Pediatric Annals

New Vaccines for Old Diseases: Trivalent Cold-adapted Influenza Vaccine

W Paul Glezen, MD

Abstract

A new influenza vaccine, the cold-adapted, live attenuated influenza vaccine (CAIV-T), was licensed on June 17, 2003, for healthy people ages 5 to 49. CAIV-T is administered by nasal spray and joins the previously licensed trivalent inactivated vaccine (TIV) as a method for prevention of influenza in school children. This article discusses advantages of CAIV-T and the rationale for use in children.

CAIV-T has proven to be remarkably efficacious in young children. The data cited previously demonstrate that one dose is usually sufficient to provide protection. The immunity is long lasting and persists through the second season. It also is broad and usually encompasses the next variant of each of the three currently circulating viruses.

SAFETYOFCAIV-T

The safety of CATV-T for young children was assessed carefully in the pivotal efficacy trial; a subset of children received three and four sequential annual doses to supplement the data from the original cohort.17 Mild respiratory, gastrointestinal, and systemic symptoms of short duration were observed in a minority of children and limited to me first dose. These symptoms consisted of nasal congestion or rhinorrhea primarily on day 2 for fewer than 10% of CATV-T recipients, some nausea and abdominal pain during the first week for about 3% of recipients, and low-grade (usually less than 1010F) fevers on day 2 after the first dose of CAIV-T for about 5% of recipients. Reactions decreased with increasing number of doses.

A large trial for assessment of safety was carried out in 3 1 clinics of the Northern California Kaiser Permanente Vaccine Study Center.18 A total of 9,689 children ages 1 to 17 were enrolled to receive CAIV-T or placebo at a ratio of 2: 1 . None of the pre-specified diagnostic categories - acute respiratory tract events, systemic bacterial infection, acute gastrointestinal events, and rare events mat have been associated wim natural influenza such as myocarditis or encephalitis - were associated with CATV-T administration.

Ad hoc analyses - not pre-specified - of encounters coded with various ICD-9 codes found differences in distribution of several categories. More were found with excess rates among placebo recipients than CAIV-T recipients, but the investigators focused on an excess of asthma codes among CAIV-T recipients ages 18 to 35 months during the first 42 days after vaccination for special consideration because they considered this to be a plausible consequence of the live, attenuated vims. No clustering of encounters with the asthma codes was found during the 42-day period. Bom younger and older CATV-T recipients had lower rates of asthma-coded encounters than did placebo recipients in me same age groups.

The excess of encounters coded for asthma was probably the result of misclassification. If all wheezing illnesses were considered, no difference in incidence was shown for the CATV-T and placebo recipients in those age groups. Furthermore, if me visits coded for asmma were examined and episodes without wheezing excluded, no difference in rates was observed. Thus, careful attention to disease classification eliminated the imbalance in distribution of wheezing-illness codes between vaccine and placebo recipients.

More than 1,500 comparisons were made in die ad hoc analyses. More man 150 differences in distribution of diagnostic categories were possible. The investigators failed to adjust for multiple comparisons, thereby nullifying the significance of the findings. In me nonrandomized, open-label field trial in central Texas, the subset of children served by a single healthcare plan - 4,749 children in me first 2 years, or approximately 50% of the total - were followed for increased use of medical facilities following vaccination.19 No increase was found for any acute respiratory condition including asthma or wheezing illness. Children with mild intermittent…

A new influenza vaccine, the cold-adapted, live attenuated influenza vaccine (CAIV-T), was licensed on June 17, 2003, for healthy people ages 5 to 49. CAIV-T is administered by nasal spray and joins the previously licensed trivalent inactivated vaccine (TIV) as a method for prevention of influenza in school children. This article discusses advantages of CAIV-T and the rationale for use in children.

Influenza is an uncontrolled epidemic disease that is vaccine preventable. The current strategy for vaccinating vulnerable people at risk for complications of influenza has not curtailed the occurrence of excess mortality; the annual number of deaths has continued to increase despite distribution of 80 to 90 million doses of vaccine each year.1 Children have the highest attack rates for influenza virus infection, and complications and serious morbidity are not limited to children with chronic underlying conditions.2 The constant variation of influenza viruses presents a special challenge for implementing control measures; CAIV-T has properties that are particularly attractive for enhancing control programs.

The cold-adapted, live attenuated influenza vaccine was developed by Hussein F. Maassab3 at the University of Michigan in the early 1960s. Dr. Maassab selected the master attenuated strains by serial passage at progressively lower temperatures until he achieved adequate growth at 250C. The phenotypic characteristics of the master strains were cold adaptation (CA), temperature sensitivity, and reduced virulence in the ferret model.4 Subsequent studies showed significant attenuation of clinical illness in human volunteers and protection against challenges with wild viruses.5

The parent attenuated strains are reassorted with currently circulating influenza viruses to produce vaccine with relevant surface antigens of the current viruses but retaining the properties of attenuation. The CA strains have shown remarkable stability with no reversion of the characteristics of attenuation after human passage. These strains produce much lower virus concentrations in respiratory secretions than do wild viruses; therefore, transmission of CA strains to susceptible contacts has not occurred from vaccinated adults and may have produced a single inapparent infection among many daycare contacts of vaccinated, preschool-aged children.3

EFFICACY OF CAIV-T

The CA vaccine strains have been extensively tested in children.5 Many of the early trials were conducted with bivalent influenza A (CAIV-bA) strains administered by nose drops. Clover et al.6 compared a single annual dose of CAIV-bA with TIV and found better heterotypic protection in children ages 3 to 9 immunized with CAIV-bA nosedrop vaccine. The vaccines contained antigens to the A/Chile/83(H1N1) strain, whereas the epidemic virus that year was A/Taiwan/86(H1N1). Many of the children, ages 3 to 18, were given three annual doses of the respective vaccines or placebo and were followed for a fourth season. The children who received CAIVbA had significant protection against influenza A(HlNl) infection, indicating persistence of immunity generated by the CAIV-bA vaccine through a second season but none from earlier TIV immunizations.7 Neuzil et al.8 reported protection against influenza A culture-positive illness in children ages 1 to 16 who received either TIV or CAIV-bA. These were relatively small studies, but they encouraged exploration of the potential benefits of the CAIV product and recognized that it was well tolerated and readily accepted by children.9

Assessment of CAIV-T for licensure was taken up by Aviron (now Medlmmune Vaccines) in 1995.10 All three influenza strains recommended by the Food and Drug Administration were combined into a trivalent preparation for testing. A device for administering the vaccine by nasal spray was shown to be safe and effective." This device allowed administration of CAIV-T to children sitting upright, which eliminated the need for children to lie down for nose drops, saving both time and space in vaccine clinics.

The pivotal efficacy trial in children ages 15 to 71 months was carried out in 10 medical centers and demonstrated greater than 90% protection against culture-positive illness caused by influenza A(H3N2) or B viruses.12 More than 1,600 children were randomized to receive CAIV-T or placebo; 288 received a single dose and 1,314 received two doses at an interval of 6 to 8 weeks. The efficacy against influenza A(H3N2) was 87% for a single dose and comparable to the protection of 96% for two doses. It should be noted, however, that many of the children randomized to a second dose did not receive it until well after influenza virus activity had commenced in the communities. The efficacy against influenza B was 91% for both one or two doses of CATV-T.

The same randomization and vaccine formula was used for the second year of the study, but the predominant circulating virus was a new variant of influenza A(H3N2), A/Sydney.13 A/Wuhan(H3N2) was used to make the CAIV-T vaccine. All children randomized to vaccine received a single dose of CAIV-T; the protection was 86% against the new variant. The protection afforded by CAIV-T was the same as seen for placebo controls who had culture-positive illnesses caused by A/Wuhan during the first year of the trial.

Influenza A(HlNl) viruses did not circulate during the two influenza seasons of this trial. To assess protection against this influenza A subtype, a subset of children was challenged with monovalent CA A(HlNl) virus in the spring after the second season.14 The children were cultured daily for 4 days for shedding of the CA A(HlNl) strain. Children vaccinated with CAIVT had 83% protection against shedding of A(HlNl) virus. This indicated protection against A(HlNl) viruses that had not circulated since the 1995 to 1996 season.

Overall, the trial demonstrated about 92% protection against culture-positive illness caused by influenza A(H3N2) and B, heterovariant protection against a new variant of A(H3N2), and evidence of some protection against influenza A(HlNl). The data suggested that a single dose was effective in this young, vulnerable age group.

Natural influenza A(HlNl) did not circulate in the United States from 1996 until 2001, when a large field trial was in progress in central Texas. More than 5,000 children between ages 1.5 and 18 were enrolled to receive a single dose of CAIV-T in a nonrandomized, open-label trial during the 2000 to 2001 season.15 The purpose of the trial was to assess indirect effectiveness, or "herd immunity," generated by CAIV-T by measuring reduction of transmission of natural influenza from children to adults. Children younger than 5 had not had an opportunity for natural infection wim influenza A(HlNl) before that season.

Combining the rates for medically attended acute respiratory illnesses with the virus isolation data from a subset who were cultured at the surveillance sites, the adjusted efficacy for all age groups combined was 92% against influenza A(HlNl) infection and 66% against a new variant of influenza B, B/Sichuan.16 The vaccine contained antigen to the previously prevalent strain, B/Beijing. Vaccinated children younger than 5 who had no previous exposure to natural influenza A(HlNl) infection had 91% protection against culture-positive illness during the epidemic. Children who had received only a single dose in the previous years of CAIV-T, which included the A/Beijing(HlNl) strain, were also protected against the new variant, New Caledonia(HlNl), demonstrating heterovariant immunity (84%) that persisted to the second season.

CAIV-T has proven to be remarkably efficacious in young children. The data cited previously demonstrate that one dose is usually sufficient to provide protection. The immunity is long lasting and persists through the second season. It also is broad and usually encompasses the next variant of each of the three currently circulating viruses.

SAFETYOFCAIV-T

The safety of CATV-T for young children was assessed carefully in the pivotal efficacy trial; a subset of children received three and four sequential annual doses to supplement the data from the original cohort.17 Mild respiratory, gastrointestinal, and systemic symptoms of short duration were observed in a minority of children and limited to me first dose. These symptoms consisted of nasal congestion or rhinorrhea primarily on day 2 for fewer than 10% of CATV-T recipients, some nausea and abdominal pain during the first week for about 3% of recipients, and low-grade (usually less than 1010F) fevers on day 2 after the first dose of CAIV-T for about 5% of recipients. Reactions decreased with increasing number of doses.

A large trial for assessment of safety was carried out in 3 1 clinics of the Northern California Kaiser Permanente Vaccine Study Center.18 A total of 9,689 children ages 1 to 17 were enrolled to receive CAIV-T or placebo at a ratio of 2: 1 . None of the pre-specified diagnostic categories - acute respiratory tract events, systemic bacterial infection, acute gastrointestinal events, and rare events mat have been associated wim natural influenza such as myocarditis or encephalitis - were associated with CATV-T administration.

Ad hoc analyses - not pre-specified - of encounters coded with various ICD-9 codes found differences in distribution of several categories. More were found with excess rates among placebo recipients than CAIV-T recipients, but the investigators focused on an excess of asthma codes among CAIV-T recipients ages 18 to 35 months during the first 42 days after vaccination for special consideration because they considered this to be a plausible consequence of the live, attenuated vims. No clustering of encounters with the asthma codes was found during the 42-day period. Bom younger and older CATV-T recipients had lower rates of asthma-coded encounters than did placebo recipients in me same age groups.

The excess of encounters coded for asthma was probably the result of misclassification. If all wheezing illnesses were considered, no difference in incidence was shown for the CATV-T and placebo recipients in those age groups. Furthermore, if me visits coded for asmma were examined and episodes without wheezing excluded, no difference in rates was observed. Thus, careful attention to disease classification eliminated the imbalance in distribution of wheezing-illness codes between vaccine and placebo recipients.

More than 1,500 comparisons were made in die ad hoc analyses. More man 150 differences in distribution of diagnostic categories were possible. The investigators failed to adjust for multiple comparisons, thereby nullifying the significance of the findings. In me nonrandomized, open-label field trial in central Texas, the subset of children served by a single healthcare plan - 4,749 children in me first 2 years, or approximately 50% of the total - were followed for increased use of medical facilities following vaccination.19 No increase was found for any acute respiratory condition including asthma or wheezing illness. Children with mild intermittent asthma were not excluded from receiving CAIV-T in this trial as they had been in the Kaiser Permanente trial previously mentioned.

More than 4,500 doses of CATV-T were administered to children younger man 5 in me first 4 years of this trial, and no evidence for triggering of wheezing episodes by CAIV-T was observed. CAIV-T is remarkably free of side effects in this experience. This is important because the limitation of die indication for CATV-T at me time of licensure to children no younger tiian 5 was imposed because of me observations reported from the Kaiser Permanente safety trial. The concern about the possibility of triggering wheezing episodes in children younger than 5, although plausible, is not supported by the evidence. The risk of hospitalization for lower respiratory illness caused by natural influenza virus infection is much greater in this age group than any possible side effect of CATV-T. This is the age group with CATV-T efficacy of greater man 90%. It is unfortunate that the group that would benefit most from the vaccine is deprived of this protection.

In contrast, the latest data on efficacy of TTV in this group show protection between 3 1 % and 45% after two doses.20 Hurwitz et al. found young children without prior priming by natural infection do not mount an effective immune response to the inactivated antigen given by injection. CAIV-T provides vulnerable, unprimed children ages 1 to 4 me best opportunity for protection.

INDIREa EFFECTIVENESS (HERD IMMUNITY)

Children have the highest annual attack rate for influenza.21 Epidemiologic studies have shown that children are most likely to spread influenza in the community and are die introducers of it into the household.2 It is reasonable to hypothesize that immunization of children would not only protect them from serious consequences of influenza but also dampen epidemics and reduce the risk for exposure of vulnerable high-risk people in the community.

This concept was affirmed by the Japanese Schoolchildren Vaccination program between 1962 and 1994.22 Improvements in influenza surveillance and vaccine production came to fruition by 1977, when an inactivated subunit vaccine became available. This vaccine was effective and less reactogenic, making it more acceptable for the students. Two doses of vaccine given 1 month apart were mandatory for school attendance for children ages 5 to 15, beginning in 1977. During the 10-year period from 1977 to 1987, a distinct dampening of wintertime excess mortality was observed for Japan. Reichert and colleagues22 estimated that influenza vaccination of schoolchildren prevented between 37,000 and 49,000 deaths per year or about one death for every 420 children vaccinated. When the program was terminated, the excess mortality rate increased. Throughout this period, influenza vaccine was recommended only for schoolchildren; Japan had no recommendation for elderly or high-risk patients. This experience provides proof for the principle of herd immunity with influenza vaccine.

Other studies also have confirmed the indirect effectiveness of influenza vaccine.23*25 Current recommendations endorse this concept by recommending that household contacts of high-risk patients receive influenza vaccine.26 A large field trial is under way in central Texas to study the effectiveness of CAIV-T vaccine for indirect effectiveness.27 The purpose of this study is to define the proportion and characteristics of people who should be vaccinated to dampen the spread of influenza in the community and reduce the exposure of high-risk people regardless of their vaccine status. For the period from 1996 to 2002, CAIV-T was employed as an investigational product and offered to all children ages 1.5 to 18 in the intervention communities of Temple and Belton. CAIV-T was not offered to children in the comparison communities of Waco and Bryan-College Station. Age-specific rates of medically attended acute respiratory illnesses (MAARI) were compared for members of the Scott & White Health Plan in the intervention and comparison communities.

In the first 3 years of CATV-T delivery, MAARI rates were significantly lower in adults age 35 or older in the intervention community by 8%, 18%, and 15%, respectively. More than 1,000 encounters for MAARI were avoided in each of the past 2 years. This trial continues to use the licensed CATV-T but is limited to children ages 5 to 18. During the first year of the extension, the number of children vaccinated in this age range was double that of any year that the investigational product was used. Analyses are now in progress to determine both direct and indirect effectiveness of CATV-T vaccination in the intervention community.

RATIONALE FOR UNIVERSAL CHILDHOOD VACCINATION

The effects of influenza on pediatric populations is gaining increased recognition. At the beginning of the 2003-2004 influenza season, the Centers for Disease Control and Prevention requested mat investigators report deaths in children with documented influenza virus infections. By early January 2004, 121 deaths were reported.28 More than 75% of these deaths were in previously healthy children without chronic underlying conditions. This represents some fraction of fatal outcomes and does not include the many children admitted to intensive care units who survived, nor does it include the children with encephalopathy who survived with neurological impairment.

Influenza-attributable hospitalization rates in healthy children younger than 2 are similar to rates for elderly people.29 This information should dispel myths that influenza is a self-limited uncomplicated infection in children. Bacterial complications are common, especially acute otitis media.30 School absenteeism rates are high and result in considerable social disruption for children and their parents. During a relatively mild influenza season in Seattle, Neuzil et al.3' found 28% of children missed school due to influenza. The secondary attack rate in the home was 22%, and almost 20% of parents missed work because of a child's illness.

SUMMARY

Schoolchildren regularly have the highest influenza attack rates.2 Schoolchildren also are accessible for vaccination; school-based vaccine clinics can facilitate delivery of vaccine to a high proportion of children in a short period of time. CATV-T has advantages for immunization of this group due to the effectiveness of a single dose, ease of administration, and ready acceptance by children. Modeling of control for an influenza epidemic by Longini et al.32 has shown vaccination of 70% of school children would dampen epidemics and significantly reduce the exposure of vulnerable people in the community.

The goal of the central Texas trial is to demonstrate this effect in the field. Universal childhood immunization could be an important supplement to current control efforts. Vaccine coverage with TIV has leveled off since 1997; no progress toward the Healthy People 2010 goals of 90% coverage has been made after 4 years in the new decade.33 The number of excess deaths is expected to double within the next 25 years if control methods are not intensified. CAIV-T may become an important adjunct to control measures and can facilitate influenza pandemic preparedness.

REFERENCES

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9. Glezen WP, Taber LH, Gruber WC, et al. Family studies of vaccine efficacy in children: comparison of protection provided by inactivated and attenuated influenza vaccines. In: Hannoun C, Kendal AP, Klenk HD, Ruben FL, eds. Options for the Control of Influenza II. Amsterdam, The Netherlands: Elsevier Science; 1993:435-437.

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11. King JC, Lagos R, Bernstein DI, et al. Safety and immunogenicity of low and high doses of trivalent live cold-adapted influenza vaccine administered intranasally as drops or spray to healthy children. J Infect Dis. 1998; 177(5): 1394- 1397.

12. Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of five attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N Engl J Med. 1998;338(20):14051412.

13. Belshe RB, Gruber WC, Mendelman PM, et al. Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine. J Pediatr. 2000;136(2):168-177.

14. Belshe RB, Gruber WC, Mendelman PM, et al. Correlates of immune protection induced by live, attenuated cold-adapted, trivalent, intranasal influenza vims vaccine. J Infect Dis. 2000;181(3):1 133-1 137.

15. Gaglani MJ, Piedra PA, Herschier GB, et al. Direct and total effectiveness of the intranasal, live-attenuated, trivalent cold-adapted influenza virus vaccine against the 2000-2001 influenza A(HlNl) and B epidemic in healthy children. Arch Pediatr Adolesc Med. 2004;158(l):65-73.

16. Halloran ME, Longini IM Jr., Gaglani MJ, et al. Estimating efficacy of trivalent, cold-adapted, influenza virus vaccine (CATV-T) against influenza A(HlNl) and B using surveillance cultures. Am J Epidemiol. 2003;158(4):305311.

17. Piedra PA, Yan L, Kotloff K, et al. Safety of the trivalent, cold-adapted influenza virus vaccine in preschool-aged children. Pediatrics. 2002;110(4):662-672.

18. Bergen R, Black S, Shinefield H, et al. Safety of cold-adapted live attenuated vaccine in a large cohort of children and adolescents. Pediatr infect Dis J. 2004;23(2): 1 38- 1 44.

19. Piedra PA. Safety of the trivalent, cold-adapted influenza vaccine (CAIV-T) in children. Semin Pediatr Infect Dis. 2002;13(2):90-96.

20. Hurwitz ES, Haber M, Chang A, et al. Studies of the 1996-1997 inactivated influenza vaccine among children attending day care: immunologic response, protection against infection and clinical effectiveness. J Infect Dis. 2000;182(4):1218-1221.

21. Glezen WP, Taber LH, Frank AL, Gruber WC, Piedra PA. Influenza virus infections in infants. Pediatr Infect Dis J. 1997;16(1 1): 1065-1068.

22. Reichert TA, Sugaya N, Fedson DS, et al. The Japanese experience with vaccinating school children against influenza. N Engl J Med. 2001;344(12):889-896.

23. Monto AS, Davenport FM, Napier JA, Francis T Jr. Modification of an outbreak of influenza in Tecumseh, Michigan by vaccination of school children. J infect Dis. 1 970; 122(1 ): 1625.

24. Rudenko LG, Slepushkin AN, Monto AS, et al. Efficacy of live attenuated and inactivated influenza vaccines in school children and their unvaccinated contacts in Novgorod, Russia. J Infect Dis. 1993;168(4):881-887.

25. Hurwitz ES, Haber M, Chang A, et al. Effectiveness of influenza vaccination of daycare children in reducing influenza-related morbidity among household contacts. JAMA. 2000;284(13):1677-I787.

26. Harper SA, Fukuda K, Uyeki TM, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 20O4;53(RR-6):1^0.

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28. Centers for Disease Control and Prevention. Update: influenza-associated deaths reported among children aged < 18 years - United States, 2003-2004 influenza season. MMWR Morb Mortal WkIy Rep. 20O4;52(53): 12861288.

29. Neuzil KM, Mellen BG, Wright PF, Mitchel EF Jr, Griffin MR. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 2000;34(4):225-231.

30. Glezen WP. Prevention of acute otitis media by prophylaxis and treatment of influenza virus infections. Vaccine. 200 1 ;9(Suppl 1 ):S56-S58.

31. Neuzil KM, Hohlbein C, Zhu Y. Illness among schoolchildren during influenza season. Arch Pediatr Adolesc Med. 2002;156(10):986-991.

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33. Harper SA, Fukuda K, Uyeki TM, Cox NJ, Bridges CB; Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2004;53(RR-6): I -40.

10.3928/0090-4481-20040801-12

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