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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 56:M391-M394 (2001)
© 2001 The Gerontological Society of America

Efficacy of Influenza Vaccine in Elderly Persons in Welfare Nursing Homes

Reduction in Risks of Mortality and Morbidity During an Influenza A (H3N2) Epidemic

Yasuhiro Deguchia and Kumi Nishimurab

a Elderly Citizens Care Office, Department of Social Welfare, Osaka Prefectural Government, Japan
b Postgraduate School of Medicine and Faculty of Medicine, Osaka University Medical School, Japan

Yasuhiro Deguchi, Elderly Citizens Care Office and Department of Social Welfare, Osaka Prefectural Government, Ohtemae, Chuo-Ku, Osaka-City, Osaka 540-8570 E-mail: yasudeguchi{at}nyc.odn.ne.jp.

Decision Editor: John E. Morley, MB, BCh


   Abstract
Top
 Abstract
Subjects and Methods
 Results
 Discussion
 References
 
Background. The effect of influenza vaccination on the occurrence and severity of influenza virus infection in a population residing in nursing homes was studied through a program by the Osaka Prefectural Government, which is the first and official support for influenza vaccination of the elderly population during an influenza A (H3N2) epidemic in Japan.

Methods. A cohort study located in the Osaka Prefecture, Japan, followed the outcomes of elderly nursing home residents who received influenza vaccinations (n = 10,739) in comparison with control subjects who did not receive influenza vaccinations (n = 11,723) and monitored clinically the onset of serious morbidity and mortality of influenza illness. Subjects were 22,462 persons older than 65 years who resided in 301 welfare nursing homes in the Osaka Prefecture, Japan during an influenza A (H3N2) epidemic in 1998 to 1999.

Results. Of 22,462 individuals living in 301 nursing homes, 10,739 received either one dose (2027 subjects) or two doses (8712 subjects) of inactivated, subunit trivalent influenza vaccine. Through the period from November 1998 to March 1999, there were 950 cases of influenza infection diagnosed clinically with cases by virus isolation and/or serology. There were statistically significantly fewer clinical cases of influenza, hospital admissions due to severe infection, and deaths due to influenza in the vaccinated cohort (256 cases, 32 hospital admissions, and one death) compared with the unvaccinated controls (694 cases, 150 hospital admissions, and five deaths). Vaccination was equally effective in those who received one dose of vaccine as in those who received two doses. No serious adverse reactions to vaccination were recorded. Thus, influenza vaccination is safe and effective in this population and should be an integral part of the routine care of persons aged 65 years and older residing in nursing homes.

Conclusions. This study provides an analysis of the clinical efficacy of influenza vaccination in a large cohort of nursing home residents in Japan. Annual influenza vaccine administration requires the attention of all nursing home attendants, physicians, and public health organizations.

INFLUENZA A and B viruses are among the most common causes of respiratory tract illnesses that bring elderly persons to seek medical care (1). Influenza infections more commonly result in medical consultation than do infections with other respiratory viruses (1). In some countries, such as the United States, annual influenza vaccination is recommended for all persons aged 65 years and older and for persons with certain chronic medical disorders (2)(3)(4)(5)(6). However, there remains a question as to the efficacy of influenza vaccination in persons aged more than 65 years in Japan, and no official support for the elderly population by the government for influenza vaccination has yet been established. More than 90% of the deaths attributed to pneumonia and influenza during epidemics occur among persons aged 65 years and older (7). In nursing homes, residents live in a group that shares a similar lifestyle. Intervention to prevent infectious diseases, including influenza, is important for these nursing home residents, as influenza viruses cause mortality and serious morbidity among those aged 65 years or more (2)(3)(4)(5)(6)(7). Currently available influenza vaccines are effective only against infectious viral strains with hemagglutinins of similar antigenic characteristics. In Japan, a severe influenza epidemic in persons aged over 65 years recently occurred. Therefore, annual influenza immunization is now considered important for the prevention of influenza. This cohort study provides an analysis of the clinical efficacy of influenza vaccination in elderly residents of welfare nursing homes in Japan.


   Subjects and Methods
Top
 Abstract
 Subjects and Methods
Results
 Discussion
 References
 
We studied 22,462 people aged more than 65 years requiring daily care and rehabilitation with the government-supported program for social welfare. All participants resided in the 301 welfare nursing homes for elderly persons in the Osaka Prefecture, Japan, during an influenza (H3N2) epidemic season (November 1998 to March 1999). Peak influenza A (H3N2) activity, as determined by laboratory diagnosis (8)(9)(10)(11)(12) described later, occurred in January of 1999.

Vaccination Protocol
This study of influenza vaccination in elderly nursing home residents, which was supported by the Osaka Prefectural Government, was announced and recommended for all welfare nursing homes (N = 301) with elderly residents in the Osaka Prefecture. The vaccinated group consisted of 10,739 persons (47.8% of the whole cohort) who voluntarily received, always with informed consent, either one (2027 subjects) or two (8712 subjects) doses of influenza vaccine (inactivated, killed, and subunit HA-influenza vaccine A, B, Japanese type, manufactured by the Research Foundation for Microbial Diseases of Osaka University and other pharmacological companies, Japan) by subcutaneous injections as recommended (13)(14). There were 11,723 (52.2%) unvaccinated persons in the control group. Differences in the mean age and gender ratios between these two groups were not statistically significant (mean age, 79.3/80.0 y for men; 83.4/82.3 y for women; 82.6/81.4 y for the total number of subjects; the gender ratio was 0.30:0.35, respectively, for the vaccinated and control groups). In both groups, other information, such as previous influenza vaccination status, underlying diseases, and prevalence of dementia, was not monitored. Vaccine strains used in this study were influenza A/Beijing/262/95 (H1N1), A/Sydney/05/97 (H3N2), and B/Mie/1/93 virus culture extracts with chick cell agglutinin in egg allantoic fluid (8)(9).

Diagnosis of Respiratory Tract Infections
Cases of influenza in this study were diagnosed clinically and cases in active surveillance with virus isolation and/or serology as described below (10)(11)(12) in a prospective study. Staff at the study-site nursing homes were instructed to collect specimens for virus culture from subjects within 4 days of onset of an illness presenting with any of the following symptoms: fever, runny nose or nasal congestion, sore throat, cough, headache, muscle aches, chills, vomiting, decreased activity, irritability, wheezing, shortness of breath, and pulmonary congestion. Rhesus monkey kidney cell cultures were inoculated with fresh respiratory secretions within 4 hours of collection, or as soon as possible thereafter, for culture of influenza viruses (10). Serum samples were also obtained from volunteer subjects with cold symptoms, stored at -20°C, and assayed for the presence of hemagglutinating-inhibiting antibodies Scientific Research Laboratory (SRL) and the Research Foundation for Microbial Diseases of Osaka University, Japan to several viral strains, including the three viral strains contained in the vaccine (11)(12). More than eight times the antibody response to the influenza viral antigen was considered seropositive for the viral infection (12)(13). Reports of illness provided by study-site staff also included whether patients were treated by a primary care provider; if so, the provider's diagnosis and treatment were recorded. Antiinfluenza medications were used for treatment in severe cases of influenza illness but not for prophylaxis.

Statistical Analysis
Statistical analyses were based on Student's t-test method (14)(15), and data analysis was performed with statistical power calculations using the SPSS/PC statistical package (SPSS, Inc, Chicago, IL) (16), which calculates a polled rate difference and provides an absolute percentage reduction between the vaccinated and control groups. Confidence intervals for the ratio of mean episodes were computed with Poisson regression, with an offset reflecting the length of time available for observation. For all analyses, p values < .05 were considered significant. The percentage of reduction in the mean number of episodes (reduction rate) was calculated with the following equation: 100 x (1 - ratio of mean episodes [vaccinated/unvaccinated]).


   Results
Top
 Abstract
 Subjects and Methods
 Results
Discussion
 References
 
There were 950 episodes of influenza illness among 22,462 subjects during the study period, diagnosed clinically with cases by virus culture and/or serodiagnosis. The temporal distribution of influenza episodes in the study cohort was similar to the overall epidemic curve as defined by isolations of influenza A (H3N2), which is the serological match to the vaccine strains used in this study in Japan (data not shown). Influenza illness was significantly less common in the vaccinated group (256 cases among 10,739 subjects) than in the unvaccinated control group (694 cases among 11,723 subjects; Table 1 ). The efficacy of vaccine was the same for both men and women. The severity of illness, patient hospitalization and mortality rates were all lower in the vaccinated group. Influenza was diagnosed clinically in 5.92% of the unvaccinated group, but in only 2.38% of the vaccinated group (reduction rate, 59.7%). The hospitalization rate was reduced by vaccination from 1.3% to 0.3% (reduction rate, 76.7%), and mortality was reduced from 0.043% to 0.009% (reduction rate, 78.2%). These differences between the vaccinated and unvaccinated groups were statistically significant (log-rank test, p < .001; Table 2 ).


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  		Table 1. Characteristics of 22,462 Nursing Home Residents From 1998–1999

 

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  		Table 2. Ratios of Cumulative Incidences of Cases to Total Number of Persons in Vaccinated and Unvaccinated (Control) Groups

 
The influenza vaccine was efficacious in preventing influenza virus infection, but not other causes of respiratory tract infection. This is illustrated in Table 3 , which shows representative data derived from nursing homes in which epidemics of respiratory tract infection occurred. In two of these, the epidemic was due to influenza virus, although in the third, the epidemic was due to other infection. The rate of illness in the latter nursing home was the same in the vaccinated and unvaccinated groups.


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  		Table 3. Data for Efficacy of Influenza Vaccine in Elderly Nursing Home Residents

 
Antibody responses to the influenza vaccine were investigated in elderly nursing home residents. We confirmed the increase of titres of antibody responses to the vaccine as more than 8-fold and detected better responses to the influenza A strains (H1N1 and H3N2) than to influenza B subtypes (data not shown). The vaccine used in this study was highly immunogenic for the influenza A strains (H1N1 and H3N2) after the first dose. Overall, in our study, after two doses of vaccine, 91% of initially low-level or seronegative elderly persons had effective antibodies to influenza A strains (H1N1 and H3N2) (data not shown). We monitored the postvaccination reactions in all 10,739 cases in this study for 1 week to evaluate whether there were any side effects due to the influenza vaccination, such as fever or local swelling and pain. However, no serious adverse events, such as anaphylaxis, were found in any case. A sore arm, with local swelling and pain, was the only event reported within 48 hours, and it healed completely after 3 days.

Sufficient immunogenic activity requires more than 2 or 3 weeks after immunization to prevent influenza (2)(3)(4). To avoid contamination of the data for the vaccinated group by influenza infections occurring prior to the acquisition of a protective immune response, we further analyzed the data after eliminating the 115 cases of influenza that were detected less than 3 weeks after the influenza vaccination. As shown in Table 4 , the efficacy of the influenza vaccination remained statistically significant (log-rank test, p < .001). Furthermore, it can be seen from Table 4 , that there was no significant difference in preventing influenza between one and two doses of vaccine.


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  		Table 4. Vaccine Effectiveness in Patients With Influenza Onset More Than 3 Weeks After Influenza Vaccination (n = 10,624)

 

   Discussion
Top
 Abstract
 Subjects and Methods
 Results
 Discussion
References
 
The results in this study of patients in welfare nursing homes are compatible with the findings of several recent studies (reviewed in (17)) on the efficacy of the influenza vaccine in elderly persons. The risk of onset of illness was moderately reduced by influenza vaccination (risk reduction rate: 100 x [1- ratio of mean episodes] = 59.8). However, the risks for both hospitalization due to severe illness and for mortality were reduced to a greater extent (reduction rate, 76.9% and 79.1%, respectively). It is known that inactivated vaccines induce serum antibody responses that can inhibit diffusion and replication of influenza viruses, but these do not induce strong local immune responses to prevent infection (13)(14). This may explain the enhanced effect of vaccination against severe illness and mortality as compared with infection. The clinical illnesses were distributed in time parallel to isolations of the influenza virus and the known epidemic period within this study. There were no serious adverse events identified through monitoring of postvaccination reactions for 1 week in all 10,739 vaccinated cases. Margolis and colleagues (18) have also shown that the incidence of local and systemic side effects in the first 48 hours after vaccination was less than 5%.

In summary, this study has demonstrated that when an influenza vaccine is administered before an epidemic, and the vaccine strain is closely related to the epidemic strain, serious morbidity and mortality in elderly nursing home residents are significantly reduced. Nichol and colleagues (19) have shown the efficacy and cost-effectiveness of vaccination against influenza among elderly persons living in the community. For elderly citizens living in the community, vaccination against influenza is associated with reductions in the rate of hospitalization and in deaths from influenza and its complications, as compared with the rates in unvaccinated elderly persons. Vaccination also produces direct dollar savings (direct savings per year averaged $117 per person vaccinated) (19). Others have emphasized the economic benefits of this approach (20)(21). Our analysis for the cost-effectiveness of this vaccine program, supported by the Osaka Prefectural Government, is in progress, and the estimation for direct savings produced by influenza vaccination in Japan could be very significant. The factors of efficacy and cost-effectiveness are also important for the official support by the government program for influenza vaccination. Almost half (47.8%) of the population in all Osaka Prefecture nursing homes voluntarily received influenza vaccines in the 1998 to 1999 season in a program supported by the Osaka Prefectural Government. This is the first and only official support in Japan for influenza vaccination of the elderly population. Annual universal influenza immunization of elderly persons in welfare nursing homes is a public health imperative that should be carried out by practicing physicians and public health organizations.


   Acknowledgments
 
The authors thank Drs. Kozo Tatara (Department of Public Health, Faculty of Medicine, Osaka University Medical School, Japan), Yutaka Takasugi (Osaka Prefectural Government), and William L. Irving (Queen's Medical Centre, Nottingham, England) for helpful comments and suggestions, and Drs. Yoshinobu Okuno (Division of Virology, Osaka Prefectural Research Center for Public Health), Shigeru Kawasaki (Kibogoaka Nursing Home and Mizuma Hospital, Osaka, Japan), Akira Yamamoto (Mino City Nursing Home, Osaka, Japan), and Shuji Kawai (Wakakokai Hospital, Osaka, Japan) for their contributions in analyzing patients' materials for influenza virus and serodiagnoses of influenza.

Received October 25, 1999

Accepted May 30, 2000


   References
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 Abstract
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Monto AS, 1987. Influenza: quantifying morbidity and mortality. Am J Med 82: (suppl 6A) 20-25.
  2. Nichol KL, Margolis KL, Wuorenma J, von Sternberg T, 1994. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med 331:778-784. [Abstract/Free Full Text]
  3. Nichol KL, Margolis KL, Wuorenma J, von Sternberg T, 1996. Effectiveness of influenza vaccine in the elderly. Gerontology. 42:274-279. [Medline]
  4. Foster DA, Talsma A, Furumoto-Dawson A, et al. 1992. Influenza vaccine effectiveness in preventing hospitalization for pneumonia in the elderly. Am J Epidemiol. 136:296-307. [Abstract/Free Full Text]
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  6. U.S. Preventive Serious Task Force. Adult immunizations in guide to clinical preventive services. Nichol KL, ed. Guide to Clinical Preventive Services. 2nd ed. Baltimore, MD: Williams & Wilkins; 1996:791–814.
  7. Williams GO, 1980. Vaccines in older patients: combating the risk of mortality. Geriatrics. 35:55-64.
  8. Massab HF, DeBorde DC, 1983. Characterization of an influenza A host range mutant. Virology. 130:342-350. [Medline]
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