actual): July 1, 2007
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: September 9, 2005
• First Submitted That Met QC Criteria: January 5, 2006
• First Posted (Estimate): January 9, 2006

Study Record Updates

• Last Update Posted (Actual): March 22, 2019
• Last Update Submitted That Met QC Criteria: March 20, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Pneumococcal Vaccines; Immunogenicity; Prematurity; Vaccines, Conjugate; Vaccine Response; NICHD Neonatal Research Network; Very Low Birth Weight (VLBW); Extremely Low Birth Weight (ELBW); 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
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia; Lung Diseases; Body Weight; Bacterial Infections; Bacterial Infections and Mycoses; Streptococcal Infections; Gram-Positive Bacterial Infections; Pneumonia, Bacterial; Pneumococcal Infections; Pneumonia, Pneumococcal; Birth Weight
• Other Study ID Numbers: NICHD-NRN-0031; M01RR000633 (U.S. NIH Grant/Contract); UL1RR024982 (U.S. NIH Grant/Contract); U10HD021385 (U.S. NIH Grant/Contract); U10HD027851 (U.S. NIH Grant/Contract); U10HD027880 (U.S. NIH Grant/Contract); U10HD034216 (U.S. NIH Grant/Contract); U10HD040492 (U.S. NIH Grant/Contract); U10HD040689 (U.S. NIH Grant/Contract); UL1RR025744 (U.S. NIH Grant/Contract); M01RR000070 (U.S. NIH Grant/Contract); U10HD021397 (U.S. NIH Grant/Contract); U10HD040498 (U.S. NIH Grant/Contract); U10HD040521 (U.S. NIH Grant/Contract); M01RR000032 (U.S. NIH Grant/Contract); M01RR000039 (U.S. NIH Grant/Contract); M01RR000044 (U.S. NIH Grant/Contract); M01RR007122 (U.S. NIH Grant/Contract); M01RR016587 (U.S. NIH Grant/Contract); UL1RR025777 (U.S. NIH Grant/Contract); UL1RR025008 (U.S. NIH Grant/Contract); M01RR000030 (U.S. NIH Grant/Contract); U01HD036790 (U.S. NIH Grant/Contract); UL1RR024160 (U.S. NIH Grant/Contract); UL1RR024128 (U.S. NIH Grant/Contract)