The Pediatric Infectious Disease Journal 2003; 22(5):394-405

A live human parainfluenza type 3 virus vaccine is attenuated and immunogenic in young infants

RUTH A. KARRON, MD; ROBERT B. BELSHE, MD; PETER F. WRIGHT, MD; BHAGVANJI THUMAR, MS; BARBARA BURNS, RN, PNP; FRANCES NEWMAN, MS; JOAN C. CANNON, RN; JULIETTE THOMPSON, RN, PNP; THEODORE TSAI, MD; MARIBEL PASCHALIS, MS; SHIN-LU WU, MS; YVONNE MITCHO, BS; JILL HACKELL, MD; BRIAN R. MURPHY, MD; JOANNE M. TATEM, PhD

Background.

Parainfluenza type 3 virus (PIV-3) infections cause lower respiratory tract illness in children throughout the world. A licensed PIV-3 vaccine is not yet available.

Methods.

A live attenuated cold-adapted (ca) and temperature-sensitive (ts) PIV-3 vaccine, designated cp-45, was evaluated sequentially in open label studies in 20 adults and in placebo-controlled, double blind studies in 24 PIV-3-seropositive children, 52 PIV-3-seronegative infants and children and 49 infants 1 to 2 months old. A single dose of this intranasal vaccine was evaluated in adults [10⁶ plaque-forming units (pfu)] and seropositive children, and 10⁴ and 10⁵ pfu were evaluated in seronegative children. In the infant study, two 10⁴ pfu doses of vaccine were administered at 1- or 3-month intervals. Safety, infectivity, immunogenicity and phenotypic stability of the vaccine were evaluated in all cohorts.

Results.

The cp-45 vaccine was well-tolerated in all age groups and infected 94% of vaccinated seronegative children and 94% of vaccinated infants. Although immunization with the first dose of cp-45 diminished the replication of a second dose in all infants, those immunized after 3 months shed vaccine virus more frequently than those immunized after 1 month (62% vs. 24%, respectively). Antibody responses to PIV-3 were readily detected in seronegative children with a variety of assays; however, the IgA response to the viral hemagglutinin-neuraminidase was the best measure of immunogenicity in young infants. Of 109 vaccine virus specimens recovered from nasal washes, 98 were ts and 11 were temperature-sensitive intermediate (tsi) viruses, with pinpoint plaques visible at 40°C. tsi viruses appeared transiently at the time of peak viral replication, represented a very small proportion of the total virus shed and were not associated with changes in clinical status. ca revertants were not detected.

Conclusions.

The cp-45 vaccine is appropriately attenuated and immunogenic in infants as young as 1 month of age. Further development of this vaccine is warranted.

Key words: Parainfluenza; live attenuated vaccine; pediatric

From the Center for Immunization Research, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (RAK, BT, BB); the Department of Medicine, Saint Louis University, St. Louis, MO (RBB, FN, JC); Vanderbilt Vaccine Center, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN (PFW, JT); Wyeth Research, Viral Vaccines, Pearl River, NY (TT, MP, SLW, YM, JH, JMT); and Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD (BRM).

Accepted for publication Jan. 9, 2003.

Address for reprints: Dr. Ruth A. Karron, Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Hampton House 117, 624 N. Broadway, Baltimore, MD 21205. Fax 410-955-2791; E-mail rkarron@jhsph.edu.

The Pediatric Infectious Disease Journal 2003; 22(5):394-405

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