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Original Contribution |

Effectiveness of Influenza Vaccination of Day Care Children in Reducing Influenza-Related Morbidity Among Household Contacts FREE

Eugene S. Hurwitz, MD; Michael Haber, PhD; Albert Chang, MD; Timothy Shope, MD; Siew Teo, MS; Michele Ginsberg, MD; Norman Waecker, MD; Nancy J. Cox, PhD
[+] Author Affiliations

Author Affiliations: Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Ga (Drs Hurwitz and Cox); Department of Biostatistics, Rollins School of Public Health, Emory University, Atlanta, Ga (Dr Haber); Graduate School of Public Health, San Diego State University (Dr Chang), Department of Pediatrics, Naval Medical Center (Drs Shope and Waecker), and San Diego County Health Department (Dr Ginsberg and Ms Teo), San Diego, Calif.


JAMA. 2000;284(13):1677-1682. doi:10.1001/jama.284.13.1677.
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Published online

Context A growing proportion of young children in the United States participate in day care, and these children are considered to be at high risk for influenza infection. Whether vaccinating day care children reduces household transmission of influenza is not known.

Objective To evaluate the effect of vaccinating day care children on reducing influenza-related morbidity among their household contacts.

Design Single-blind, randomized controlled trial conducted during the 1996-1997 influenza season.

Setting Ten day care centers for children of US Navy personnel in San Diego, Calif.

Participants A total of 149 day care attendees (aged 24-60 months) and their families were randomized; 127 children and their 328 household contacts received 2 vaccine doses and were included in the analysis.

Interventions Inactivated influenza vaccine was administered to 60 children with 162 household contacts, and hepatitis A vaccine as a control was administered to 67 age-matched children with 166 household contacts.

Main Outcome Measures Information regarding febrile respiratory illnesses and related morbidity for household contacts of influenza-vaccinated vs control children (subgrouped by influenza-vaccinated and unvaccinated contacts), obtained by telephone interviews with parents every 2 weeks from November 1996 through April 1997.

Results Influenza-unvaccinated household contacts (n = 120) of influenza-vaccinated day care children had 42% fewer febrile respiratory illnesses (P = .04) compared with unvaccinated household contacts of control children. Among school-aged household contacts (aged 5-17 years), there was an 80% reduction among contacts of vaccinated children (n = 28) vs contacts of unvaccinated children (n = 31) in febrile respiratory illnesses (P = .01), as well as reductions of more than 70% in school days missed (P = .02), reported earaches (P = .02), physician visits (P = .007), physician-prescribed antibiotics (P = .02), and adults who missed work to take care of ill children (P = .04).

Conclusions These results indicate that vaccinating day care children against influenza helps reduce influenza-related morbidity among their household contacts, particularly among school-aged contacts. Future studies should be conducted in civilian populations to assess the full effect of vaccinating day care children against influenza.

In the past decade, the proportion of US children younger than 5 years in day care has increased substantially. Currently, as many as 70% of children younger than 5 years spend 10 or more hours per week in some form of out-of-home child care.1 Numerous studies27 have suggested that children in larger day care facilities are at greater risk for respiratory infections than are children cared for at home or in smaller child care settings (ie, ≤6 children). The increased risk of these illnesses is associated with excess morbidity and related medical costs for these children and may extend to their household contacts as well.

One important respiratory illness affecting day care children is influenza. Day care children are considered to be at high risk for influenza infections; in a recent study,8 50% of children attending day care centers were infected in a single season. Influenza-related illnesses may be associated with considerable economic impact, including medical costs, workdays lost, school absences, physician visits, antibiotic use, and the costs of arrangements for sick child care.

A previous study9 suggested that day care children are more likely than school-aged children or adults to transmit respiratory illnesses to their household contacts. Consequently, measures to re duce or prevent transmission of such illnesses to household contacts would be useful. In view of the high rate of influenza illnesses among day care children, 1 possible benefit of influenza vaccination of day care children would be to reduce transmission of influenza to household members.

Although recent studies10,11 have assessed the effectiveness of influenza vaccine in preventing otitis media among day care children, few studies have examined whether vaccinating day care children can reduce household transmission of influenza. This article describes the impact of administering influenza vaccine to children attending day care centers in reducing respiratory illnesses among their household contacts.

Subjects and Study Design

Detailed methods for this study, which was conducted during the 1996-1997 influenza period, have been described elsewhere.12 Briefly, children 24 to 60 months of age (matched for 2 age groups, 24 to 36 months and 37 to 60 months) attending 10 US Navy–affiliated day care centers in the San Diego, Calif, area were invited to participate. Children were randomized and received either influenza vaccine or hepatitis A vaccine as a placebo control. Parents were blinded to the treatment assignment of their children. Commercially available subunit influenza (FluShield purified subviron, Wyeth Lederle Vaccines, Philadelphia, Pa) and hepatitis A (SmithKline Beecham, Philadelphia, Pa) vaccines were administered in the standard recommended doses and schedules for age; for both vaccines, this regimen was 2 doses administered 1 month apart. Children with prior influenza vaccination were excluded.

To define the period of influenza activity, surveillance of influenza and other respiratory viruses was conducted by obtaining pharyngeal specimens from 5 to 10 children with new-onset respiratory illness twice weekly in pediatric clinics where day care children were most likely to seek care. Viral identification used monoclonal antibodies in an indirect fluorescent assay.

Information concerning respiratory illnesses and related morbidity among children attending these day care centers and all other household members was obtained through telephone interviews conducted every 2 weeks between November 1996 and April 1997 by trained interviewers using standardized questionnaires. The overall completion rate for the questionnaires was more than 90%.

The definitions of respiratory illnesses used for the analysis included any respiratory illness reported by the care provider, a respiratory illness associated with a fever, and a respiratory illness associated with a temperature of 38°C (101°F) or higher. Symptoms of a respiratory illness included at least 1 of the following: cough, sore throat, and/or runny nose. Respiratory illnesses had to be preceded by at least 3 symptomatic days, and only 1 new-onset illness could be included in a 2-week period.

To assess vaccine response and serologic evidence of infection, blood specimens were obtained from the children attending day care 3 times during the study: before vaccination, 1 month after the second vaccination, and at the end of the study. Hemagglutination inhibition antibody titers to influenza A(H1N1), A(H3N2), and B were obtained; a 4-fold or greater rise defined infection.

Human subjects approval for this study was obtained from the institutional review boards of the Naval Medical Center, San Diego, Calif, the Centers for Disease Control and Prevention, and the San Diego State University School of Public Health. Written informed consent for participation was obtained from parents or legal guardians.

Effectiveness Among Household Contacts

Estimates of the effectiveness of vaccination of day care children in reducing influenza-related morbidity among household contacts were based on rates of respiratory illnesses and febrile respiratory illnesses among household contacts of vaccinated and control children during the influenza period. Because a large proportion of adult household contacts had also received influenza vaccine (as a result of military requirements), analyses of effectiveness among household contacts were completed for contacts who had and had not received influenza vaccine. The influenza period was defined as the weeks during which influenza isolates were detected with active surveillance. Respiratory-related morbidity was assessed among household contacts of vaccinated and unvaccinated day care children by comparing several factors, including missed school, adults who missed work to care for ill children, physician visits, earache, antibiotics prescribed, and over-the-counter medicines used.

Statistical Analysis

To estimate vaccine effectiveness in preventing respiratory illnesses in household contacts, a logistic model was fitted with the illness status of the household contact as the dependent variable and the vaccination status of the day care child as the predictor variable. We tested the hypothesis that there was no difference in the rate of respiratory illnesses and related morbidity between the household contacts of vaccinated and unvaccinated day care children. One-sided P values were used to evaluate the protective effect of influenza vaccine. The generalized estimation equations method was used to account for correlations among members of the same household.13

Subject Recruitment and Demographics

A description of the number of subjects enrolled and available for analysis has been provided elsewhere.12 Of 748 children attending the day care centers, 149 (20%) were randomized. Excluding children lost to follow-up and those who did not receive 2 vaccine doses, there were 127 day care children and their household contacts (60 influenza vaccinated and 67 control children) included in the analysis. The racial distribution among vaccinated and control children was not significantly different; overall, 42% were white, 27% were black, and 31% were Hispanic. The mean age in both groups was 3.7 years.

The age distribution and influenza vaccination status of the 328 household contacts of study children are shown in Table 1. The mean family size was 3.8 for vaccinated children and 3.7 for control children. For both vaccinated and control children, the mean age of household contacts younger than 18 years was 7 years. Less than 10% of household contacts younger than 18 years received influenza vaccines during the study period. Forty percent of the adults had been vaccinated, because at least 1 of the adults in each household was a member of the military, for whom influenza vaccination is routinely required.

Table Graphic Jump LocationTable 1. Household Contacts Who Received Influenza Vaccine During the Study Period by Age Group*
Respiratory Virus Surveillance and the Influenza Period

Of the 143 isolates obtained, the most frequently detected were influenza B (31%) and A(H3N2) (29%). No influenza A(H1N1) isolates were identified. Influenza activity began in mid November, peaked in mid January, and continued through early February. Both influenza A(H3N2) and influenza B isolates were obtained during this period; there was no apparent period when 1 isolate was more prevalent. During the influenza period, 75% of all isolates were influenza viruses.

Efficacy and Clinical Effectiveness Among Day Care Children

The influenza vaccine efficacy and clinical effectiveness among these children have been described elsewhere.12 Vaccine efficacy in preventing serologically proven influenza virus infection was 45% (95% confidence interval [CI], −2% to 69%) for influenza B and 31% (95% CI, −95% to 73%) for influenza A(H3N2). For both influenza A(H3N2) and B, children without pre-existing hemagglutination inhibition antibody to these antigens had lower antibody responses to vaccine, were less likely to develop a serologic response that was protective against infection, and were more likely to develop serologic evidence of influenza infection. Although there were no statistically significant reductions in respiratory or febrile respiratory illnesses among all vaccinated children, there was a trend for reductions in such illnesses among vaccinated children with preexisting hemagglutination inhibition antibodies to influenza A(H3N2) and B. Among children with prevaccination hemagglutination inhibition titers of 5 or lower to influenza A(H3N2) or B, the vaccine effectiveness for respiratory illnesses was −23% (95% CI, −56% to 3%) compared with 11% (95% CI, −9% to 26%) for those with prevaccination titers of 10 or higher (P = .04).

Effectiveness of Vaccination of Day Care Children in Reducing Illness Among Household Contacts

Among unvaccinated household contacts, influenza vaccination of day care children resulted in a 16% reduction in respiratory illnesses (P = .10), a 42% reduction in respiratory illnesses associated with fever (P = .04), and a 47% reduction in respiratory illnesses with a temperature of 38°C (101°F) or higher (P = .04) (Table 2). Among vaccinated household contacts, there was a 28% reduction in respiratory illnesses (P = .04) and a 22% reduction in respiratory illnesses with a temperature of 101°F or higher (P = .38), both not significant.

Table Graphic Jump LocationTable 2. Vaccine Effectiveness for Influenza-Vaccinated and Unvaccinated Household Contacts of Vaccinated and Control Day Care Children

Assessment of vaccine effectiveness among unvaccinated household contacts by age group demonstrated that the greatest impact of vaccinating day care children was among school-aged household contacts (Table 3). Among household contacts 5 to 17 years of age, respiratory illnesses were reduced 50% (P = .007); febrile respiratory illnesses, including those with a temperature of 38°C (101°F) or higher, were reduced 80% (P = .01). No significant reductions in respiratory illnesses with or without fevers were observed among household contacts who were younger than 5 years. Among adults, there was a 40% reduction in febrile respiratory illnesses and a 31% reduction in illnesses associated with a temperature of 38°C (101°F) or higher, but these differences were not statistically significant.

Table Graphic Jump LocationTable 3. Effectiveness of Influenza Vaccination of Day Care Children in Reducing Respiratory Illnesses Among Unvaccinated Household Contacts

In addition to reductions in respiratory and febrile respiratory illnesses, analysis of the illnesses with the highest reported temperature among 5- to 17-year-old household contacts of vaccinated children demonstrated reductions of more than 70% in the following respiratory-related morbidity events: missed school, adults who missed work to care for ill children, physician visits, earache, and antibiotics prescribed. Over-the-counter medicine use decreased 45% (Table 4). No similar reductions were observed for adults or children younger than 5 years who were household contacts.

Table Graphic Jump LocationTable 4. Respiratory-Related Morbidity Among Unvaccinated 5- to 17-Year-Old Household Contacts of Study Children*

Among day care children who had serologic specimens available for testing, influenza A(H3N2) infections were confirmed in 8 (16%) of 51 controls compared with 5 (11%) of 46 vaccinated day care children, and influenza B infections were confirmed in 22 (43%) of 51 controls and 11 (24%) of 46 vaccinated children. For household contacts of these children with serologic evidence of influenza A(H3N2) or B infection, there was more than a 60% reduction in febrile respiratory illnesses, including those associated with a temperature of 38°C (101°F) or higher, among the contacts of vaccinated, infected children when compared with the contacts of infected control children (Table 5). These reductions were not statistically significant, but the number of household contacts available for this analysis was small. Assessment of 5- to 17-year-old household contacts of influenza-infected study children demonstrated that the contacts of vaccinated children had a 60% or greater incidence of fewer respiratory and febrile respiratory illnesses than contacts of infected control subjects. These reductions were statistically significant for all respiratory illnesses of the contacts of influenza B–infected children.

Table Graphic Jump LocationTable 5. Respiratory Illness Among Unvaccinated Household Contacts of Study Children With Influenza Infections*

Analyses were also completed of the effectiveness of influenza vaccination of household contacts, although the study was not designed for this purpose, and these subjects were aware of their vaccination status. Among vaccinated household contacts of control children, there was a 61% reduction in febrile respiratory illnesses (P = .04) and a 57% reduction in respiratory illnesses (P = .06) associated with a temperature of 38°C (101°F) or higher (Table 6). In contrast, for vaccinated household contacts of vaccinated day care children, there was a 29% reduction in febrile respiratory illnesses and a 37% reduction in respiratory illnesses associated with a temperature of 38°C (101°F) or higher. These differences, however, were not statistically significant.

Table Graphic Jump LocationTable 6. Respiratory Illnesses Among Influenza-Vaccinated and Unvaccinated Household Contacts of Day Care Study Children

These findings show that the benefits of influenza vaccination of children attending day care centers extend to their family members, particularly school-aged children 5 to 17 years of age, even in military families, among which a large proportion of adults have also received influenza vaccine. In addition to reductions in respiratory illnesses, 5- to 17-year-old household contacts of vaccinated day care children had significant reductions in respiratory-related morbidity, such as missed school days, physician visits, antibiotics, and lost parental work to care for the children during their respiratory illness with the highest temperature. Thus, prevention of spread of influenza-related illnesses from day care children to their household contacts may have an important economic impact on the households in which these children live.

The large number of household contacts of study children, primarily adults, who received influenza vaccine as part of the military health care program undoubtedly reduced the ability of this study to detect the full potential impact of influenza vaccination of day care children. In most households in this study, at least 1 adult had received influenza vaccine, which reduced the number of household contacts at risk for influenza infections and further reduced the potential for transmission of influenza among unvaccinated contacts. It is possible that had this study been conducted in a nonmilitary population with few vaccinated household contacts, the effect of reducing respiratory illnesses among household contacts might have been even greater and might have included adults and children younger than 5 years.

In addition to the large number of household contacts who had received influenza vaccine, there are several other factors that may have contributed to the inability to detect an impact on household contacts who were outside the 5- to 17-year-old age range. A relatively small number of children younger than 5 years were available for analysis when compared with the number of school-aged children and adults. Moreover, younger children have high rates of respiratory illnesses associated with many different respiratory pathogens, and, in contrast to school-aged children and adults, these illnesses may be difficult to distinguish from influenza-related infections. Furthermore, a large proportion of the adult household contacts, in contrast to school-aged children and children younger than 5 years, may have been more likely to have natural immunity to the prevalent strains of influenza, which may have been protective against infection.

The serologically determined vaccine efficacy in the day care children in this study was 45%.12 As was observed for household contacts younger than 5 years, there were no significant reductions in respiratory or febrile respiratory illnesses among vaccinated day care children. However, children with pre-existing titers to influenza A(H3N2) and B were significantly less likely to have respiratory illnesses and influenza infections, suggesting that preexisting immunity to influenza may have been important for vaccine efficacy and effectiveness in this age group. The inability to identify reductions in clinical illnesses among these children may have occurred, as suggested for household contacts younger than 5 years, because of the limited number of children available for analysis and the difficulty in distinguishing influenza illnesses from the many other respiratory illnesses that may occur in this age group.

This study demonstrated that even among influenza-vaccinated children who subsequently became infected with influenza, there may be a reduction in respiratory illnesses among household contacts. This finding suggests that influenza vaccine may work not only by preventing infection, but also by reducing the likelihood of virus being spread from vaccinated, infected individuals to susceptible persons. One possible explanation is that the apparent reduction in transmission was a result of IgA antibody in the respiratory tract of these influenza-vaccinated subjects.

Although this study was not designed to assess vaccine effectiveness among household contacts who had received influenza vaccine, our analysis did demonstrate that influenza vaccination of household contacts (almost all of whom were adults) led to a reduction in respiratory illnesses among those contacts in households in which the day care child had not been vaccinated. In contrast, in households in which the day care child had received influenza vaccine, influenza vaccination of household contacts did not result in statistically significant reductions in respiratory or febrile respiratory illnesses. This difference probably occurred in large part because rates of respiratory illnesses were already reduced in these households among unvaccinated contacts because of vaccination of the day care child.

Recent concern has been raised about the emergence of drug-resistant organisms, including Streptococcus pneumoniae, as a result of increased antibiotic use, particularly among children attending day care centers.14 Although the number of subjects included in the study was small, the study suggests that influenza vaccination of children attending day care centers might lead to major reductions in respiratory illnesses and antibiotic use among their household contacts. Additional larger studies are needed to further assess the potential effect of influenza vaccination of day care children in reducing antibiotic use and antimicrobial resistance among household contacts.

A previous study9 demonstrated that day care children are at high risk for respiratory illnesses, including influenza infections, and as a result may be more likely to be a primary source of such illnesses in their households. Another study15 suggested that vaccination of children, primarily school-aged, may reduce the prevalence of influenza-related illnesses in communities. Although similar studies involving vaccination of day care children have not been conducted, in view of the large proportion of children in day care, the high risks of respiratory illnesses in these children, and their importance in transmission of these illnesses within households, influenza vaccination of day care children may have a similar impact on reducing related morbidity in households and communities. Recently, there has been concern about the possibility of an influenza pandemic and optimal measures to control such a pandemic, including vaccination of target populations such as young children, to reduce spread of influenza.16 Our results suggest that during such pandemics, vaccination programs targeting day care children may be 1 effective strategy to reduce influenza transmission in households and perhaps communities.

This study suggests that even in a military population in which a large proportion of active-duty personnel have been vaccinated, influenza vaccination of day care children may have additional benefits to families, including reduced illness, family disruption, lost parental work to take care of ill children and visit physicians, and antibiotic use among household contacts. Future studies in military and civilian populations are needed to define the role of such a targeted influenza vaccine program. These studies should further elucidate the cost-effectiveness and potential benefits in preventing household and community spread of influenza and the possible role of such programs in reducing morbidity during influenza pandemics.

Dawson DA, Cain VS. Child Care Arrangements: Health of Our Nation's Children: United States, 1988Hyattsville, Md: Public Health Service, Centers for Disease Control and Prevention; 1990. Advance Data, No. 187.
Fleming DW, Cochi SL, Hightower AW, Broome CV. Childhood upper respiratory tract infections: to what degree is incidence affected by day care attendance?  Pediatrics.1987;79:55-60.
Wald ER, Dashefsky B, Byers C.  et al.  Frequency and severity of infections in day care.  J Pediatr.1988;112:540-546.
Strangert K. Respiratory illness in preschool children with different forms of day care.  Pediatrics.1976;57:191-196.
Doyle A. Incidence of illness in early group and family day care.  Pediatrics.1976;58:607-613.
Bell DM, Gleiber DW, Mercer AA.  et al.  Illness associated with childcare: a study of incidence and cost.  Am J Public Health.1989;79:479-484.
Hurwitz ES, Gunn WJ, Pinsky PF, Schonberger LB. Risk of respiratory illness associated with day care attendance: a nationwide study.  Pediatrics.1991;87:62-69.
Hurwitz ES, Haeber M, Chang A.  et al.  Effectiveness of inactivated influenza vaccination of children attending day care in reducing influenza-like illness and related morbidity. In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy; September 24, 1998; San Diego, Calif.
Hurwitz ES, Nizham A, Longini I.  et al.  Household transmission of respiratory illnesses among children attending day care. In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy; September 15-18, 1996; New Orleans, La.
Heikkinen T, Ruuskanen O, Wons M.  et al.  Influenza vaccination in the prevention of acute otitis media in children.  Am J Dis Child.1991;145:445-448.
Clements DA, Langdon L, Bland C, Walter E. Influenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old children in day care.  Arch Pediatr Adolesc Med.1995;149:1113-1121.
Hurwitz ES, Haber M, Chang A.  et al.  Studies of the 1996-97 inactivated influenza vaccine among children attending day care.  J Infect Dis.2000;182:1218-1221.
Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models.  Biometrika.1986;73:13-22.
Hofman J, Cetron MS, Farley MM.  et al.  The prevalence of resistant Streptococcus pneumoniae in Atlanta.  N Engl J Med.1995;333:481-486.
Monto A. Prospects for pandemic influenza control with currently available vaccines.  J Infect Dis.1997;176(suppl 1):S32-S37.
Workshop 6.  Clinical design issues in the pandemic situation.  J Infect Dis.1997;176(suppl 1):S85-S86.

Figures

Tables

Table Graphic Jump LocationTable 1. Household Contacts Who Received Influenza Vaccine During the Study Period by Age Group*
Table Graphic Jump LocationTable 2. Vaccine Effectiveness for Influenza-Vaccinated and Unvaccinated Household Contacts of Vaccinated and Control Day Care Children
Table Graphic Jump LocationTable 3. Effectiveness of Influenza Vaccination of Day Care Children in Reducing Respiratory Illnesses Among Unvaccinated Household Contacts
Table Graphic Jump LocationTable 4. Respiratory-Related Morbidity Among Unvaccinated 5- to 17-Year-Old Household Contacts of Study Children*
Table Graphic Jump LocationTable 5. Respiratory Illness Among Unvaccinated Household Contacts of Study Children With Influenza Infections*
Table Graphic Jump LocationTable 6. Respiratory Illnesses Among Influenza-Vaccinated and Unvaccinated Household Contacts of Day Care Study Children

References

Dawson DA, Cain VS. Child Care Arrangements: Health of Our Nation's Children: United States, 1988Hyattsville, Md: Public Health Service, Centers for Disease Control and Prevention; 1990. Advance Data, No. 187.
Fleming DW, Cochi SL, Hightower AW, Broome CV. Childhood upper respiratory tract infections: to what degree is incidence affected by day care attendance?  Pediatrics.1987;79:55-60.
Wald ER, Dashefsky B, Byers C.  et al.  Frequency and severity of infections in day care.  J Pediatr.1988;112:540-546.
Strangert K. Respiratory illness in preschool children with different forms of day care.  Pediatrics.1976;57:191-196.
Doyle A. Incidence of illness in early group and family day care.  Pediatrics.1976;58:607-613.
Bell DM, Gleiber DW, Mercer AA.  et al.  Illness associated with childcare: a study of incidence and cost.  Am J Public Health.1989;79:479-484.
Hurwitz ES, Gunn WJ, Pinsky PF, Schonberger LB. Risk of respiratory illness associated with day care attendance: a nationwide study.  Pediatrics.1991;87:62-69.
Hurwitz ES, Haeber M, Chang A.  et al.  Effectiveness of inactivated influenza vaccination of children attending day care in reducing influenza-like illness and related morbidity. In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy; September 24, 1998; San Diego, Calif.
Hurwitz ES, Nizham A, Longini I.  et al.  Household transmission of respiratory illnesses among children attending day care. In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy; September 15-18, 1996; New Orleans, La.
Heikkinen T, Ruuskanen O, Wons M.  et al.  Influenza vaccination in the prevention of acute otitis media in children.  Am J Dis Child.1991;145:445-448.
Clements DA, Langdon L, Bland C, Walter E. Influenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old children in day care.  Arch Pediatr Adolesc Med.1995;149:1113-1121.
Hurwitz ES, Haber M, Chang A.  et al.  Studies of the 1996-97 inactivated influenza vaccine among children attending day care.  J Infect Dis.2000;182:1218-1221.
Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models.  Biometrika.1986;73:13-22.
Hofman J, Cetron MS, Farley MM.  et al.  The prevalence of resistant Streptococcus pneumoniae in Atlanta.  N Engl J Med.1995;333:481-486.
Monto A. Prospects for pandemic influenza control with currently available vaccines.  J Infect Dis.1997;176(suppl 1):S32-S37.
Workshop 6.  Clinical design issues in the pandemic situation.  J Infect Dis.1997;176(suppl 1):S85-S86.
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