The efficacy of the intranasal, live-attenuated, trivalent cold-adapted influenza virus vaccine (CAIV-T) against influenza A(H3N2) and B infections in healthy persons is established, but its effectiveness against natural influenza A(H1N1) infection is unknown.
To assess the effectiveness of CAIV-T in healthy children during the 2000-2001 influenza A(H1N1) and B epidemic.
Community-based, nonrandomized, open-label trial from August 1998 through April 2001.
Intervention and comparison communities in central Texas.
Healthy children, aged 1.5 to 18 years, from the intervention communities received a single dose of CAIV-T at least 1 time or more in 1998, 1999, and/or 2000.
Main Outcome Measures
The incidence of medically attended acute respiratory illnesses during the 2000-2001 influenza epidemic was compared in 3794 health plan CAIV-T recipients with age-eligible, health plan nonrecipients in the intervention communities for direct effectiveness (n = 9325), and with those in the 2 comparison communities for total effectiveness (n = 16 264).
The 2281 CAIV-T recipients in 2000 had significant direct protection against medically attended acute respiratory illness of 18% to 20% during the biphasic influenza A(H1N1) and B epidemic, and 17% to 26% during influenza A(H1N1) predominance. The 931 recipients of CAIV-T in 1999 containing influenza A/Beijing/262/95(H1N1) and B/Beijing/184/93–like viruses had persistent heterovariant protection against the 2000-2001 influenza A/New Caledonia/20/99(H1N1) and B/Sichuan/379/99 variants. The 616 recipients of a single CAIV-T dose in 1999 only, including those younger than 5 years with no prior natural exposure to influenza A(H1N1) viruses, showed persistent protection.
Healthy children who received CAIV-T in 2000 or 1999 were protected against new variants of influenza A(H1N1) and B in the 2000-2001 influenza epidemic.
LOWER RESPIRATORY TRACT infections are the leading cause of morbidity and mortality in children worldwide.1 Each winter influenza causes significant morbidity in all age groups.2 Hospitalization rates due to influenza-associated lower respiratory tract infections are as high in infants as in the elderly.3,4 Preschool and school children have the highest attack rates and are important disseminators of influenza.2 A prospective survey of 313 school children showed an excess of 28 illness episodes and 63 missed school days per 100 children during the 2000-2001 influenza epidemic. It also accounted for 22 secondary illnesses in families and 20 days of missed parental work per 100 children.5
The US Food and Drug Administration recently approved a live-attenuated, cold-adapted trivalent influenza virus vaccine (CAIV-T) administered as a nasal spray for use in healthy children and adults, 5 through 49 years of age. A 2-year randomized, placebo-controlled trial of CAIV-T in children aged 15 to 71 months showed an efficacy of 92% in preventing culture-confirmed influenza A(H3N2) and B infections, and 86% efficacy against a drifted influenza A/Sydney/05/97(H3N2) variant.6- 8 A significant reduction in influenza-associated otitis media and antibiotic use was found.6,7 A large, randomized placebo-controlled trial of CAIV-T in healthy working adults showed significant protection against febrile upper respiratory tract illnesses during the drifted influenza A/Sydney/05/97(H3N2) epidemic.9 Influenza A(H1N1) did not circulate during these trials.
We have conducted a large field trial in central Texas from 1998 through 2001 to assess the ability of CAIV-T administered annually to healthy preschool and school children to limit the spread of influenza in the community. Our analysis of this purpose is in preparation and previous reports are described elsewhere.10 The first opportunity to measure effectiveness of CAIV-T against influenza A(H1N1) infections in healthy children presented in the winter of 2000 through 2001, when this virus caused an epidemic for the first time since the winter of 1995 through 1996. This report will provide an assessment of effectiveness of a single dose of CAIV-T in naive children against new variants of influenza A(H1N1) and influenza B and persistence of this protection through the second year.
This report will specifically assess the following 2 measures of effectiveness during the 2000-2001 influenza A(H1N1) and B epidemic11,12: (1) the direct effectiveness of CAIV-T, by comparing medically attended acute respiratory illness (MAARI) for CAIV-T recipients with that in age-eligible nonrecipients in the intervention communities, and (2) total effectiveness of CAIV-T by comparing MAARI for CAIV-T recipients with that for nonrecipients in comparison communities where CAIV-T was not offered.
The intervention communities are adjacent cities of Temple and Belton and the surrounding area in Bell County, Texas, with 19 700 children aged 1.5 through 18 years. Bell County has a total population of 237 974, a median age of 29.2 years, and households with individuals younger than 18 years at 43.3% (US Census Bureau, Census 2000; available at: http://censtats.census.gov/pub/Profiles.shtml). The Scott & White health care system has a 483-bed teaching hospital and a multispecialty clinic in Temple and 18 regional clinics in central Texas. Urgent care is offered at all clinics. The Scott & White Health Plan (hereafter referred to as the health plan) has more than 177 000 members who constitute 50% of patients at these clinics. Children are seen at general and subspecialty pediatric clinics and 3 family practice clinics in Temple and Belton. Eligible healthy children aged 1.5 through 18 years from the intervention communities were enrolled each year and received a single dose of CAIV-T each year.
The comparison communities are Waco in McLennan County, Texas, 40 miles north of Temple, and Bryan and College Station, adjacent cities in Brazos County, Texas, 90 miles southeast of Temple. McLennan County has a population of 213 517, a median age of 31.9 years, and households with individuals younger than 18 years at 37.0%. Brazos County has a population of 152 415, a median age of 23.6 years, and households with individuals younger than 18 years at 30.3%. Children are seen at 4 family practice clinics in McLennan County and a large multispecialty clinic (including pediatrics) in Waco and College Station. The racial distribution of the 3 counties in the intervention and comparison communities is 57% to 66% non-Hispanic white, 16% to 18% Hispanic, 10% to 20% African American, and 2% to 6% others. At the comparison sites, CAIV-T was not offered.
Healthy children and adolescents aged 1.5 through 18 years who were not pregnant and not planning a pregnancy within 6 weeks, had not participated in an investigational product trial in the past month and were not planning to participate in the next 6 weeks, and had no significant hypersensitivity to eggs or a long-term need for aspirin-containing products were eligible to enroll. Children with chronic underlying conditions for whom influenza virus vaccine is recommended were offered the licensed trivalent inactivated influenza virus vaccine (TIV). Children with a history of mild intermittent wheezing illness, asthma, or reactive airway disease were enrolled, provided that they did not receive daily or every-other-day medications for asthma, had no emergency department visit or hospitalization for asthma within the past year (in the past 6 months if aged <2 years), and had no wheezing in the 2 weeks before enrollment. Children using daily nasal steroids or bronchodilators before exercise only were included.
Enrollment was postponed for children who had a fever 48 hours earlier, had a significant nasal discharge or congestion, or received an inactivated vaccine within 14 days or a live vaccine within 28 days. A signed informed consent was obtained from a legal guardian. A brief physical assessment to exclude an acute illness was performed. The protocol was approved each year by the institutional review boards of the clinic; Baylor College of Medicine, Houston, Tex; and the Texas Department of Health, Austin.
MedImmune, Inc (Mountain View, Calif [formerly Aviron]) supplied CAIV-T frozen in single-dose nasal-spray applicators that were held in the palm for less than 5 minutes to thaw CAIV-T before administration. This syringelike device was divided to deliver a 0.25-mL aliquot in each nostril as a large-particle aerosol. It was transported from a freezer at −70°C to dry ice and stored in a freezer at −20°C (manual defrost). The vaccine contained a median tissue culture–infective dose of 106 to 107 of each of 3 attenuated strains as recommended by the Food and Drug Administration for the 1998-1999, 1999-2000, and 2000-2001 influenza seasons. Influenza A/Sydney/05/97(H3N2) and B/Beijing/184/93–like strains were included all 3 years. In 2000, influenza A/New Caledonia/20/99(H1N1) replaced influenza A/Beijing/262/95(H1N1). The dose of CAIV-T also contained egg allantoic fluid with a combination of sucrose, phosphate, and glutamate.
Influenza virus surveillance was conducted each year in the intervention and comparison communities, including Austin, 70 miles south of Temple. Health care providers obtained a throat swab (or a nasal wash in young infants) for an influenza virus culture as a standard of care from individuals of any age presenting with a febrile acute respiratory illness, irrespective of influenza vaccination status. The results of all influenza virus surveillance cultures were tabulated by week. Consecutive weeks on each side of the peak that included approximately 80% of cultures that were positive for influenza virus determined the epidemic period, similar to the method described by Nichol et al.9 The Centers for Disease Control and Prevention laboratory, Atlanta, Ga, further characterized a sample of isolates.
The subset of age-comparable health plan members from the intervention and comparison communities provided reliable denominators of a population with presumably similar socioeconomic status and access to the health care system that was thus used for the effectiveness analyses. We included all age-eligible health plan members as of January 7, 2001, the midpoint of the influenza epidemic, with a primary care provider at the clinics in the intervention and comparison communities. Those who ever received CAIV-T were compared with age-eligible children who never received CAIV-T. During the 3 years (1998, 1999, and 2000) of the study, the participants may have received CAIV-T 1 or more times. These children were divided into the following 3 CAIV-T groups to include each child only once: year 1–only, year 2–cumulative, and year 3–cumulative (Table 1). In addition, year 2–only (a subset of the year 2–cumulative group) and year 3–only (a subset of the year 3–cumulative group) groups were analyzed to assess the effectiveness of a single CAIV-T dose.
Since younger children have higher rates of MAARI, we used the following stratification by age: 1.5 to 4 years, 5 to 9 years, and 10 to 18 years. Age at the time of vaccination was used for those who received CAIV-T in year 3 (2000). For those who never received CAIV-T or received it before 2000, the first day of enrollment for 2000 was used to compute age. By then, the youngest children vaccinated in 1998 and 1999 were aged 3.5 and 2.5 years, respectively. Therefore, the comparison groups were adjusted for analysis of groups younger than 5 years.
The health plan administrative database was used to extract demographic data and MAARI events. All International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes for acute upper and lower respiratory tract illnesses, otitis media, and sinusitis (codes 381-383, 460-487, 490x-496x, 510x-513x, 515x-516x, 518x, and 786.1) were searched. Each visit had 1 or 2 ICD-9-CM diagnosis codes. Clinic and emergency department visits were included. Multiple entries on the data set (due to charges for procedures) were counted as 1 visit per day. Visits with an asthma diagnosis associated with a respiratory infection were included. Hospitalizations were not analyzed because of small numbers.
Enrollment continued during the first wave of the 2000-2001 influenza epidemic, primarily caused by an influenza A/New Caledonia/20/99(H1N1) strain. Replication of the vaccine virus has been shown to interfere with that of wild influenza virus and result in a reduced illness.13,14 Thus, unlike TIV, CAIV-T may be effective on the day of vaccination, so we included all CAIV-T recipients in 2000 for the analyses.
The demographics and age-specific incidence rates of MAARI were compared in each of the 3 CAIV-T groups (year 3–cumulative, year 2–cumulative, and year 1–only) with the CAIV-T nonrecipients from the intervention communities (direct effectiveness) and the comparison communities (total effectiveness). We compared demographic characteristics using the χ2 test. Incidence rates of MAARI and ratios were calculated using standard methods. To control for the difference in the distributions among the age categories between populations being compared, stratified incidence rates and ratios were calculated using Mantel-Haenszel estimates. The Mantel-Haenszel test of homogeneity was used to examine the effect of the exposure across each age category. The point estimates of incidence rates and ratios and their 95% confidence intervals (CIs) were used to determine statistical differences between populations. Vaccine effectiveness was calculated as 1 minus the relative risk for MAARI, expressed as a percentage (lower bound of 95% CI >1 indicates statistically significant effectiveness).11,12 Recurrent and related MAARI during a short interval of time in the same individual were rare; thus, multiple MAARI events for the same individual were assumed to be independent. The year 2–only and year 3–only groups were similarly analyzed. We used 2001 Stata statistical software (release 7.0; Stata Corp, College Station, Tex).
During the 3 years of the study, a total of 14 699 CAIV-T doses (year 1, n = 4298; year 2, n = 5251; and year 3, n = 5150) were administered to 9765 children. Each year approximately 50% of enrollees were health plan members. Of the 9765 CAIV-T recipients, 3794 were health plan members on January 7, 2001, and were divided into the 3 mutually exclusive groups described above (year 3–cumulative, n = 2281; year 2–cumulative, n = 931; and year 1–only, n = 582 [Table 1]). Age-specific MAARI rates for CAIV-T recipients were compared with those for 9325 age-eligible health plan nonrecipients from the intervention communities and those for 16 264 nonrecipients from the comparison communities.
Demographic data for the study participants are tabulated in Table 2. The CAIV-T recipients tended to be younger, and this was controlled for in the analyses. No clinically important differences were seen in frequency of asthma or TIV. The racial distribution for CAIV-T recipients in the year 3–cumulative and year 2–cumulative groups showed the following: non-Hispanic white, 79.4% and 77.2%, respectively; Hispanic, 12.6% and 11.9%, respectively; African American, 3.8% and 5.3%, respectively; and others, 4.1% and 5.2%, respectively. African Americans were underrepresented in the study population compared with the general population in these communities (3.8% vs 10%-20%).
Influenza A(H1N1) and B were prevalent in these communities, as seen nationwide in the 2000-2001 influenza season. The Centers for Disease Control and Prevention characterized 23 isolates as influenza A/New Caledonia/20/99(H1N1) (8 from intervention and 15 from comparison communities), 8 isolates as influenza B/Sichuan/379/99–like (6 from intervention and 2 from comparison communities), and 2 as influenza B/Beijing/184/93–like (from comparison communities). Influenza viruses were isolated from 5 (9.6%) of 52 CAIV-T recipients for the year 3–cumulative group (P<.001, χ2 test) and from 4 (15.4%) of 26 for year 2–cumulative group (P<.025) compared with 133 (40.7%) of 327 age-eligible CAIV-T nonrecipients from the intervention communities.
We charted the relative risk for MAARI by week for CAIV-T recipients in 2000 (year 3–cumulative group) temporally related to the influenza A and B virus surveillance in the intervention communities (Figure 1). During the biphasic epidemic caused by influenza A(H1N1) and B, the relative risk for MAARI dropped as low as 0.7 and 0.6, respectively. We observed statistically significant direct effectiveness against MAARI in CAIV-T recipients of each age group for the entire influenza A(H1N1) and B epidemic, encompassing the period from December 3, 2000, through February 24, 2001 (week 49 of 2000 through week 8 of 2001) (Table 3). During the first 6-week predominance period of influenza A(H1N1), a significant decrease in the risk for MAARI was seen for all children and for those aged 1.5 to 4 and 5 to 9 years (Table 3). Thus, for the year 3–cumulative group, a direct effectiveness of 20% (95% CI, 14%-25%) was measured during the influenza A and B epidemic and of 17% (95% CI, 9%-27%) during influenza A(H1N1) predominance. During the 6-week postinfluenza period (weeks 12-17 of 2001), we observed a significantly higher incidence of MAARI in children in the year 3–cumulative group compared with CAIV-T nonrecipients in the intervention communities (P<.01), suggesting higher utilization of health care for respiratory illnesses other than influenza in CAIV-T recipients of 2000.
Total (A) and direct (B) effectiveness of live-attenuated, trivalent cold-adapted influenza virus vaccine (CAIV-T) in Scott & White Health Plan recipients in 2000 (year 3–cumulative group [n = 2281]) during the 2000-2001 influenza A(H1N1) and B epidemic. Direct effectiveness (B) is shown in comparison with age-eligible health plan nonrecipients from the intervention communities (n = 9325), on a logarithm scale, during the influenza A(H1N1) (week 49 of 2000 through week 2 of 2001) and B (weeks 3-8 of 2001) epidemic. The horizontal line shows a relative risk of 1 (no difference). The bar graph shows the number of influenza A and B isolates by week from patients of all ages with febrile respiratory illness from the intervention communities. Total effectiveness (A) is shown in comparison with age-eligible health plan nonrecipients from 2 comparison communities (n = 16 264), on a logarithm scale, during the influenza A(H1N1) (week 49 of 2000 through week 2 of 2001) and B (weeks 3-8 of 2001) epidemic. The horizontal line shows a relative risk of 1 (no difference). The bar graph shows the number of influenza A and B isolates by week from patients of all ages with febrile respiratory illness from the 2 comparison communities. MAARI indicates medically attended acute respiratory infection.
For the year 3–only group (n = 848), statistically significant effectiveness was observed for all children and for the groups aged 5 to 9 and 10 to 18 years, but not for the youngest age group during the entire influenza A and B epidemic period (data not shown). During the 6-week predominance of influenza A(H1N1), we did not observe significant effectiveness in the year 3–only group. However, only one third of children in this group had received a single dose of CAIV-T before the influenza A(H1N1) outbreak started.
Significant direct effectiveness during the influenza A and B epidemic was observed for children who received CAIV-T in 1999, but not in 2000 (Table 4), similar to that for the year 3–cumulative group. This was true for all children vaccinated in 1999 (year 2–cumulative group) and for the subset who received a single dose of CAIV-T in 1999 only (year 2–only group) (Table 4). The sample size was insufficient to test the outcome in the year 1–only group (n = 582; data not shown).
We compared MAARI rates for health plan CAIV-T recipients from the intervention communities with those for health plan nonrecipients from the comparison communities. Most of the influenza viruses, including A and B, in the comparison communities were isolated during the first 6 weeks of the epidemic (Figure 1). We observed statistically significant total effectiveness for all age groups for the year 3–cumulative group for the entire epidemic and the first 6 weeks of the influenza A(H1N1) outbreak (Table 5).
Total effectiveness for the year 3–only group was significant for the entire influenza A and B epidemic period for all children and for the group aged 10 to 18 years only (data not shown). Total effectiveness was not observed during the influenza A(H1N1) predominance period, similar to a lack of direct effectiveness in this group. For the year 2–cumulative and year 2–only groups (Table 6), total effectiveness during the entire influenza A and B epidemic was statistically significant for CAIV-T recipients younger than 5 years, aged 5 to 9 years, and the total group, but not for those aged 10 to 18 years. The sample size was insufficient to test the outcome in the year 1–only group (n = 582; data not shown).
Our study is the first to examine the effectiveness of CAIV-T in healthy children during an influenza A(H1N1) epidemic. Significant direct effectiveness of CAIV-T for prevention of MAARI in all age groups and in all children vaccinated in 2000 was observed during the entire influenza A and B epidemic. Direct effectiveness in all children and children aged 1.5 to 4 and 5 to 9 years during the 6 weeks when influenza A(H1N1) viruses predominated documented effectiveness of CAIV-T against natural influenza A(H1N1) infection for the first time.
Influenza A(H1N1) had last circulated in the 1995-1996 season; therefore, children younger than 5 years were naive for this subtype. The only protection available for them was CAIV-T. Significant protection against MAARI in children younger than 5 years who received CAIV-T only in 1999 suggests the effectiveness of a single dose and persistence of immunity for 2 influenza seasons. However, significant protection was not evident during influenza A(H1N1) predominance for the subset of children who received their first dose of CAIV-T in 2000, probably because only a third of these children had been vaccinated before the start of the influenza A(H1N1) epidemic.
Although this was a nonrandomized open-label trial, the health plan populations compared were homogenous. Virus culture surveillance documented the epidemics to be temporally related to the period of effectiveness (Figure 1). Since influenza vaccines are trivalent, minor differences in the proportion of influenza A and B isolates during the outbreak in different communities should not affect total effectiveness. The MAARI rates tended to be slightly higher in the vaccinated children before and after the epidemic, suggesting that parents of children who volunteered for the investigational vaccine may bring their children in for acute respiratory illness more readily than those who did not. This would bias against detection of effectiveness and make our conclusions stronger. Furthermore, clinicians providing health care made decisions about obtaining a culture, irrespective of vaccination status, without instructions from the study team. The proportions of cultures positive for influenza viruses from CAIV-T recipients (9.6% in the year 3–cumulative and 15.4% in the year 2–cumulative groups) were significantly lower than that (40.7%) for age-eligible nonrecipients from the intervention communities, again supporting direct effectiveness. However, it is possible that vaccinated children were seen for a mild afebrile influenza illness that did not warrant a culture.
The direct and total effectiveness noted in children who received CAIV-T in 1999 containing strain A/Beijing/262/95(H1N1) is evidence of cross-protection against a drifted variant, influenza A/New Caledonia/20/99(H1N1), in the 2000-2001 epidemic. The Centers for Disease Control and Prevention reported lower titers of cross-reactive antibodies to influenza A/New Caledonia/20/99 with the 1999-2000 inactivated vaccines that contained an influenza A/Beijing/262/95–like strain.15 Our results suggest a heterovariant immunity conferred by CAIV-T that may last through 2 influenza seasons. Also, CAIV-T for all 3 study years contained an influenza B/Beijing/184/93–like virus, and the effectiveness during the 2000-2001 epidemic was seen against influenza B/Sichuan/379/99, a drifted variant. Antibodies produced against the influenza B/Beijing/184/93–like vaccine strain are cross-reactive, but lower in titer and frequency against the influenza B/Sichuan/379/99 variant.16
Before this study, evidence on the efficacy and immunogenicity of live-attenuated vaccines against H1N1 viruses was inconclusive. For example, a randomized, controlled trial of the bivalent CAIV and TIV from 1985 through 1990 in 5210 healthy subjects included 791 children younger than 16 years. Vaccine efficacy of 95.5% (95% CI, 66.7%-99.4%) for the bivalent CAIV and that of 91.4% (95% CI, 63.8%-98.0%) for TIV was found against culture-confirmed influenza A(H1N1) illness in these children.17,18 The bivalent CAIV showed a vaccine efficacy of 77.9% (95% CI, 64.3%-86.4%) against seroconversion to influenza A(H1N1).18 However, with CAIV-T, H1N1 seroconversion to a single dose was low at 16% compared with 90% and 50% for H3N2 and B antigens, respectively, in children aged 18 to 71 months.19
In year 1 of the pivotal efficacy trial, Belshe et al6 found a 4-fold increase in serum antibody response to H1N1 antigen in 16% and 61% of seronegative children after 1 and 2 doses of CAIV-T, respectively. After the year 2 revaccination, 82% of subjects in the vaccine group had a hemagglutination inhibition antibody titer of greater than 1:8 for H1N1 compared with 20% of the placebo subjects.7 An experimental intranasal challenge with monovalent attenuated influenza A(H1N1) was performed in 144 previously vaccinated children and 78 placebo recipients.20 The vaccine reduced nasal shedding of influenza A(H1N1) by 83% (95% CI, 60%-93%). Any detectable serum hemagglutination inhibition antibody or nasal wash IgA antibody present before the challenge correlated with significant protection against H1N1 virus detection. Using the sample of age-eligible health plan children who underwent specimen culture during our open-label trial, Halloran et al11 estimated adjusted efficacy of 92% (95% CI, 42%-99%) against culture-positive MAARI caused by bx;1influenza A(H1N1). Therefore, despite the lack of demonstrable humoral immunity, significant protection is evident.
In contrast to culture-confirmed influenza, measurement of MAARI outcomes is nonspecific. In large community trials, MAARI events occur with time-varying incidence rates; thus the effectiveness estimates are severely attenuated.11,12 However, they are vital as a measure of vaccine effectiveness after licensure, when randomized trials cannot be performed easily. Although influenza is a vaccine-preventable illness, new strategies to control epidemics are needed. Administered as a nasal spray, CAIV-T is easily accepted and generally well tolerated. A strategy for annual universal influenza immunization of healthy children is under consideration.21,22 As licensed for healthy children and administered in convenient group-based settings, CAIV-T has the potential for reducing influenza-related morbidity.
The efficacy of CAIV-T against natural exposure of healthy children to influenza A(H1N1) is unknown. Our study shows significant protection generated by CAIV-T in healthy children against influenza A(H1N1) and a new variant of influenza B for the first time. The effectiveness of a single CAIV-T dose against 2 successive variants of each virus and the persistence of protection for at least 2 years are important findings.
Corresponding author and reprints: Manjusha J. Gaglani, MBBS, Section of Pediatric Infectious Diseases, Scott & White Memorial Hospital and Clinic, 2401 S 31st St, Temple, TX 76508 (e-mail: email@example.com).
Accepted for publication June 12, 2003.
This study was supported by grant UO1AI41050 from the National Institutes of Health, Bethesda, Md, and MedImmune, Inc, Mountain View, Calif, which provided the investigational intranasal influenza vaccine.
We thank the influenza program officer at the National Institute of Allergy and Infectious Diseases, and Paul Mendelman, MD, and Pat Fast, MD, from MedImmune, Inc. Sonia Holleman, Hope Gonzales, Nancy Arden, and Carolyn Kamenicky (and Neil Pascoe and Dwyane Haught from the Texas Department of Health, Austin) supported viral surveillance. We also appreciate the extraordinary support from the communities of central Texas and the staff of Baylor College of Medicine, Scott & White Memorial Hospital and Clinics and the Scott & White Health Plan, including Nadine Zimmerman, of the Scott & White Health Plan, who performed data extraction.
Gaglani MJ, Piedra PA, Herschler GB, Griffith ME, Kozinetz CA, Riggs MW, Fewlass C, Halloran ME, Longini IM, Glezen WP. Direct and Total Effectiveness of the Intranasal, Live-Attenuated, Trivalent Cold-Adapted Influenza Virus Vaccine Against the 2000-2001 Influenza A(H1N1) and B Epidemic in Healthy Children. Arch Pediatr Adolesc Med. 2004;158(1):65-73. doi:10.1001/archpedi.158.1.65