15 October 1992
Volume 117
Number 8
Annals of Internal Medicine Protective Efficacy of Combined Live Intranasal and Inactivated Influenza A Virus Vaccines in the Elderly John J. Treanor, MD; H. Reid Mattison, MD; Ghinwa Dumyati, MD; Amos Yinnon, MD; Shirley Erb, RN; Diane O'Brien, RN; Raphael Dolin, MD; and Robert F. Betts, MD
• Objective: To evaluate the efficacy of adding intranasal live attenuated cold-adapted influenza A vaccine to inactivated influenza vaccine to prevent influenza A in elderly residents of long-term-care institutions. • Design: Randomized, double-blind, placebocontrolled study conducted over 3 years. • Setting: Three large nursing homes. • Participants: A total of 523 residents of nursing homes (mean age, 84.2 years). • Interventions: All participants received trivalent inactivated influenza vaccine parenterally and were randomly assigned to receive either live attenuated influenza A (H3N2) virus vaccine or placebo intranasally. • Measurements: Laboratory-documented influenza A was defined as a respiratory illness plus isolation of influenza A virus from nasal secretions, significant serologic response, or both. Participants were considered to have been exposed to influenza A if they resided in an institution in which cases of influenza A were documented. Outbreak-associated illnesses were defined as those occurring between the first and last isolation of influenza virus from within the institution, ± 3 days. • Results: Participants who received intranasal vaccine and were subsequently exposed to influenza A had significantly lower rates of laboratory-documented influenza A (9 of 162 vaccine recipients compared with 24 of 169 placebo recipients; vaccine protective efficacy, 60.6%; 95% CI, 18% to 82%), outbreak-associated respiratory illnesses (13 of 162 vaccine recipients compared with 34 of 169 placebo recipients; vaccine protective efficacy, 56.8%; CI 23% to 76%), and outbreakassociated influenza-like illnesses (6 of 162 vaccine recipients compared with 18 of 169 placebo recipients; vaccine protective efficacy, 65.0%; CI 17% to 86%). • Conclusions: Intranasal immunization with live attenuated influenza A virus vaccine provided additional protection against influenza A when added to parenteral trivalent inactivated influenza vaccine among elderly nursing home residents. Annals of Internal Medicine. 1992;117:625-633. From the University of Rochester, Rochester, New York. For current author addresses, see end of text.
Influenza is an important cause of morbidity and mortality, especially among high-risk groups such as the elderly and those with chronic cardiac or pulmonary conditions (1-4). Inactivated influenza vaccines are effective in preventing influenza-related morbidity and mortality in the elderly (5-10), but variable degrees of protection have been observed, and significant influenza illness continues to occur in the elderly despite the availability of inactivated vaccine (11-17). Development of more effective control measures for influenza in these persons is, therefore, highly desirable. Live, attenuated influenza A viruses generated by genetic reassortment between a wild-type influenza A virus and the cold-adapted influenza A/Ann Arbor/6/60 (H2N2) virus are currently being evaluated as potential vaccines in humans. The cold-adapted influenza A/Ann Arbor/6/60 virus was isolated after step-wise passage of the influenza A/Ann Arbor/60 wild-type virus at gradually decreasing temperatures to generate a virus that would replicate efficiently at low temperatures, a characteristic which has been empirically found to be associated with loss of virulence for many viruses (18). Subsequent genetic studies have established that several mutations, in addition to those responsible for cold-adaptation, are involved in the attenuation of the cold-adapted A/Ann Arbor/6/60 virus and its reassortants for humans (19, 20). Viruses that derive the gene segments encoding the viral hemagglutinin and neuraminidase from a wild-type influenza A virus and all other gene segments from the cold-adapted A/Ann Arbor/6/60 virus are safe and immunogenic in seronegative young adults and children (21, 22). Such viruses also effectively stimulate local immunity (23, 24) and provide protection against experimental challenge with homologous wild-type viruses at least equal to that provided by inactivated influenza vaccines in adults (25-27). Relatively little is known, however, about the potential protective efficacy of coldadapted influenza A virus vaccines against naturally acquired infection, especially in high-risk groups such as the elderly. We therefore conducted a randomized, double-blind, placebo-controlled study comparing the protective efficacy of combined monovalent cold-adapted H3N2 influenza A virus vaccine plus trivalent inactivated influenza vaccine with that of trivalent inactivated influenza vac© 1992 American College of Physicians
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Table 1. Characteristics of Participants by Type of Intranasal Vaccine and Follow-up before Influenza Surveillance* Year
Study Site
T y p e of Vaccine
Participants
Mean Age (±SD)
n 1987
SAH SJH
1988
SAH SJH MCH
1989
SAH SJH
Placebo ca A/Beth/85 Placebo ca A/Beth/85 Placebo ca A / L A / 8 7 Placebo ca A / L A / 8 7 Placebo ca A / L A / 8 7 Placebo ca A / L A / 8 7 Placebo ca A / L A / 9 7
58 57 34 35 39 37 55 52 31 31 67 76 78 82
Women
%
y 86.4 86.4 82.8 80.4 87.0 85.8 82.8 85.2 75.5 75.5 86.2 85.4 82.6 84.9
HRF L e v e l of Caret
± ± ± ± ± ± ± ± ± ± ± ± ± ±
6 7 7 11 6 7 10 9 13 11 9 10 10 8
84 88 71 66 85 76 80 79 77 74 82 79 73 76
L o s s e s before Influenza Surveillance Deaths
L o s t to Follow-up^
Yl ^~^~
3 5 2 1 0 2 1 1 0 1 7 3 3 5
0 0 0 0 0 1 0 1 0 2 1 1 0 2
55 52 32 34 39 34 54 50 31 28 60 72 75 75
* HRF = health-•related facility; MCH = Monroe Connmunity H 0.2 comparing placebo recipients who received vaccine, placebo, or no vaccine in the previous year. t Chi-square = 2.02; P > 0.2 comparing vaccine recipients who received vaccine, placebo, or no vaccine in the previous year.
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tion, administration of cold-adapted A/Washington/80 and A/Korea/82 viruses to a similar group of volunteers resulted in increased peripheral blood lymphoproliferative responses to the vaccine viruses (41). The potential relation of these observations to the increased protection seen in our study requires further study. Although rates of influenza A virus outbreak associated illnesses were lower in those receiving combined live and inactivated vaccine, the addition of live influenza A vaccine did not influence rates of respiratory illness occurring at other times during the winter and in institutions that did not experience influenza A outbreaks. This result is as expected, because these illnesses were probably not caused by influenza A virus. In particular, we saw no effect of intranasal influenza A vaccine on the rates of respiratory illness in the three outbreaks associated with influenza B virus or in the outbreak caused by respiratory syncytial virus infection. Results of previous studies have also suggested that influenza B and respiratory syncytial viruses may cause significant disease in the elderly (42, 43). Thus, it is necessary to develop additional vaccines to provide more complete protection against respiratory infections in this group. Cold-adapted reassortant influenza B virus vaccines have recently been developed using a similar strategy to that used for development of cold-adapted influenza A viruses, and preliminary results in young adults suggest that these vaccines will also be safe, immunogenic, and genetically stable (44-46). Studies to evaluate the safety and immunogenicity of cold-adapted influenza B virus vaccines and of bivalent cold-adapted influenza A and B virus vaccines in the elderly are currently under way. Use of human volunteers for research purposes followed guidelines of the Clinical Research Subpanel of the National Institute of Allergy and Infectious Diseases, and study protocols were reviewed and approved by the Research Subjects Review Boards of the University of Rochester and the participating institutions. Acknowledgments: The authors thank Paul Miller, Anna-Marie GrothJunker, James Wood, Diane Kane, David Bentley, and the staffs of the St. Ann's and St. John's Homes and the Monroe Community Hospital of Rochester, New York, for their cooperation and assistance. The authors also thank B. Cromie, R. Buja, M.B. Stenard, and R. Simons for technical assistance; Mary Anne Riley for her assistance; and K. Bohn and M. Aldrich for secretarial assistance. Grant Support: By contract N01-AI-05049 from the National Institute of Allergy and Infectious Disease. Requests for Reprints: John J. Treanor, MD, Infectious Disease Unit, University of Rochester, Box 689, 601 Elmwood Avenue, Rochester, NY 14642. Current Author Addresses: Drs. Treanor, Mattison, Dumyati, Yinnon, Dolin, and Betts and Ms. Erb and Ms. O'Brien: University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642.
References 1. Barker WH. Excess pneumonia and influenza associated hospitalization during influenza epidemics in the United States. Am J Public Health. 1986;76:761-5. 2. Williams WW, Hickson MA, Kane MA, Kendal AP, Spika JS, Hinman AR. Immunization policies and vaccine coverage among adults: the risk for missed opportunities. Ann Intern Med. 1988;108:616-25. 3. Barker WH, Mullooly JP. Pneumonia and influenza deaths during epidemics: implications for prevention. Arch Intern Med. 1982; 142: 85-9. 4. Barker WH, Mullooly JP. Impact of epidemic type A influenza in a defined adult population. Am J Epidemiol. 1980;112:798-811. 5. Barker WH, Mullooly JP. Influenza vaccination of elderly persons: reduction in pneumonia and influenza hospitalizations and deaths. JAMA. 1980;244:2547-9. 6. Barker WH, Mullooly JP. Effectiveness of inactivated influenza vaccine among non-institutionalized elderly persons. In: Kendal AP,
632
Patriarca PA; eds. Options for the Control of Influenza. New York: Alan R. Liss; 1986:169-82. 7. Betts RF, Dolin R, Treanor JJ, Roth FK, O'Brien D, Erb S. Inactivated influenza vaccine reduces frequency and severity of illness in the elderly [abstract]. In: Program and Abstracts of the 24th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1984 Oct 8-10; Washington D.C.: American Society for Microbiology 1984; Abstract 289. 8. Gross PA, Quinnan GV, Rodstein M, Lamontagne JR, Kaslow RA, Saah AJ, et al. Association of influenza immunization with reduction in mortality in an elderly population. Arch Intern Med. 1988; 148:562-5. 9. Patriarca PA, Weber JA, Rarker RA, Hall WN, Kendal AP, Bregman DJ, et al. Efficacy of influenza vaccine in nursing homes: reduction in illness and complications during an influenza A (H3N2) epidemic. JAMA. 1985;253:1136-9. 10. Patriarca PA, Weber JA, Parker RA, Orenstein WA, Hall WN, Kendal AP, et al. Risk factors for outbreaks of influenza in nursing homes: a case-control study. Am J Epidemiol. 1986;124:114-9. 11. Feery BJ, Evered MG, Morrison EI. Different protection rates in various groups of volunteers given subunit influenza virus vaccines in 1976. J Infect Dis. 1979;139:237-41. 12. Saah AJ, Neufeld R, Rodstein M, LaMontagne JR, Blackwelder WC, Gross P, et al. Influenza vaccine and pneumonia mortality in a nursing home population. Arch Intern Med. 1986;146:2353-7. 13. Carter ML, Renzullo PO, Helgerson SD, Martin SM, Jekel JF. Influenza outbreaks in nursing homes: how effective is influenza vaccine in the institutionalized elderly? Infect Control Hosp Epidemiol. 1986;11:473-8. 14. Arden NH, Patriarca PA, Kendal AP. Experiences in the use and efficacy of inactivated influenza vaccine in nursing homes. In: Kendal AO, Patriarca PA; eds. Options for the Control of Influenza. New York: Alan R. Liss;1986:155-168. 15. Arroyo JC, Postic B, Brown A, Harrison K, Birgenheier R, Dowda H. Influenza A/Philippines/2/82 outbreak in a nursing home: limitations of influenza vaccination in the aged. Am. J Infect Control. 1984;12:329-34. 16. Ruben FL, Johnston F, Streiff EJ. Influenza in a partially immunized aged population: effectiveness of killed Hong Kong Vaccine against infection with the England Strain. JAMA. 1974;230:863-6. 17. Horman JT, Stetler HC, Israel E, Sorley D, Schipper MT, Joseph JM. An outbreak of influenza A in a nursing home. Am J Public Health. 1986;76:501-4. 18. Maassab HF, DeBorde DC. Development and characterization of cold-adapted viruses for use as live virus vaccines. Vaccine. 1985; 3:355-69. 19. Cox NJ, Kitame F, Kendal AP, Maassab HF, Naeve C. Identification of sequence changes in the cold-adapted, live attenuated influenza vaccine strain, A/Ann Arbor/6/60. Virology. 1988;167:554-67. 20. Snyder MH, Betts RF, DeBorde D, Tierney EL, Clements ML, Herrington D, et al. Four viral genes independently contribute to the attenuation of live influenza A/Ann Arbor/6/60 (H2N2) cold-adapted reassortant virus vaccines. J Virol. 1988;62:488-95. 21. Johnson PR, Feldman S, Thompson JM, Mahoney JD, Wright PF. Immunity to influenza A virus infection in young children: a comparison of natural infection, live cold-adapted vaccine, and inactivated vaccine. J Infect Dis. 1986;154:121-7. 22. Johnson PR, Feldman S, Thompson JM, Mahoney JD, Wright PF. Comparison of long-term systemic and secretory antibody responses in children given live, attenuated, or inactivated influenza A vaccine. J Med Virol. 1985;17:325-35. 23. Anderson EL, Belshe RB, Burk B, Bartram J, Maassab HF. Evaluation of cold-recombinant influenza A/Korea (CR-59) virus vaccine in infants. J Clin Microbiol. 1989;27:909-14. 24. Belshe RB, Van Voris LP, Bartram J, and Crookshanks FK. Live attenuated influenza A virus vaccines in children: results of a field trial. J Infect Dis. 1984;150:834-40. 25. Betts RF, Douglas RG, and Murphy BR. Resistance to challenge with influenza A/Hong Kong/123/77 (H1N1) wild-type virus induced by live attenuated A/Hong Kong/123/77 (H1N1) cold-adapted reassortant virus. J Infect Dis. 1985;151:744-5. 26. Clements ML, Betts RF, Murphy BR. Advantage of live attenuated cold-adapted influenza A virus over inactivated vaccine for A/Washington/80 (H3N2) wild-type virus infection. Lancet. 1984;1:704-8. 27. Clements ML, Betts RF, Tierney EL, and Murphy BR. Resistance of adults to challenge with influenza A wild-type virus after receiving live or inactivated virus vaccine. J Clin Microbiol. 1986;23:73-6. 28. Sears SD, Clements ML, Betts RF, Maassab HF, Murphy BR, Snyder MH. Comparison of live attenuated H1N1 and H3N2 coldadapted and avian-human influenza A reassortant viruses and inactivated virus vaccine in adults. J Infect Dis. 1988;158:1209-18. 29. Murphy BR, Chanock RM, Clements ML, Anthony WC, Sear AJ, Cisneros LA, et al. Evaluation of A/Alaska/6/77 (H3N2) coldadapted recombinant viruses derived from A/Ann Arbor/6/60 coldadapted donor virus in adult seronegative volunteers. Infect Immun. 1981;32:693-7.
15 October 1992 • Annals of Internal Medicine • Volume 117 • Number 8
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30. Hall CB, Douglas RG Jr. Respiratory syncytial virus and influenza: practical community surveillance. Am Jour Dis Child. 1976; 130:61520. 31. Madore HP, Reichman RC, Dolin R. Serum antibody responses in naturally occurring influenza A virus infection determined by enzyme-linked immunosorbent assay, hemagglutination inhibition, and complement fixation. J Clin Microbiol. 1983;18:1345-50. 32. Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic Research: Principles and Quantitative Methods. 1982, Lifetime Learning Publications, Belmont, California. 33. Anonymous. Prevention and control of influenza. Recommendations of the immunization practices advisory committee (ACIP). MMWR. 1990;39 RR 7:1-15. 34. Falsey AR, Treanor JJ, Betts RF, Walsh EE. Viral Respiratory Infections in the Institutionalized Elderly: Clinical and Epidemiological Findings. J Am Ger Soc. 1992;40:115-9. 35. Budnick LD, Stricof RL, Ellis F. An outbreak of influenza A in a nursing home, 1982. N Y State J Med. 1984;84:235-8. 36. Powers DC, Sears SD, Murphy BR, Thumar B, Clements ML. Systemic and local antibody responses in elderly subjects given live or inactivated influenza A virus vaccines. J Clin Microbiol. 1989;27: 2666-71. 37. Gorse GJ, Belshe RB, Munn NJ. Safety of and serum antibody response to cold-recombinant influenza A and inactivated trivalent influenza virus vaccines in older adults with chronic diseases. J Clin Microbiol. 1986;24:336-42. 38. Gorse GJ, Belshe RB, and Munn NJ. Local and systemic antibody responses in high-risk adults given live attenuated and inactivated influenza A virus vaccines. J Clin Microbiol. 1986;26:911-8. 39. Powers DC, Fries LF, Murphy BR, Thumar JB, Clements ML. In
40.
41.
42.
43.
44.
45.
46.
elderly persons live attenuated influenza A virus vaccines do not offer an advantage over inactivated virus vaccine in inducing serum or secretory antibodies or local immunologic memory. J Clin Microbiol. 1991;29:498-505. Gorse GJ, Belshe RB. Enhancement of anti-influenza A virus cytotoxicity following influenza A virus vaccination in older, chronically ill adults. J Clin Microbiol. 1990;28:2539-50. Gorse GJ, Belshe RB. Enhanced lymphoproliferation to influenza a virus following vaccination of older chronically ill adults with liveattenuated viruses. Scand J Infect Dis. 1990;23:7-16. Gross PA, Rodstein M, LaMontagne JR, Kaslow RA, Saah AJ, Wallenstein S, et al. Epidemiology of acute respiratory illness during an influenza outbreak in a nursing home. Arch Intern Med. 1988; 148:559-61. Mathur U, Bentley DW, Hall CB. Concurrent respiratory syncytial virus and influenza A infections in the institutionalized elderly and chronically ill. Ann Intern Med. 1980;93:49-52. Atmar RL, Bloom K, Keitel W, Couch RB, Greenberg SB. Effect of live attenuated cold recombinant (CR) influenza virus vaccines on pulmonary function in healthy and asthmatic adults. Vaccine. 1990; 8:217-24. Snyder MH, London WT, Maassab HF, Murphy BR. Attenuation and phenotypic stability of influenza B/Texas/1/84 cold-adapted reassortant virus: studies in hamsters and chimpanzees. J Infect Dis. 1989;160:604-10. Clements ML, Snyder MH, Sears SD, Maassab HF, Murphy BR. Evaluation of the infectivity, immunogenicity and efficacy of live cold-adapted influenza B/Ann Arbor/1/86 reassortant virus vaccine in adult volunteers. J Infect Dis. 1990;161:869-77.
According to an old story, a lord of ancient China once asked his physician, a member of a family of healers, which of them was the most skilled in the art. The physician, whose reputation was such that his name became synonymous with medical science in China, replied, "My eldest brother sees the spirit of sickness and removes it before it takes shape, so his name does not get out of the house. "My elder brother cures sickness when it is still extremely minute, so his name does not get out of the neighborhood. "As for me, I puncture veins, prescribe potions, and massage skin, so from time to time my name gets out and is heard among the lords." Thomas Cleary Translator's Introduction to The Art of War by Sun Tzu, Shambhala Boston: Shambhala; 1988, p. 1 Submitted by: Barbara Barnes, MD Erie, PA
Submissions from readers are welcomed. If the quotation is published, the sender's name will be acknowledged. Please include a complete citation, as done for any reference.—The Editors
15 O c t o b e r 1992 • Annals
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• V o l u m e 117 • N u m b e r 8
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Volume 117
Number 8
Annals of Internal Medicine Protective Efficacy of Combined Live Intranasal and Inactivated Influenza A Virus Vaccines in the Elderly John J. Treanor, MD; H. Reid Mattison, MD; Ghinwa Dumyati, MD; Amos Yinnon, MD; Shirley Erb, RN; Diane O'Brien, RN; Raphael Dolin, MD; and Robert F. Betts, MD
• Objective: To evaluate the efficacy of adding intranasal live attenuated cold-adapted influenza A vaccine to inactivated influenza vaccine to prevent influenza A in elderly residents of long-term-care institutions. • Design: Randomized, double-blind, placebocontrolled study conducted over 3 years. • Setting: Three large nursing homes. • Participants: A total of 523 residents of nursing homes (mean age, 84.2 years). • Interventions: All participants received trivalent inactivated influenza vaccine parenterally and were randomly assigned to receive either live attenuated influenza A (H3N2) virus vaccine or placebo intranasally. • Measurements: Laboratory-documented influenza A was defined as a respiratory illness plus isolation of influenza A virus from nasal secretions, significant serologic response, or both. Participants were considered to have been exposed to influenza A if they resided in an institution in which cases of influenza A were documented. Outbreak-associated illnesses were defined as those occurring between the first and last isolation of influenza virus from within the institution, ± 3 days. • Results: Participants who received intranasal vaccine and were subsequently exposed to influenza A had significantly lower rates of laboratory-documented influenza A (9 of 162 vaccine recipients compared with 24 of 169 placebo recipients; vaccine protective efficacy, 60.6%; 95% CI, 18% to 82%), outbreak-associated respiratory illnesses (13 of 162 vaccine recipients compared with 34 of 169 placebo recipients; vaccine protective efficacy, 56.8%; CI 23% to 76%), and outbreakassociated influenza-like illnesses (6 of 162 vaccine recipients compared with 18 of 169 placebo recipients; vaccine protective efficacy, 65.0%; CI 17% to 86%). • Conclusions: Intranasal immunization with live attenuated influenza A virus vaccine provided additional protection against influenza A when added to parenteral trivalent inactivated influenza vaccine among elderly nursing home residents. Annals of Internal Medicine. 1992;117:625-633. From the University of Rochester, Rochester, New York. For current author addresses, see end of text.
Influenza is an important cause of morbidity and mortality, especially among high-risk groups such as the elderly and those with chronic cardiac or pulmonary conditions (1-4). Inactivated influenza vaccines are effective in preventing influenza-related morbidity and mortality in the elderly (5-10), but variable degrees of protection have been observed, and significant influenza illness continues to occur in the elderly despite the availability of inactivated vaccine (11-17). Development of more effective control measures for influenza in these persons is, therefore, highly desirable. Live, attenuated influenza A viruses generated by genetic reassortment between a wild-type influenza A virus and the cold-adapted influenza A/Ann Arbor/6/60 (H2N2) virus are currently being evaluated as potential vaccines in humans. The cold-adapted influenza A/Ann Arbor/6/60 virus was isolated after step-wise passage of the influenza A/Ann Arbor/60 wild-type virus at gradually decreasing temperatures to generate a virus that would replicate efficiently at low temperatures, a characteristic which has been empirically found to be associated with loss of virulence for many viruses (18). Subsequent genetic studies have established that several mutations, in addition to those responsible for cold-adaptation, are involved in the attenuation of the cold-adapted A/Ann Arbor/6/60 virus and its reassortants for humans (19, 20). Viruses that derive the gene segments encoding the viral hemagglutinin and neuraminidase from a wild-type influenza A virus and all other gene segments from the cold-adapted A/Ann Arbor/6/60 virus are safe and immunogenic in seronegative young adults and children (21, 22). Such viruses also effectively stimulate local immunity (23, 24) and provide protection against experimental challenge with homologous wild-type viruses at least equal to that provided by inactivated influenza vaccines in adults (25-27). Relatively little is known, however, about the potential protective efficacy of coldadapted influenza A virus vaccines against naturally acquired infection, especially in high-risk groups such as the elderly. We therefore conducted a randomized, double-blind, placebo-controlled study comparing the protective efficacy of combined monovalent cold-adapted H3N2 influenza A virus vaccine plus trivalent inactivated influenza vaccine with that of trivalent inactivated influenza vac© 1992 American College of Physicians
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Table 1. Characteristics of Participants by Type of Intranasal Vaccine and Follow-up before Influenza Surveillance* Year
Study Site
T y p e of Vaccine
Participants
Mean Age (±SD)
n 1987
SAH SJH
1988
SAH SJH MCH
1989
SAH SJH
Placebo ca A/Beth/85 Placebo ca A/Beth/85 Placebo ca A / L A / 8 7 Placebo ca A / L A / 8 7 Placebo ca A / L A / 8 7 Placebo ca A / L A / 8 7 Placebo ca A / L A / 9 7
58 57 34 35 39 37 55 52 31 31 67 76 78 82
Women
%
y 86.4 86.4 82.8 80.4 87.0 85.8 82.8 85.2 75.5 75.5 86.2 85.4 82.6 84.9
HRF L e v e l of Caret
± ± ± ± ± ± ± ± ± ± ± ± ± ±
6 7 7 11 6 7 10 9 13 11 9 10 10 8
84 88 71 66 85 76 80 79 77 74 82 79 73 76
L o s s e s before Influenza Surveillance Deaths
L o s t to Follow-up^
Yl ^~^~
3 5 2 1 0 2 1 1 0 1 7 3 3 5
0 0 0 0 0 1 0 1 0 2 1 1 0 2
55 52 32 34 39 34 54 50 31 28 60 72 75 75
* HRF = health-•related facility; MCH = Monroe Connmunity H 0.2 comparing placebo recipients who received vaccine, placebo, or no vaccine in the previous year. t Chi-square = 2.02; P > 0.2 comparing vaccine recipients who received vaccine, placebo, or no vaccine in the previous year.
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tion, administration of cold-adapted A/Washington/80 and A/Korea/82 viruses to a similar group of volunteers resulted in increased peripheral blood lymphoproliferative responses to the vaccine viruses (41). The potential relation of these observations to the increased protection seen in our study requires further study. Although rates of influenza A virus outbreak associated illnesses were lower in those receiving combined live and inactivated vaccine, the addition of live influenza A vaccine did not influence rates of respiratory illness occurring at other times during the winter and in institutions that did not experience influenza A outbreaks. This result is as expected, because these illnesses were probably not caused by influenza A virus. In particular, we saw no effect of intranasal influenza A vaccine on the rates of respiratory illness in the three outbreaks associated with influenza B virus or in the outbreak caused by respiratory syncytial virus infection. Results of previous studies have also suggested that influenza B and respiratory syncytial viruses may cause significant disease in the elderly (42, 43). Thus, it is necessary to develop additional vaccines to provide more complete protection against respiratory infections in this group. Cold-adapted reassortant influenza B virus vaccines have recently been developed using a similar strategy to that used for development of cold-adapted influenza A viruses, and preliminary results in young adults suggest that these vaccines will also be safe, immunogenic, and genetically stable (44-46). Studies to evaluate the safety and immunogenicity of cold-adapted influenza B virus vaccines and of bivalent cold-adapted influenza A and B virus vaccines in the elderly are currently under way. Use of human volunteers for research purposes followed guidelines of the Clinical Research Subpanel of the National Institute of Allergy and Infectious Diseases, and study protocols were reviewed and approved by the Research Subjects Review Boards of the University of Rochester and the participating institutions. Acknowledgments: The authors thank Paul Miller, Anna-Marie GrothJunker, James Wood, Diane Kane, David Bentley, and the staffs of the St. Ann's and St. John's Homes and the Monroe Community Hospital of Rochester, New York, for their cooperation and assistance. The authors also thank B. Cromie, R. Buja, M.B. Stenard, and R. Simons for technical assistance; Mary Anne Riley for her assistance; and K. Bohn and M. Aldrich for secretarial assistance. Grant Support: By contract N01-AI-05049 from the National Institute of Allergy and Infectious Disease. Requests for Reprints: John J. Treanor, MD, Infectious Disease Unit, University of Rochester, Box 689, 601 Elmwood Avenue, Rochester, NY 14642. Current Author Addresses: Drs. Treanor, Mattison, Dumyati, Yinnon, Dolin, and Betts and Ms. Erb and Ms. O'Brien: University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642.
References 1. Barker WH. Excess pneumonia and influenza associated hospitalization during influenza epidemics in the United States. Am J Public Health. 1986;76:761-5. 2. Williams WW, Hickson MA, Kane MA, Kendal AP, Spika JS, Hinman AR. Immunization policies and vaccine coverage among adults: the risk for missed opportunities. Ann Intern Med. 1988;108:616-25. 3. Barker WH, Mullooly JP. Pneumonia and influenza deaths during epidemics: implications for prevention. Arch Intern Med. 1982; 142: 85-9. 4. Barker WH, Mullooly JP. Impact of epidemic type A influenza in a defined adult population. Am J Epidemiol. 1980;112:798-811. 5. Barker WH, Mullooly JP. Influenza vaccination of elderly persons: reduction in pneumonia and influenza hospitalizations and deaths. JAMA. 1980;244:2547-9. 6. Barker WH, Mullooly JP. Effectiveness of inactivated influenza vaccine among non-institutionalized elderly persons. In: Kendal AP,
632
Patriarca PA; eds. Options for the Control of Influenza. New York: Alan R. Liss; 1986:169-82. 7. Betts RF, Dolin R, Treanor JJ, Roth FK, O'Brien D, Erb S. Inactivated influenza vaccine reduces frequency and severity of illness in the elderly [abstract]. In: Program and Abstracts of the 24th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1984 Oct 8-10; Washington D.C.: American Society for Microbiology 1984; Abstract 289. 8. Gross PA, Quinnan GV, Rodstein M, Lamontagne JR, Kaslow RA, Saah AJ, et al. Association of influenza immunization with reduction in mortality in an elderly population. Arch Intern Med. 1988; 148:562-5. 9. Patriarca PA, Weber JA, Rarker RA, Hall WN, Kendal AP, Bregman DJ, et al. Efficacy of influenza vaccine in nursing homes: reduction in illness and complications during an influenza A (H3N2) epidemic. JAMA. 1985;253:1136-9. 10. Patriarca PA, Weber JA, Parker RA, Orenstein WA, Hall WN, Kendal AP, et al. Risk factors for outbreaks of influenza in nursing homes: a case-control study. Am J Epidemiol. 1986;124:114-9. 11. Feery BJ, Evered MG, Morrison EI. Different protection rates in various groups of volunteers given subunit influenza virus vaccines in 1976. J Infect Dis. 1979;139:237-41. 12. Saah AJ, Neufeld R, Rodstein M, LaMontagne JR, Blackwelder WC, Gross P, et al. Influenza vaccine and pneumonia mortality in a nursing home population. Arch Intern Med. 1986;146:2353-7. 13. Carter ML, Renzullo PO, Helgerson SD, Martin SM, Jekel JF. Influenza outbreaks in nursing homes: how effective is influenza vaccine in the institutionalized elderly? Infect Control Hosp Epidemiol. 1986;11:473-8. 14. Arden NH, Patriarca PA, Kendal AP. Experiences in the use and efficacy of inactivated influenza vaccine in nursing homes. In: Kendal AO, Patriarca PA; eds. Options for the Control of Influenza. New York: Alan R. Liss;1986:155-168. 15. Arroyo JC, Postic B, Brown A, Harrison K, Birgenheier R, Dowda H. Influenza A/Philippines/2/82 outbreak in a nursing home: limitations of influenza vaccination in the aged. Am. J Infect Control. 1984;12:329-34. 16. Ruben FL, Johnston F, Streiff EJ. Influenza in a partially immunized aged population: effectiveness of killed Hong Kong Vaccine against infection with the England Strain. JAMA. 1974;230:863-6. 17. Horman JT, Stetler HC, Israel E, Sorley D, Schipper MT, Joseph JM. An outbreak of influenza A in a nursing home. Am J Public Health. 1986;76:501-4. 18. Maassab HF, DeBorde DC. Development and characterization of cold-adapted viruses for use as live virus vaccines. Vaccine. 1985; 3:355-69. 19. Cox NJ, Kitame F, Kendal AP, Maassab HF, Naeve C. Identification of sequence changes in the cold-adapted, live attenuated influenza vaccine strain, A/Ann Arbor/6/60. Virology. 1988;167:554-67. 20. Snyder MH, Betts RF, DeBorde D, Tierney EL, Clements ML, Herrington D, et al. Four viral genes independently contribute to the attenuation of live influenza A/Ann Arbor/6/60 (H2N2) cold-adapted reassortant virus vaccines. J Virol. 1988;62:488-95. 21. Johnson PR, Feldman S, Thompson JM, Mahoney JD, Wright PF. Immunity to influenza A virus infection in young children: a comparison of natural infection, live cold-adapted vaccine, and inactivated vaccine. J Infect Dis. 1986;154:121-7. 22. Johnson PR, Feldman S, Thompson JM, Mahoney JD, Wright PF. Comparison of long-term systemic and secretory antibody responses in children given live, attenuated, or inactivated influenza A vaccine. J Med Virol. 1985;17:325-35. 23. Anderson EL, Belshe RB, Burk B, Bartram J, Maassab HF. Evaluation of cold-recombinant influenza A/Korea (CR-59) virus vaccine in infants. J Clin Microbiol. 1989;27:909-14. 24. Belshe RB, Van Voris LP, Bartram J, and Crookshanks FK. Live attenuated influenza A virus vaccines in children: results of a field trial. J Infect Dis. 1984;150:834-40. 25. Betts RF, Douglas RG, and Murphy BR. Resistance to challenge with influenza A/Hong Kong/123/77 (H1N1) wild-type virus induced by live attenuated A/Hong Kong/123/77 (H1N1) cold-adapted reassortant virus. J Infect Dis. 1985;151:744-5. 26. Clements ML, Betts RF, Murphy BR. Advantage of live attenuated cold-adapted influenza A virus over inactivated vaccine for A/Washington/80 (H3N2) wild-type virus infection. Lancet. 1984;1:704-8. 27. Clements ML, Betts RF, Tierney EL, and Murphy BR. Resistance of adults to challenge with influenza A wild-type virus after receiving live or inactivated virus vaccine. J Clin Microbiol. 1986;23:73-6. 28. Sears SD, Clements ML, Betts RF, Maassab HF, Murphy BR, Snyder MH. Comparison of live attenuated H1N1 and H3N2 coldadapted and avian-human influenza A reassortant viruses and inactivated virus vaccine in adults. J Infect Dis. 1988;158:1209-18. 29. Murphy BR, Chanock RM, Clements ML, Anthony WC, Sear AJ, Cisneros LA, et al. 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30. Hall CB, Douglas RG Jr. Respiratory syncytial virus and influenza: practical community surveillance. Am Jour Dis Child. 1976; 130:61520. 31. Madore HP, Reichman RC, Dolin R. Serum antibody responses in naturally occurring influenza A virus infection determined by enzyme-linked immunosorbent assay, hemagglutination inhibition, and complement fixation. J Clin Microbiol. 1983;18:1345-50. 32. Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic Research: Principles and Quantitative Methods. 1982, Lifetime Learning Publications, Belmont, California. 33. Anonymous. Prevention and control of influenza. Recommendations of the immunization practices advisory committee (ACIP). MMWR. 1990;39 RR 7:1-15. 34. Falsey AR, Treanor JJ, Betts RF, Walsh EE. Viral Respiratory Infections in the Institutionalized Elderly: Clinical and Epidemiological Findings. J Am Ger Soc. 1992;40:115-9. 35. Budnick LD, Stricof RL, Ellis F. An outbreak of influenza A in a nursing home, 1982. N Y State J Med. 1984;84:235-8. 36. Powers DC, Sears SD, Murphy BR, Thumar B, Clements ML. Systemic and local antibody responses in elderly subjects given live or inactivated influenza A virus vaccines. J Clin Microbiol. 1989;27: 2666-71. 37. Gorse GJ, Belshe RB, Munn NJ. Safety of and serum antibody response to cold-recombinant influenza A and inactivated trivalent influenza virus vaccines in older adults with chronic diseases. J Clin Microbiol. 1986;24:336-42. 38. Gorse GJ, Belshe RB, and Munn NJ. Local and systemic antibody responses in high-risk adults given live attenuated and inactivated influenza A virus vaccines. J Clin Microbiol. 1986;26:911-8. 39. Powers DC, Fries LF, Murphy BR, Thumar JB, Clements ML. In
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elderly persons live attenuated influenza A virus vaccines do not offer an advantage over inactivated virus vaccine in inducing serum or secretory antibodies or local immunologic memory. J Clin Microbiol. 1991;29:498-505. Gorse GJ, Belshe RB. Enhancement of anti-influenza A virus cytotoxicity following influenza A virus vaccination in older, chronically ill adults. J Clin Microbiol. 1990;28:2539-50. Gorse GJ, Belshe RB. Enhanced lymphoproliferation to influenza a virus following vaccination of older chronically ill adults with liveattenuated viruses. Scand J Infect Dis. 1990;23:7-16. Gross PA, Rodstein M, LaMontagne JR, Kaslow RA, Saah AJ, Wallenstein S, et al. Epidemiology of acute respiratory illness during an influenza outbreak in a nursing home. Arch Intern Med. 1988; 148:559-61. Mathur U, Bentley DW, Hall CB. Concurrent respiratory syncytial virus and influenza A infections in the institutionalized elderly and chronically ill. Ann Intern Med. 1980;93:49-52. Atmar RL, Bloom K, Keitel W, Couch RB, Greenberg SB. Effect of live attenuated cold recombinant (CR) influenza virus vaccines on pulmonary function in healthy and asthmatic adults. Vaccine. 1990; 8:217-24. Snyder MH, London WT, Maassab HF, Murphy BR. Attenuation and phenotypic stability of influenza B/Texas/1/84 cold-adapted reassortant virus: studies in hamsters and chimpanzees. J Infect Dis. 1989;160:604-10. Clements ML, Snyder MH, Sears SD, Maassab HF, Murphy BR. Evaluation of the infectivity, immunogenicity and efficacy of live cold-adapted influenza B/Ann Arbor/1/86 reassortant virus vaccine in adult volunteers. J Infect Dis. 1990;161:869-77.
According to an old story, a lord of ancient China once asked his physician, a member of a family of healers, which of them was the most skilled in the art. The physician, whose reputation was such that his name became synonymous with medical science in China, replied, "My eldest brother sees the spirit of sickness and removes it before it takes shape, so his name does not get out of the house. "My elder brother cures sickness when it is still extremely minute, so his name does not get out of the neighborhood. "As for me, I puncture veins, prescribe potions, and massage skin, so from time to time my name gets out and is heard among the lords." Thomas Cleary Translator's Introduction to The Art of War by Sun Tzu, Shambhala Boston: Shambhala; 1988, p. 1 Submitted by: Barbara Barnes, MD Erie, PA
Submissions from readers are welcomed. If the quotation is published, the sender's name will be acknowledged. Please include a complete citation, as done for any reference.—The Editors
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