Juliette Thompson

Burden of Interpandemic Influenza in Children Younger than 5 Years: A 25-Year Prospective Study

Many respiratory viruses cause morbidity in young children, but a licensed vaccine and effective oral therapy are available only for influenzavirus. To determine the incidence of laboratory-confirmed influenza illness, we prospectively followed up 1665 healthy children aged <5 years who were enrolled in the Vanderbilt Vaccine Clinic at some point from 1974 through 1999. Viral cultures were obtained when the children presented with clinical illness. The isolation of influenzavirus was associated with an estimated 95 health care visits for children with symptoms of influenza, 46 episodes of acute otitis media, and 8 episodes of lower respiratory tract disease per 1000 children yearly. Rates of acute otitis media and lower respiratory tract disease were highest among children aged <2 years. Hospitalizations associated with culture-positive influenza occurred at an annual rate of 3-4 per 1000 children aged <2 years. Influenza is associated with substantial morbidity in otherwise healthy children aged <5 years.

Evaluation of a Live, Cold-Passaged, Temperature-Sensitive, Respiratory Syncytial Virus Vaccine Candidate in Infancy

A live-attenuated, intranasal respiratory syncytial virus (RSV) candidate vaccine, cpts-248/404, was tested in phase 1 trials in 114 children, including 37 1-2-month-old infants-a target age for RSV vaccines. The cpts-248/404 vaccine was infectious at 104 and 105 plaque-forming units in RSV-naive children and was broadly immunogenic in children >6 months old. Serum and nasal antibody responses in 1-2 month olds were restricted to IgA, had a dominant response to RSV G protein, and had no increase in neutralizing activity. Nevertheless, there was restricted virus shedding on challenge with a second vaccine dose and preliminary evidence for protection from symptomatic disease on natural reexposure. The cpts-248/404 vaccine candidate did not cause fever or lower respiratory tract illness. In the youngest infants, however, cpts-248/404 was unacceptable because of upper respiratory tract congestion associated with peak virus recovery. A live attenuated RSV vaccine for the youngest infant will use cpts-248/404 modified by additional attenuating mutations.

Evaluation of Two Live, Cold-Passaged, Temperature-Sensitive Respiratory Syncytial Virus Vaccines in Chimpanzees and in Human Adults, Infants, and Children

Two live-attenuated, cold-passaged (cp), temperature-sensitive (ts) candidate vaccines, designated cpts530/1009 and cpts248/955, were attenuated, genetically stable, and immunogenic in chimpanzees and were highly attenuated for human adults. In respiratory syncytial virus (RSV)-seropositive children, cpts530/1009 was more restricted in replication than cpts248/955. In seronegative children, 10(4) pfu of cpts248/955 was insufficiently attenuated, and a high titer of vaccine virus was shed (mean peak titer, 10(4.4) pfu/mL), whereas 10(4) pfu of cpts530/1009 was relatively attenuated and restricted in replication (mean peak titer, 10(2.0) pfu/mL). At a dose of 10(5) pfu, cpts530/1009 was immunogenic in seronegative children (geometric mean titer of RSV neutralizing antibodies, 1:724). Transmission of either vaccine to seronegative placebo recipients occurred at a frequency of 20%-25%. Of importance, vaccine viruses recovered from chimpanzees and humans were ts. In contrast to previous studies, this study indicates that live attenuated RSV vaccines that are immunogenic and phenotypically stable can be developed. Additional studies are being conducted to identify a live RSV vaccine that is slightly more attenuated and less transmissible than cpts530/1009.

Epidemiology and Clinical Impact of Parainfluenza Virus Infections in Otherwise Healthy Infants and Young Children < 5 Years Old

Over a 20-year period in a population of otherwise healthy children, respiratory viruses have been cultured from nasal wash specimens from each child with a clinically significant respiratory illness. Since efforts are underway to develop vaccines for prevention of illness due to parainfluenza virus (PIV) type 3, the epidemiologic characteristics of PIVs were reviewed, and the population size necessary to demonstrate vaccine efficacy was estimated. A population of 1429 children was followed through early childhood. PIVs were isolated from 286 samples, 17.4% of positive viral cultures. PIV-3 was the most common: 10% of the children had at least one symptomatic, culture-proven PIV-3 infection. PIV-3 was endemic during the study period, while the other two PIVs, PIV-1 and -2, caused biennial flu epidemics. Only four PIV-related hospitalizations were seen. The efficacy of a PIV-3 vaccine could be demonstrated in a trial of 600 carefully monitored children vaccinated by 3 months and followed to 15 months of age.

Streptococcus pneumoniae colonization in the young child: Association with otitis media and resistance to penicillin

OBJECTIVE To determine the nasopharyngeal colonization rate of penicillin-susceptible and penicillin-resistant strains of Streptococcus pneumoniae in young children, and to assess its relationship with the incidence of otitis media. DESIGN Observational study in 215 children younger than 6 years of age who received care in the Vanderbilt Vaccine Clinic from September 1, 1992, to August 31, 1993. RESULTS Of 842 nasopharyngeal cultures obtained, results for 44% of the cultures were positive for S. pneumoniae; 73% of the isolates were serotypes 6, 14, 19, or 23. Younger children had significantly higher rates of pneumococcal colonization than older children, with a peak at 1 year of age. By microdilution susceptibility testing, 37% of the cultures with positive results were intermediately or highly resistant to penicillin. Significantly more serotype 19 and 23 isolates were penicillin resistant than organisms of other serotypes. Children younger than 2 years of age had a twofold higher percentage of resistant isolates than those older than 2 years of age. A significant association was noted between nasopharyngeal carriage of S. pneumoniae and acute otitis media (p = 0.0002); however, the incidence of acute otitis media did not differ significantly between children colonized with penicillin-susceptible or penicillin-resistant strains. Unresolved otitis media was diagnosed more often in children who were colonized with resistant organisms than in children colonized with susceptible strains (p = 0.04). CONCLUSIONS There was a high rate of nasopharyngeal carriage of penicillin-resistant S. pneumoniae in this population of young children. Nasopharyngeal colonization was associated with an increased incidence of acute otitis media, and penicillin resistance was associated with an increased incidence of unresolved otitis media.

Evaluation of a live, attenuated respiratory syncytial virus vaccine in infants

Respiratory syncytial virus ts-1 is a live attenuated experimental vaccine which was administered intranasally to 25 infants 11 to 19 months of age. Clinical evaluation was carried out following a controlled, double-blind protocol which eliminated observer bias, assessed intercurrent illness, and was designed to detect virus transmission. At the low dose of virus of virus used (100 TCID50) 8 of the 25 recipients were successfully infected with RS virus ts-1 as determined by virus shedding or antibody response.

Influenza A infections in young children. Primary natural infection and protective efficacy of live-vaccine-induced or naturally acquired immunity.

To assess the impact of an influenza A/Port Chalmers infection on normal young children, we monitored 147 children during an epidemic; 121 were seronegative. There was a high attack rate (61 of 147), and a high rate of symptomatic disease (38 of 147), which resulted in frequent physician visits (25 of 38). Influenza accounted for 76 per cent of the sick-child visits during the two-month epidemic period. Young children undergoing primary influenza infection produced hemagglutination inhibition and antineuraminidase antibodies. Because of the immunologic responsiveness of young children, we examined the serologic correlates of protection. Ten children previously infected with influenza A/London and 16 who received live, attenuated A/Hong Kong ts-1[E] vaccine were protected against infection with the non-homologous A/Port Chalmers strain. The morbidity of influenza and ability of the young child to produce protective antibody should encourage evaluation of life, attenuated influenza vaccines in this age group.

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

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.

Impact of recurrent otitis media on middle ear function, hearing, and language.

Whether recurrent otitis media in infants and young children is followed by delayed language development was addressed by following 210 normal subjects longitudinally through the first 2 years of life with pneumatic otoscopy and tympanometry performed at every physician encounter. Otitis accounted for 26% of the medical visits. One hundred fifty-six of these children had speech and hearing evaluation at 2 years of age. Thirty percent of the children with recurrent otitis media had a mild or moderate hearing loss. However, after multiple speech and language tests, we could not identify a delay in language acquisition in the otitis-prone children. At 3 to 4 years old, 36 children, including nine with a hearing loss at 2 years of age, were retested; all nine had normal hearing. Recurrent otitis media induced a temporary decrease in hearing sensitivity demonstrable at 2 years of age, which appeared to resolve as the children matured and which was not associated with delay in language acquisition.

Clinical reactions and serologic response following inactivated monovalent influenza type B vaccine in young children and infants

A monovalent, zonally purified, inactivated influenza B vaccine was administered to 29 children, 3 to 6 years of age, and 16 infants, 12 to 28 months of age, as a single dose of 0.25 ml containing 250 chick cell agglutinating units. The vaccine was both antigenic and well tolerated in the older group of preschool children. In the infants the vaccine was also antigenic but poorly tolerated clinically. Febrile reactions to 102 or greater were seen in 9 of the 16 infants, and two of these infants experienced a seizure following vaccination. The clinical reactions observed with the administration of influenza B vaccine in the dose used in this study would suggest significant limitations on its use in children under 3 years of age.